JP2017104044A - Method for improving catalytic activity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for improving the catalytic activity of a plant processed product in an asymmetric ring-opening reaction.SOLUTION: The present invention provides a method for improving the catalytic activity of a plant processed product that promotes the reaction for obtaining a compound represented by formula (3) by the reaction between a compound represented by formula (1) and a compound represented by formula (2), the method including the step for subjecting the plant processed product to an enzyme treatment (where X is -O- or -NR-, R is a hydrogen atom and the like, R, R, Rand Rindependently represent a hydrogen atom and the like, Y is -O-, -NR- or -S-, Rand Rindependently represent a hydrogen atom and the like, where, the compound represented by formula (2) is not water or hydrogen sulfide).SELECTED DRAWING: None

Description

  The present invention relates to a method for improving catalytic activity.

なお、式中、Ｘは−Ｏ−または−ＮＲ^ｆ−を示し、Ｙは−Ｏ−、−ＮＲ^ｇ−または−Ｓ−を示し、Ｒ^ａ、Ｒ^ｂ、Ｒ^ｃ、Ｒ^ｄ、Ｒ^ｅ、Ｒ^ｆおよびＲ^ｇは、それぞれ独立に水素原子または有機基を示し、アスタリスクはその炭素原子が不斉炭素であることを示す。 The compound represented by the formula (Z) (hereinafter, also referred to as “compound (Z)”) is a compound in which an oxygen atom or a nitrogen atom is bonded to two consecutive carbon atoms, and at least in one molecule. Since it has two asymmetric carbons, there are multiple optical isomers. The optically active compound (Z) is one of chemical structures widely used in the field of pharmaceutical or agricultural chemical development, and can also be used as a ligand for a transition metal catalyst used in an asymmetric reaction.

In the formula, X represents —O— or —NR ^f —, Y represents —O—, —NR ^g — or —S—, and R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^g each independently represent a hydrogen atom or an organic group, and an asterisk indicates that the carbon atom is an asymmetric carbon.

  Specifically, the compound (Z) includes, for example, 1,2-diol (when X and Y are both —O—), 1,2-aminoalcohol (where X is —O— and Y is —NH—). Or X is —NH— and Y is —O—), 1,2-diamine (when both X and Y are —NH—), 1,2-mercaptoalcohol (where X is -O- and Y is -S-), 1,2-mercaptoamine (when X is -NH- and Y is -S-).

  To date, many studies have been conducted on methods for producing optically active compounds (Z). Among them, a method of obtaining an optically active compound (Z) by reacting a compound having an epoxide structure or an aziridine structure, which is readily available, with a nucleophile, and performing stereoselective ring opening has high atomic efficiency and is useful. is there.

  For example, as a method of obtaining an optically active compound (Z) by reacting a compound having an epoxide structure with a nucleophile, (A) a method of optically resolving a racemate (for example, Patent Documents 1 to 3, Non-Patent Documents) Documents 1, 2), (B) a method of introducing an asymmetric carbon at another position and separating the resulting diastereomers (for example, Patent Document 4, Non-Patent Document 3), (C) Optically active catalyst There are methods for performing an asymmetric ring-opening reaction between a compound having an epoxide structure and a nucleophile in the presence (for example, Patent Document 5, Non-Patent Documents 4 to 6). In particular, as the method (A), a method using an optically active acid as a resolving agent, a method using a column chromatography using an optically active filler, and an enzyme derived from an animal or a microorganism are used. Methods are known.

  Further, as a method of obtaining a compound (Z) by reacting a compound having an aziridine structure with a nucleophile, (D) a method of optically resolving a racemate (for example, Patent Document 6), (E) an optically active compound There are methods for performing asymmetric ring-opening reaction between a compound having an aziridine structure and a nucleophile in the presence of a catalyst (for example, Non-Patent Documents 7 and 8).

Japanese Patent No. 4406483 Japanese Patent No. 4406482 US Pat. No. 5,981,267 JP-A-9-157258 JP 2003-206266 A JP 2011-83934 A Japanese Patent No. 3331870 Japanese Patent No. 3018622

Tetrahedron, 56, 9773-9779 (2000) Synth. Commun. , 29, 1369-1377 (1999) J. et al. Med. Chem. 41, 38-45 (1998) Tetrahedron: Asymmetry, 9, 1747-1752 (1998) Bull. Chem. Soc. Jpn. 61, 1213-1220 (1988). Chemistry Letters, 36, 34-35 (2007) Org. Biomol. Chem. , 9, 6205-6207 (2011) J. et al. Org. Chem. 68, 5160-5167 (2003) Biosci. Biotechnol. Biochem. 60 (12), 2028-2031, 1996 Biosci. Biotechnol. Biochem. 65 (10), 2249-2258, 2001 Biosci. Biotechnol. Biochem. 66 (5), 1155-1158, 2002 J. et al. Agric. Food Chem. 2004, 52, 5506-5512. J. et al. Agric. Food Chem. 2007, 55, 502-509. Food industry, 1994, 71-76. Food Processing Technology, Vol. 19, no. 4, 1-8 (1999). Journal of Japanese Society for Food Science and Technology, Vol.58, No.11, November 2011, 559-566. Jpn. J. et al. Crop Sci. 66 (1), 62-66 (1997).

The present inventors react a compound represented by the formula (1) (hereinafter also referred to as “compound (1)”) and a compound (2) in the presence of a processed plant product, particularly a water-soluble soybean polysaccharide. It was found that the reaction proceeds stereoselectively and efficiently, and compound (3) corresponding to compound (Z) can be obtained.

  There have been reports on component analysis of water-soluble soybean polysaccharides and their application as food function agents, but there are no reports on the above-mentioned catalytic activity (for example, Patent Documents 7 to 8, Non-Patent Documents 9 to 17).

  The objective of this invention is providing the method of improving the catalytic activity of the plant processed material in the said reaction.

（式中、Ｘは、−Ｏ−または−ＮＲ−であり、Ｒは、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基、置換基を有してもよいＣ_６−１０アリール基、置換基を有してもよいＣ_１−６アルキルカルボニル基、置換基を有してもよいＣ_６−１０アリールカルボニル基、置換基を有してもよいＣ_１−６アルキルスルホニル基またはＣ_６−１０アリールスルホニル基であり、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ独立に、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基または置換基を有してもよいＣ_６−１０アリール基であり、前記置換基が、Ｃ_１−４アルキル基、Ｃ_２−４アルケニル基、Ｃ_２−４アルキニル基、Ｃ_１−４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ^２およびＲ^３が互いに結合して式（１ｂ）で表される化合物となっていてもよく、Ｙは、−Ｏ−、−ＮＲ^６−または−Ｓ−であり、Ｒ^５およびＲ^６は、それぞれ独立に、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基または置換基を有してもよいＣ_６−１０アリール基であり、前記置換基が、Ｃ_１−４アルコキシ基、Ｃ_６−１０アリール基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ^５およびＲ^６が互いに結合して式（２ａ）で表される化合物となっていてもよく、ただし、式（２）で表される化合物は水または硫化水素ではない。）

（式中、Ｘ、Ｒ^１およびＲ^４は、上記定義と同一であり、Ｒ^７は、Ｒ^２およびＲ^３が互いに結合して形成される基を示す。）

（式中、Ｒ^８は、Ｒ^５およびＲ^６が互いに結合して形成される基を示す。）
［２］ 酵素処理が、植物加工物を、脂質分解酵素、タンパク質分解酵素、糖分解酵素及び糖転移酵素から選択される少なくとも１種の酵素で処理することを含む、［１］に記載の方法。
［３］ 植物加工物が、水溶性大豆多糖類、柑橘類粉末、ニンジン粉末、ウコン粉末、緑茶粉末を含む、［１］又は［２］に記載の方法。
［４］ 式（１）で表される化合物と式（２）で表される化合物を反応させて式（３）で表される化合物を得る反応を促進する触媒であって、
植物加工物を酵素処理して得られる組成物を含む、触媒。

（式中、Ｘは、−Ｏ−または−ＮＲ−であり、Ｒは、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基、置換基を有してもよいＣ_６−１０アリール基、置換基を有してもよいＣ_１−６アルキルカルボニル基、置換基を有してもよいＣ_６−１０アリールカルボニル基、置換基を有してもよいＣ_１−６アルキルスルホニル基またはＣ_６−１０アリールスルホニル基であり、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ独立に、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基または置換基を有してもよいＣ_６−１０アリール基であり、前記置換基が、Ｃ_１−４アルキル基、Ｃ_２−４アルケニル基、Ｃ_２−４アルキニル基、Ｃ_１−４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ^２およびＲ^３が互いに結合して式（１ｂ）で表される化合物となっていてもよく、Ｙは、−Ｏ−、−ＮＲ^６−または−Ｓ−であり、Ｒ^５およびＲ^６は、それぞれ独立に、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基または置換基を有してもよいＣ_６−１０アリール基であり、前記置換基が、Ｃ_１−４アルコキシ基、Ｃ_６−１０アリール基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ^５およびＲ^６が互いに結合して式（２ａ）で表される化合物となっていてもよく、ただし、式（２）で表される化合物は水または硫化水素ではない。）

（式中、Ｘ、Ｒ^１およびＲ^４は、上記定義と同一であり、Ｒ^７は、Ｒ^２およびＲ^３が互いに結合して形成される基を示す。）

（式中、Ｒ^８は、Ｒ^５およびＲ^６が互いに結合して形成される基を示す。）
［５］ 酵素処理が、植物加工物を、脂質分解酵素、タンパク質分解酵素、糖分解酵素及び糖転移酵素から選択される少なくとも１種の酵素で処理することを含む、［４］に記載の触媒。
［６］ 植物加工物が、水溶性大豆多糖類、柑橘類粉末、ニンジン粉末、ウコン粉末、緑茶粉末を含む、［４］又は［５］に記載の触媒。
［７］ 植物加工物を酵素処理して得られる触媒の存在下、式（１）で表される化合物と式（２）で表される化合物を反応させる工程を含む、式（３）で表される化合物の製造方法。

（式中、Ｘは、−Ｏ−または−ＮＲ−であり、Ｒは、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基、置換基を有してもよいＣ_６−１０アリール基、置換基を有してもよいＣ_１−６アルキルカルボニル基、置換基を有してもよいＣ_６−１０アリールカルボニル基、置換基を有してもよいＣ_１−６アルキルスルホニル基またはＣ_６−１０アリールスルホニル基であり、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ独立に、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基または置換基を有してもよいＣ_６−１０アリール基であり、前記置換基が、Ｃ_１−４アルキル基、Ｃ_２−４アルケニル基、Ｃ_２−４アルキニル基、Ｃ_１−４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ^２およびＲ^３が互いに結合して式（１ｂ）で表される化合物となっていてもよく、Ｙは、−Ｏ−、−ＮＲ^６−または−Ｓ−であり、Ｒ^５およびＲ^６は、それぞれ独立に、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基または置換基を有してもよいＣ_６−１０アリール基であり、前記置換基が、Ｃ_１−４アルコキシ基、Ｃ_６−１０アリール基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ^５およびＲ^６が互いに結合して式（２ａ）で表される化合物となっていてもよく、ただし、式（２）で表される化合物は水または硫化水素ではない。）

（式中、Ｘ、Ｒ^１およびＲ^４は、上記定義と同一であり、Ｒ^７は、Ｒ^２およびＲ^３が互いに結合して形成される基を示す。）

（式中、Ｒ^８は、Ｒ^５およびＲ^６が互いに結合して形成される基を示す。）
［８］ 酵素処理が、植物加工物を、脂質分解酵素、タンパク質分解酵素、糖分解酵素及び糖転移酵素から選択される少なくとも１種の酵素で処理することを含む、［７］に記載の方法。
［９］ 植物加工物が、水溶性大豆多糖類、柑橘類粉末、ニンジン粉末、ウコン粉末、緑茶粉末を含む、［７］又は［８］に記載の方法。
［１０］ 式（１）で表される化合物と式（２）で表される化合物を反応させて式（３）で表される化合物を得る反応を促進するための、植物加工物を酵素処理して得られる組成物の使用。

（式中、Ｘは、−Ｏ−または−ＮＲ−であり、Ｒは、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基、置換基を有してもよいＣ_６−１０アリール基、置換基を有してもよいＣ_１−６アルキルカルボニル基、置換基を有してもよいＣ_６−１０アリールカルボニル基、置換基を有してもよいＣ_１−６アルキルスルホニル基またはＣ_６−１０アリールスルホニル基であり、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ独立に、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基または置換基を有してもよいＣ_６−１０アリール基であり、前記置換基が、Ｃ_１−４アルキル基、Ｃ_２−４アルケニル基、Ｃ_２−４アルキニル基、Ｃ_１−４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ^２およびＲ^３が互いに結合して式（１ｂ）で表される化合物となっていてもよく、Ｙは、−Ｏ−、−ＮＲ^６−または−Ｓ−であり、Ｒ^５およびＲ^６は、それぞれ独立に、水素原子、置換基を有してもよいＣ_１−６アルキル基、置換基を有してもよいＣ_３−６シクロアルキル基、置換基を有してもよいＣ_２−６アルケニル基、置換基を有してもよいＣ_３−６シクロアルケニル基、置換基を有してもよいＣ_２−６アルキニル基または置換基を有してもよいＣ_６−１０アリール基であり、前記置換基が、Ｃ_１−４アルコキシ基、Ｃ_６−１０アリール基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ^５およびＲ^６が互いに結合して式（２ａ）で表される化合物となっていてもよく、ただし、式（２）で表される化合物は水または硫化水素ではない。）

（式中、Ｘ、Ｒ^１およびＲ^４は、上記定義と同一であり、Ｒ^７は、Ｒ^２およびＲ^３が互いに結合して形成される基を示す。）

（式中、Ｒ^８は、Ｒ^５およびＲ^６が互いに結合して形成される基を示す。）
［１１］ 酵素処理が、植物加工物を、脂質分解酵素、タンパク質分解酵素、糖分解酵素及び糖転移酵素から選択される少なくとも１種の酵素で処理することを含む、［１０］に記載の使用。
［１２］ 植物加工物が、水溶性大豆多糖類、柑橘類粉末、ニンジン粉末、ウコン粉末、緑茶粉末を含む、［１０］又は［１１］に記載の使用。 The present invention provides the following [1] to [12].
[1] Improve the catalytic activity of the processed plant product that promotes the reaction of reacting the compound represented by formula (1) with the compound represented by formula (2) to obtain the compound represented by formula (3) A method,
A method comprising the step of enzyme-treating a processed plant product.

(In the formula, X represents —O— or —NR—, and R represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a C _3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted _{C 6-10} aryl group, an optionally substituted _{C 1-6} alkylcarbonyl group, an optionally substituted _{C 6-10} arylcarbonyl group, a substituent A C _1-6 alkylsulfonyl group or a C _6-10 arylsulfonyl group which may have, and R ¹ , R ² , R ³ and R ⁴ may each independently have a hydrogen atom or a substituent. a _{C 1-6} alkyl group, an optionally substituted _{C 3-6} cycloalkyl group, Yes which may have a substituent C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally C _2-6 alkynyl group or a substituted group may have a substituent An optionally substituted C _6-10 aryl group, and the substituent is a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a C _1-4 alkoxy group, an amino group, or an imino group. A group, a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, and R ² and R ³ may be bonded to each other to form a compound represented by the formula (1b), Y is —O—, —NR ⁶ — or —S—, and R ⁵ and R ⁶ each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a substituent. which may have a C _3-6 cycloalkyl group, substituted Which may C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, which may have a good C _2-6 alkynyl group or a substituted group may have a substituent C _{6 -10} aryl group, wherein the _{substituents, C 1-4} alkoxy _{groups, C 6-10} aryl group, an amino group, an imino group, a nitro group, hydroxy group, oxo group, nitrile group, mercapto group or a halogen atom And R ⁵ and R ⁶ may be bonded to each other to form a compound represented by the formula (2a), provided that the compound represented by the formula (2) is not water or hydrogen sulfide.

(In the formula, X, R ¹ and R ⁴ are the same as defined above, and R ⁷ represents a group formed by bonding R ² and R ³ to each other.)

(In the formula, R ⁸ represents a group formed by combining R ⁵ and R ⁶ with each other.)
[2] The method according to [1], wherein the enzyme treatment includes treating the plant processed product with at least one enzyme selected from a lipolytic enzyme, a proteolytic enzyme, a glycolytic enzyme, and a glycosyltransferase. .
[3] The method according to [1] or [2], wherein the plant processed product contains water-soluble soybean polysaccharide, citrus powder, carrot powder, turmeric powder, and green tea powder.
[4] A catalyst that promotes a reaction in which a compound represented by formula (1) and a compound represented by formula (2) are reacted to obtain a compound represented by formula (3),
A catalyst comprising a composition obtained by enzymatic treatment of a processed plant product.

(In the formula, X represents —O— or —NR—, and R represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a C _3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted _{C 6-10} aryl group, an optionally substituted _{C 1-6} alkylcarbonyl group, an optionally substituted _{C 6-10} arylcarbonyl group, a substituent A C _1-6 alkylsulfonyl group or a C _6-10 arylsulfonyl group which may have, and R ¹ , R ² , R ³ and R ⁴ may each independently have a hydrogen atom or a substituent. a _{C 1-6} alkyl group, an optionally substituted _{C 3-6} cycloalkyl group, Yes which may have a substituent C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally C _2-6 alkynyl group or a substituted group may have a substituent An optionally substituted C _6-10 aryl group, and the substituent is a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a C _1-4 alkoxy group, an amino group, or an imino group. A group, a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, and R ² and R ³ may be bonded to each other to form a compound represented by the formula (1b), Y is —O—, —NR ⁶ — or —S—, and R ⁵ and R ⁶ each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a substituent. which may have a C _3-6 cycloalkyl group, substituted Which may C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, which may have a good C _2-6 alkynyl group or a substituted group may have a substituent C _{6 -10} aryl group, wherein the _{substituents, C 1-4} alkoxy _{groups, C 6-10} aryl group, an amino group, an imino group, a nitro group, hydroxy group, oxo group, nitrile group, mercapto group or a halogen atom And R ⁵ and R ⁶ may be bonded to each other to form a compound represented by the formula (2a), provided that the compound represented by the formula (2) is not water or hydrogen sulfide.

(In the formula, X, R ¹ and R ⁴ are the same as defined above, and R ⁷ represents a group formed by bonding R ² and R ³ to each other.)

(In the formula, R ⁸ represents a group formed by combining R ⁵ and R ⁶ with each other.)
[5] The catalyst according to [4], wherein the enzyme treatment includes treating the plant processed product with at least one enzyme selected from a lipolytic enzyme, a proteolytic enzyme, a glycolytic enzyme, and a glycosyltransferase. .
[6] The catalyst according to [4] or [5], wherein the plant processed product contains water-soluble soybean polysaccharide, citrus powder, carrot powder, turmeric powder, and green tea powder.
[7] Represented by the formula (3), comprising a step of reacting the compound represented by the formula (1) and the compound represented by the formula (2) in the presence of a catalyst obtained by enzymatic treatment of a plant processed product. The manufacturing method of the compound made.

(In the formula, X represents —O— or —NR—, and R represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a C _3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted _{C 6-10} aryl group, an optionally substituted _{C 1-6} alkylcarbonyl group, an optionally substituted _{C 6-10} arylcarbonyl group, a substituent A C _1-6 alkylsulfonyl group or a C _6-10 arylsulfonyl group which may have, and R ¹ , R ² , R ³ and R ⁴ may each independently have a hydrogen atom or a substituent. a _{C 1-6} alkyl group, an optionally substituted _{C 3-6} cycloalkyl group, Yes which may have a substituent C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally C _2-6 alkynyl group or a substituted group may have a substituent An optionally substituted C _6-10 aryl group, and the substituent is a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a C _1-4 alkoxy group, an amino group, or an imino group. A group, a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, and R ² and R ³ may be bonded to each other to form a compound represented by the formula (1b), Y is —O—, —NR ⁶ — or —S—, and R ⁵ and R ⁶ each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a substituent. which may have a C _3-6 cycloalkyl group, substituted Which may C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, which may have a good C _2-6 alkynyl group or a substituted group may have a substituent C _{6 -10} aryl group, wherein the _{substituents, C 1-4} alkoxy _{groups, C 6-10} aryl group, an amino group, an imino group, a nitro group, hydroxy group, oxo group, nitrile group, mercapto group or a halogen atom And R ⁵ and R ⁶ may be bonded to each other to form a compound represented by the formula (2a), provided that the compound represented by the formula (2) is not water or hydrogen sulfide.

(In the formula, X, R ¹ and R ⁴ are the same as defined above, and R ⁷ represents a group formed by bonding R ² and R ³ to each other.)

(In the formula, R ⁸ represents a group formed by combining R ⁵ and R ⁶ with each other.)
[8] The method according to [7], wherein the enzyme treatment includes treating the plant processed product with at least one enzyme selected from a lipolytic enzyme, a proteolytic enzyme, a glycolytic enzyme, and a glycosyltransferase. .
[9] The method according to [7] or [8], wherein the processed plant product contains water-soluble soybean polysaccharide, citrus powder, carrot powder, turmeric powder, and green tea powder.
[10] Enzymatic treatment of a plant processed product for promoting the reaction of reacting the compound represented by formula (1) with the compound represented by formula (2) to obtain the compound represented by formula (3) Use of the resulting composition.

(In the formula, X represents —O— or —NR—, and R represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a C _3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted _{C 6-10} aryl group, an optionally substituted _{C 1-6} alkylcarbonyl group, an optionally substituted _{C 6-10} arylcarbonyl group, a substituent A C _1-6 alkylsulfonyl group or a C _6-10 arylsulfonyl group which may have, and R ¹ , R ² , R ³ and R ⁴ may each independently have a hydrogen atom or a substituent. a _{C 1-6} alkyl group, an optionally substituted _{C 3-6} cycloalkyl group, Yes which may have a substituent C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally C _2-6 alkynyl group or a substituted group may have a substituent An optionally substituted C _6-10 aryl group, and the substituent is a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a C _1-4 alkoxy group, an amino group, or an imino group. A group, a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, and R ² and R ³ may be bonded to each other to form a compound represented by the formula (1b), Y is —O—, —NR ⁶ — or —S—, and R ⁵ and R ⁶ each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a substituent. which may have a C _3-6 cycloalkyl group, substituted Which may C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, which may have a good C _2-6 alkynyl group or a substituted group may have a substituent C _{6 -10} aryl group, wherein the _{substituents, C 1-4} alkoxy _{groups, C 6-10} aryl group, an amino group, an imino group, a nitro group, hydroxy group, oxo group, nitrile group, mercapto group or a halogen atom And R ⁵ and R ⁶ may be bonded to each other to form a compound represented by the formula (2a), provided that the compound represented by the formula (2) is not water or hydrogen sulfide.

(In the formula, X, R ¹ and R ⁴ are the same as defined above, and R ⁷ represents a group formed by bonding R ² and R ³ to each other.)

(In the formula, R ⁸ represents a group formed by combining R ⁵ and R ⁶ with each other.)
[11] The use according to [10], wherein the enzyme treatment includes treating the plant product with at least one enzyme selected from a lipolytic enzyme, a proteolytic enzyme, a glycolytic enzyme, and a glycosyltransferase. .
[12] The use according to [10] or [11], wherein the processed plant product contains water-soluble soybean polysaccharide, citrus powder, carrot powder, turmeric powder, and green tea powder.

  According to the present invention, the catalytic activity of the processed plant product in the above reaction can be improved.

  Hereinafter, the present invention will be described in detail.

The reaction of obtaining the compound represented by the formula (3) by reacting the compound represented by the formula (1) and the compound represented by the formula (2) is an asymmetric ring-opening reaction represented by the scheme shown below. It is.

<Compound represented by Formula (1) (Compound (1))>
In the formula (1), X is —O— or —NR—. That is, the compound (1) means a compound having an epoxide structure or a compound having an aziridine structure.

R is a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, or a C _2-6 alkenyl which may have a substituent. Group, C _3-6 cycloalkenyl group which may have a substituent, C _2-6 alkynyl group which may have a substituent, C _6-10 aryl group which may have a substituent, substituent A C _1-6 alkylcarbonyl group which may have a substituent, a C _6-10 arylcarbonyl group which may have a substituent, a C _1-6 alkylsulfonyl group which may have a substituent or a C _6-10 An arylsulfonyl group.

R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _2-6 alkenyl group, or a C _3-6 cycloalkenyl. A group, a C _2-6 alkynyl group or a C _6-10 aryl group.

The C _1-6 alkyl group means an alkyl group having 1 to 6 carbon atoms. Examples of the C _1-6 alkyl group include a methyl group, an ethyl group, a propan-1-yl group, a propan-2-yl group (isopropyl group), a butan-1-yl group, a butan-2-yl group, and pentane. Examples include a -1-yl group, a pentan-2-yl group, a pentan-3-yl group, a hexane-1-yl group, a hexane-2-yl group, and a 3-hexyl group.

The C _3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms. Examples of the C _3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

The C _2-6 alkenyl group means an alkenyl group having 2 to 6 carbon atoms. Examples of the C _2-6 alkenyl group include a vinyl group, 1-propen-1-yl group, 2-propen-1-yl group, propen-2-yl group, 2-buten-1-yl group, 2- Buten-2-yl group, 3-buten-1-yl group, 2-penten-1-yl group, 3-penten-1-yl group, 2-hexen-1-yl group, 3-hexen-1-yl Groups, 4-hexen-1-yl group and 5-hexen-1-yl group.

The C _3-6 cycloalkenyl group means a cycloalkenyl group having 3 to 6 carbon atoms. Examples of the C _3-6 cycloalkenyl group include a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.

The C _2-6 alkynyl group means an alkynyl group having 2 to 6 carbon atoms. Examples of the C _2-6 alkynyl group include an ethynyl group, a propargyl group, and a 3-butyn-1-yl group.

The C _6-10 aryl group means an aryl group having 6 to 10 carbon atoms. Examples of the C _6-10 aryl group include a phenyl group and a naphthyl group.

The C _1-6 alkyl group, C _3-6 cycloalkyl group, C _2-6 alkenyl group, C _3-6 cycloalkenyl group, C _2-6 alkynyl group and C _6-10 aryl group were each unsubstituted. Alternatively, it may have a substituent. Examples of the substituent include a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a C _1-4 alkoxy group, an amino group, an imino group, a nitro group, a hydroxy group, an oxo group, and a nitrile group. , A mercapto group or a halogen atom. Examples of the C _1-4 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, and a butoxy group.

  Examples of compound (1) include Cis-2,3-epoxybutane.

  Further, instead of the compound (1), a compound having a thiirane structure in which X is —S— may be used. When a compound having a thiirane structure is used, 1,2-mercaptoamine, 1,2-mercaptoalcohol, and 1,2-dithiol can be obtained.

式中、Ｘ、Ｒ^１およびＲ^４は、上記定義と同一であり、Ｒ^７は、Ｒ^２およびＲ^３が互いに結合して形成される基を示す。 In addition, the compound (1) may be the compound (1b).

In the formula, X, R ¹ and R ⁴ are the same as defined above, and R ⁷ represents a group formed by combining R ² and R ³ with each other.

In formula (1b), X represents —O— or —NR—, and R ⁷ represents a group formed by combining R ² and R ³ with each other. The groups R ² and R ³ are bonded to each other to form, when R ² or R ³ has a substituent, may be coupled to be connected via the substituent. That is, R ⁷ is not only a C _1-6 alkylene group, a C _2-6 alkenylene group, a C _2-6 alkynylene group and a C _6-10 arylene group, but R ² and R ³ are bonded via a substituent. The aspect formed as above is also included.

A C _1-6 alkylene group, a C _2-6 alkenylene group, a C _2-6 alkynylene group and a C _6-10 arylene group are each a C _1-6 alkyl group defined by the formula (1), C _2-6 A group obtained by further removing one hydrogen atom from an alkenyl group, a C _2-6 alkynyl group and a C _6-10 aryl group.

Examples of the mode in which R ² and R ³ are bonded via a substituent include, for example, 2-oxapropylene group (—CH ₂ OCH ₂ —), 3-oxapentylene group (—CH ₂ CH ₂ OCH ₂ CH ₂ -), 3- oxo pentylene group _{(-CH 2 CH 2 C (=} O) CH 2 CH 2 -) and the like.

  Specific examples of the compound represented by the formula (1b) include 6-oxabicyclo [3.1.0] hexane, 7-oxabicyclo [4.1.0] heptane, 8-oxabicyclo [5.1. 0] octane and 3,6-dioxabicyclo [3.1.0] hexane.

<Compound represented by formula (2) (compound (2))>
In the formula (2), Y is —O—, —NR ⁶ — or —S—. That is, the compound (2) means alcohol, amine or thiol. However, water and hydrogen sulfide are excluded from the range of the compound (2).

R ⁵ and R ⁶ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _2-6 alkenyl group, a C _3-6 cycloalkenyl group, or a C _2-6. An alkynyl group or a C _6-10 aryl group.

Examples of the C _1-6 alkyl group include a methyl group, an ethyl group, a propan-1-yl group, a propan-2-yl group (isopropyl group), a butan-1-yl group, a butan-2-yl group, and pentane. Examples include a -1-yl group, a pentan-2-yl group, a pentan-3-yl group, a hexane-1-yl group, a hexane-2-yl group, and a 3-hexyl group.

Examples of the C _3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

Examples of the C _2-6 alkenyl group include a vinyl group, 1-propen-1-yl group, 2-propen-1-yl group, propen-2-yl group, 2-buten-1-yl group, 2- Buten-2-yl group, 3-buten-1-yl group, 2-penten-1-yl group, 3-penten-1-yl group, 2-hexen-1-yl group, 3-hexen-1-yl Groups, 4-hexen-1-yl group and 5-hexen-1-yl group.

Examples of the C _3-6 cycloalkenyl group include a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.

Examples of the C _2-6 alkynyl group include an ethynyl group, a propargyl group, and a 3-butyn-1-yl group.

Examples of the C _6-10 aryl group include a phenyl group and a naphthyl group.

The C _1-6 alkyl group, C _3-6 cycloalkyl group, C _2-6 alkenyl group, C _3-6 cycloalkenyl group, C _2-6 alkynyl group and C _6-10 aryl group were each unsubstituted. Alternatively, it may have a substituent. Examples of the substituent include a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a C _6-10 aryl group, a C _1-4 alkoxy group, an amino group, an imino group, a nitro group, and a hydroxy group. Group, oxo group, nitrile group, mercapto group or halogen atom. Examples of the C _1-4 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, and a butoxy group.

  Specific examples of the compound (2) include methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, phenol, ammonia, methylamine, Ethylamine, propylamine, 2-propylamine (isopropylamine), 2-pentylamine, 3-pentylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, tert-butylamine, allylamine, propargylamine, benzylamine, 2 -Phenylethylamine, aniline, dimethylamine, diethylamine, 3-methoxypropylamine, 3-ethoxypropylamine, methanethiol, ethanethiol, 1-propanethiol, - propanethiol include butanethiol.

式中、Ｒ^８は、Ｒ^５およびＲ^６が互いに結合して形成される基を示す。 In addition, the compound (2) may be the compound (2a).

In the formula, R ⁸ represents a group formed by combining R ⁵ and R ⁶ with each other.

In formula (2a), R ⁸ represents a group formed by combining R ⁵ and R ⁶ with each other. The groups R ⁵ and R ⁶ are bonded to each other to form, when R ⁵ or R ⁶ has a substituent may be attached so as to be connected via the substituent. That is, R ⁸ is a C _1-6 alkylene group, a C _3-6 cycloalkylene group, a C _2-6 alkenylene group, a C _3-6 cycloalkenylene group, a C _2-6 alkynylene group and a C _6-10 arylene group only. In addition, an embodiment in which R ⁵ and R ⁶ are bonded via a substituent is also included.

C _1-6 alkylene group, C _3-6 cycloalkylene group, C _2-6 alkenylene group, C _3-6 cycloalkenylene group, C _2-6 alkynylene group and C _6-10 arylene group are each represented by the formula (2 And a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group and a C _6-10 aryl group defined in (1) above.

Examples of the mode in which R ⁵ and R ⁶ are bonded through a substituent include, for example, 2-oxapropylene group (—CH ₂ OCH ₂ —), 3-oxapentylene group (—CH ₂ CH ₂ OCH ₂ CH ₂ -), 3- oxo pentylene group _{(-CH 2 CH 2 C (=} O) CH 2 CH 2 -) and the like.

  Specific examples of the compound (2a) are pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, and thiomorpholine.

<Compound represented by formula (3) (compound (3))>
The compound (3) is a compound represented by the formula (3), in which X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are Is the same as defined above.

Moreover, when the compound (1) is the compound (1b) and the case where the compound (2) is the compound (2a) is considered, the compound (3) includes the compounds (3a) to (3c).

  Specific examples of the compound (3) include 1,2-diol (when both X and Y are —O—), 1,2-amino alcohol (when X is —O— and Y is —NH—). Or X is —NH— and Y is —O—), 1,2-diamine (when both X and Y are —NH—), 1,2-mercaptoalcohol (X is —O—). And Y is -S-), 1,2-mercaptoamine (when X is -NH- and Y is -S-).

<Processed plant products>
In this specification, a plant processed material is a powder or extract obtained by processing a part of a plant. An example of a plant is an edible plant.

  The above “edible plant” means a plant generally known as a plant that a human can eat a part of. The edible plant is, for example, a plant classified into cereals, beans, vegetables, fruits or potatoes, and part of the edible plant is the whole fruit, pulp, pericarp, stem, seed, germ, root, bulb and It can be appropriately selected from leaves. Specific examples of edible plants include legumes (for example, soybeans, black beans, red kidney beans, peas), oleaceae (for example, olives), salamanders (for example, bananas), gramineae (for example, wheat), Cucurbitaceae (eg, pumpkin), solanaceae (eg, tomato, potato), urushiaceae (eg, pistachio, cashew nut), ginger (eg, turmeric), camellia family (eg, tea), citrus (eg, nutmican) , Eggplant, flower bud, buntan), Amaryllidaceae (eg, garlic), celery family (eg, carrot), Brassicaceae (eg, radish), lotus family (eg, lotus root), matabidae (eg, kiwi), rose Plants of the family (eg apple) and leeks (eg leek) are mentioned. Edible plants include legumes (e.g., soybeans, black beans, red kidney beans, peas), camellia (e.g., tea), serpentaceae (e.g., carrots), matabidae (e.g., kiwi) and lily families (e.g., Preferably selected from the group consisting of leek). In addition, a leek may be classified as a leek family.

  The above-mentioned “processing” means, if necessary, processing such as drying, heating, baking, roasting, oiling, fermenting, removing unnecessary parts, etc. It means to pulverize until it becomes or to extract components. In addition, the processed plant product includes a powder obtained by extracting an extract of an edible plant and then pulverizing a dried product. Therefore, the tea may be green tea or black tea. In addition, the soybean may be kinako or natto.

  As the processed plant product, a product marketed in a powdered or liquid state may be used, or a product marketed in a processed state may be appropriately pulverized into a powder and used. Examples of commercially available products include kina flour, defatted soybean flour (for example, Fujipro F (Fuji Oil Co., Ltd., trade name), Sunrich F (Showa Sangyo Co., Ltd., trade name), Soya Flower FT-N ( Nisshin Oilio Co., Ltd., trade name), Essan Meat Special (Ajinomoto Co., trade name), Toyotomi Soipro (J-Oil Mills Co., trade name), water-soluble soybean polysaccharide (for example, It is preferable to use processed soybeans such as Soya Five S-DN (product name, manufactured by Fuji Oil Co., Ltd.), and more preferably Kina Flour, Soya Flower FT-N or Soya Five S-DN.

<Asymmetric ring opening reaction>
The amount of the compound (2) can be any amount in consideration of economy and recoverability. Such an amount is, for example, 0.01 to 100 equivalents, preferably 0.1 to 10 equivalents, more preferably 0.5 to 2 equivalents, relative to the number of moles of the compound (1).

  As the amount of the processed plant product, any amount in consideration of economic efficiency and recoverability can be used. The amount of such processed plant product is, for example, 0.01 to 100 times, preferably 0.1 to 10 times, and more preferably 0.1 to 10 times the mass of the compound represented by formula (1). The amount is preferably 1 to 5 times.

  The asymmetric ring opening reaction may be performed in a solvent. When carried out in a solvent, an organic solvent well known in organic synthetic chemistry and water can be usually used as long as they do not react with the compound (1) and the compound (2). Examples of such organic solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; hydrocarbons such as hexane, cyclohexane, and heptane; diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether, and cyclopentyl. Examples include ethers such as methyl ether; esters such as ethyl acetate and butyl acetate; and halogenated hydrocarbons such as dichloromethane and chloroform. These solvents may be used alone or in combination of two or more. When using a mixture of two or more, it is preferable to use a mixture of an organic solvent and water, and it is particularly preferable to use a mixed solvent of toluene or heptane and water from the viewpoint of recoverability, safety and economy. .

  The amount of the solvent that can be used for the asymmetric ring-opening reaction can be used in consideration of economic efficiency in either a single solvent or a mixed solvent. The amount of such a solvent is, for example, 0 to 100 times, preferably 0.5 to 50 times, and more preferably 2 to 10 times the volume of the compound (1) by volume.

  The content of water that can be used in the asymmetric ring-opening reaction can be 0.05 to 1 times the mass of water with respect to the catalyst, and 0.20 to 0.50 of water with respect to the catalyst. More preferably, it is in the range of double amount. Within such a range, the conversion rate of the reaction and the optical purity of the product are further improved.

  The reaction temperature is preferably -20 ° C to 100 ° C, particularly preferably 30 ° C to 50 ° C. After completion of the reaction, the corresponding compound (3) can be obtained by filtering off the catalyst. When carrying out the asymmetric ring-opening reaction of the present invention, the catalyst recovered by filtration can be reused.

  With respect to the reaction time, the reaction can be carried out until a time when an arbitrary conversion rate considering economic efficiency is obtained. Such a reaction time is, for example, 1 to 500 hours, preferably 1 to 100 hours, and more preferably 1 to 48 hours.

  Next, a method for improving the catalytic activity of a processed plant product in the above-described asymmetric ring-opening reaction will be described.

  The method for improving the catalytic activity of a processed plant product includes a step of enzymatically treating the processed plant product.

  The step of enzyme-treating a plant processed product is a step of obtaining an enzyme-treated product by bringing an enzyme into contact with the plant processed product.

  The enzyme is preferably one or more enzymes selected from the group consisting of lipolytic enzymes, proteolytic enzymes, glycolytic enzymes, and glycosyltransferases.

  The lipolytic enzyme may be an enzyme that hydrolyzes lipids (lipase) or an enzyme that hydrolyzes phospholipids (phospholipase). A preferred lipolytic enzyme is lipase.

  The proteolytic enzyme may be an endopeptidase or an exopeptidase. The proteolytic enzyme may be a serine proteinase, a thiol proteinase, a metal proteinase, an aspartic proteinase, an acid proteinase, a neutral proteinase, or an alkaline proteinase. Examples of the proteolytic enzyme include pepsin, trypsin, α-chymotrypsin, subtilisin, papain, elastase, carboxypeptidase, aminopeptidase and the like. The proteolytic enzyme may be a mixture of enzymes such as rennet.

  Examples of the glycolytic enzyme include amylase, cellulase, hemicellulase, pectinase, maltase, lactase, saccharase, hesperidinase, galactosidase and the like.

  Examples of the glycosyltransferase include cyclodextrin glucanotransferase, glycosyltransferase and the like.

  The temperature of enzyme treatment should just be the temperature by which the enzyme to be used is activated, for example, is 0-100 degreeC. The time for enzyme treatment can be appropriately set by those skilled in the art in consideration of practicality, and is, for example, 0.1 to 120 hours.

  The enzyme treatment may be performed in a buffer solution. The buffer is not limited as long as it is a buffer that can maintain the pH within the optimum range for the enzyme reaction. Examples of the buffer include borate buffer, Tris buffer, and phosphate buffer, and phosphate buffer is preferable. What is necessary is just to set the range of pH optimal for enzyme treatment according to the kind of enzyme to be used, and it is 1-11 normally.

  After the enzyme treatment for a specific time, the enzyme treatment product may be obtained by inactivating the enzyme remaining in the mixture. As means for inactivating the enzyme, there are means such as heating, adding an acid, and adding a proteolytic enzyme such as proteinase K. A preferred enzyme deactivation means is a method of adding proteinase K.

  The obtained enzyme-treated product may be used as it is as a catalyst for an asymmetric ring-opening reaction, or may be used after being dried and stored as a solid.

  The enzyme-treated product not only improves the catalytic activity of the asymmetric ring-opening reaction but also lowers the viscosity as compared with the processed plant product. Compared with processed plant products, the enzyme-treated product has less adhesion to the container, improves filterability, and facilitates post-treatment of the asymmetric ring-opening reaction.

  After inactivating the enzyme, filtration purification may be performed using an ultrafiltration membrane or the like. By performing filtration purification, unnecessary substances can be removed from the enzyme-treated product, the catalytic activity per unit weight can be further increased, and the dispersibility of the catalyst during the asymmetric ring-opening reaction is further improved.

  Further, the enzyme-treated product may be further purified by gel filtration chromatography. Purification by gel filtration chromatography includes, for example, a method of collecting a fraction in which a peak is observed in a chromatogram obtained by measurement with a differential refractometer. By purifying the enzyme-treated product by gel filtration chromatography, the catalytic activity per unit weight can be further increased.

  In this specification, the term “catalytic activity is improved” means that the conversion rate of the asymmetric ring-opening reaction is increased as compared to the case where the processed plant product is used as it is, and the selectivity of the asymmetric ring-opening reaction is increased. Used to mean that the reaction rate of the asymmetric ring-opening reaction increases or increases.

  EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention concretely, this invention is not limited to a following example, unless the summary is exceeded.

The structural formula of the synthesized compound was determined by ¹ H-NMR and ¹³ C-NMR spectra using tetramethylsilane as an internal standard. The data described the chemical shift value (δ) when TMS (tetramethylsilane) used as an internal standard was 0 ppm. In addition, in the case of broad peaks such as a hydroxyl group and an amino group, it is not described.

The “conversion rate” used in the specification is a value calculated based on the following formula. Specifically, the conversion rate calculation method is as follows. First, a small amount of a reaction solution is collected when the reaction between the compound (1) and the compound (2) is performed in the presence of the processed plant product. Next, the reaction solution collected using gas chromatography is measured to obtain the peak areas of compound (1) and compound (3). From the obtained peak areas, the molar ratio of the compound (1) and the compound (3) is calculated by the effective carbon number method (ECN), and is a value calculated based on the following formula. The effective carbon number method (ECN) is described in, for example, Gas Chromatography, Academic Press, New York, 1962, p207 and the Analytical Chemistry Handbook 5th edition (Seishiro Murata, edited by Japan Analytical Chemical Society, Maruzen Co., Ltd.) It is a method. For example, the effective carbon number of 7-oxabicyclo [4.1.0] heptane is 5.00, and the effective carbon number of 2-cyclopropylamino-1-cyclohexanol is 7.50.
Conversion rate (%) = 100 × number of moles of compound (3) / (number of moles of compound (1) + number of moles of compound (3))

  The optical purity was described by calculating the enantiomeric excess (% ee). The measurement conditions are as follows.

The “selectivity (% ee)” was calculated based on the following formula from the ratio of peak areas after measurement using gas chromatography (GC) unless otherwise specified. That is, when the selectivity is a negative value, it indicates that the value of “peak area of short GC holding time” is larger than the value of “peak area of long GC holding time”. When “selectivity (R, R)% ee” is described, the selectivity for (R, R) isomers is indicated.
Selectivity (% ee) = 100 × {(peak area of peak with long retention time) − (peak area of peak with short retention time)} / {(peak area of peak with long retention time) + (short retention time) Peak area)}

Analysis Conditions (1) Gas Chromatography Method The analysis conditions of the obtained compound were measured under the conditions described in Table 1. Items common to all analysis conditions are as described in the following common conditions.
Common conditions Carrier gas: Helium detector: Hydrogen flame ionization detector Pressure: 94 kPa
Vaporization chamber temperature: 220 ° C
Detector temperature: 300 ° C
Split ratio: 1: 150
Injection volume: 0.5 μL
Sample pretreatment: About 1 mg of a sample was dissolved in dichloromethane, trimethylsilane chloride and triethylamine were added and stirred, and insoluble matter was filtered off.
column:
BETADEX 120 (length: 30 m, inner diameter: 0.25 μm, manufactured by Supelco)
CP-CHIRASIL-DEX CB (length: 25 m, inner diameter: 0.25 mm, film thickness: 0.25 μm, manufactured by Varian)

(2) Liquid Chromatography Method The analysis conditions of the obtained compound were measured under the conditions described in Table 2. Items common to all analysis conditions are as described in the following common conditions.
Common condition injection volume: 5 μL
Detector: UV absorption detector (wavelength 254 nm)
column:
CHIRALCEL OB-H (4.6 × 250mm, manufactured by Daicel Corporation)
CHIRALPAK AS-RH (4.6 x 150 mm, manufactured by Daicel Corporation)
CHIRALCEL OD-H (4.6 x 250 mm, manufactured by Daicel Corporation)

  The racemic synthesis and analysis method for analysis are shown in the following reference examples.

Reference Example 1 trans-2- (isopropylamino) cyclohexanol synthesis 1.45 g of 7-oxabicyclo [4.1.0] heptane and 0.87 g of isopropylamine were weighed into a 50 mL eggplant flask, 8 mL of methanol, 2 mL of water, and chloride. 0.13 g of lithium was added and reacted at 50 ° C. for 48 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was distilled under reduced pressure in a glass tube oven GTO-250RS (Kugel Roll) manufactured by Shibata Kagaku Co., Ltd. to obtain 1.26 g of trans-2- (isopropylamino) cyclohexanol. (Outer bath temperature 135-140 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.82-0.94 (m, 1H), 1.00 (d, J = 6.31 Hz, 3H), 1.06 (d, J = 6 .31 Hz, 3H), 1.20-1.31 (m, 3H), 1.69-1.73 (m, 2H), 2.06-2.10 (m, 2H), 2.18-2 .26 (m, 1H), 2.96 (sep, J = 6.31 Hz, 1H), 3.09 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 22.79 (CH ₃ ), 24.28 (CH 2), 24.73 (CH 3), 25.36 (CH 2), 31.29 (CH 2), 32. 98 (CH2), 45.05 (CH), 60.64 (CH), 73.87 (CH)
Analysis condition A Retention time 12.9 minutes, 13.2 minutes

Reference Example 2 synthesis of trans-2- (cyclopropylamino) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that cyclopropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.19-0.55 (m, 4H), 0.94-1.07 (m, 1H), 1.18-1.30 (m, 3H) ), 1.71-1.76 (m, 2H), 2.00-2.06 (m, 1H), 2.19-2.36 (m, 3H), 3.06-3.14 (m) , 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 5.69 (CH 2), 7.22 (CH 2), 24.19 (CH 2), 24.85 (CH 2), 27.50 (CH), 30. 71 (CH2), 33.26 (CH2), 63.54 (CH), 72.94 (CH)
Analysis condition B Retention time (S, S) isomer: 26.9 minutes, (R, R) isomer: 27.4 minutes

Reference Example 3 synthesis of trans-2- (propylamino) cyclohexaneanol All operations were performed in the same manner as in Reference Example 1 except that propylamine was used instead of isopropylamine. (Outer bath temperature 115-120 ° C., pressure 0.2 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.90-0.99 (m, 4H), 1.21-1.29 (m, 3H), 1.42-1.55 (m, 2H) ), 1.71-1.73 (m, 2H), 2.02-2.22 (m, 3H), 2.39-2.47 (m, 1H), 2.70-2.79 (m , 1H), 3.10-3.18 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 11.69 (CH ₃ ), 23.60 (CH 2), 24.39 (CH 2), 25.03 (CH 2), 30.43 (CH 2), 33. 52 (CH2), 48.54 (CH2), 63.47 (CH), 73.46 (CH)
Analysis condition B Retention time 20.0 minutes, 20.3 minutes

Reference Example 4 synthesis of trans-2- (3-pentylamino) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that 3-aminopentane was used instead of isopropylamine. (Outer bath temperature 150-155 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.83-0.94 (m, 7H), 1.20-1.56 (m, 7H), 1.69-1.73 (m, 2H) ), 2.05 to 2.09 (m, 2H), 2.14 to 2.22 (m, 1H), 2.44 to 2.52 (m, 1H), 3.02 to 3.10 (m) , 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 8.99 (CH ₃ ), 10.26 (CH 3), 24.28 (CH 2), 25.40 (CH 2), 26.19 (CH 2), 26. 89 (CH2), 31.41 (CH2), 32.89 (CH2), 56.76 (CH), 61.14 (CH), 74.12 (CH)
Analysis condition B Retention time 30.3 minutes, 31.3 minutes

Reference Example 5 synthesis of trans-2- (tert-butylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that tert-butylamine was used instead of isopropylamine. (Outer bath temperature 100-105 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.90-1.19 (m, 1H), 1.13 (s, 9H), 1.24-1.32 (m, 3H), 1. 67-1.71 (m, 2H), 1.98-2.07 (m, 2H), 2.19-2.27 (m, 1H), 2.89-2.97 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 24.47 (CH2), 25.88 (CH2), 30.63 (CH3), 32.64 (CH2), 34.88 (CH2), 50. 68 (C), 58.13 (CH), 74.31 (CH)
Analysis condition B retention time 15.6 minutes, 16.0 minutes

Reference Example 6 synthesis of trans-2- (allylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that allylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.92-1.04 (m, 1H), 1.19-1.31 (m, 3H), 1.70-1.72 (m, 2H) ), 1.97-2.07 (m, 2H), 2.24-2.32 (m, 1H), 3.11-3.26 (m, 2H), 3.36-3.42 (m) , 1H), 5.06-5.22 (m, 2H), 5.84-5.97 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 24.28 (CH2), 24.71 (CH2), 30.07 (CH2), 33.62 (CH2), 49.17 (CH2), 62. 65 (CH), 73.27 (CH), 115.61 (CH2), 136.85 (CH)
Analysis condition A Retention time 34.8 minutes, 35.2 minutes

Reference Example 7 synthesis of trans-2- (propargylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that propargylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.92-1.05 (m, 1H), 1.21-1.38 (m, 3H), 1.68-1.73 (m, 2H) ), 1.96-2.08 (m, 2H), 2.24 (t, J = 2.40 Hz, 1H), 2.40-2.48 (m, 1H), 3.21-3.29. (M, 1H), 3.47 (dq, J1 = 16.82 Hz, J2 = 2.40 Hz, 2H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 24.31 (CH2), 24.56 (CH2), 29.79 (CH2), 33.80 (CH2), 35.35 (CH2), 62. 01 (CH), 71.30 (C), 73.61 (CH), 82.22 (CH)
Analysis condition C Retention time 47.1 minutes, 47.6 minutes

Reference Example 8 synthesis of trans-2- (cyclopentylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that cyclopentylamine was used instead of isopropylamine. (Outer bath temperature 170-175 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.87-0.95 (m, 1H), 1.20-1.38 (m, 5H), 1.50-1.87 (m, 8H) ), 2.01-2.22 (m, 3H), 3.01-3.09 (m, 1H), 3.19-3.27 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl3) δ 23.59 (CH2), 23.79 (CH2), 24.31 (CH2), 25.27 (CH2), 30.91 (CH2), 33.08 (CH2), 33.12 (CH2), 34.59 (CH2), 56.14 (CH), 61.86 (CH), 73.75 (CH)
Analysis condition D Retention time 24.7 minutes, 25.1 minutes

Reference Example 9 trans-2- (Cyclohexylamino) cyclohexanol synthesis All operations were performed in the same manner as Reference Example 1 except that cyclohexylamine was used instead of isopropylamine. (Outer bath temperature 170-175 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.83-1.04 (m, 2H), 1.08-1.36 (m, 7H), 1.62-1.73 (m, 6H) ), 1.90 (d, J = 12.32 Hz, 1H), 1.97-2.08 (m, 2H), 2.21-2.30 (m, 1H), 2.51-2.60. (M, 1H), 3.01-3.09 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl3) δ 24.29 (CH2), 24.56 (CH2), 25.06 (CH2), 25.29 (CH2), 26.00 (CH2), 31.47 (CH2), 33.04 (CH2), 33.50 (CH2), 35.19 (CH2), 53.18 (CH), 60.26 (CH), 73.77 (CH)
Analysis condition E Retention time 31.4 minutes, 31.9 minutes

Reference Example 10 synthesis of trans-2- (dimethylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that dimethylamine was used instead of isopropylamine. (Outer bath temperature 70-75 ° C., pressure 0.2 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.03-1.31 (m, 4H), 1.69-1.78 (m, 3H), 2.07-2.33 (m, 8H) ), 3.27-3.35 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 20.16 (CH 2), 23.97 (CH 2), 25.14 (CH 2), 33.05 (CH 2), 39.98 (CH 3), 69. 11 (CH), 69.36 (CH)
Analysis condition F Retention time 46.5 minutes, 47.1 minutes

Reference Example 11 synthesis of trans-2- (diethylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that diethylamine was used instead of isopropylamine. (Outer bath temperature 80-85 ° C., pressure 0.2 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.04 (t, J = 6.91 Hz, 6H), 1.13-1.31 (m, 4H), 1.69-1.77 (m 3H), 2.10-2.14 (m, 1H), 2.26-2.42 (m, 3H), 2.57-2.69 (m, 2H), 3.26-3.34. (M, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 14.58 (CH ₃ ), 22.69 (CH 2), 24.04 (CH 2), 25.61 (CH 2), 33.07 (CH 2), 43. 08 (CH2), 66.05 (CH), 68.89 (CH)
Analysis condition G Retention time 29.7 minutes, 30.6 minutes

Reference Example 12 synthesis of trans-2- (1-pyrrolidinyl) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that pyrrolidine was used instead of isopropylamine. (Outer bath temperature 100-105 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.17-1.27 (m, 4H), 1.69-1.78 (m, 7H), 2.05-2.15 (m, 1H) ), 2.4-2.59 (m, 3H), 2.64-2.71 (m, 2H), 3.29-3.37 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 20.99 (CH2), 23.43 (CH2), 24.03 (CH2), 25.16 (CH2), 33.13 (CH2), 47. 03 (CH2), 64.78 (CH), 70.51 (CH)
Analysis condition H Retention time 23.0 minutes, 23.2 minutes

Reference Example 13 trans-2- (1-piperidinyl) cyclohexanol synthesis All operations were performed in the same manner as Reference Example 1 except that piperidine was used instead of isopropylamine. (Outer bath temperature 105-115 ° C., pressure 0.2 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.12-1.26 (m, 4H), 1.43-1.79 (m, 9H), 2.10-2.17 (m, 2H) ), 2.31-2.34 (m, 2H), 2.62-2.70 (m, 2H), 3.31-3.39 (m, 2H)
¹³ C-NMR (75.45 MHz, CDCl3) δ 22.06 (CH2), 24.04 (CH2), 24.79 (CH2), 25.56 (CH2), 26.67 (CH2), 33.19 (CH2), 49.63 (CH2), 68.45 (CH), 70.93 (CH)
Analysis condition H Retention time 35.6 minutes, 35.8 minutes

Reference Example 14 synthesis of trans-2- (phenylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that aniline was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.98-1.11 (m, 1H), 1.24-1.47 (m, 3H), 1.70-1.79 (m, 2H) ), 2.10-2.14 (m, 2H), 3.10-3.18 (m, 1H), 3.31-3.39 (m, 1H), 6.70-6.77 (m) , 3H), 7.15-7.25 (m, 2H)
¹³ C-NMR (75.45 MHz, CDCl 3) δ 24.15 (CH 2), 24.82 (CH 2), 31.42 (CH 2), 33.09 (CH 2), 59.89 (CH), 74.25 (CH), 114.17 (CH), 118.07 (CH), 129.18 (CH), 147.73 (C)
Analysis condition α Retention time 27.5 minutes, 29.7 minutes

Reference Example 15 synthesis of trans-2- (2-phenylethylamino) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that 2-phenylethylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.84-0.96 (m, 1H), 1.18-1.32 (m, 3H), 1.67-1.71 (m, 2H) ), 1.99-2.07 (m, 2H), 2.16-2.25 (m, 1H), 2.70-2.86 (m, 3H), 3.00-3.15 (m , 2H), 7.18-7.32 (m, 5H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 24.29 (CH 2), 25.15 (CH 2), 30.55 (CH 2), 33.25 (CH 2), 37.01 (CH 2), 47. 89 (CH2), 63.55 (CH), 73.62 (CH), 126.06 (CH), 128.36 (CH), 128.63 (CH), 140.06 (C)
Analysis condition α Retention time 25.0 minutes, 35.0 minutes

Reference Example 16 synthesis of trans-2- (benzylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that benzylamine was used instead of isopropylamine. (Outer bath temperature 175-180 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.91-1.05 (m, 1H), 1.16-1.35 (m, 3H), 1.71-1.74 (m, 2H) ), 2.01-2.07 (m, 1H), 2.15-2.21 (m, 1H), 2.25-2.33 (m, 1H), 3.16-3.24 (m) , 1H), 3.69 (d, J = 12.92 Hz, 1H), 3.96 (d, J = 12.92 Hz, 1H), 7.22-7.36 (m, 5H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 24.25 (CH2), 24.85 (CH2), 30.20 (CH2), 33.40 (CH2), 50.68 (CH2), 62. 89 (CH), 73.41 (CH), 126.81 (CH), 127.96 (CH), 128.25 (CH), 140.32 (C)
Analysis condition α Retention time 16.9 minutes, 26.9 minutes

Reference Example 17 synthesis of trans-2- (3-ethoxypropylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that 3-ethoxypropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.91-1.03 (m, 1H), 1.15-1.30 (m, 6H), 1.70-1.79 (m, 4H) ), 1.99-2.09 (m, 2H), 2.17-2.25 (m, 1H), 2.52-2.61 (m, 1H), 2.82-2.91 (m) , 1H), 3.14-3.22 (m, 1H), 3.43-3.51 (m, 4H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 14.98 (CH3), 24.26 (CH2), 24.86 (CH2), 30.21 (CH2), 30.33 (CH2), 33. 42 (CH2), 43.90 (CH2), 63.35 (CH), 65.98 (CH2), 68.80 (CH2), 73.27 (CH)
Analysis condition AA Retention time 25.6 minutes, 25.8 minutes

Reference Example 18 synthesis of trans-2- (isopropylamino) cyclopentanol The same operation as in Reference Example 1 was performed except that 6-oxabicyclo [3.1.0] hexane was used as the epoxide. (Outer bath temperature 95-100 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.05-1.10 (m, 6H), 1.21-1.31 (m, 1H), 1.48-1.78 (m, 3H ), 1.88-2.08 (m, 2H), 2.67-2.95 (m, 2H), 3.78-3.85 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 20.03 (CH2), 22.44 (CH3), 23.85 (CH3), 30.41 (CH2), 32.18 (CH2), 47. 03 (CH), 63.90 (CH), 77.78 (CH)
Analysis condition I Retention time 14.3 minutes, 14.7 minutes

Reference Example 19 synthesis of trans-2- (cyclopropylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that cyclopropylamine was used instead of isopropylamine. (Outer bath temperature 105-110 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.31-0.52 (m, 4H), 1.27-1.40 (m, 1H), 1.48-1.79 (m, 3H) ), 1.88-1.99 (m, 1H), 2.03-2.19 (m, 2H), 2.90-2.97 (m, 1H), 3.85 (q, J = 6) .31Hz, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 5.89 (CH 2), 6.46 (CH 2), 20.08 (CH 2), 29.30 (CH), 30.13 (CH 2), 32. 12 (CH2), 66.95 (CH), 77.21 (CH)
Analysis condition J Retention time 15.5 minutes, 15.7 minutes

Reference Example 20 synthesis of trans-2- (propylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that propylamine was used instead of isopropylamine. (Outer bath temperature 100-105 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.71 (t, J = 7.51 Hz, 3H), 1.22-1.35 (m, 1H), 1.45-1.78 (m , 5H), 1.88-2.11 (m, 2H), 2.50-2.66 (m, 2H), 2.78-2.86 (m, 1H), 3.85 (q, J = 6.61Hz, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 11.66 (CH ₃ ), 20.15 (CH 2), 23.22 (CH 2), 29.93 (CH 2), 32.53 (CH 2), 50. 41 (CH2), 66.57 (CH), 77.43 (CH)
Analysis condition K Retention time 17.3 minutes, 17.6 minutes

Reference Example 21 synthesis of trans-2- (allylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that allylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.23-1.36 (m, 1H), 1.48-1.78 (m, 3H), 1.89-2.06 (m, 2H) ), 2.82-2.90 (m, 1H), 3.18-3.34 (m, 4H), 3.83-3.89 (m, 1H), 5.10 (d, J = 10) .21 Hz, 1H), 5.18 (dd, J1 = 17.12 Hz, J2 = 1.50 Hz, 1H), 5.85-5.98 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 20.02 (CH 2), 29.67 (CH 2), 32.38 (CH 2), 50.87 (CH 2), 65.81 (CH), 77. 31 (CH), 115.97 (CH2), 136.31 (CH)
Analysis condition L Retention time 32.9 minutes, 34.0 minutes

Reference Example 22 synthesis of trans-2- (propargylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that propargylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.25-1.37 (m, 1H), 1.51-1.81 (m, 3H), 1.89-2.07 (m, 2H) ), 2.27-2.29 (m, 1H), 3.01-3.08 (m, 1H), 3.35-3.54 (m, 2H), 3.89 (q, J = 6) .31Hz, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 20.12 (CH2), 29.39 (CH2), 32.48 (CH2), 36.57 (CH2), 64.97 (CH), 71. 50 (C), 77.53 (CH), 81.89 (CH)
Analysis condition M Retention time 40.1 minutes, 41.9 minutes

Reference Example 23 synthesis of trans-2- (cyclopentylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that cyclopentylamine was used instead of isopropylamine. (Outer bath temperature 165-170 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.22-1.36 (m, 3H), 1.47-1.77 (m, 7H), 1.82-2.06 (m, 4H) ), 2.82-2.89 (m, 1H), 3.11 (quin, J = 7.21 Hz, 1H), 3.81 (q, J = 6.91 Hz, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 19.83 (CH2), 23.57 (CH2), 23.66 (CH2), 29.98 (CH2), 32.10 (CH2), 32. 63 (CH2), 33.65 (CH2), 58.34 (CH), 65.01 (CH), 77.25 (CH)
Analysis condition N Retention time 24.3 minutes, 24.5 minutes

Reference Example 24 synthesis of trans-2- (1-pyrrolidinyl) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that pyrrolidine was used instead of isopropylamine. (Outer bath temperature 125-130 ° C, pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.46-1.83 (m, 8H), 1.86-2.00 (m, 2H), 2.41-2.48 (m, 1H) ), 2.59-2.61 (m, 4H), 4.06-4.12 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 21.34 (CH2), 22.96 (CH2), 29.70 (CH2), 34.51 (CH2), 52.46 (CH2), 73. 19 (CH), 76.28 (CH)
Analysis condition O Retention time 19.9 minutes, 20.3 minutes

Reference Example 25 synthesis of trans-2- (1-piperidinyl) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that piperidine was used instead of isopropylamine. (Outer bath temperature 125-130 ° C, pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.41-1.75 (m, 10H), 1.80-1.97 (m, 2H), 2.48-2.56 (m, 5H) ), 4.10-4.16 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 21.71 (CH 2), 24.29 (CH 2), 25.76 (CH 2), 26.92 (CH 2), 34.36 (CH 2), 52. 14 (CH2), 74.38 (CH), 75.17 (CH)
Analysis condition N Retention time 23.1 minutes, 23.4 minutes

Reference Example 26 synthesis of trans-2- (phenylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that aniline was used instead of isopropylamine. (Outer bath temperature 160-165 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.29-1.38 (m, 1H), 1.41-2.02 (m, 4H), 2.16-2.28 (m, 1H) ), 3.52-3.58 (m, 1H), 3.96-4.01 (m, 1H), 6.62-6.73 (m, 3H), 7.09-7.21 (m , 2H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 20.84 (CH 2), 30.97 (CH 2), 32.61 (CH 2), 61.93 (CH), 77.97 (CH), 113. 30 (CH), 117.42 (CH), 129.17 (CH), 147.64 (C)
Analysis condition P Retention time 51.3 minutes, 51.6 minutes

Reference Example 27 synthesis of trans-2- (2-phenylethylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that 2-phenylethylamine was used instead of isopropylamine. (Outer bath temperature 160-165 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.18-1.31 (m, 1H), 1.47-1.76 (m, 3H), 1.86-2.04 (m, 2H) ), 2.72-2.96 (m, 5H), 3.82 (q, J = 6.31 Hz, 1H), 7.18-7.30 (m, 5H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 20.24 (CH2), 30.02 (CH2), 32.63 (CH2), 36.32 (CH2), 49.63 (CH2), 66. 50 (CH), 77.61 (CH), 126.07 (CH), 128.36 (CH), 128.54 (CH), 139.69 (C)
Analysis condition α Retention time 13.6 minutes, 18.3 minutes

Reference Example 28 synthesis of trans-2- (benzylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that benzylamine was used instead of isopropylamine. (Outer bath temperature 160-165 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.23-1.36 (m, 1H), 1.43-1.57 (m, 1H), 1.59-1.75 (m, 2H) ), 1.84-2.04 (m, 2H), 2.81-2.88 (m, 1H), 3.66-3.85 (m, 3H), 7.20-7.32 (m , 5H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 20.22 (CH2), 29.96 (CH2), 32.46 (CH2), 52.45 (CH2), 66.03 (CH), 77. 69 (CH), 126.88 (CH), 128.07 (CH), 128.30 (CH), 140.04 (C)
Analysis condition β retention time 33.2 minutes, 34.9 minutes

Reference Example 29 synthesis of trans-2- (3-ethoxypropylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that 3-ethoxypropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.19 (t, J = 6.91 Hz, 3H), 1.26-1.36 (m, 1H), 1.48-1.81 (m , 5H), 1.89-2.07 (m, 2H), 2.64-2.86 (m, 3H), 3.35-3.51 (m, 4H), 3.83-3.89 (M, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 15.01 (CH3), 20.18 (CH2), 29.90 (CH2), 29.99 (CH2), 32.48 (CH2), 45. 91 (CH2), 66.02 (CH2), 66.04 (CH), 68.98 (CH2), 77.42 (CH)
Analysis condition γ Retention time 23.6 minutes, 24.7 minutes

Reference Example 30 synthesis of trans-4- (isopropylamino) -3-tetrahydrofuran-3-ol The same operation as in Reference Example 1 was conducted except that 3,6-dioxabicyclo [3.1.0] hexane was used as the epoxide. (Outer bath temperature 120-125 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.08 (d, J = 6.31 Hz, 3H), 1.08 (d, J = 6.31 Hz, 3H), 2.86 (sep, J = 6.31 Hz, 1H), 3.23-3.26 (m, 1H), 3.55 (dd, J1 = 9.01 Hz, J2 = 3.91 Hz, 1H), 3.62-3.66 ( m, 1H), 3.98 (dd, J1 = 9.61 Hz, J2 = 5.11 Hz, 1H), 4.05 (dd, J1 = 9.31 Hz, J2 = 5.71 Hz, 1H), 4.11 -4.15 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 22.46 (CH3), 23.11 (CH3), 46.70 (CH), 63.73 (CH), 72.17 (CH2), 73. 63 (CH2), 76.33 (CH)
Analysis condition γ Retention time 25.5 minutes, 25.7 minutes

Reference Example 31 synthesis of trans-4- (cyclopropylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that cyclopropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.41-0.53 (m, 4H), 2.12-2.19 (m, 1H), 3.27-3.31 (m, 1H) ), 3.61-3.68 (m, 2H), 3.97 (dd, J1 = 9.61 Hz, J2 = 4.81 Hz, 1H), 4.06 (dd, J1 = 9.01 Hz, J2 = 5.41 Hz, 1H), 4.21 (q, J = 2.40 Hz, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 6.18 (CH2), 6.35 (CH2), 28.93 (CH), 66.57 (CH), 71.90 (CH2), 73. 62 (CH2), 75.59 (CH)
Analysis condition γ Retention time 26.2 minutes, 28.2 minutes

Reference Example 32 synthesis of trans-4- (propylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that propylamine was used instead of isopropylamine. (Outer bath temperature 150-155 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.93 (t, J = 7.21 Hz, 3H), 1.50 (sext, J = 7.21 Hz, 2H), 2.58 (t, J = 7.21 Hz, 2H), 3.13-3.15 (m, 1H), 3.58 (dd, J1 = 9.31 Hz, J2 = 3.60 Hz, 1H), 3.65 (dd, J1 = 9.61 Hz, J2 = 2.70 Hz, 1H), 3.99 (dd, J1 = 9.61 Hz, J2 = 4.81 Hz, 1H), 4.05 (dd, J1 = 9.31 Hz, J2 = 5. 71 Hz, 1H), 4.13-4.14 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 11.54 (CH3), 23.02 (CH2), 49.96 (CH2), 66.52 (CH), 71.96 (CH2), 73. 80 (CH2), 75.98 (CH)
Analysis condition Q Retention time 18.3 minutes, 18.9 minutes

Reference Example 33 synthesis of trans-4- (allylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as Reference Example 30 except that allylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 3.17-3.27 (m, 3H), 3.56-3.68 (m, 2H), 3.95-4.05 (m, 2H) ), 4.10-4.16 (m, 1H) 5.11-5.23 (m, 2H), 5.81-5.95 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 50.39 (CH 2), 65.59 (CH), 71.78 (CH 2), 73.70 (CH 2), 75.86 (CH), 116. 58 (CH2), 135.67 (CH)
Analysis condition R Retention time 20.3 minutes, 20.7 minutes

Reference Example 34 synthesis of trans-4- (propargylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that propargylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 2.31 (s, 1H), 3.37-3.52 (m, 3H), 3.57-3.72 (m, 2H), 3. 97-4.18 (m, 3H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 36.28 (CH 2), 64.88 (CH), 71.94 (CH 2), 72.07 (C), 73.87 (CH 2), 75. 97 (CH), 81.48 (CH)
Analysis condition S Retention time 24.5 minutes, 25.1 minutes

Reference Example 35 synthesis of trans-4- (cyclopentylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that cyclopentylamine was used instead of isopropylamine. (Outer bath temperature 170-175 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.22-1.36 (m, 2H), 1.53-1.74 (m, 4H), 1.87-1.90 (m, 2H) ), 3.06-3.22 (m, 2H), 3.56 (dd, J1 = 9.01 Hz, J2 = 3.91 Hz, 1H), 3.65 (dd, J1 = 9.61 Hz, J2 = 2.70 Hz, 1H), 3.95-4.15 (m, 3H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 23.67 (CH 2), 33.00 (CH 2), 33.38 (CH 2), 58.13 (CH), 65.27 (CH), 72. 33 (CH2), 73.73 (CH2), 76.37 (CH)
Analysis condition γ Retention time 28.5 minutes, 28.7 minutes

Reference Example 36 synthesis of trans-4- (diethylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that diethylamine was used instead of isopropylamine. (Outer bath temperature 115-120 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.05 (t, J = 7.21 Hz. 6H), 2.62 (q, J = 7.21 Hz, 4H), 3.21 (dt, J1 = 6.61 Hz, J2 = 3.00 Hz, 1H), 3.61-3.69 (m, 2H), 3.93-4.03 (m, 2H), 4.27-4.32 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 11.55 (CH ₃ ), 43.97 (CH 2), 69.59 (CH 2), 70.33 (CH), 74.48 (CH), 74. 76 (CH2)
Analysis condition T Retention time 15.8 minutes, 16.1 minutes

Reference Example 37 synthesis of trans-4- (1-piperidinyl) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that piperidine was used instead of isopropylamine. (Outer bath temperature 150-155 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.47 (d, J = 4.81 Hz, 2H), 1.56-1.63 (m, 4H), 2.34-2.40 (m , 2H), 2.54-2.57 (m, 2H), 2.81 (dt, J1 = 6.61 Hz, J2 = 2.70 Hz, 1H), 3.66-3.71 (m, 2H) 3.95 (dd, J1 = 9.61 Hz, J2 = 5.71 Hz, 1H), 4.02 (dd, J1 = 9.01 Hz, J2 = 7.21 Hz, 1H), 4.32-4.36 (M, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 23.99 (CH2), 25.48 (CH2), 52.39 (CH2), 69.63 (CH2), 74.11 (CH), 74. 95 (CH), 75.13 (CH2)
Analysis condition U Retention time 16.6 minutes, 17.0 minutes

Reference Example 38 synthesis of trans-4- (phenylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that aniline was used instead of isopropylamine. (Outer bath temperature 195-200 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CD ₃ OD) δ 3.66-3.78 (m, 3H), 3.95 (dd, J1 = 9.61 Hz, J2 = 3.91 Hz, 1H), 4. 16-4.21 (m, 2H), 6.60-6.68 (m, 3H), 7.08-7.13 (m, 2H)
¹³ C-NMR (75.45 MHz, CD ₃ OD) δ 62.66 (CH), 72.96 (CH 2), 74.95 (CH 2), 76.52 (CH), 114.11 (CH), 118 .24 (CH), 130.07 (CH), 148.72 (C)
Analysis condition V Retention time 50.8 minutes, 51.2 minutes

Reference Example 39 synthesis of trans-4- (2-phenylethylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that 2-phenylethylamine was used instead of isopropylamine. (Outer bath temperature 190-195 ° C, pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 2.76-2.90 (m, 4H), 3.15 (s, 1H), 3.51 (dd, J1 = 9.01 Hz, J2 = 3 .30 Hz, 1H), 3.63 (dd, J1 = 9.61 Hz, J2 = 1.80 Hz, 1H), 3.93 (dd, J1 = 9.61 Hz, J2 = 4.81 Hz, 1H), 4. 00-4.08 (m, 2H), 7.17-7.31 (m, 5H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 36.17 (CH2), 49.28 (CH2), 66.56 (CH), 72.17 (CH2), 73.92 (CH2), 76. 28 (CH), 126.27 (CH), 128.47 (CH), 128.53 (CH), 139.34 (C)
Analysis condition γ Retention time 29.2 minutes, 29.4 minutes

Reference Example 40 synthesis of trans-4- (benzylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that benzylamine was used instead of isopropylamine. (Outer bath temperature 185-190 ° C, pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 3.15 (s, 1H), 3.54 (dd, J1 = 9.31 Hz, J2 = 3.30 Hz, 1H), 3.62 (dd, J1 = 9.61 Hz, J2 = 1.80 Hz, 1H), 3.74 (s, 2H), 3.94 (dd, J1 = 9.61 Hz, J2 = 4.51 Hz, 1H), 4.00 (dd, J1 = 9.31 Hz, J2 = 5.71 Hz, 1H), 4.08-4.10 (m, 1H), 7.22-7.34 (m, 5H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 52.03 (CH2), 65.82 (CH), 72.08 (CH2), 73.82 (CH2), 76.18 (CH), 127. 15 (CH), 128.07 (CH), 128.42 (CH), 139.37 (C)
Analysis condition γ Retention time 29.1 minutes, 29.3 minutes

Reference Example 41 synthesis of trans-4- (3-ethoxypropylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that 3-ethoxypropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.19 (t, J = 6.91 Hz, 3H), 1.76 (quin, J = 6.61 Hz, 2H), 2.69-2.73 (M, 2H), 3.13-3.17 (m, 1H), 3.46-3.51 (m, 4H), 3.57 (dd, J1 = 9.01 Hz, J2 = 3.30 Hz, 1H), 3.66 (dd, J1 = 9.61 Hz, J2 = 2.40 Hz, 1H), 3.98 (dd, J1 = 9.61 Hz, J2 = 4.81 Hz, 1H), 4.06 (dd , J1 = 9.01 Hz, J2 = 5.41 Hz, 1H), 4.14 (quin, J = 2.40 Hz, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 14.98 (CH3), 29.78 (CH2), 45.74 (CH2), 66.05 (CH2), 66.55 (CH), 68. 89 (CH2), 72.08 (CH2), 73.84 (CH2), 75.91 (CH)
Analysis condition ζ Retention time 7.3 minutes, 9.1 minutes

Reference Example 42 synthesis of trans-2- (isopropylamino) cycloheptanol The same operation as in Reference Example 1 was conducted except that 8-oxabicyclo [5.1.0] octane was used as the epoxide. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.02 (d, J = 6.01 Hz, 3H), 1.06 (d, J = 6.01 Hz, 3H), 1.36-1.72 (M, 8H), 1.88-2.05 (m, 2H), 2.23-2.31 (m, 1H), 2.94 (sep, J = 6.01 Hz, 1H), 3.08 -3.14 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 22.35 (CH ₃ ), 22.56 (CH 2), 24.07 (CH 3), 24.38 (CH 2), 26.50 (CH 2), 30. 69 (CH2), 32.96 (CH2), 45.56 (CH), 62.52 (CH), 75.09 (CH)
Analysis condition W Retention time 9.4 minutes, 9.5 minutes

Reference Example 43 synthesis of trans-2- (cyclopropylamino) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that cyclopropylamine was used instead of isopropylamine.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.22-0.56 (m, 4H), 1.21-1.32 (m, 1H), 1.39-1.71 (m, 7H) ), 1.89-1.99 (m, 1H), 2.07-2.14 (m, 1H), 2.21-2.28 (m, 1H), 2.33-2.41 (m , 1H), 3.06-3.16 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 6.20 (CH2), 7.13 (CH2), 22.03 (CH2), 23.71 (CH2), 26.55 (CH2), 27. 62 (CH), 29.90 (CH2), 32.75 (CH2), 65.76 (CH), 74.90 (CH)
Analysis condition γ Retention time 25.8 minutes, 30.8 minutes

Reference Example 44 synthesis of trans-2- (2-phenylethylamino) cycloheptanol All operations were performed in the same manner as Reference Example 42 except that 2-phenylethylamine was used instead of isopropylamine.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.09-1.20 (m, 1H), 1.33-1.67 (m, 7H), 1.83-1.98 (m, 2H) ), 2.24 (dt, J1 = 9.31 Hz, J2 = 2.70 Hz, 1H), 2.67-3.07 (m, 5H), 3.13-3.20 (m, 1H), 7 .15-7.29 (m, 5H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 21.95 (CH2), 23.80 (CH2), 26.52 (CH2), 29.27 (CH2), 33.25 (CH2), 36. 55 (CH2), 47.99 (CH2), 65.39 (CH), 74.96 (CH), 125.83 (CH), 128.11 (CH), 128.34 (CH), 139.65 (C)
Analysis condition β retention time 9.7 minutes, 12.4 minutes

Reference Example 45 synthesis of trans-2- (benzylamino) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that benzylamine was used instead of isopropylamine.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.17-1.30 (m, 1H), 1.34-1.72 (m, 7H), 1.89-2.02 (m, 2H) ), 2.32 (dt, J1 = 9.31 Hz, J2 = 3.00 Hz, 1H), 3.19-3.26 (m, 1H), 3.64 (d, J = 12.62 Hz, 1H) , 3.90 (d, J = 12.62 Hz, 1H), 7.19-7.30 (m, 5H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 22.00 (CH2), 23.80 (CH2), 26.65 (CH2), 29.11 (CH2), 33.31 (CH2), 50. 88 (CH2), 64.90 (CH), 75.22 (CH), 126.81 (CH), 127.97 (CH), 128.19 (CH), 139.89 (C)
Analysis condition β Retention time 8.1 minutes, 10.1 minutes

Reference Example 46 synthesis of trans-2- (propargylamino) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that propargylamine was used instead of isopropylamine.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.20-1.31 (m, 1H), 1.34-1.74 (m, 7H), 1.81-1.98 (m, 2H) ), 2.21-2.26 (m, 1H), 2.44-2.52 (m, 1H), 3.26-3.33 (m, 1H), 3.38-3.55 (m , 2H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 22.00 (CH2), 23.54 (CH2), 26.76 (CH2), 28.63 (CH2), 33.69 (CH2), 35. 65 (CH2), 64.42 (CH), 71.10 (C), 75.41 (CH), 82.03 (CH)
Analysis condition X Retention time 22.0 minutes, 22.3 minutes

Reference Example 47 synthesis of trans-2- (cyclopentylamino) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that cyclopentylamine was used instead of isopropylamine.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.10-2.05 (m, 18H), 2.23 (dt, J1 = 9.31 Hz, J2 = 3.00 Hz, 1H), 3.07 -3.14 (m, 1H), 3.22 (quin, J = 6.01 Hz, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 22.28 (CH 2), 23.47 (CH 2), 23.69 (CH 2), 24.03 (CH 2), 26.49 (CH 2), 30. 15 (CH2), 32.77 (CH2), 33.03 (CH2), 34.26 (CH2), 56.33 (CH), 63.63 (CH), 75.09 (CH)
Analysis condition Y Retention time 21.0 minutes, 21.2 minutes

Reference Example 48 synthesis of trans-2- (diethylamino) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that diethylamine was used instead of isopropylamine.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.09 (t, J = 7.21 Hz, 6H), 1.19-1.78 (m, 9H), 2.01-2.09 (m , 1H), 2.34-2.52 (m, 3H), 2.64-2.76 (m, 2H), 3.38-3.45 (m, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 14.08 (CH3), 22.00 (CH2), 22.47 (CH2), 24.74 (CH2), 26.90 (CH2), 33. 52 (CH2), 43.59 (CH2), 67.37 (CH), 71.27 (CH)
Analysis condition C Retention time 21.0 minutes, 21.2 minutes

Reference Example 49 synthesis of trans-2- (1-piperidinyl) cycloheptanol All operations were performed in the same manner as Reference Example 42 except that piperidine was used instead of isopropylamine.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.14-1.26 (m, 1 H), 1.30-1.83 (m, 14 H), 2.01-2.08 (m, 1 H) ), 2.14-2.21 (m, 1H), 2.31-2.33 (m, 2H), 2.60-2.67 (m, 2H), 3.33-3.41 (m) , 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 21.46 (CH2), 21.67 (CH2), 24.02 (CH2), 24.40 (CH2), 26.22 (CH2), 26. 44 (CH2), 33.03 (CH2), 48.96 (CH2), 70.60 (CH), 71.88 (CH)
Analysis condition Z Retention time 21.0 minutes, 21.2 minutes

Reference Example 50 trans-2-aminocyclohexanol Trans-2-aminocyclohexane-1-ol was used as it was by Sigma-Aldrich.
Analysis condition A Retention time (S, S) isomer: 18.3 minutes, (R, R) isomer: 18.7 minutes

Reference Example 51 trans-3-cyclopropylamino-2-butanol The same operation as in Reference Example 1 was performed except that Cis-2,3-epoxybutane and cyclopropylamine were used. The obtained crude product was used for analysis as it was. (Outer bath temperature 135-140 ° C., pressure 0.1 mmHg)
Analysis condition G Retention time 11.0 minutes, 11.3 minutes

Reference Example 52 trans-2- (2-propylthio) cyclohexanol 50 mL of 7-oxabicyclo [4.1.0] heptane and 1.70 mL of 2-propanethiol were weighed into a 50 mL eggplant flask, 8 mL of methanol, and 2 mL of water. Then, 2.84 mL of triethylamine was added and reacted at 50 ° C. for 20 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 3.12 g of a residue. 1.00 g of the residue was distilled under reduced pressure in a glass tube oven GTO-250RS (Kugel Roll) manufactured by Shibata Kagaku Co., Ltd., to obtain 0.77 g of trans-2- (2-propylthio) cyclohexane-1-ol. (Outer bath temperature 140-150 ° C., pressure 0.1 mmHg)
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.20-1.51 (m, 4H), 1.29 (d, J = 6.61 Hz, 3H), 1.30 (d, J = 6) .61 Hz, 3H), 1.68-1.79 (m, 2H), 2.07-2.15 (m, 2H), 2.38-2.46 (m, 1H), 3.03 (sep ., J = 6.61 Hz, 1H), 3.26 (dt, J1 = 4.51 Hz, J2 = 9.91 Hz, 1H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 24.24 (CH3), 24.31 (CH2), 24.39 (CH3), 26.23 (CH2), 33.67 (CH2), 34. 05 (CH2), 35.08 (CH), 53.58 (CH), 72.56 (CH)
Analysis condition AB Retention time 17.6 minutes, 18.8 minutes

Reference Example 53 7-tosyl-7-azabicyclo [4.1.0] heptane To a 50 mL four-necked flask equipped with a thermometer and a stirrer was added 1.00 g of 2-aminocyclohexanol, 15 mL of THF, and 1.81 mL of triethylamine. The mixture was ice-cooled and 1.74 g of tosyl chloride was added at an internal temperature of 3 ° C. At this time, the internal temperature rose to 10 ° C. After stirring for 30 minutes under ice cooling and 30 minutes at room temperature (26 ° C.), 20 mL of water and 20 mL of toluene were added for liquid separation, and the toluene layer was washed twice with 10 mL of water. The toluene layer after washing was dried over sodium sulfate and concentrated under reduced pressure using a rotary evaporator. The obtained oil was dried with a vacuum pump to obtain 2.27 g of trans-N-tosyl-2-aminocyclohexanol (crystal).
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.10-1.30 (m, 4H), 1.53-1.76 (m, 3H), 2.00-2.04 (m, 1H) ), 2.43 (s, 3H), 2.65 (d, J = 3.30 Hz, 1H), 2.80-2.90 (m, 1H), 3.26-3.35 (m, 1H) ), 4.96 (d, J = 6.91 Hz, 1H), 7.32 (d, J = 8.11 Hz, 1H), 7.80 (d, J = 8.11 Hz, 1H)
To a 50 mL four-necked flask equipped with a thermometer, a stirrer, and a calcium chloride tube were added 2.17 g of trans-N-tosyl-2-aminocyclohexanol, 2.75 g of triphenylphosphine, and 22 mL of THF, and the mixture was cooled with ice and the internal temperature At 2 ° C., 2.17 g of diisopropyl azodicarboxylate (90.0 +%) was added dropwise using a dropping funnel over 10 minutes. At this time, the internal temperature rose to 5 ° C. After stirring for 80 minutes under ice cooling and 60 minutes at room temperature (26 ° C.), 20 mL of water and 30 mL of ethyl acetate were added for liquid separation, and the ethyl acetate layer was concentrated under reduced pressure using a rotary evaporator to obtain 7.21 g of a residue. . The residue was subjected to column chromatography using 140 g of silica gel and developing solvent toluene: ethyl acetate = 5: 1 to obtain 1.33 g of 7-tosyl-7-azabicyclo [4.1.0] heptane.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 1.15-1.27 (m, 2H), 1.35-1.44 (m, 2H), 1.79 (t, J = 5.11 Hz) , 4H), 2.44 (s, 3H), 2.97-2.98 (m, 2H), 7.32 (d, J = 8.11 Hz, 2H), 7.82 (d, J = 8 .11Hz, 2H)

Reference Example 54 trans-N-tosyl- (2- (2-phenylethylamino) cyclohexylamine)
Reference Example except that 2-phenylethylamine is used in place of isopropylamine and 7-tosyl-7-azabicyclo [4.1.0] heptane is used in place of 7-oxabicyclo [4.1.0] heptane The same operation as in 1 was performed. The obtained crude product was used for analysis as it was.
¹ H-NMR (300.4 MHz, CDCl ₃ ) δ 0.83-0.94 (m, 1H), 1.06-1.25 (m, 3H), 1.57-1.63 (m, 2H) ), 1.97-2.07 (m, 2H), 2.16-2.24 (m, 1H), 2.38 (s, 3H), 2.54-2.69 (m, 4H), 2.78-2.87 (m, 1H), 7.13-7.30 (m, 7H), 7.70 (d, J = 8.11 Hz, 2H)
¹³ C-NMR (75.45 MHz, CDCl ₃ ) δ 21.27 (CH3), 24.23 (CH2), 24.42 (CH2), 30.89 (CH2), 32.32 (CH2), 36. 43 (CH2), 46.90 (CH2), 57.07 (CH), 60.11 (CH), 125.92 (CH), 126.97 (CH), 128.22 (CH), 128.39 (CH), 129.35 (CH), 137.09 (C), 139.68 (C), 142.89 (C)
Analysis condition θ Retention time: 37.2 minutes, 40.6 minutes

<Examples of processed plant preparation>
The processed plant product was obtained as follows.
The defatted soybean powder, pectin (citrus-derived), water-soluble soybean polysaccharide, pumpkin, lotus root, potato, carrot, wheat germ, and turmeric were processed into powder.
Unprocessed plant pieces such as kiwi, buntan, natsum, flower aubergine, garlic, soy, leek, pistachio, cashew nut, tea (tea, green tea), red kidney beans, peas, etc. are heated in a desiccator if necessary. After drying, about 5 g was pulverized for 30 seconds with a small pulverizer “Crushing kun” (SCM-40A, manufactured by Shibata Chemical Instruments Co., Ltd.), dispersed by adding 50 mL of hexane, and obtained after removing hexane. The powder was dried under reduced pressure.

＊：ペクチンとして、「ペクチン（柑橘類由来）」（関東化学製、Ｃａｔ Ｎｏ．３２５３６−３２）を使用した。 <Reference Examples 55-81>
To a 5 mL test tube, 100 mg of the processed plant product described in Table 3 was weighed, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 34 mg of cyclopropylamine, and 17 mg of water were added. Sealed and shaken in a 37 ° C. bath for 16 hours. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. Pumpkin powder (made by Kodama Foods) as pumpkin, Mashed Potato (made by Miki Foods) as potato, Carrot Powder (made by Kodama Foods) as carrot, Tomato Powder (made by Kodama Foods) as tomato, Japanese radish “Dried radish grated” (manufactured by Kodama Foods) and “renkon powder” (manufactured by Kodama Foods) were ground and used as lotus root. The pistachio used was degreased and then pulverized.

*: “Pectin (derived from citrus fruits)” (Cat No. 32536-32, manufactured by Kanto Kagaku) was used as the pectin.

  The results are shown in Table 3. In Reference Examples 55 to 81, the compound (3) was obtained stereoselectively. In particular, Reference Examples 55, 56, 65 and 67 were excellent in both conversion rate and stereoselectivity.

Reference Examples 82-101
To a 5 mL test tube, 100 mg of the processed plant product described in Table 4 was weighed, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 29 mg of isopropylamine, and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. Pumpkin powder (made by Kodama Foods) as pumpkin, Mashed Potato (made by Miki Foods) as potato, Carrot Powder (made by Kodama Foods) as carrot, Tomato Powder (made by Kodama Foods) as tomato, Japanese radish “Dried radish grated” (manufactured by Kodama Foods), “Loren powder” (manufactured by Kodama Foods) as a lotus root was pulverized into a powder form, and pistachio was degreased and pulverized.

  The results are shown in Table 4. In Examples 82 to 101, compound (3) was obtained stereoselectively. In particular, Reference Examples 82 to 85, 87, 93, 97 and 100 were excellent in both conversion rate and stereoselectivity.

Reference Examples 102-117
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, compound (2) shown in Table 5 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.

  The results are shown in Table 5. In Reference Examples 102 to 117, the compound (3) was obtained with good yield in a stereoselective manner.

Reference Examples 118-130
To a 5 mL test tube, 100 mg of carrot was weighed, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 1.2 equivalents of the compound (2) described in Table 6 and 17 mg of water were added. . Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.

  The results are shown in Table 6. In Reference Examples 118 to 130, compound (3) was obtained stereoselectively. In particular, Reference Examples 123 and 129 were excellent in both conversion rate and stereoselectivity.

Reference Examples 131-142
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, 0.4 mL of toluene, 41 mg of 6-oxabicyclo [3.1.0] hexane, compound (2) described in Table 7 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.

  The results are shown in Table 7. All of Reference Examples 131 to 142 were excellent in both stereoselectivity and yield.

Reference Examples 143 to 154
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, 0.4 mL of toluene, 42 mg of 3,6-dioxabicyclo [3.1.0] hexane, and the compounds described in Table 8 (2) 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.

  The results are shown in Table 8. All of Reference Examples 143 to 154 were excellent in both stereoselectivity and yield.

Reference examples 155 to 162
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) was weighed, 0.4 mL of toluene, 41 mg of 8-oxabicyclo [5.1.0] octane, compound (2) shown in Table 9 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.

  The results are shown in Table 9. Reference Examples 155 to 162 all gave compound (3) stereoselectively. In particular, Example 107 was excellent in both conversion rate and stereoselectivity.

Reference Example 163
In a 5 mL test tube, 1.1 g of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, 2.87 mL of toluene, 41 mg of Cis-2,3-epoxybutane, 1.2 equivalents of cyclopropylamine, and 390 mg of water. added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. As a result, the conversion was 55% and the selectivity was 4% ee.

Reference examples 164 to 168
In a 1 L four-necked flask equipped with a stirrer and a thermometer, 70.0 g of processed soybean, 198 mL of toluene, 28.0 mL of water, 35.0 g of 7-oxabicyclo [4.1.0] heptane and 24. 4 g was added and stirred at 40 ° C. under a nitrogen atmosphere. Table 1 shows the processed soybean and reaction time used in each example. A small amount of the reaction solution was collected, and the conversion rate and selectivity at a predetermined reaction time were calculated using gas chromatography.

  The results are shown in Table 10. Reference Examples 164 to 168 all gave compound (3) stereoselectively. In particular, Reference Examples 166 to 168 were excellent in both conversion rate and stereoselectivity.

Reference Example 169
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, and 0.4 mL of toluene, 100 mg of 7-oxabicyclo [4.1.0] heptane, 109 mg of 2-propanethiol, and 17 mg of water are added. added. Sealed and shaken in a 50 ° C. bath for 5 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. As a result, the conversion rate was 7% and the selectivity rate was 72% ee.

Reference Example 170
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, and 0.4 mL of toluene, 100 mg of 7-tosyl-7-azabicyclo [4.1.0] heptane, 58 mg of 2-phenylethylamine, 17 mg of water was added. Sealed and shaken in a 50 ° C. bath for 5 days. After the reaction, the catalyst was filtered, and the filtrate was concentrated to obtain 120 mg of a crude product of trans-N-tosyl (2- (2-phenylethylamino) cyclohexylamine). The crude yield was 81% and the selectivity was 4% ee.

Reference Example 171 Synthesis of (1R, 2R) -2- (cyclopropylamino) cyclohexanol Into a 1 L four-necked flask equipped with a stirrer and a thermometer, 70.0 g of Soya Five S-DN, 198 mL of toluene, 28.0 mL of water, 7 -Oxabicyclo [4.1.0] heptane (35.0 g) and cyclopropylamine (24.4 g) were added, and the mixture was stirred at 40 ° C for 26 hours under a nitrogen atmosphere. Soya Five S-DN was filtered off using Nutsche and washed with 140 mL of toluene. The obtained filtrate was concentrated under reduced pressure, and (1R, 2R) -2- (cyclopropylamino) cyclohexanol 58.4 g (content 51.0 g, 64% ee, yield 92%) was obtained as a crude product. Obtained. Here, the content was calculated based on the mass of the crude product by measuring the ¹ H-NMR spectrum of the crude product and using the integral ratio of protons of 2- (cyclopropylamino) cyclohexanol and toluene. Value.
In a 5 L four-necked flask equipped with a stirrer and a thermometer, 317.5 g (content 272.4 g, 64% ee) of (1R, 2R) -2- (cyclopropylamino) cyclohexanol of the obtained crude product was obtained. After adding 2724 mL of isopropanol and raising the temperature to 40 ° C., 61.1 g of fumaric acid, 10 mg of seed crystal A, and 27.2 g of activated carbon (refined birch (Nippon Enviro Chemicals, Inc., trade name)) were added and left for 30 minutes. At this time, racemic 2-cyclopropylaminocyclohexanol fumarate was used as seed crystal A. After cooling to room temperature and allowing to stand for another 60 minutes, the precipitated racemic 2- (cyclopropylamino) cyclohexanol fumarate crystals and activated carbon were filtered off using Nutsche, and the crystals were washed with 272 mL of isopropanol. . The obtained filtrate was concentrated under reduced pressure using a rotary evaporator. To the obtained (1R, 2R) -2- (cyclopropylamino) cyclohexanol, 1498 mL of toluene, 34.5 mL of water and 40.3 g of potassium hydroxide were added to convert to a free form, and the toluene layer was separated. The obtained toluene layer was washed with 68 mL of water three times and concentrated under reduced pressure using a rotary evaporator to obtain 154.1 g (content 135.6 g) of a solid. To a 1 L four-necked flask equipped with a stirrer and a thermometer, add 154.1 g (content 135.6 g) of the solid and 407 mL of heptane, adjust the internal temperature to 25 ° C., add 135 mg of seed crystal B, and take 30 minutes. Left to stand. At this time, (1R, 2R) -2- (cyclopropylamino) cyclohexanol was used as seed crystal B. Furthermore, after allowing to stand at an internal temperature of 10 to 15 ° C. for 60 minutes and at 0 ° C. for 60 minutes, the precipitated crystals were collected by filtration. The obtained crystals were washed with 68 mL of heptane at 0 ° C. and dried under reduced pressure at room temperature to obtain 103.0 g (100% ee) of primary crystals of white (1R, 2R) -2- (cyclopropylamino) cyclohexanol. It was. The filtrate was concentrated on a rotary evaporator under reduced pressure to obtain 11.0 g (100% ee) of secondary crystals in the same manner as when primary crystals were obtained. A step of obtaining crystals of (1R, 2R) -2- (cyclopropylamino) cyclohexanol, which are a combination of primary and secondary crystals, from the crude product (1R, 2R) -2- (cyclopropylamino) cyclohexanol The yield of was 42%.

Reference Example 172 Synthesis of optically active trans-2- (isopropylamino) cyclohexanol To a 1 L four-necked flask equipped with a stirrer and a thermometer, Soya Five S-DN 14.4 g, heptane 36 mL, water 4.3 mL, 7-oxabicyclo [4.1.0] 12 g of heptane and 8.7 g of isopropylamine were added, and the mixture was stirred at 40 ° C. for 49 hours under a nitrogen atmosphere. Soya Five S-DN was filtered off using Nutsche and washed with 50 mL of heptane. The obtained filtrate was concentrated under reduced pressure, dissolved again in 36 mL of heptane, and the resulting crystals were filtered. The crystals were washed with 5 mL of heptane, and the mother liquor was concentrated to obtain 11 g of optically active trans-2- (isopropylamino) cyclohexanol (isomer 82% ee with a long retention time).

Reference Example 173 Synthesis of optically active trans-2- (propargylamino) cyclohexanol In a 50 mL four-necked flask equipped with a stirrer and a thermometer, 1.2 g Soya Five S-DN, 3 mL heptane, 0.36 mL water, 7-oxabicyclo [4.1.0] Heptane (0.858 g) and propargylamine (0.407 g) were added, and the mixture was stirred at 40 ° C. for 6 days under a nitrogen atmosphere. Toluene (3 mL) was added and stirred, and Soya Five S-DN was filtered off using Nutsche and washed with toluene (3 mL). The obtained filtrate was concentrated under reduced pressure to obtain 1.19 g (45% ee, 91% yield) of optically active trans-2- (propargylamino) cyclohexanol as a crude product.
To a 50 mL four-necked flask equipped with a stirrer and a thermometer, 1.19 g (45% ee) of the optically active trans-2- (propargylamino) cyclohexanol of the obtained crude product and 12 mL of ethanol were added. After the temperature was raised, 0.595 g of fumaric acid and 10 mg of seed crystals were added and allowed to stand for 30 minutes. At this time, racemic trans-2- (propargylamino) cyclohexanol fumarate was used as a seed crystal. After cooling to room temperature and allowing to stand for another 60 minutes, the precipitated racemic trans-2- (propargylamino) cyclohexanol fumarate crystals were filtered off using Nutsche, and the crystals were washed with 1 mL of ethanol. The obtained filtrate was concentrated under reduced pressure using a rotary evaporator. To the obtained optically active trans-2- (propargylamino) cyclohexanol, 10 mL of toluene, 1 mL of water and 0.480 g of potassium hydroxide were added to convert to a free form, and the toluene layer was separated. The obtained toluene layer was washed 3 times with 1 mL of water and concentrated under reduced pressure using a rotary evaporator to obtain 0.440 g (90% ee) of optically active trans-2- (propargylamino) cyclohexanol. The total yield at this time was 31%.

Example 1 Preparation of Catalyst S-G1 Water-soluble soybean polysaccharide (Soya Five S-DN (trade name), manufactured by Fuji Oil Co., Ltd., hereinafter abbreviated as “plant processed product S-O”) was 25 mg / mL, Contizyme 100 mL of a solution prepared so that 50 mg / mL (manufactured by Amano Enzyme Co., Ltd.) and 25 mM sodium phosphate buffer (pH 7.0) could be prepared was prepared, and shaken at 37 ° C. for 18 hours. In order to decompose the enzyme used for digesting the processed plant product S-O, 1 mL of proteinase K (manufactured by Qiagen) was added and shaken at 37 ° C. for 2 hours or more to obtain a solution (catalyst S-G1-G). Got.
The catalyst S-G1-G was desalted and purified according to the instruction manual using an ultrafiltration membrane (VIVASPIN 20, Sartorius Japan Co., Ltd.) having a pore size of 100 kDa and a purified liquid (catalyst S-G1). )

Example 2 Preparation of catalyst S-G2 Instead of the contigzyme being 50 mg / mL, the contizyme was added at 50 mg / mL and lactase F “Amano” (manufactured by Amano Enzyme Inc.) was added at 5 mg / mL. Except for the above, catalyst S-G2 was obtained in the same manner as catalyst S-G1.

Example 3 Preparation of Catalyst S-G3 Instead of the contizyme being 50 mg / mL, the contizyme was 50 mg / mL, lactase F “Amano” was 5 mg / mL, and soluble hesperidinase <Tanabe> (Tanabe Seiyaku Co., Ltd.) The catalyst S-G3 was obtained in the same manner as the catalyst S-G2, except that the product was added so as to be 5 mg / mL.

Example 4 Preparation of Catalyst S-G4 Instead of the contizyme being 50 mg / mL, the contizyme is 50 mg / mL, the lactase F “Amano” is 5 mg / mL, and the soluble hesperidinase <Tanabe> is 5 mg / mL And except that it added so that Luxel DJ (made by Toto Kasei Kogyo Co., Ltd.) might be 5 mg / mL, catalyst S-G4 was obtained by the method similar to the preparation method of catalyst S-G2.

Example 5 Preparation of catalyst S-G5 Instead of contigzyme being 50 mg / mL, contizyme is 50 mg / mL, lactase F “Amano” is 5 mg / mL and soluble hesperidinase <Tanabe> is 5 mg / mL The catalyst S-G2 was prepared in the same manner as in the preparation of the catalyst S-G2, except that the Luxel DJ was 5 mg / mL and the pancerase BR (manufactured by Yakult Pharmaceutical Co., Ltd.) was added to 5 mg / mL. G5 was obtained.

Example 6 Preparation of catalyst S-L1 Instead of contigzyme being 50 mg / mL, lipase A “Amano” 6 (manufactured by Amano Enzyme Co., Ltd.) was added except that it was 5 mg / mL. Catalyst S-L1 was obtained by a method similar to the preparation method.

Example 7 Preparation of catalyst S-P1 Similar to the preparation method of catalyst S-G2, except that pro leather (manufactured by Amano Enzyme Co., Ltd.) was added to 5 mg / mL instead of the contizyme being 50 mg / mL. In this way, catalyst S-P1 was obtained.

Example 8 Preparation of catalyst S-P2 Contizyme was added so that proleather was 5 mg / mL and proleather FG-F (manufactured by Amano Enzyme Inc.) was 5 mg / mL instead of 50 mg / mL. Except for the above, catalyst S-P2 was obtained in the same manner as the method for preparing catalyst S-G2.

Test Example 1 Measurement of catalytic activity Plant processed product S-O, catalyst S-G1-G, catalyst S-G1, catalyst S-G2, catalyst S-G3, catalyst S-G4, catalyst S-G5, catalyst S-L1 The sugar concentrations of catalyst S-P1 and catalyst S-P2 were measured. The sugar concentration was measured by the phenol-sulfuric acid method (Biotechnology, 2012, Vol. 90, page 790), and maltose was used as a standard substance.
After measuring the sugar concentration, each catalyst was freeze-dried and powdered. A powdered catalyst is placed in a glass vial so that the sugar content is 25 mg, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 34 mg of cyclopropylamine, 5 mg of water, and 10 mg of saturated saline are added thereto. Was added. The glass vial was sealed and shaken in a 37 ° C. warm bath for 16 hours. After 16 hours, the catalyst was filtered and subjected to gas chromatography (GC) analysis. Based on the peak area of the chromatogram, the conversion rate and selectivity to trans-2- (cyclopropylamino) cyclohexanol were calculated.

The GC analysis was performed under the following conditions.
Equipment: GC-2010 Plus (trade name, manufactured by Shimadzu Corporation)
Mobile phase: Helium pressure: 94 kPa
Detector: Hydrogen flame ionization detector Vaporization chamber temperature: 220 ° C
Detector temperature: 300 ° C
Split ratio: 1: 150
Injection volume: 0.5 μL
Column: BETADEX 120 (length: 30 m, inner diameter: 0.25 μm, manufactured by Supelco)
Column temperature: 130 ° C

When plant processed product S-O was used as a catalyst, the conversion rate was 46%, and the selectivity was 67%. The value of the conversion rate of each catalyst relative to the conversion rate of the plant processed product S-O was calculated as a relative activity value. As shown in Table 11, the catalytic activity of each catalyst was improved with respect to the plant processed product S-O.

Example 9 Purification by gel filtration chromatography 1
A solution of 15 mL of catalyst S-L1 adjusted to pH 5 with 1N acetic acid was applied to the column, and 10 mL of the first eluted solution was added to fraction No. It was set to 1. Fraction No. 31-No. 33 was mixed to obtain catalyst S-L1-C. In addition, fraction no. 34-No. 36 was mixed to obtain catalyst S-L1-D.
The purification by gel filtration chromatography was performed under the following conditions.
Column: Sephacryl S-400 HR (manufactured by GE Healthcare Japan, diameter: 2.4 cm, height: 96 cm)
Elution solvent: 50 mM sodium acetate buffer (pH 5.0)
Temperature: Volume per room temperature fraction: 10 mL

Example 10 Purification by gel filtration chromatography 2
15 mL of catalyst S-G5 was adjusted to pH 5 with 1N acetic acid, and size fractionation was performed by gel filtration in the same manner as in Example 9. Fraction No. 31-No. 33 was mixed to obtain catalyst S-G5-I.

Example 11 Purification by gel filtration chromatography 3
15 mL of catalyst S-P2 was adjusted to pH 5 with 1N acetic acid, and size fractionation was performed by gel filtration in the same manner as in Example 9. Fraction No. 35-No. 37 was mixed to obtain catalyst S-P2-T.

Test Example 2 Measurement of catalyst activity Conversion rate when using catalyst S-L1-C, catalyst S-L1-D, catalyst S-G5-I and catalyst S-P2-T in the same manner as in Test Example 1 Was calculated respectively. Moreover, the value (relative activity value) of the conversion rate using each catalyst with respect to the conversion rate when using the corresponding plant processed product S-O was calculated and shown in Table 12. As shown in Table 12, the catalytic activity of each catalyst was improved with respect to plant powder S-O.

Example 12 Preparation of Catalyst P-L1 Citrus-derived component (pectin (trade name), manufactured by Kanto Chemical Co., Inc., hereinafter abbreviated as “plant processed product PO”) was 2.5 mg / mL, Lipase A “Amano” 50 mL of a solution prepared so that 6 had a concentration of 5 mg / mL and sodium phosphate buffer (pH 7.0) had a concentration of 25 mM was prepared and subjected to a shaking reaction at 37 ° C. for 18 hours. In order to degrade the enzyme used to digest the plant processed product S-O, 1 mL of proteinase K (manufactured by Qiagen) was added, and the mixture was shaken at 37 ° C. for 2 hours or more. Using an ultrafiltration membrane (VIVASPIN 20, Sartorius Japan Co., Ltd.) having a pore size of a molecular weight cut off of 30 kDa, desalting and purification were performed according to the instruction manual to obtain a purified solution (catalyst P-L1).

Example 13 Preparation of catalyst C-L1 Carrot derived components (carrot powder (trade name), manufactured by Kodama Foods Co., Ltd., hereinafter abbreviated as “plant processed product C-O”) were used instead of the plant processed product P—O. Except for the above, catalyst C-L1 was obtained in the same manner as in the preparation of catalyst P-L1.

Example 14 Preparation of Catalyst U-L1 Turmeric-derived component (organic turmeric powder (trade name), manufactured by Nippon Powdery Chemical Co., Ltd., hereinafter abbreviated as “plant processed product U-O”) instead of plant processed product PO A catalyst U-L1 was obtained in the same manner as in the preparation of the catalyst P-L1, except that was used.

Example 15 Preparation of catalyst T-L1 Green tea-derived component (powdered green tea E Life (trade name), manufactured by Sankoen Shoten Co., Ltd., hereinafter “plant processed product TO”) instead of plant processed product PO ) Was used in the same manner as in the preparation of the catalyst T-L1, except that the catalyst U-L1 was obtained.

Example 16 Preparation of catalyst C-P2 Catalyst C-L1 and lipase A “Amano” 6 except that Pro Leather was added at 5 mg / mL and Pro Leather FG-F was added at 5 mg / mL. Catalyst C-P2 was obtained by the same method.

Test Example 3 Measurement of catalytic activity By the same method as in Example 2 except that the reaction time was changed from 16 hours to 48 hours, plant processed product PO, plant processed product C-O, plant processed product U-O, Processed plant product T-O, catalyst P-L1, catalyst C-L1, catalyst U-L1, catalyst T-L1 and catalyst C-P2 are used for the reaction to trans-2- (cyclopropylamino) cyclohexanol The conversion rate and selectivity were calculated.
Table 13 shows the conversion rate in the reaction using each catalyst. The catalytic activity was improved by enzymatic treatment of processed plant products.
Furthermore, the selectivity was 40% ee when the plant processed product TO was used, whereas it was 60% ee when the catalyst T-L1 was used, and a marked improvement in selectivity was observed. .

Test Example 4 Measurement of catalytic activity Plant processed product S-O, plant processed product C-O, plant processed product P-O, catalyst S-L1-C, catalyst S-L1-D, catalyst S-P2-T, catalyst The sugar concentrations of C-L1, Catalyst C-P2, Catalyst P-L1, and Catalyst T-L1 were measured. The sugar concentration was measured by the phenol-sulfuric acid method (Biotechnology, 2012, Vol. 90, page 790), and maltose was used as a standard substance.
After measuring the sugar concentration, each catalyst was freeze-dried and powdered. A powdered catalyst is placed in a glass vial so that the sugar content is 12.5 mg, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 34 mg of isopropylamine, 5 mg of water, and saturated saline 10 mg was added. The glass vial was sealed and shaken in a 37 ° C. bath for 60 hours. After 60 hours, the catalyst was filtered, and gas chromatography (GC) analysis was performed in the same manner as in Test Example 1. Based on the peak area of the chromatogram, the conversion rate and selectivity to trans-2- (isopropylamino) cyclohexanol were calculated.
The conversion rates of the plant processed product S-O, the plant processed product C-O, and the plant processed product P-O were 47%, 3%, and 6%, respectively. The conversion rate values (relative activity values) using the respective catalysts with respect to the conversion rate when using the corresponding processed plant product were calculated and shown in Tables 14-16. The catalytic activity of each catalyst was improved by performing an enzyme treatment.
Furthermore, the selectivity of plant processed material TO was measured. The processed plant product T-O was 6%, while the catalyst T-L1 was 23% ee, and a marked improvement in selectivity was observed.

Claims (6)

It is a method for improving the catalytic activity of a processed plant product that promotes the reaction of reacting a compound represented by formula (1) with a compound represented by formula (2) to obtain a compound represented by formula (3). And
A method comprising the step of enzyme-treating a processed plant product.

(In the formula, X represents —O— or —NR—, and R represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a C _3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted _{C 6-10} aryl group, an optionally substituted _{C 1-6} alkylcarbonyl group, an optionally substituted _{C 6-10} arylcarbonyl group, a substituent A C _1-6 alkylsulfonyl group or a C _6-10 arylsulfonyl group which may have, and R ¹ , R ² , R ³ and R ⁴ may each independently have a hydrogen atom or a substituent. a _{C 1-6} alkyl group, an optionally substituted _{C 3-6} cycloalkyl group, Yes which may have a substituent C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally C _2-6 alkynyl group or a substituted group may have a substituent An optionally substituted C _6-10 aryl group, and the substituent is a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a C _1-4 alkoxy group, an amino group, or an imino group. A group, a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, and R ² and R ³ may be bonded to each other to form a compound represented by the formula (1b), Y is —O—, —NR ⁶ — or —S—, and R ⁵ and R ⁶ each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a substituent. which may have a C _3-6 cycloalkyl group, substituted Which may C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, which may have a good C _2-6 alkynyl group or a substituted group may have a substituent C _{6 -10} aryl group, wherein the _{substituents, C 1-4} alkoxy _{groups, C 6-10} aryl group, an amino group, an imino group, a nitro group, hydroxy group, oxo group, nitrile group, mercapto group or a halogen atom And R ⁵ and R ⁶ may be bonded to each other to form a compound represented by the formula (2a), provided that the compound represented by the formula (2) is not water or hydrogen sulfide.

(Wherein X, R ¹ and R ⁴ are the same as defined above, and R ⁷ represents a group formed by bonding R ² and R ³ to each other.)

(In the formula, R ⁸ represents a group formed by combining R ⁵ and R ⁶ with each other.)   The method according to claim 1, wherein the enzyme treatment comprises treating the plant processed product with at least one enzyme selected from a lipolytic enzyme, a proteolytic enzyme, a glycolytic enzyme, and a glycosyltransferase.   The method of Claim 1 or 2 with which the said plant processed material contains water-soluble soybean polysaccharide, citrus powder, carrot powder, turmeric powder, and green tea powder. A catalyst for promoting a reaction of reacting a compound represented by formula (1) with a compound represented by formula (2) to obtain a compound represented by formula (3),
A catalyst comprising a composition obtained by enzymatic treatment of a processed plant product.

(In the formula, X represents —O— or —NR—, and R represents a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a C _3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted _{C 6-10} aryl group, an optionally substituted _{C 1-6} alkylcarbonyl group, an optionally substituted _{C 6-10} arylcarbonyl group, a substituent A C _1-6 alkylsulfonyl group or a C _6-10 arylsulfonyl group which may have, and R ¹ , R ² , R ³ and R ⁴ may each independently have a hydrogen atom or a substituent. a _{C 1-6} alkyl group, an optionally substituted _{C 3-6} cycloalkyl group, Yes which may have a substituent C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, an optionally C _2-6 alkynyl group or a substituted group may have a substituent An optionally substituted C _6-10 aryl group, and the substituent is a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a C _1-4 alkoxy group, an amino group, or an imino group. A group, a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, and R ² and R ³ may be bonded to each other to form a compound represented by the formula (1b), Y is —O—, —NR ⁶ — or —S—, and R ⁵ and R ⁶ each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a substituent. which may have a C _3-6 cycloalkyl group, substituted Which may C _2-6 alkenyl group, an optionally substituted C _3-6 cycloalkenyl group, which may have a good C _2-6 alkynyl group or a substituted group may have a substituent C _{6 -10} aryl group, wherein the _{substituents, C 1-4} alkoxy _{groups, C 6-10} aryl group, an amino group, an imino group, a nitro group, hydroxy group, oxo group, nitrile group, mercapto group or a halogen atom And R ⁵ and R ⁶ may be bonded to each other to form a compound represented by the formula (2a), provided that the compound represented by the formula (2) is not water or hydrogen sulfide.

(Wherein X, R ¹ and R ⁴ are the same as defined above, and R ⁷ represents a group formed by bonding R ² and R ³ to each other.)

(In the formula, R ⁸ represents a group formed by combining R ⁵ and R ⁶ with each other.)   The catalyst according to claim 4, wherein the enzyme treatment comprises treating a plant processed product with at least one enzyme selected from a lipolytic enzyme, a proteolytic enzyme, a glycolytic enzyme and a glycosyltransferase. The catalyst according to claim 4 or 5, wherein the processed plant product contains water-soluble soybean polysaccharide, citrus powder, carrot powder, turmeric powder, and green tea powder.