JPWO2012070509A1 - Method for producing nitrogen-containing heterocycle - Google Patents

Abstract

General formula (II) (wherein R1 represents an amino-protecting group, R2, R3 and R4 each represent H, OH, an optionally substituted alkenyl group or an alkoxy group, and R5 represents OH, an alkylcarbonyloxy group or an alkoxy group.) Is reacted with XCOOH (X represents an organic group substituted with a halogen) or a reactive derivative thereof. A carbonyl derivative represented by XCO (X is as defined above) is introduced into the β-position, wherein R 1, R 2, R 3, R 4, and X are And R5 ′ is H), its enantiomers, mixtures thereof, or salts thereof.

Description

  The present invention relates to a method for producing a nitrogen-containing heterocycle useful as an intermediate used for the production of various compounds, particularly the production of a nitrogen-containing heterocycle useful as an intermediate for a redox catalyst or a pharmaceutical having a β amino acid structure. Regarding the method.

  Compounds having reactive groups such as aldehyde groups, carbonyl groups, amino groups, imino groups, halogens, and vinyl groups are important building blocks in organic synthetic chemistry. Particularly, compounds having a plurality of reactive groups include various chemical groups. Useful as an intermediate for the reaction. It is desired to provide an industrially advantageous production method for such a synthetic intermediate. For example, the oxidation of alcohols to carbonyl compounds is one of the most basic reactions in organic synthesis, and many excellent oxidation catalysts and oxidation methods have been developed. The oxidation catalyst compound is produced, for example, by reacting an N-protected nitrogen-containing heterocycle with an acid and allyltrimethylsilane and substituting the α-position of the heterocycle with allyl (Patent Document 1). The emergence of an intermediate which is a raw material for such a catalyst compound and an industrially advantageous production method thereof is highly desired. The present inventors have focused on cyclic β-amino acids, which are useful synthesis blocks as the above intermediates, and have developed invention activities.

International Publication No. 2008/117871 Pamphlet

  An object of the present invention is to provide an industrially advantageous method for producing various compounds, for example, compounds having a carbonyl group at the β-position of a cyclic amine skeleton useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, redox catalysts, etc. It is an object of the present invention to provide a method for producing various compounds using an intermediate having a carbonyl group at the β-position of the cyclic amine skeleton. Another object of the present invention is to provide a novel intermediate that can be produced by such a production method.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have surprisingly found that a nitrogen-containing heterocycle in which a carbonyl derivative is introduced at the β-position is efficient by an easy operation using a specific reagent. In addition, the present inventors have found that such nitrogen-containing heterocycles are useful as intermediates for synthesizing various compounds such as pharmaceuticals, agricultural chemicals, and redox catalysts. It came to complete.

  Specifically, in the conventional carbonyl-derived group introduction reaction at the β-position, enamineation after the electrode oxidation reaction is required in the previous stage of the carbonyl group introduction reaction, and an acid is used to introduce a carbonyl group into the enamine. Although one equivalent or more was necessary, it was found that these problems were solved by using a specific electrophile, and a trichloroacetyl group was efficiently introduced into the β-position. Furthermore, the present inventors have found that a trichloroacetyl group can be easily converted into an ester group or an amide group, and that a β-amino acid can be easily synthesized, thereby completing the present invention.

（式中、Ｒ_１はアミノ基の保護基を示し、Ｒ_２、Ｒ_３、及びＲ_４は各々、Ｈ、ＯＨ、置換されていてもよいアルケニル基、又はアルコキシ基を意味し、Ｒ_５はＯＨ、アルキルカルボニルオキシ基又はアルコキシ基を意味する。）
で表される化合物と、ＸＣＯＯＨ（Ｘはハロゲンで置換されている有機基を示す）又はその反応性誘導体とを反応させて、該化合物のβ位にＸＣＯ（Ｘは前記と同意義である）で表されるカルボニル誘導基を導入することを特徴とする
一般式(I)

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、及びＸは前記と同意義であり、Ｒ_５’はＨである）
で表される化合物又はその塩の製造方法、
［２］ Ａ：一般式（II）

（式中、Ｒ_１はアミノ基の保護基を示し、Ｒ_２は置換されていてもよいアルケニル基を意味し、Ｒ_３及びＲ_４は各々、Ｈ、ＯＨ、置換されていてもよいアルケニル基、又はアルコキシ基を意味し、Ｒ_５はＯＨ、アルキルカルボニルオキシ基又はアルコキシ基を意味する。）
で表される化合物と、ＸＣＯＯＨ（Ｘはハロゲンで置換されている有機基を示す）又はその反応性誘導体とを反応させて、該化合物のβ位にＸＣＯ（Ｘは前記と同意義である）で表されるカルボニル誘導基を導入して、
一般式(I)

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、及びＸは前記と同意義であり、Ｒ_５’はＨである）
で表される化合物又はその塩を得ること、
Ｂ−１：塩基存在下、前記一般式（I）で表される化合物又はその塩と、アルコールとを反応させて、前記一般式（I）で表される化合物又はその塩をエステル化して
一般式（V）

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、及びＲ_５’は前記と同意義であり、Ｙはアルキル基、アラルキル基、又はアリール基である）
で表される化合物又はその塩を得ること、又は
Ｂ−２：前記一般式（I）で表される化合物又はその塩と、アミン化合物とを反応させて、前記一般式（I）で表される化合物又はその塩をアミド化して
一般式（VI）

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、及びＲ_５’は前記と同意義であり、Ｒ_６及びＲ_７は各々、Ｈ、アリール基、アラルキル基、又はアルキル基であるか、又は両方が結合して窒素原子と環状構造を形成する）
で表される化合物又はその塩を得ること、
Ｃ： 前記一般式（I）、（V）又は（VI）で表される化合物又はその塩と、酸とを反応させて、前記一般式（I）、（V）又は（VI）で表される化合物又はその塩を環化して
一般式（VII）

（式中、Ｒ_１はアミノ基の保護基であり、Ａはハロゲン原子、ＯＨ又はホルミルオキシ基であり、Ｗは前記Ｘ、Ｏ−Ｙ又はＮＲ_６Ｒ_７である）
で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩を得ること、及び
Ｄ：前記一般式（VII）で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩のアミノ基の保護基を除去して、得られる化合物を酸化させること
を含むことを特徴とする
一般式（VIII）

（式中、Ａはハロゲン原子、ＯＨ又はホルミルオキシ基であり、Ｗは前記Ｘ、Ｏ−Ｙ又はＮＲ_６Ｒ_７であり、・はフリーラジカルを示す）
で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩の製造方法、
［３］ ハロゲンで置換されている有機基がクロロ又はフルオロ（Ｃ_１−Ｃ_６）アルキル又はクロロ及びフルオロ（Ｃ_１−Ｃ_６）アルキルである［１］又は［２］記載の製造方法、
［４］ 反応性誘導体が酸ハライド、活性エステル又は酸無水物である［１］〜［３］いずれか記載の製造方法、
［５］ 一般式（VII）で表される化合物又はその塩と、塩基とを反応させて、一般式(VII)中のトリクロロアルキル基を加水分解することを含む、［２］〜［４］いずれか記載の製造方法、
［６］ 一般式（VII）で表される化合物又はその塩と、還元剤とを反応させて、一般式(VII)中のエステル基を還元することを含む、［２］〜［４］いずれか記載の製造方法、
［７］ ［５］記載の製造方法の過程で得られたトリクロロアルキル基が加水分解された化合物又はその塩と、アミンとを反応させて、該化合物のカルボキシル基をアミド化することを含む、［５］記載の製造方法、
［８］ 一般式（IV）

(式中、Ｒ_１はアミノ基の保護基を示し、Ｒ_２及びＲ_３は各々、Ｈ、ＯＨ、置換されていてもよいアルケニル基、又はアルコキシ基を意味し、Ｒ_５はＯＨ、アルキルカルボニルオキシ基又はアルコキシ基を意味する。)
で表される化合物と、ＸＣＯＯＨ（Ｘはハロゲンで置換されている有機基を示す）又はその反応性誘導体とを反応させて、該化合物のβ位にＸＣＯ（Ｘは前記と同意義である）で表されるカルボニル誘導基を導入することを特徴とする
一般式（III）

（式中、Ｒ_１、Ｒ_２、Ｒ_３及びＸは前記と同意義であり、Ｒ_５’はＨである）
で表される化合物又はその塩の製造方法、
［９］ Ａ’：一般式（IV）

(式中、Ｒ_１はアミノ基の保護基を示し、Ｒ_２は置換されていてもよいアルケニル基を意味し、Ｒ_３はＨ、ＯＨ、置換されていてもよいアルケニル基、又はアルコキシ基を意味し、Ｒ_５はＯＨ、アルキルカルボニルオキシ基又はアルコキシ基を意味する。)
で表される化合物と、ＸＣＯＯＨ（Ｘはハロゲンで置換されている有機基を示す）又はその反応性誘導体とを反応させて、該化合物のβ位にＸＣＯ（Ｘは前記と同意義である）で表されるカルボニル誘導基を導入して、
一般式（III）

（式中、Ｒ_１、Ｒ_２、Ｒ_３及びＸは前記と同意義であり、Ｒ_５’はＨである）
で表される化合物又はその塩を得ること、
Ｂ’−１：塩基存在下、前記一般式（III）で表される化合物又はその塩と、アルコールとを反応させて、前記一般式（III）で表される化合物又はその塩をエステル化して
一般式（IX）

（式中、Ｒ_１、Ｒ_２、Ｒ_３及びＲ_５’は前記と同意義であり、Ｙはアルキル基、アラルキル基、又はアリール基である）
で表される化合物又はその塩を得ること、又は
Ｂ’−２：前記一般式（III）で表される化合物又はその塩と、アミン化合物とを反応させて、前記一般式（III）で表される化合物又はその塩をアミド化して
一般式（X）

（式中、Ｒ_１、Ｒ_２、Ｒ_３及びＲ_５’は前記と同意義であり、Ｒ_６及びＲ_７は各々、Ｈ、アリール基、アラルキル基、又はアルキル基であるか、又は両方が結合して窒素原子と環状構造を形成する）
で表される化合物又はその塩を得ること、
Ｃ’： 前記一般式(III)、（IX）又は（X）で表される化合物又はその塩と、酸とを反応させて、前記一般式(III)、（IX）又は（X）で表される化合物又はその塩を環化して
一般式（XI）

（式中、Ｒ_１はアミノ基の保護基であり、Ａはハロゲン原子、ＯＨ又はホルミルオキシ基であり、Ｗは前記Ｘ、Ｏ−Ｙ又はＮＲ_６Ｒ_７である）
で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩を得ること、及び
Ｄ’：前記一般式（XI）で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩のアミノ基の保護基を除去して、得られる化合物を酸化させること
を含むことを特徴とする
一般式（XII）

（式中、Ａはハロゲン原子、ＯＨ又はホルミルオキシ基であり、Ｗは前記Ｘ、Ｏ−Ｙ又はＮＲ_６Ｒ_７であり、・はフリーラジカルを示す）
で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩の製造方法、
［１０］ ハロゲンで置換されている有機基がクロロ又はフルオロ（Ｃ_１−Ｃ_６）アルキル又はクロロ及びフルオロ（Ｃ_１−Ｃ_６）アルキルである［８］又は［９］記載の製造方法、
［１１］ 反応性誘導体が酸ハライド、活性エステル又は酸無水物である［８］〜［１０］いずれか記載の製造方法、
［１２］ 一般式（XI）で表される化合物又はその塩と、塩基とを反応させて、一般式(XI)中のトリクロロアルキル基を加水分解することを含む、［９］〜［１１］いずれか記載の製造方法、
［１３］ 一般式（XI）で表される化合物又はその塩と、還元剤とを反応させて、一般式(XI)中のエステル基を還元することを含む、［９］〜［１１］いずれか記載の製造方法、
［１４］ ［１２］記載の製造方法の過程で得られたトリクロロアルキル基が加水分解された化合物又はその塩と、アミンとを反応させて、該化合物のカルボキシル基をアミド化することを含む、［１２］記載の製造方法、
［１５］ 以下の化合物からなる群より選択される、一般式(I)、(III)、（V）、（VI）、（VII）、（VIII）、（XI）又は（XII）で表される化合物又はその塩、

［１６］ ［１５］記載の一般式(I)、(III)、(V)、(VI)、(VII)、（VIII）、(XI)又は（XII）で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩のレドックス用触媒又はβアミノ酸構造を有する医薬の製造のための中間体としての使用
を提供する。That is, the present invention
[1] General formula (II)

(Wherein R ₁ represents an amino-protecting group, R ₂ , R ₃ , and R ₄ each represent H, OH, an optionally substituted alkenyl group, or an alkoxy group, and R ₅ represents OH means an alkylcarbonyloxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. A carbonyl derivative represented by the general formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , and X are as defined above, and R _{5 ′} is H)
A method for producing a compound represented by the formula:
[2] A: General formula (II)

(Wherein R ₁ represents an amino-protecting group, R ₂ represents an optionally substituted alkenyl group, and R ₃ and R ₄ each represent H, OH, or an optionally substituted alkenyl group. Or an alkoxy group, and R ₅ represents OH, an alkylcarbonyloxy group, or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. Introducing a carbonyl derivative represented by
Formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , and X are as defined above, and R _{5 ′} is H)
A compound represented by the formula:
B-1: In the presence of a base, the compound represented by the general formula (I) or a salt thereof and an alcohol are reacted with each other to esterify the compound represented by the general formula (I) or a salt thereof. Formula (V)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R _{5 ′} are as defined above, and Y is an alkyl group, an aralkyl group, or an aryl group)
Or a compound represented by the general formula (I) or a salt thereof, and an amine compound, and represented by the general formula (I). Or a salt thereof may be amidated to give a general formula (VI)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R _{5 ′} are as defined above, and are R ₆ and R ₇ each an H, an aryl group, an aralkyl group, or an alkyl group? , Or both combine to form a ring structure with the nitrogen atom)
A compound represented by the formula:
C: The compound represented by the above general formula (I), (V) or (VI) or a salt thereof and an acid are reacted with each other to represent the above general formula (I), (V) or (VI). A compound of the formula (VII)

(In the formula, R ₁ is an amino-protecting group, A is a halogen atom, OH or formyloxy group, and W is X, OY or NR ₆ R ₇ )
Or a compound represented by the general formula (VII), an enantiomer thereof, a mixture thereof or a salt thereof. General formula (VIII) characterized in that it comprises removing the protecting group of the amino group and oxidizing the resulting compound

(In the formula, A is a halogen atom, OH or formyloxy group, W is X, O—Y or NR ₆ R ₇ , and • represents a free radical)
A process for producing a compound represented by the following: or an enantiomer thereof, a mixture thereof, or a salt thereof;
[3] The production method according to [1] or [2], wherein the organic group substituted with halogen is chloro or fluoro (C ₁ -C ₆ ) alkyl or chloro and fluoro (C ₁ -C ₆ ) alkyl.
[4] The production method according to any one of [1] to [3], wherein the reactive derivative is an acid halide, an active ester, or an acid anhydride,
[5] The method includes reacting a compound represented by the general formula (VII) or a salt thereof with a base to hydrolyze a trichloroalkyl group in the general formula (VII) [2] to [4] Any one of the manufacturing methods,
[6] Any of [2] to [4], which comprises reacting a compound represented by the general formula (VII) or a salt thereof with a reducing agent to reduce the ester group in the general formula (VII). Or manufacturing method according to
[7] The method includes reacting a compound obtained by hydrolyzing a trichloroalkyl group obtained by the process of [5] or a salt thereof with an amine to amidate a carboxyl group of the compound. [5] The production method according to [5],
[8] General formula (IV)

(Wherein R ₁ represents an amino-protecting group, R ₂ and R ₃ each represent H, OH, an alkenyl group which may be substituted, or an alkoxy group; R ₅ represents OH, alkylcarbonyl; (It means an oxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. General formula (III) characterized by introducing a carbonyl derivative represented by the formula (III)

(Wherein R ₁ , R ₂ , R ₃ and X are as defined above, and R _{5 ′} is H)
A method for producing a compound represented by the formula:
[9] A ′: General formula (IV)

(Wherein R ₁ represents an amino-protecting group, R ₂ represents an optionally substituted alkenyl group, R ₃ represents H, OH, an optionally substituted alkenyl group, or an alkoxy group. And R ₅ represents OH, an alkylcarbonyloxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. Introducing a carbonyl derivative represented by
General formula (III)

(Wherein R ₁ , R ₂ , R ₃ and X are as defined above, and R _{5 ′} is H)
A compound represented by the formula:
B′-1: In the presence of a base, the compound represented by the general formula (III) or a salt thereof is reacted with an alcohol to esterify the compound represented by the general formula (III) or a salt thereof. General formula (IX)

Wherein R ₁ , R ₂ , R ₃ and R _{5 ′} are as defined above, and Y is an alkyl group, an aralkyl group or an aryl group.
Or a compound represented by the general formula (III) or a salt thereof, and an amine compound are reacted to obtain the compound represented by the general formula (III). The compound or its salt is amidated to give a general formula (X)

Wherein R ₁ , R ₂ , R ₃ and R _{5 ′} are as defined above, and R ₆ and R ₇ are each H, an aryl group, an aralkyl group, an alkyl group, or both are To form a ring structure with nitrogen atom)
A compound represented by the formula:
C ′: The compound represented by the general formula (III), (IX) or (X) or a salt thereof and an acid are reacted with each other to represent the compound represented by the general formula (III), (IX) or (X). A compound of the formula (XI)

(In the formula, R ₁ is an amino-protecting group, A is a halogen atom, OH or formyloxy group, and W is X, OY or NR ₆ R ₇ )
And a compound represented by the formula (XI), an enantiomer thereof, a mixture thereof or a salt thereof, and D ′: a compound represented by the general formula (XI), an enantiomer thereof, a mixture thereof or a salt thereof. General formula (XII) characterized in that it comprises removing the protecting group of the amino group and oxidizing the resulting compound

(In the formula, A is a halogen atom, OH or formyloxy group, W is X, O—Y or NR ₆ R ₇ , and • represents a free radical)
A process for producing a compound represented by the following: or an enantiomer thereof, a mixture thereof, or a salt thereof;
[10] The production method according to [8] or [9], wherein the organic group substituted with halogen is chloro or fluoro (C ₁ -C ₆ ) alkyl or chloro and fluoro (C ₁ -C ₆ ) alkyl.
[11] The production method according to any one of [8] to [10], wherein the reactive derivative is an acid halide, an active ester or an acid anhydride,
[12] The method includes reacting a compound represented by the general formula (XI) or a salt thereof with a base to hydrolyze a trichloroalkyl group in the general formula (XI) [9] to [11] Any one of the manufacturing methods,
[13] Any of [9] to [11], which comprises reacting the compound represented by the general formula (XI) or a salt thereof with a reducing agent to reduce the ester group in the general formula (XI). Or manufacturing method according to
[14] The method comprises reacting a compound or a salt thereof obtained by hydrolyzing a trichloroalkyl group obtained in the course of the production method according to [12] with an amine to amidate a carboxyl group of the compound. [12] The production method according to [12],
[15] It is represented by the general formula (I), (III), (V), (VI), (VII), (VIII), (XI) or (XII) selected from the group consisting of the following compounds: Or a salt thereof,

[16] The compound represented by the general formula (I), (III), (V), (VI), (VII), (VIII), (XI) or (XII) according to [15] or an enantiomer thereof The present invention provides the use of a product or a mixture thereof or a salt thereof as a redox catalyst or intermediate for the manufacture of a medicament having a β-amino acid structure.

  According to the present invention, a nitrogen-containing heterocycle having a carbonyl derivative introduced at the β-position can be efficiently and economically produced by an easy operation using a specific compound. Furthermore, these nitrogen-containing heterocycles are useful as synthetic intermediates for various compounds such as pharmaceuticals, agricultural chemicals, and redox catalysts.

（式中、Ｒ_１はアミノ基の保護基を示し、Ｒ_２、Ｒ_３及びＲ_４は各々、Ｈ、ＯＨ、置換されていてもよいアルケニル基、又はアルコキシ基を意味し、Ｒ_５はＯＨ、アルキルカルボニルオキシ基又はアルコキシ基を意味する。）
で表される化合物と、ＸＣＯＯＨ（Ｘはハロゲンで置換されている有機基を示す）又はその反応性誘導体とを反応させて、該化合物のβ位にＸＣＯ（Ｘは前記と同意義である）で表されるカルボニル誘導基を導入することを特徴とする
一般式(I)

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４及びＸは前記と同意義であり、Ｒ_５’はＨである）
で表される化合物又はその塩の製造方法である。One aspect (production method A) of the production method of the present invention is as follows.
Formula (II)

(Wherein R ₁ represents an amino-protecting group, R ₂ , R ₃ and R ₄ each represent H, OH, an optionally substituted alkenyl group or an alkoxy group, and R ₅ represents OH Represents an alkylcarbonyloxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. A carbonyl derivative represented by the general formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above, and R _{5 ′} is H)
Or a salt thereof.

In the general formula (II), the protecting group for the amino group represented by R ₁ (which may be represented as PG in the present invention) includes a tert-butoxycarbonyl group (Boc group), a benzyloxycarbonyl group (Cbz Group), methoxycarbonyl group (also referred to as Moc group, CO ₂ Me), ethoxycarbonyl group (CO ₂ Et), benzoyl group (Bz group) and the like. From the viewpoint of increasing the yield of the resulting compound, among them, tert-butoxycarbonyl group (Boc group), methoxycarbonyl group (Moc group, CO ₂ Me), and ethoxycarbonyl group (CO ₂ Et) are preferable, tert-butoxycarbonyl A group (Boc group) is more preferred. These can be introduced by a known method.

In R ₂ , R ₃ and R ₄ of the general formula (II), examples of the alkenyl group which may be substituted include alkenyl groups having 2 to 40 carbon atoms, such as vinyl group, allyl group, 1-butenyl. Group, 2-butenyl group, 3-butenyl group, 1,3-butanedienyl group, 1-methylvinyl group, styryl group, 2,2-diphenylvinyl group, 1,2-diphenylvinyl group, 1-methylallyl group, 1 , 1-dimethylallyl group, 2-methylallyl group, 1-phenylallyl group, 2-phenylallyl group, 3-phenylallyl group, 3,3-diphenylallyl group, 1,2-dimethylallyl group, 1-phenyl- Examples thereof include, but are not limited to, a 1-butenyl group and a 3-phenyl-1-butenyl group. Of these, an allyl group is preferable. “Optionally substituted” means that the alkenyl group may be substituted with any substituent. Examples of the substituent include an alkyl group (preferably an alkyl group having 1 to 4 carbon atoms), an aryl group (preferably an aryl group having 6 to 20 carbon atoms, more preferably a phenyl group and a naphthyl group), a carboxyl group, and an alkoxy group ( Preferable examples include an alkoxy group having 1 to 3 carbon atoms) and an acyl group (preferably an acetyl group). The number of substituents is preferably 0 to 5, more preferably 0 to 3. When the number of substituents is 2 or more, each substituent may be the same or different. Among these, R ₂ is particularly preferably a methylallyl group, an ethylallyl group, a dimethylallyl group, or a phenylallyl group. The number of substituents is preferably 0 to 5, more preferably 0 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

In R ₂ , R ₃ and R ₄ of the general formula (II), examples of the alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, a tert-butoxy group, and a pentyloxy group. It is done. A C1-C10 alkoxy group is preferable and a C1-C3 alkoxy group is more preferable. Of these, a methoxy group is preferred.

R _{5 in the} general formula (II) means OH, an alkylcarbonyloxy group or an alkoxy group. The alkylcarbonyloxy group is preferably an alkylcarbonyloxy group having 2 to 4 carbon atoms, more preferably an acetoxy group. The alkoxy group may be the same as described above.

  The compound represented by formula (II) can be obtained, for example, by subjecting piperidine having an amino-protecting group to electrode oxidation in methanol. Electrode oxidation is performed by a known method.

  In the compound represented by the general formula (II), when the carbon atom constituting the heterocycle is an asymmetric carbon, the nitrogen-containing heterocycle may be d-form, l-form or racemate. The compound having such a structure can also be used to produce a configuration-specific compound.

XCOOH (X represents an organic group substituted with halogen) used in the production method of the present invention has a carbonyl derivative group represented by XCO (X is as defined above) at the β-position of the compound. The organic group substituted with halogen is preferably chloro or fluoro (C ₁ -C ₆ ) alkyl or chloro and fluoro (C ₁ -C ₆ ) alkyl, more preferably trichloro. Methyl or trifluoromethyl or chlorodifluoromethyl. The reactive derivative of XCOOH is preferably an acid halide, an active ester or an acid anhydride, and more preferably an acid halide or an acid anhydride. The acid halide is preferably one substituted with chlorine, fluorine, bromine, iodine or the like, and more preferably one substituted with chlorine. The acid anhydride is preferably substituted with acetic acid or the like, and may be further substituted with chloro or fluoro or chloro and fluoro. XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof is preferably trichloroacetyl chloride or trifluoroacetyl chloride or chlorodifluoroacetic anhydride or trifluoroacetic anhydride, more preferably Trichloroacetyl chloride or trifluoroacetic anhydride. In the production method of the present invention, the amount of XCOOH (X represents an organic group substituted with a halogen) or a reactive derivative thereof is used with respect to 1.0 equivalent of the compound represented by the general formula (II). And preferably 0.5 to 10 equivalents, more preferably 1.5 to 6 equivalents. Examples of the active ester include pentachlorophenyl ester of a compound represented by XCOOH. XCOOH is preferably used in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

In the present invention, XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof may cause the following reaction. For example, an electron pair on the oxygen atom of a methoxy group may be added to Cl ₃ CCOCl, and the resulting ester moiety may be a leaving group to form an iminium ion from N, O-acetal, followed by a Cl anion. May act as a base and pull the proton at the β-position to form an enamine, or the enamine may be added to Cl ₃ CCOCl to introduce a trichloroacetyl group at the β-position, and finally the Cl anion is again at the β-position. The target product may be obtained by withdrawing protons.

  In the production method of the present invention, the reaction temperature may be appropriately selected in consideration of the solvent to be used or reaction efficiency, but is preferably 0 to 40 ° C, more preferably 10 to 30 ° C. Although reaction time changes with reaction scale, reaction temperature, etc., Preferably it may be suitably selected in the range of 0.5 to 48 hours, more preferably 1 to 15 hours. The reaction proceeds even in the presence of oxygen in the air, but the reaction may be performed in an inert gas atmosphere such as nitrogen gas or argon gas. The solvent used in the reaction is not limited as long as it exhibits the reaction of the present invention, but the compound represented by the general formula (II) is previously dissolved in a solvent such as tetrahydrofuran (hereinafter sometimes referred to as THF). Also good. The amount of the solvent used is preferably 0.05 ml to 50 ml, more preferably 0.5 to 10 ml with respect to 1 mmol of the compound represented by the general formula (II). Further, in the reaction, an acid scavenger may be used simultaneously with the above XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof. The acid scavenger is preferably a neutral acid scavenger. For example, 2-methyl-2-butene, propylene oxide, ethylene oxide, or the like can be used. Of these, 2-methyl-2-butene is preferable. When such an acid scavenger is used, the yield of the resulting compound is improved. Although the usage-amount of an acid scavenger is not specifically limited, Preferably it is 0.5-10 equivalent with respect to 1 equivalent of raw material compounds, More preferably, it is 1.5-3 equivalent.

In the general formula (I), R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above, and R _{5 ′} is H.

但し、rtは室温を、hは時間を、Meはメチル基を、eqは原料に対する当量を、PGは保護基を、yieldは収率を示す（以下同じ）。Specific examples of the reaction from the compound represented by the general formula (II) to the compound represented by the general formula (I) include the following. In addition, the manufacturing method of this invention is not limited to the following illustrations.

However, rt represents room temperature, h represents time, Me represents a methyl group, eq represents an equivalent to the raw material, PG represents a protecting group, and yield represents a yield (the same applies hereinafter).

  After completion of the reaction, the target compound may be isolated from the reaction system containing it by a conventional method, and may be purified by column chromatography or the like as necessary. Further, it may be used directly in the next reaction without isolation.

（式中、Ｒ_１はアミノ基の保護基を示し、Ｒ_２は置換されていてもよいアルケニル基を意味し、Ｒ_３及びＲ_４は各々、Ｈ、ＯＨ、置換されていてもよいアルケニル基、又はアルコキシ基を意味し、Ｒ_５はＯＨ、アルキルカルボニルオキシ基又はアルコキシ基を意味する。）
で表される化合物と、ＸＣＯＯＨ（Ｘはハロゲンで置換されている有機基を示す）又はその反応性誘導体とを反応させて、該化合物のβ位にＸＣＯ（Ｘは前記と同意義である）で表されるカルボニル誘導基を導入して、
一般式(I)

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４及びＸは前記と同意義であり、Ｒ_５’はＨである）
で表される化合物又はその塩を得ること、
Ｂ−１：塩基存在下、前記一般式（I）で表される化合物又はその塩と、アルコールとを反応させて、前記一般式（I）で表される化合物又はその塩をエステル化して
一般式（V）

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４及びＲ_５’は前記と同意義であり、Ｙはアルキル基、アラルキル基、又はアリール基である）
で表される化合物又はその塩を得ること、又は
Ｂ−２：前記一般式（I）で表される化合物又はその塩と、アミン化合物とを反応させて、前記一般式（I）で表される化合物又はその塩をアミド化して
一般式（VI）

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４及びＲ_５’は前記と同意義であり、Ｒ_６及びＲ_７は各々、Ｈ、アリール基、アラルキル基、又はアルキル基であるか、又は両方が結合して窒素原子と環状構造を形成する）
で表される化合物又はその塩を得ること、
Ｃ： 前記一般式（I）、（V）又は（VI）で表される化合物又はその塩と、酸とを反応させて、前記一般式（I）、（V）又は（VI）で表される化合物又はその塩を環化して
一般式（VII）

（式中、Ｒ_１はアミノ基の保護基であり、Ａはハロゲン原子、ＯＨ又はホルミルオキシ基であり、Ｗは前記Ｘ、Ｏ−Ｙ又はＮＲ_６Ｒ_７である）
で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩を得ること、及び
Ｄ：前記一般式（VII）で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩のアミノ基の保護基を除去して、得られる化合物を酸化させること
を含むことを特徴とする
一般式（VIII）

（式中、Ａはハロゲン原子、ＯＨ又はホルミルオキシ基であり、Ｗは前記Ｘ、Ｏ−Ｙ又はＮＲ_６Ｒ_７であり、・はフリーラジカルを示す）
で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩の製造方法である。Another aspect (production method B) of the production method of the present invention is as follows.
A: General formula (II)

(Wherein R ₁ represents an amino-protecting group, R ₂ represents an optionally substituted alkenyl group, and R ₃ and R ₄ each represent H, OH, or an optionally substituted alkenyl group. Or an alkoxy group, and R ₅ represents OH, an alkylcarbonyloxy group, or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. Introducing a carbonyl derivative represented by
Formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above, and R _{5 ′} is H)
A compound represented by the formula:
B-1: In the presence of a base, the compound represented by the general formula (I) or a salt thereof and an alcohol are reacted with each other to esterify the compound represented by the general formula (I) or a salt thereof. Formula (V)

(In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R _{5 ′} are as defined above, and Y is an alkyl group, an aralkyl group, or an aryl group)
B-2: A compound represented by the general formula (I) or a salt thereof, and an amine compound are reacted to represent the compound represented by the general formula (I). Or a salt thereof may be amidated to give a general formula (VI)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and R _{5 ′} are as defined above, and R ₆ and R ₇ are each H, an aryl group, an aralkyl group or an alkyl group, Or both combine to form a ring structure with the nitrogen atom)
A compound represented by the formula:
C: The compound represented by the above general formula (I), (V) or (VI) or a salt thereof and an acid are reacted with each other to represent the above general formula (I), (V) or (VI). A compound of the formula (VII)

(In the formula, R ₁ is an amino-protecting group, A is a halogen atom, OH or formyloxy group, and W is X, OY or NR ₆ R ₇ )
Or a compound represented by the general formula (VII), an enantiomer thereof, a mixture thereof or a salt thereof. General formula (VIII) characterized in that it comprises removing the protecting group of the amino group and oxidizing the resulting compound

(In the formula, A is a halogen atom, OH or formyloxy group, W is X, O—Y or NR ₆ R ₇ , and • represents a free radical)
Or a enantiomer thereof, a mixture thereof or a salt thereof.

In the production method B of the present invention, step A is substantially the same as the production method A, and the reagents, reaction temperature, reaction time, solvent, acid scavenger and the like used are as described above. In R ₂ , R ₃ and R ₄ , the alkenyl group which may be substituted may be the same as the above (Production Method A), or may be an allyl group from the viewpoint of cyclization. . The term “which may be substituted” means that it may be substituted with any substituent, and examples of the substituent include an alkyl group (preferably an alkyl group having 1 to 4 carbon atoms), an aryl group ( Preferably an aryl group having 6 to 20 carbon atoms, more preferably a phenyl group or a naphthyl group), a carboxyl group, an alkoxy group (preferably an alkoxy group having 1 to 3 carbon atoms), an acyl group (preferably an acetyl group), or the like. It is done. The number of substituents is preferably 0 to 5, more preferably 0 to 3. When the number of substituents is 2 or more, each substituent may be the same or different. Among these, R ₂ is particularly preferably a methylallyl group, an ethylallyl group, a dimethylallyl group, or a phenylallyl group.

  In step B-1 of production method B of the present invention, any base that is commonly used and has a low nucleophilicity can be used, such as organic bases such as pyridine, diisopropylethylamine and triethylamine, and alkali metal carbonates. Inorganic bases such as salts, alkaline earth metal carbonates, alkali metal hydrogen carbonates can be used. Examples of the alkali metal carbonate include sodium carbonate, potassium carbonate, cesium carbonate and the like. Examples of the alkaline earth metal carbonate include magnesium carbonate and calcium carbonate. Examples of the alkali metal hydrogen carbonate include sodium hydrogen carbonate and potassium hydrogen carbonate. Among these, sodium hydrogen carbonate is preferable. The bicarbonate can be used as it is or as an aqueous solution. Examples of the alcohol include methanol, ethanol, propanol, butanol, phenol, benzyl alcohol and the like. Of these, methanol is preferable. The reaction can be carried out in a solvent amount of alcohol or in an organic solvent inert to the reaction. Examples of the organic solvent inert to the reaction include halogen solvents such as dichloromethane, ester solvents such as ethyl acetate, nitrile solvents such as acetonitrile, aromatic solvents such as toluene, and ether solvents such as tetrahydrofuran. The amount of the solvent used is preferably 0.3 ml to 10 ml, more preferably 0.5 to 5 ml, based on 1 mmol of the compound represented by the general formula (I). The amount of the base used is preferably 0.5 mmol to 30 mmol, more preferably 0.8 mmol to 10 mmol, relative to 1 mmol of the compound represented by the general formula (I). When the reaction is carried out in the organic solvent, the amount of alcohol used is preferably 0.5 to 30 mmol, more preferably 0.8 to 3 mmol per 1 mmol of the compound represented by the general formula (I). Millimolar. When the organic solvent is not used, the amount of alcohol used is preferably 0.1 ml to 10 ml, more preferably 0.5 to 5 ml, based on 1 mmol of the compound represented by the general formula (I). The reaction temperature may be appropriately selected in consideration of the solvent to be used or reaction efficiency, but is preferably 0 to 40 ° C, more preferably 10 to 30 ° C. Although reaction time changes with reaction scale, reaction temperature, etc., Preferably it may be suitably selected in the range of 0.5 to 48 hours, more preferably 1 to 15 hours. The reaction proceeds even in the presence of oxygen in the air, but the reaction may be performed in an inert gas atmosphere such as nitrogen gas or argon gas.

  After the reaction, the alcohol was distilled off under reduced pressure, extracted with ethyl acetate, the collected organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to bring the target compound into the next reaction. May be used. In addition, the target compound may be used directly in the next reaction without isolation.

In the general formula (V), R ₁ , R ₂ , R ₃ , R ₄ and R _{5 ′} are as defined above, and Y is an alkyl group, an aryl group, or an aralkyl group.

  In general formula (V), Y is an alkyl group, an aryl group, or an aralkyl group, preferably an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 20 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms. More preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a phenyl group, a naphthyl group, a benzyl group and a phenethyl group, and more preferably a methyl group (Me) and an ethyl group (Et). .

  In step B-2 of production method B of the present invention, the amine compound is not particularly limited as long as the target reaction proceeds. For example, known primary amines, secondary amines, and cyclic amines can be used as those that react with carboxylic acid halides or carboxylic acid anhydrides to form amides, and those that can form the desired amide can be appropriately selected. Examples of amine compounds include alkylamines, arylamines, aralkylamines, and cyclic amines. Preferred amine compounds are alkyl (C1-C6) amine, dialkylamine having the same or different alkyl group having 1 to 6 carbon atoms, benzylamine, phenethylamine, aniline, phenylamine, naphthylamine, pyrrolidine, piperidine and the like.

  The amount of the amine compound used when the following organic solvent is used is preferably 0.1 to 30 mmol, more preferably 0.3 to 3 mmol, relative to 1 mmol of the compound represented by the general formula (I). is there. When the following organic solvent is not used, the amount of the amine compound used is preferably 0.1 ml to 10 ml, more preferably 0.5 to 5 ml with respect to 1 mmol of the compound represented by the general formula (I). The reaction temperature may be appropriately selected in consideration of the solvent to be used or reaction efficiency, but is preferably 0 to 40 ° C, more preferably 10 to 30 ° C. Although reaction time changes with reaction scale, reaction temperature, etc., Preferably it may be suitably selected in the range of 0.5 to 48 hours, more preferably 1 to 15 hours. The reaction proceeds even in the presence of oxygen in the air, but the reaction may be performed in an inert gas atmosphere such as nitrogen gas or argon gas. The compound represented by the general formula (I) is preferably dissolved in a solvent and reacted before reacting with the amine compound. Such a solvent is preferably acetonitrile, dichloromethane, ethyl acetate, butyl acetate, toluene, benzene, more preferably acetonitrile.

  After the reaction, the solvent was distilled off under reduced pressure, an aqueous hydrochloric acid solution was added, and the mixture was extracted with chloroform. The collected organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, followed by silica gel column chromatography. The target compound may be used in the next reaction after purification by chromatography. In addition, the target compound may be used directly in the next reaction without isolation.

In general formula (VI), R ₁ , R ₂ , R ₃ , R ₄ and R _{5 ′} are as defined above, and R ₆ and R ₇ are each H, an aryl group, an aralkyl group, or an alkyl group. Some or both combine to form a ring structure with the nitrogen atom. A preferable aryl group, aralkyl group or alkyl group is an aryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 12 carbon atoms or an alkyl group having 1 to 4 carbon atoms, more preferably a phenyl group, a biphenyl group or a benzyl group. Phenethyl group, methyl group, ethyl group, propyl group, butyl group or pentyl group. A preferred cyclic structure is a piperidine ring or a pyrrolidine ring.

In step C of production method B of the present invention, the acid is preferably formic acid, BF ₃ .Et ₂ O, TiCl ₄ , TiBr ₄ , AlCl ₃ , InCl ₃ , more preferably TiCl ₄ . The amount of acid used is preferably 0.25 to 3 mol, more preferably 0.5 to 2 mol, relative to 1 mol of the compound represented by formula (I), (V) or (VI). It is. The reaction temperature is not particularly limited as long as the reaction proceeds, but is preferably -78 to 50 ° C, more preferably -78 to 30 ° C. The reaction time is preferably 0.5 hours to 48 hours, more preferably 2 hours to 15 hours. The solvent used for the reaction may be the same as described above.

  After the reaction, a saturated aqueous sodium hydrogen carbonate solution is added, extracted with chloroform, and the collected organic layer is dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, and the target compound is used in the next reaction. May be. In addition, the target compound may be used directly in the next reaction without isolation.

In the general formula (VII), R ₁ is an amino-protecting group, A is a halogen atom, OH or formyloxy group, W is X, O—Y or NR ₆ R ₇ , preferably monochloro An alkyl group, a dichloroalkyl group, a trichloroalkyl group, an alkoxy group, an aryloxy group, an aralkyloxy group, an aralkylamide group, an arylamide group, or an alkylamide group.

R ₁ is as described above. A may be a halogen atom (fluorine atom, chlorine atom, iodine element, bromine atom), OH, or formyloxy group. When formic acid is used as the acid, a formyloxy group is introduced into A, but the formyloxy group may be hydrolyzed to an OH group depending on the reaction conditions. In W, the trichloroalkyl group may be a trichloromethyl group, a trichloroethyl group, a trichloropropyl group, or the like. In W, the alkoxy group may be a methoxy group, an ethoxy group, a propoxy group, or the like. In W, the aryloxy group may be a phenoxy group, a naphthyloxy group, or the like. In W, the aralkyloxy group may be a benzyloxy group, a methylbenzyloxy group, a methoxybenzyloxy group, a phenoxybenzyloxy group, or the like. In W, the aralkylamide group may be a benzylamide group (—NHBn) or the like. In W, the arylamide group may be a phenylamide group (—NHPh) or the like. In W, the alkylamide group may be a normal pentylamide group (—NH (n-Pen)) or the like. The azabicyclotrichloroacetyl compound may be converted to an amide, or the monochloroalkyl group, dichloroalkyl group, or trichloroacetyl group may be hydrolyzed to amide-condensate an azabicyclocarboxylic acid, or an azabicycloester compound The ester group may be reduced.

  For example, C in the production method B of the present invention is (i) reacting a compound represented by the general formula (VII) or a salt thereof with a base to hydrolyze a trichloroalkyl group of the general formula (VII). Or (ii) reducing the ester group of the general formula (VII) by reacting a compound represented by the general formula (VII) or a salt thereof with a reducing agent. Or (iii) a compound obtained by hydrolyzing a trichloroalkyl group obtained in the process of the above (i) or a salt thereof and an amine to react with an amidation of the carboxyl group of the compound. May include.

  In (i), the trichloroacetyl group of the compound of general formula (VII) is hydrolyzed with a base to give the corresponding carboxylic acid, and an amine is added to this carboxylic acid and reacted in the presence of an amide condensing agent to give the corresponding amide. Can be obtained. In the production of the corresponding carboxylic acid, the base is preferably sodium hydroxide, and the filtrate may be concentrated under reduced pressure to obtain the corresponding carboxylic acid.

In (ii), a corresponding alcohol can be obtained by reacting a compound represented by the general formula (VII) in which a carbonyl ester is introduced at the 6-position with a reducing agent. By subjecting the corresponding alcohol form to Step D, the corresponding N oxime form can be obtained via the corresponding NH form while retaining the OH group of the alcohol form. The reducing agent is preferably diisobutylaluminum hydride (DIBAL-H). The amount of the reducing agent to be used is preferably 0.5 mmol to 30 mmol, more preferably 0.8 mmol to 5 mmol, relative to 1 mmol of the compound represented by the general formula (VII). The reaction temperature is not particularly limited as long as the reaction proceeds, but is preferably -78 to 50 ° C, more preferably -78 to 25 ° C. The reaction time is preferably 0.5 hours to 48 hours, more preferably 2 hours to 15 hours. In the reaction, the raw material may be dissolved in toluene, cooled to −40 ° C., and the above diisobutylaluminum hydride in toluene may be dropped and reacted while allowing the temperature to rise naturally. After the reaction, an aqueous HCl solution is added and the mixture is extracted with CHCl _{3. The} collected organic layer is dried and concentrated under reduced pressure, and the residue may be subjected to silica gel column chromatography to obtain the target compound.

In (iii), an amidation reaction with an amine can be applied to the amidation. The amine may be appropriately selected according to the desired amide compound. For example, when phenylamine, naphthylamine or benzylamine is used, a compound having an N-phenylcarbamoyl group corresponding to the 6-position, a compound having an N-naphthylcarbamoyl group, or a compound having an N-benzylcarbamoyl group can be obtained. The amine is an alkylamine, arylamine, aralkylamine, or cyclic amine. Preferred examples include alkyl (C1-C6) amine, dialkylamine having the same or different alkyl group having 1 to 6 carbon atoms, benzylamine phenethylamine, aniline, phenylamine, naphthylamine, pyrrolidine, and piperidine. The other reaction conditions are the same as in Step B-2, but the preferred reaction time is 0.5 to 96 hours, the more preferred reaction time is 1 to 48 hours, and it is used for amide condensation within the range where the desired compound is obtained. Other reaction reagents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) can be used, and the amount used is appropriately determined. Although it can be changed, the amount is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, relative to 1 mol of the starting carboxylic acid compound. After the reaction, the reaction solution is concentrated and dissolved in ethyl acetate. Aqueous hydrochloric acid, water and saturated brine are added, dried over anhydrous MgSO ₄ , filtered, and the filtrate is concentrated to obtain the desired amide compound. May be.

  In step D of production method B of the present invention, a method known per se can be used to remove the amino-protecting group. The reagent for removing the protecting group of the amino group is preferably acid, base, ultraviolet light, hydrazine, phenylhydrazine, palladium acetate, trimethylsilane, and the optimum deprotection method is selected depending on the type of protecting group. You can choose. For example, when it is protected with a methoxycarbonyl group, it can be easily deprotected with trimethylsilane iodide. The amount of the reagent used is preferably 0.5 mmol to 50 mmol, more preferably 1 mmol to 10 mmol, relative to 1 mmol of the compound represented by the general formula (VII). The reaction time is preferably 0.5 to 48 hours, more preferably 1 to 15 hours. The reaction temperature is preferably 0 to 100 ° C, more preferably 20 to 70 ° C. Further, after the reaction, a saturated aqueous sodium hydrogen carbonate solution and saturated sodium thiosulfate may be added and extracted with trichloromethane. The organic layer containing the target compound is dried and concentrated under reduced pressure to obtain a deprotected compound. May be. In addition, the target compound may be used directly in the next reaction without isolation.

  It is preferred to oxidize the resulting compound after removal of the amino protecting group. The oxidizing agent is preferably metachloroperbenzoic acid. The amount of the oxidizing agent used is preferably 0.8 mmol to 5 mmol, more preferably 1 mmol to 3 mmol, with respect to 1 mmol of the compound represented by the general formula (VII). Although reaction temperature is not specifically limited as long as reaction advances, Preferably it is -78-50 degreeC, More preferably, it is 0-30 degreeC. The reaction time is preferably 0.5 hours to 48 hours, and more preferably 1 hour to 15 hours. The solvent used for the reaction may be the same as described above. After the reaction, a saturated aqueous sodium hydrogen carbonate solution is added, the organic layer containing the target compound is extracted with chloroform, the organic layer is dried, concentrated under reduced pressure, and the residue may be purified by silica gel chromatography.

  In the general formula (VIII), each symbol is the same as described above. Further, “·” represents a free radical, but the compound of the present invention can exist with the free radical (this compound is referred to as “N-oxyl form” in the present specification). Sometimes).

なお、一般式(I)で表される化合物又はその塩は、上記の化合物又はその塩に限定されない。The present invention relates to a compound represented by the general formula (I) or a salt thereof produced by the production method of the present invention.

The compound represented by the general formula (I) or a salt thereof is not limited to the above compound or a salt thereof.

The present invention relates to a compound represented by the general formula (V) or a salt thereof produced by the production method of the present invention.

The present invention relates to a compound represented by the general formula (VI) or a salt thereof produced by the production method of the present invention.

The present invention relates to a compound represented by the general formula (VII) or a salt thereof produced by the production method of the present invention.

The present invention includes (a) reacting a compound represented by the general formula (VII) or a salt thereof with a base to hydrolyze a trichloroalkyl group of the general formula (VII), (b) a general formula ( VII) or a salt thereof and a reducing agent are reacted to reduce the ester group of general formula (VII), or (c) the compound or salt thereof obtained in (a), The present invention relates to a compound obtained by reacting with an amine to amidate the carboxyl group of the compound or a salt thereof.

The present invention relates to a compound represented by the general formula (VIII) or a salt thereof produced by the production method of the present invention.

  In addition, the compound represented by the general formula (I), (V), (VI), (VII) or (VIII) obtained by the production method of the present invention can also form a salt. Examples of the salt include a metal salt, an ammonium salt, a salt with an organic base (such as triethylamine), a salt with an inorganic acid (such as hydrochloric acid) or an organic acid (such as fumaric acid), and the like.

  Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.

  Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, And salts with tris (hydroxymethyl) methylamine, tert-butylamine and the like.

  Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromide, nitric acid, sulfuric acid, phosphoric acid and the like.

  Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.

Hereinafter, still another embodiment (production method C) of the production method of the present invention will be described. This embodiment is substantially the same except that a pyrrolidine derivative is used instead of the piperidine derivative as the nitrogen-containing heterocycle. Accordingly, R ₁ , R ₂ , R ₃ , R ₅ , R _{5 ′} and X in the following general formula (IV) or (III) are the same as those in the general formula (II) or (I).

(式中、Ｒ_１はアミノ基の保護基を示し、Ｒ_２及びＲ_３は各々、Ｈ、ＯＨ、置換されていてもよいアルケニル基、又はアルコキシ基を意味し、Ｒ_５はＯＨ、アルキルカルボニルオキシ基又はアルコキシ基を意味する。)
で表される化合物と、ＸＣＯＯＨ（Ｘはハロゲンで置換されている有機基を示す）又はその反応性誘導体とを反応させて、該化合物のβ位にＸＣＯ（Ｘは前記と同意義である）で表されるカルボニル誘導基を導入することを特徴とする
一般式（III）

（式中、Ｒ_１、Ｒ_２、Ｒ_３及びＸは前記と同意義であり、Ｒ_５’はＨである）
で表される化合物又はその塩の製造方法である。Still another embodiment (production method C) of the production method of the present invention is as follows.
Formula (IV)

(Wherein R ₁ represents an amino-protecting group, R ₂ and R ₃ each represent H, OH, an alkenyl group which may be substituted, or an alkoxy group; R ₅ represents OH, alkylcarbonyl; (It means an oxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. General formula (III) characterized by introducing a carbonyl derivative represented by the formula (III)

(Wherein R ₁ , R ₂ , R ₃ and X are as defined above, and R _{5 ′} is H)
Or a salt thereof.

  In the compound represented by the general formula (IV), when the carbon atom constituting the heterocycle is an asymmetric carbon, the nitrogen-containing heterocycle may be d-form, l-form or racemic form. The compound having such a structure can also be used to produce a configuration-specific compound.

  In another embodiment of the production method of the present invention (Production Method C), the reagents used, reaction temperature, reaction time, solvent, acid scavenger and the like are as described above.

但し、Ｘは０eq又は２．２eqを意味する。Specific examples of the reaction from the compound represented by the general formula (IV) to the compound represented by the general formula (III) include the following. In addition, the manufacturing method of this invention is not limited to the following illustrations.

However, X means 0eq or 2.2eq.

  After completion of the reaction, the target compound may be isolated from the reaction system containing it by a conventional method, and may be purified by column chromatography or the like as necessary. Further, it may be used directly in the next reaction without isolation.

(式中、Ｒ_１はアミノ基の保護基を示し、Ｒ_２は置換されていてもよいアルケニル基を意味し、Ｒ_３はＨ、ＯＨ、置換されていてもよいアルケニル基、又はアルコキシ基を意味し、Ｒ_５はＯＨ、アルキルカルボニルオキシ基又はアルコキシ基を意味する。)
で表される化合物と、ＸＣＯＯＨ（Ｘはハロゲンで置換されている有機基を示す）又はその反応性誘導体とを反応させて、該化合物のβ位にＸＣＯ（Ｘは前記と同意義である）で表されるカルボニル誘導基を導入して、
一般式（III）

（式中、Ｒ_１、Ｒ_２、Ｒ_３及びＸは前記と同意義であり、Ｒ_５’はＨである）
で表される化合物又はその塩を得ること、
Ｂ’−１：塩基存在下、前記一般式（III）で表される化合物又はその塩と、アルコールとを反応させて、前記一般式（III）で表される化合物又はその塩をエステル化して
一般式（IX）

（式中、Ｒ_１、Ｒ_２、Ｒ_３及びＲ_５’は前記と同意義であり、Ｙはアルキル基、アラルキル基、又はアリール基である）
で表される化合物又はその塩を得ること、又は
Ｂ’−２：前記一般式（III）で表される化合物又はその塩と、アミン化合物とを反応させて、前記一般式（III）で表される化合物又はその塩をアミド化して
一般式（X）

（式中、Ｒ_１、Ｒ_２、Ｒ_３及びＲ_５’は前記と同意義であり、Ｒ_６及びＲ_７は各々、Ｈ、アリール基、アラルキル基、又はアルキル基であるか、又は両方が結合して窒素原子と環状構造を形成する。）
で表される化合物又はその塩を得ること、
Ｃ’： 前記一般式(III)、（IX）又は（X）で表される化合物又はその塩と、酸とを反応させて、前記一般式(III)、（IX）又は（X）で表される化合物又はその塩を環化して
一般式（XI）

（式中、Ｒ_１はアミノ基の保護基であり、Ａはハロゲン原子、ＯＨ又はホルミルオキシ基であり、Ｗは前記Ｘ、Ｏ−Ｙ又はＮＲ_６Ｒ_７である）
で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩を得ること、及び
Ｄ’：前記一般式（XI）で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩のアミノ基の保護基を除去して、得られる化合物を酸化させること
を含むことを特徴とする
一般式（XII）

（式中、Ａはハロゲン原子、ＯＨ又はホルミルオキシ基であり、Ｗは前記Ｘ、Ｏ−Ｙ又はＮＲ_６Ｒ_７であり、・はフリーラジカルを示す）
で表される化合物又はその鏡像異性体又はそれらの混合物又はそれらの塩の製造方法である。Further another embodiment (production method D) of the production method of the present invention is as follows.
A ': General formula (IV)

(Wherein R ₁ represents an amino-protecting group, R ₂ represents an optionally substituted alkenyl group, R ₃ represents H, OH, an optionally substituted alkenyl group, or an alkoxy group. And R ₅ represents OH, an alkylcarbonyloxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. Introducing a carbonyl derivative represented by
General formula (III)

(Wherein R ₁ , R ₂ , R ₃ and X are as defined above, and R _{5 ′} is H)
A compound represented by the formula:
B′-1: In the presence of a base, the compound represented by the general formula (III) or a salt thereof is reacted with an alcohol to esterify the compound represented by the general formula (III) or a salt thereof. General formula (IX)

Wherein R ₁ , R ₂ , R ₃ and R _{5 ′} are as defined above, and Y is an alkyl group, an aralkyl group or an aryl group.
B'-2: A compound represented by the general formula (III) or a salt thereof and an amine compound are reacted with each other to obtain a compound represented by the general formula (III). The compound or its salt is amidated to give a general formula (X)

Wherein R ₁ , R ₂ , R ₃ and R _{5 ′} are as defined above, and R ₆ and R ₇ are each H, an aryl group, an aralkyl group, an alkyl group, or both are Combines to form a ring structure with the nitrogen atom.)
A compound represented by the formula:
C ′: The compound represented by the general formula (III), (IX) or (X) or a salt thereof and an acid are reacted with each other to represent the compound represented by the general formula (III), (IX) or (X). A compound of the formula (XI)

(In the formula, R ₁ is an amino-protecting group, A is a halogen atom, OH or formyloxy group, and W is X, OY or NR ₆ R ₇ )
And a compound represented by the formula (XI), an enantiomer thereof, a mixture thereof, or a salt thereof. General formula (XII) characterized in that it comprises removing the protecting group of the amino group and oxidizing the resulting compound

(In the formula, A is a halogen atom, OH or formyloxy group, W is X, O—Y or NR ₆ R ₇ , and • represents a free radical)
Or a enantiomer thereof, a mixture thereof or a salt thereof.

Step A ′ of production method D of the present invention is substantially the same as production method C, and the reagents, reaction temperature, reaction time, solvent, acid scavenger and the like used are as described above. In R ₂ and R ₃ , the alkenyl group which may be substituted may be the same as in the above (Production Method A), and may be an allyl group from the viewpoint of cyclization. The term “which may be substituted” means that it may be substituted with any substituent, and examples of the substituent include an alkyl group (preferably an alkyl group having 1 to 4 carbon atoms), an aryl group ( Preferably an aryl group having 6 to 20 carbon atoms, more preferably a phenyl group or a naphthyl group), a carboxyl group, an alkoxy group (preferably an alkoxy group having 1 to 3 carbon atoms), an acyl group (preferably an acetyl group), or the like. It is done. The number of substituents is preferably 0 to 5, more preferably 0 to 3. When the number of substituents is 2 or more, each substituent may be the same or different. Among these, R ₂ is particularly preferably a methylallyl group, an ethylallyl group, a dimethylallyl group, or a phenylallyl group.

  The production method D of the present invention substantially corresponds to the production method B except that a pyrrolidine derivative is used instead of the piperidine derivative. Therefore, the reaction conditions in the production method D are described in the production method B. Reaction conditions etc. apply.

なお、一般式(III)で表される化合物又はその塩は、上記の化合物又はその塩に限定されない。The present invention relates to a compound represented by the general formula (III) or a salt thereof produced by the production method of the present invention.

The compound represented by the general formula (III) or a salt thereof is not limited to the above compound or a salt thereof.

The present invention relates to a compound represented by the general formula (XI) or a salt thereof produced by the production method of the present invention.

The present invention relates to a compound represented by the general formula (XII) or a salt thereof produced by the production method of the present invention.

  Moreover, the compound represented by general formula (III), (XI), or (XII) obtained by the manufacturing method of this invention can also form a salt. Examples of the salt include a metal salt, an ammonium salt, a salt with an organic base (such as triethylamine), a salt with an inorganic acid (such as hydrochloric acid) or an organic acid (such as fumaric acid), and the like.

  Suitable examples of the metal salt, the salt with an organic base, the salt with an inorganic acid, and the salt with an organic acid are the same as described above.

  A compound represented by the general formula (I), (III), (V), (VI), (VII), (VIII), (XI) or (XII) obtained by the above method, or an enantiomer thereof or the like Or a salt thereof is preferably a redox catalyst or an intermediate for the production of a medicament having a β-amino acid structure. Therefore, the present invention relates to a compound represented by the general formula (I), (III), (V), (VI), (VII), (VIII), (XI) or (XII) or an enantiomer thereof or It relates to the use of mixtures thereof or their salts as redox catalysts or intermediates for the preparation of medicaments having a β-amino acid structure. Examples of the medicine having a β-amino acid structure include a contrast agent.

但し、quantは定量的収率であることを示し、以下同じ。
N-保護 ピペリジン（Piperidine）1の電極酸化により得られるN,O-アセタール（acetal） 2aをTHFに溶かし、2.2当量のCl₃CCOClを加え、室温にて反応させるとβ-トリクロロアセチル（trichloroacetyl）体 3aが得られた。3aはエステル 4、アミド 5へ容易に変換可能であった(1)。さらにこの反応をアリル体 6aに適用すると7aを経由して新規アザビシクロアミノ酸 8aが光学活性体として得られた(2)。この反応は対応する5員環化合物にも適用可能であり、効率的にβ-トリクロロアセチル（trichloroacetyl）体 3b、7b、ビシクロ体 8bが得られる。Hereinafter, application examples to esters, amides and azabicyclo-β-amino acids using the compounds obtained by the production method of the present invention will be given. Moreover, the manufacture example of these compounds is not limited to the following.

However, quant indicates a quantitative yield, and the same applies hereinafter.
N-Protected N, O-acetal 2a obtained by the electrode oxidation of piperidine 1 is dissolved in THF, 2.2 equivalents of Cl ₃ CCOCl is added, and reacted at room temperature to produce β-trichloroacetyl Body 3a was obtained. 3a could be easily converted to ester 4, amide 5 (1). Furthermore, when this reaction was applied to allyl derivative 6a, novel azabicycloamino acid 8a was obtained as an optically active substance via 7a (2). This reaction can also be applied to the corresponding 5-membered ring compounds, and β-trichloroacetyl bodies 3b and 7b and bicyclo body 8b can be efficiently obtained.

但し、Phはフェニル基を、Bnはベンジル基を、n-Penはn-ペンチル基を示し、aqは水溶液を示す。For example, the compound represented by the general formula (I) or a salt thereof can be reacted as follows.

Here, Ph represents a phenyl group, Bn represents a benzyl group, n-Pen represents an n-pentyl group, and aq represents an aqueous solution.

Examples of synthesizing other azabicyclo-β-amino acids from the above compound 8a will be given below, but the present invention is not limited thereto.

TMS-Iはヨードトリメチルシランを、m-CPBAはメタクロロ過安息香酸を示す。Hereinafter, although the synthesis | combination of the azabicyclo- (beta) -amino acid using the compound etc. which are represented with general formula (I), and the induction | guidance | derivation to NO radical (N-oxyl) are illustrated, this invention is not limited to these.

TMS-I represents iodotrimethylsilane, and m-CPBA represents metachloroperbenzoic acid.

Hereinafter, synthesis of an azabicyclo-β-amino acid derivative using a compound represented by the general formula (III) and the like will be exemplified.

  Typical examples of the present invention are shown below, but the present invention is not limited thereto.

In this example, the equipment used for structure determination, measurement of physical property values, and the like are as follows.
Oxidation potential: Measured using BAS 100B / W (CV-50W) manufactured by Bioanalytical System, Inc.
Melting point: Measured using MICRO MELTING POINT APPARATUS (Yanaco), all measured values are uncorrected.
Infrared absorption spectrum (IR): measured using FT-IR 8100A or FT-IR 8400S manufactured by Shimadzu Corporation.
Nuclear magnetic resonance spectrum (NMR): Measured using VARIAN Gemini-300 (300 MHz). Tetramethylsilane (TMS) was measured as an internal standard substance at room temperature using CDCl ₃ as a measurement solvent, and all measured values were expressed in δ (ppm).
Measurement of optical rotation: JASCO DIP-1000 was used.
Column chromatography: Silica gel 60 (70-230 mesh) manufactured by MERCK or Silica gel 60 manufactured by Nacalai Tesque was used.
Unless otherwise indicated, the commercially available products and the solvents and reagents used in the reaction were used. In addition, anhydrous magnesium sulfate was used for drying of the extraction solvent.

無色油状物
IR ν = 2978, 1720, 1664 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.01 (br s, 1H), 3.90 (t, J = 9.6 Hz, 2H), 3.03 (t, J = 9.6 Hz, 2H), 1.53 (s, 9H).
¹³C-NMR (400MHz, CDCl₃) δ 178.1, 145.8, 95.7, 83.0, 46.4, 28.5, 27.9 (3C), 19.7.
[HR-EI]: m/z calcd for C₁₁H₁₄Cl₃NO₃ [M]⁺ 313.0039 : found 313.0021. （calcdは計算値、foundは実測値を示す。以下同様）Introduction of trichloroacetyl group into cyclic amine skeleton
Synthesis of Nt-butoxycarbonyl-2,3-didehydro-3-trichloroacetylpyrrolidine
Nt-butoxycarbonyl-2-methoxypyrrolidine (1 mmol; 201 mg) and 2-methyl-2-butene (2.2 mmol; 0.233 ml) were dissolved in THF (5 ml). Trichloroacetyl chloride (2.2 mmol; 0.240 ml) was added, and the mixture was stirred at room temperature for 12 hours. Aqueous NaHCO ₃ solution (10 ml) was added, and the mixture was extracted with Et ₂ O (3 × 10 ml). Thereafter, the collected organic layer was dried over anhydrous MgSO ₄ and filtered, and the filtrate was distilled off under reduced pressure. The obtained compound was purified by silica gel column chromatography (n-Hexane: AcOEt = 10: 1) to obtain the following target compound in a yield of 61%. Further, the target compound was obtained in a yield of 41% in the same manner except that no acid scavenger (2-methyl-2-butene) was used. Further, except that the starting compound was replaced with Nt-butoxycarbonyl-2-hydroxy-pyrrolidine, the target compound was obtained in a yield of 54% (using an acid scavenger) and 42% (no acid scavenger used).

Colorless oil
IR ν = 2978, 1720, 1664 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.01 (br s, 1H), 3.90 (t, J = 9.6 Hz, 2H), 3.03 (t, J = 9.6 Hz, 2H), 1.53 (s, 9H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 178.1, 145.8, 95.7, 83.0, 46.4, 28.5, 27.9 (3C), 19.7.
[HR-EI]: m / z calcd for C ₁₁ H ₁₄ Cl ₃ NO ₃ [M] ⁺ 313.0039: found 313.0021. (Calcd is the calculated value, found is the measured value, and so on)

  The following compounds were prepared in the same manner as described above except for those shown in Chemical Reaction Formulas I and II.

N-メトキシカルボニル-2,3-ジデヒドロ-3-トリクロロアセチルピロリジン
収率36％
無色油状物
IR ν = 2956, 2360, 1726, 1626 cm^-1
1H NMR (300MHz, CDCl₃) δ = 7.98 (s, 1H), 3.95 (t, J = 9.6 Hz, 2H), 3.86 (s, 3H), 3.05 (t, J = 9.6 Hz, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 178.1, 145.2 及び 144.7 (1C), 112.1, 95.6, 53.8, 46.4, 29.1 及び 28.1 (1C).
[HR-FAB(+)]: m/z calcd for C₈H₉Cl₃NO₃ [M+H]⁺ 271.9570 : found 271.9578.

N-methoxycarbonyl-2,3-didehydro-3-trichloroacetylpyrrolidine yield 36%
Colorless oil
IR ν = 2956, 2360, 1726, 1626 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 7.98 (s, 1H), 3.95 (t, J = 9.6 Hz, 2H), 3.86 (s, 3H), 3.05 (t, J = 9.6 Hz, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 178.1, 145.2 and 144.7 (1C), 112.1, 95.6, 53.8, 46.4, 29.1 and 28.1 (1C).
[HR-FAB (+)]: m / z calcd for C ₈ H ₉ Cl ₃ NO ₃ [M + H] ⁺ 271.9570: found 271.9578.

N-メトキシカルボニル-2,3-ジデヒドロ-3-トリクロロアセチルピペリジン
収率70％（トリクロロアセチルクロライドを５当量使用）
収率53％（トリクロロアセチルクロライドを２．２当量使用）
白色固体, mp = 61-64 ℃
IR ν = 2956, 1728, 1674 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.71 (s, 1H), 3.89 (s, 1H), 3.68 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 6.0 Hz, 2H), 1.96-1.89 (m, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 180.1, 153.3, 141.9, 107.7, 95.8, 54.1, 42.5, 21.5, 20.3.
[HR-EI]: m/z calcd for C₉H₁₀Cl₃NO₃ [M]⁺ 284.9726 : found 284.9714.

N-methoxycarbonyl-2,3-didehydro-3-trichloroacetylpiperidine yield 70% (uses 5 equivalents of trichloroacetyl chloride)
Yield 53% (using 2.2 equivalents of trichloroacetyl chloride)
White solid, mp = 61-64 ℃
IR ν = 2956, 1728, 1674 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.71 (s, 1H), 3.89 (s, 1H), 3.68 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 6.0 Hz, 2H), 1.96 -1.89 (m, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 180.1, 153.3, 141.9, 107.7, 95.8, 54.1, 42.5, 21.5, 20.3.
[HR-EI]: m / z calcd for C ₉ H ₁₀ Cl ₃ NO ₃ [M] ⁺ 284.9726: found 284.9714.

N-エトキシカルボニル-2,3-ジデヒドロ-3-トリクロロアセチルピペリジン
無色油状物
IR ν = 2981, 2958, 1728, 1676 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.74 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 6.0 Hz, 2H), 1.96-1.88 (m, 2H), 1.36 (t, J = 6.9 Hz, 3H).
¹³C-NMR (400MHz, CDCl₃) δ 180.1, 162.7, 142.1, 107.5, 95.9, 63.4, 40.4, 30.2, 20.4, 14.2.
[HR-EI]: m/z calcd for C₁₀H₁₂Cl₃NO₃ [M]⁺ 298.9883 : found 298.9863.

N-ethoxycarbonyl-2,3-didehydro-3-trichloroacetylpiperidine colorless oil
IR ν = 2981, 2958, 1728, 1676 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.74 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 6.0 Hz , 2H), 1.96-1.88 (m, 2H), 1.36 (t, J = 6.9 Hz, 3H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 180.1, 162.7, 142.1, 107.5, 95.9, 63.4, 40.4, 30.2, 20.4, 14.2.
[HR-EI]: m / z calcd for C ₁₀ H ₁₂ Cl ₃ NO ₃ [M] ⁺ 298.9883: found 298.9863.

N-t-ブトキシカルボニル-2,3-ジデヒドロ-3-トリクロロアセチルピペリジン
収率88％（トリクロロアセチルクロライド及び酸捕捉剤を各２．２当量使用）
収率81％（トリクロロアセチルクロライドを２．２当量使用、酸捕捉剤不使用）
収率76％（トリクロロアセチルクロライドを５当量使用、酸捕捉剤不使用）
黄色固体, mp = 82-84 ℃（mpは融点を示す。以下同様。）
IR ν = 2980, 1728, 1676 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.75 (s, 1H), 3.64-3.60 (t, J = 5.7 Hz, 2H), 2.47-2.43 (t, J = 6.0 Hz, 2H), 1.94-1.86 (m, 2H), 1.54 (s, 9H).
¹³C-NMR (400MHz, CDCl₃) δ 180.0, 142.7, 96.0, 83.3, 42.1, 27.9 (3C), 21.3, 20.3.
[HR-EI]: m/z calcd for C₁₂H₁₆Cl₃NO₃ [M]⁺ 327.0196 : found 327.0171.

Nt-butoxycarbonyl-2,3-didehydro-3-trichloroacetylpiperidine yield 88% (using 2.2 equivalents each of trichloroacetyl chloride and acid scavenger)
Yield 81% (2.2 equivalents of trichloroacetyl chloride used, no acid scavenger used)
Yield 76% (5 equivalents of trichloroacetyl chloride used, no acid scavenger used)
Yellow solid, mp = 82-84 ° C (mp indicates melting point, and so on)
IR ν = 2980, 1728, 1676 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.75 (s, 1H), 3.64-3.60 (t, J = 5.7 Hz, 2H), 2.47-2.43 (t, J = 6.0 Hz, 2H), 1.94-1.86 ( m, 2H), 1.54 (s, 9H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 180.0, 142.7, 96.0, 83.3, 42.1, 27.9 (3C), 21.3, 20.3.
[HR-EI]: m / z calcd for C ₁₂ H ₁₆ Cl ₃ NO ₃ [M] ⁺ 327.0196: found 327.0171.

N-ベンジルオキシカルボニル-2,3-ジデヒドロ-3-トリクロロアセチルピペリジン
収率33％
黄色油状物
IR ν = 2951, 2854, 1726, 1674 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.77 (s, 1H), 7.40-7.33 (m, 5H), 5.28 (s, 2H), 3.69 (t, J = 5.7 Hz, 2H), 2.46 (t, J = 6.0 Hz, 2H), 1.91-1.87 (m, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 180.2, 142.0, 135.0, 128.7〜128.2 (5C), 108.1, 95.9, 68.9, 42.6, 21.5, 20.3.
[HR-EI]: m/z calcd for C₁₅H₁₄Cl₃NO₃ [M]⁺ 361.0039 : found 361.0034.

N-benzyloxycarbonyl-2,3-didehydro-3-trichloroacetylpiperidine yield 33%
Yellow oil
IR ν = 2951, 2854, 1726, 1674 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.77 (s, 1H), 7.40-7.33 (m, 5H), 5.28 (s, 2H), 3.69 (t, J = 5.7 Hz, 2H), 2.46 (t, J = 6.0 Hz, 2H), 1.91-1.87 (m, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 180.2, 142.0, 135.0, 128.7-128.2 (5C), 108.1, 95.9, 68.9, 42.6, 21.5, 20.3.
[HR-EI]: m / z calcd for C ₁₅ H ₁₄ Cl ₃ NO ₃ [M] ⁺ 361.0039: found 361.0034.

N-ベンゾイル-2,3-ジデヒドロ-3-トリクロロアセチルピペリジン
収率30％
白色固体, mp = 58-62 ℃
IR ν = 2939, 2852, 1687 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.46 (s, 1H), 8.12 (d, J = 9.3 Hz, 2H), 7.66-7.45 (m, 3H), 3.85 (t, J = 5.7 Hz, 2H), 2.54 (t, J = 6.3 Hz, 2H), 2.04-2.00 (m, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 180.1, 171.5, 143.4, 133.7, 132.8, 131.6, 130.2, 128.7, 128.4, 128.3, 108.4, 42.2, 22.1, 20.4.
[HR-EI]: m/z calcd for C₁₄H₁₂Cl₃NO₂ [M]⁺ 330.9934 : found 330.9987.

N-benzoyl-2,3-didehydro-3-trichloroacetylpiperidine yield 30%
White solid, mp = 58-62 ℃
IR ν = 2939, 2852, 1687 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.46 (s, 1H), 8.12 (d, J = 9.3 Hz, 2H), 7.66-7.45 (m, 3H), 3.85 (t, J = 5.7 Hz, 2H) , 2.54 (t, J = 6.3 Hz, 2H), 2.04-2.00 (m, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 180.1, 171.5, 143.4, 133.7, 132.8, 131.6, 130.2, 128.7, 128.4, 128.3, 108.4, 42.2, 22.1, 20.4.
[HR-EI]: m / z calcd for C ₁₄ H ₁₂ Cl ₃ NO ₂ [M] ⁺ 330.9934: found 330.9987.

N-メトキシカルボニル-2-アリル-4,5-ジデヒドロ-4-トリクロロアセチルピロリジン
収率80％
黄色油状物
IR ν = 2924, 1726, 1666, 1591 cm^-1
1H NMR (300MHz, CDCl₃) δ = 7.97 (br s, 1H), 5.77-5.64 (m, 1H), 5.17-5.12 (m, 2H), 4.43-4.38 (m, 1H), 3.89 (s, 3H), 3.18-3.09 (m, 1H), 2.82-2.76 (m, 1H), 2.57-2.38 (m, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 178.0, 152.0, 144.5, 131.6, 119.1, 110.7, 95.3, 58.1, 53.5, 44.0, 37.8.
[HR-EI]: m/z calcd for C₁₁H₁₂Cl₃NO₃ [M]⁺ 310.9883 : found 310.9875.

N-methoxycarbonyl-2-allyl-4,5-didehydro-4-trichloroacetylpyrrolidine yield 80%
Yellow oil
IR ν = 2924, 1726, 1666, 1591 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 7.97 (br s, 1H), 5.77-5.64 (m, 1H), 5.17-5.12 (m, 2H), 4.43-4.38 (m, 1H), 3.89 (s, 3H), 3.18-3.09 (m, 1H), 2.82-2.76 (m, 1H), 2.57-2.38 (m, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 178.0, 152.0, 144.5, 131.6, 119.1, 110.7, 95.3, 58.1, 53.5, 44.0, 37.8.
[HR-EI]: m / z calcd for C ₁₁ H ₁₂ Cl ₃ NO ₃ [M] ⁺ 310.9883: found 310.9875.

N-メトキシカルボニル-（2S）-アリル-5，6-ジデヒドロ-5-トリクロロアセチルピペリジン
収率72％
白色固体, mp = 70-72 ℃
[α]_D ²³ = −99.6 (c 1.00, CHCl₃)
IR ν = 2924, 1726, 1666, 1591 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.69 (s, 1H), 5.82-5.69 (m, 1H), 5.12-5.07 (m, 2H), 4.38 (br s, 1H), 3.89 (s, 3H), 2.63 (dd, J = 3.8, 13.8 Hz, 1H), 2.41-2.02 (m, 3H), 1.75-1.60 (m, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 180.0, 152.8, 140.7, 133.1, 118.1, 107.0, 95.7, 83.3, 54.0, 50.3, 35.9, 22.2, 17.3.
[HR-EI]: m/z calcd for C₁₂H₁₄Cl₃NO₃ [M]⁺ 325.0039 : found 325.0016.
HPLC: AD カラム, n-Hexane：EtOH = 100:1, 波長: 254nm, 流速: 0.3ml/分, 保持時間: 18.0 [(S)-, enriched], 20.9 [(R)-] 分.

N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-trichloroacetylpiperidine yield 72%
White solid, mp = 70-72 ℃
[α] _D ²³ = −99.6 (c 1.00, CHCl ₃ )
IR ν = 2924, 1726, 1666, 1591 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.69 (s, 1H), 5.82-5.69 (m, 1H), 5.12-5.07 (m, 2H), 4.38 (br s, 1H), 3.89 (s, 3H) , 2.63 (dd, J = 3.8, 13.8 Hz, 1H), 2.41-2.02 (m, 3H), 1.75-1.60 (m, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 180.0, 152.8, 140.7, 133.1, 118.1, 107.0, 95.7, 83.3, 54.0, 50.3, 35.9, 22.2, 17.3.
[HR-EI]: m / z calcd for C ₁₂ H ₁₄ Cl ₃ NO ₃ [M] ⁺ 325.0039: found 325.0016.
HPLC: AD column, n-Hexane: EtOH = 100: 1, wavelength: 254 nm, flow rate: 0.3 ml / min, retention time: 18.0 [(S)-, enriched], 20.9 [(R)-] min.

N-メトキシカルボニル-(2R)-アリル-5,6-ジデヒドロ-5-トリクロロアセチルピペリジン
白色固体, mp = 73 ℃
[α]_D ²⁰ = ＋97.0 (c 1.00, CHCl₃)
HPLC: ADカラム, n-Hexane：EtOH = 100:1, 波長: 254nm, 流速: 0.3ml/分, 保持時間: 18.7 [(S)-], 20.7 [(R)- , enriched]分.

N-methoxycarbonyl- (2R) -allyl-5,6-didehydro-5-trichloroacetylpiperidine white solid, mp = 73 ° C
[α] _D ²⁰ = +97.0 (c 1.00, CHCl ₃ )
HPLC: AD column, n-Hexane: EtOH = 100: 1, wavelength: 254 nm, flow rate: 0.3 ml / min, retention time: 18.7 [(S)-], 20.7 [(R)-, enriched] min.

N-メトキシカルボニル-（2S）-アリル-5，6-ジデヒドロ-5-メトキシカルボニルピペリジン
無色油状物
[α]_D ²³ = −88.3 (c 1.00, CHCl₃)
IR ν = 2953, 2856, 1724, 1697, 1633 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.01 (brs, 1H), 5.82-5.69 (m, 1H), 5.09-5.05 (m, 2H), 4.33 (brs, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 2.46-1.94 (m, 4H), 1.68-1.65 (m, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 167.8, 153.3, 134.3, 133.7, 117.8, 107.6, 53.4, 51.2, 50.2, 35.7, 22.5, 16.7.
[HR-EI]: m/z calcd for C₁₂H₁₇NO₄ [M]⁺ 239.1157 : found 239.1140.Conversion of trichloroacetyl group to ester
Synthesis of N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-methoxycarbonylpiperidine
N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-trichloroacetylpiperidine (1 mmol) was dissolved in MeOH (5 ml). NaHCO ₃ aqueous solution (1 ml) was added and stirred at room temperature for 6 hours. MeOH was removed under reduced pressure and extracted with AcOEt (3 × 10 mL). The collected organic layer was dried over anhydrous MgSO ₄ , filtered, and the filtrate was distilled off under reduced pressure to quantitatively remove N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-methoxycarbonylpiperidine. Obtained.

N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-methoxycarbonylpiperidine colorless oil
[α] _D ²³ = −88.3 (c 1.00, CHCl ₃ )
IR ν = 2953, 2856, 1724, 1697, 1633 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.01 (brs, 1H), 5.82-5.69 (m, 1H), 5.09-5.05 (m, 2H), 4.33 (brs, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 2.46-1.94 (m, 4H), 1.68-1.65 (m, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 167.8, 153.3, 134.3, 133.7, 117.8, 107.6, 53.4, 51.2, 50.2, 35.7, 22.5, 16.7.
[HR-EI]: m / z calcd for C ₁₂ H ₁₇ NO ₄ [M] ⁺ 239.1157: found 239.1140.

N-メトキシカルボニル-2,3-ジデヒドロ-3-メトキシカルボニルピペリジン
無色油状物
¹H NMR (300MHz, CDCl₃) δ = 8.01 (br s, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.63-3.59 (t, J = 6.0 Hz, 2H), 2.34-2.30 (t, J = 6.0 Hz, 2H), 1.89-1.82 (m, 2H).N-methoxycarbonyl-2,3-didehydro-3-methoxycarbonylpiperidine was quantitatively obtained in the same manner except that the starting compound was changed to N-methoxycarbonyl-2,3-didehydro-3-trichloroacetylpiperidine.

N-methoxycarbonyl-2,3-didehydro-3-methoxycarbonylpiperidine colorless oil
¹ H NMR (300MHz, CDCl ₃ ) δ = 8.01 (br s, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.63-3.59 (t, J = 6.0 Hz, 2H), 2.34-2.30 (t, J = 6.0 Hz, 2H), 1.89-1.82 (m, 2H).

無色油状物
[α]_D ²⁰ = −65.4 (c 1.00, CHCl₃)
IR ν = 3319, 2953, 2926, 1718 cm^-1
1H NMR (300MHz, CDCl₃) δ = 7.90 (s, 1H), 7.38-7.24 (m, 5H), 5.85-5.68 (m, 2H), 5.08-5.04 (m, 2H), 4.54 (t, J = 5.1, 2H), 4.35 (br s, 1H), 3.79 (s, 3H), 2.35-1.98 (m, 4H), 1.72-1.61 (m, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 167.0, 153.2, 138.6, 133.7, 128.5 (2C), 127.7 (3C), 127.2, 117.7, 53.2, 49.6, 43.5, 35.3, 22.5, 16.9.
[HR-EI]: m/z calcd for C₁₈H₂₂N₂O₃ [M]⁺ 314.1631 : found 314.1618.Conversion of trichloroacetyl group to amide
Synthesis of N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5- (N-benzylcarbamoyl) piperidine
N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-trichloroacetylpiperidine (2.4 mmol; 791 mg) was dissolved in CH ₃ CN (12 ml). BnNH ₂ (1.5 eq; 0.397 ml) was added and stirred at room temperature for 6 hours. CH ₃ CN was distilled off under reduced pressure, 3% aqueous HCl (10 ml) was added, and the mixture was extracted with CHCl ₃ (3 × 10 mL). Thereafter, the collected organic layer was dried over anhydrous MgSO ₄ and filtered, and the filtrate was distilled off under reduced pressure. The obtained compound was purified by silica gel column chromatography (n-Hexane: AcOEt = 1: 1), and N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5- (N-benzylcarbamoyl) piperidine Was obtained quantitatively.

Colorless oil
[α] _D ²⁰ = −65.4 (c 1.00, CHCl ₃ )
IR ν = 3319, 2953, 2926, 1718 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 7.90 (s, 1H), 7.38-7.24 (m, 5H), 5.85-5.68 (m, 2H), 5.08-5.04 (m, 2H), 4.54 (t, J = 5.1, 2H), 4.35 (br s, 1H), 3.79 (s, 3H), 2.35-1.98 (m, 4H), 1.72-1.61 (m, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 167.0, 153.2, 138.6, 133.7, 128.5 (2C), 127.7 (3C), 127.2, 117.7, 53.2, 49.6, 43.5, 35.3, 22.5, 16.9.
[HR-EI]: m / z calcd for C ₁₈ H ₂₂ N ₂ O ₃ [M] ⁺ 314.1631: found 314.1618.

Except for changing the BnNH ₂ to n-PenNH ₂ was prepared the following compounds by the same manner as described above.

N-メトキシカルボニル-(2S)-アリル-5,6-ジデヒドロ-5-(N-n-ペンチルカルバモイル）ピペリジン
定量的に得られた
無色油状物
[α]_D ²⁰ = −73.9 (c 1.00, CHCl₃)
IR ν = 3307, 2954, 2927, 2858, 1716, 1658 cm^-1
1H NMR (300MHz, CDCl₃) δ = 7.87 (s, 1H), 5.78-5.62 (m, 2H), 5.08 (d, J =9.7 Hz 2H), 4.39 (br s, 1H), 3.83 (s, 3H), 3.38-3.32 (m, 2H), 2.32-2.01 (m, 5H), 1.74-1.65 (m, 1H), 1.61-1.54 (m, 2H), 1.40-1.30 (m, 4H), 0.95-0.92 (t, J = 5.3 Hz, 3H).
¹³C-NMR (400MHz, CDCl₃) δ 167.1, 153.3, 140.7, 133.8, 130.4, 117.7, 109.6, 53.3, 49.6, 39.6, 35.3, 29.3, 29.0, 22.6, 22.3, 16.9, 13.8.
[HR-EI]: m/z calcd for C₁₆H₂₆N₂O₃ [M]⁺ 294.1943 : found 294.1946.

N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5- (Nn-pentylcarbamoyl) piperidine quantitatively obtained colorless oil
[α] _D ²⁰ = −73.9 (c 1.00, CHCl ₃ )
IR ν = 3307, 2954, 2927, 2858, 1716, 1658 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 7.87 (s, 1H), 5.78-5.62 (m, 2H), 5.08 (d, J = 9.7 Hz 2H), 4.39 (br s, 1H), 3.83 (s, 3H), 3.38-3.32 (m, 2H), 2.32-2.01 (m, 5H), 1.74-1.65 (m, 1H), 1.61-1.54 (m, 2H), 1.40-1.30 (m, 4H), 0.95- 0.92 (t, J = 5.3 Hz, 3H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 167.1, 153.3, 140.7, 133.8, 130.4, 117.7, 109.6, 53.3, 49.6, 39.6, 35.3, 29.3, 29.0, 22.6, 22.3, 16.9, 13.8.
[HR-EI]: m / z calcd for C ₁₆ H ₂₆ N ₂ O ₃ [M] ⁺ 294.1943: found 294.1946.

The following compounds were prepared by the same method as described above except that BnNH ₂ was replaced with PhNH ₂ and 2 equivalents of triethylamine was used for the trichloroacetyl compound, and the reaction time was 24 hours.

N-メトキシカルボニル-(2S)-アリル-5,6-ジデヒドロ-5-(N-フェニルカルバモイル)ピペリジン
収率63％
無色油状物
[α]_D ¹⁵ = −103.9 (c 1.00, CHCl₃)
IR ν = 2954, 2931, 2856, 1722, 1662 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.14 (br s, 1H), 8.00 (s, 1H), 7.57 (d, J = 5.7, 2H), 7.37-7.35 (m, 2H), 7.20-7.10 (m, 1H), 5.85-5.78 (m, 1H), 5.14-5.10 (m, 2H), 4.42 (br s, 1H), 3.85 (s, 3H), 2.35-2.06 (m, 5H), 1.79-1.70 (m, 1H).
¹³C-NMR (400MHz, CDCl₃) δ 172.7, 153.1, 138.1, 136.3, 133.6, 128.9 (2C), 124.0, 120.1, 118.0, 53.7, 50.3, 35.8, 22.4, 16.4.
[HR-EI]: m/z calcd for C₁₇H₂₀N₂O₃ [M]⁺ 300.1474 : found 300.1467.

N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5- (N-phenylcarbamoyl) piperidine yield 63%
Colorless oil
[α] _D ¹⁵ = −103.9 (c 1.00, CHCl ₃ )
IR ν = 2954, 2931, 2856, 1722, 1662 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.14 (br s, 1H), 8.00 (s, 1H), 7.57 (d, J = 5.7, 2H), 7.37-7.35 (m, 2H), 7.20-7.10 ( m, 1H), 5.85-5.78 (m, 1H), 5.14-5.10 (m, 2H), 4.42 (br s, 1H), 3.85 (s, 3H), 2.35-2.06 (m, 5H), 1.79-1.70 (m, 1H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 172.7, 153.1, 138.1, 136.3, 133.6, 128.9 (2C), 124.0, 120.1, 118.0, 53.7, 50.3, 35.8, 22.4, 16.4.
[HR-EI]: m / z calcd for C ₁₇ H ₂₀ N ₂ O ₃ [M] ⁺ 300.1474: found 300.1467.

Synthesis of azabicyclo-β-amino acid precursors
Synthesis of N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-trichloroacetylpiperidine
6-Methoxy-N-methoxycarbonyl-D-pipecolic acid methyl ester (32.6 mmol; 7.53 g), and allyltrimethylsilane (39.1 mmol; 6.2 ml) were dissolved in CH ₂ Cl ₂ (200 ml) at −78 ° C. Cooled to. BF ₃ · OEt ₂ (34.2 mmol; 8.92 ml) was added dropwise thereto over 10 minutes, and the mixture was stirred for 3 hours while naturally heating. After the reaction, water (300 ml) was added and extracted with CHCl ₃ (3 × 300 ml). The organic layer was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-Hexane: AcOEt = 5: 1) to obtain N-methoxycarbonyl- (2S) -allyl- (6S) -methoxycarbonylpiperidine. Was obtained in a yield of 62%. 1N NaOH aqueous solution (16 ml) was added to a solution of N-methoxycarbonyl- (2S) -allyl- (6S) -methoxycarbonylpiperidine (7.94 mmol; 1.91 g) in MeOH (25 ml) and stirred at room temperature for 1 hour. . The solution was acidified with 3% aqueous HCl, MeOH was evaporated under reduced pressure, and extracted with AcOEt (3 × 30 ml). The organic layer was dried and concentrated under reduced pressure. This residue was dissolved in a mixed solution of an aqueous solution (2 ml) of NaHCO ₃ (7.94 mmol; 0.429 g) and a MeCN: MeOH = 5: 1 solution (32 ml), and two platinum plates were used as the cathode plate. A current of 3 F / mol was applied at 0.5 A at ° C. After energization, the reaction mixture was evaporated under reduced pressure, water (100 ml) was added, and the mixture was extracted with ethyl acetate (3 × 100 ml). The organic layer is dried and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-Hexane: AcOEt = 2: 1)) to yield N-methoxycarbonyl- (2S) -allyl-6-methoxypiperidine. Obtained at a rate of 70%. N-methoxycarbonyl- (2S) -allyl-6-methoxypiperidine (23 mmol; 4.90 g) was dissolved in THF (120 ml). Trichloroacetyl chloride (115 mmol; 5.68 ml) was added, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous NaHCO ₃ solution (200 ml) was added, and the mixture was extracted with Et ₂ O (3 × 150 ml). Thereafter, the collected organic layer was dried over anhydrous MgSO ₄ and filtered, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-Hexane: AcOEt = 10: 1) to obtain N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-trichloroacetylpiperidine at a yield of 90%. Was obtained.

Synthesis of N-methoxycarbonyl-2-methoxy-6S-methoxycarbonylpiperidine L-lysine (500 mmol, 73.0 g) and 10N NaOH aqueous solution (200 ml) were added to the reaction vessel and stirred. Under ice cooling, MeCO ₂ Cl (100 mmol, 38.4 ml) was added dropwise. The mixture is then stirred at room temperature for 12 hours. After stirring, the reaction solution was acidified with 15% aqueous HCl (200 ml) under ice-cooling, and extracted with CH ₂ Cl ₂ (350 mL × 3). The organic layer was dried and concentrated under reduced pressure.
To the residue was added 1N HCl-MeOH (300 mL), and the mixture was refluxed at room temperature for 12 hours. After completion of the reaction, the solvent was concentrated under reduced pressure and dissolved in AcOEt (500 ml). Then, it was washed with a saturated aqueous NaHCO ₃ solution (200 ml), H ₂ O (50 ml), and saturated brine (50 ml). The organic layer was dried and concentrated under reduced pressure to obtain methyl (2S, 6) -bismethoxycarbonylhexanoate in a yield of 72%.
MeOH (100 ml) and Et ₄ NBF ₄ (10 mmol, 2.2 g) were added to and stirred with methyl (2S, 6) -bismethoxycarbonylhexanoate (100 mmol; 27.6 g). Two platinum plates (5 cm × 10 cm) were used as electrodes, and a current of 6 F / mol was applied at −10 ° C. and 0.5 A (terminal voltage: 15 V). After energization, concentrated sulfuric acid (5 ml) was added dropwise. After 1.5 hours, the reaction solution was neutralized with a saturated aqueous NaHCO ₃ solution and concentrated under reduced pressure. Purified water (100 ml) was added to the residue and extracted with AcOEt (300 ml × 3). The organic layer was dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-Hexane: AcOEt = 5: 1) to obtain N-methoxycarbonyl-2-methoxy-6S-methoxycarbonylpiperidine at a yield of 37%. Was obtained.

(6S)-トリクロロアセチル-(3S)-クロロ-9-(N-メトキシカルボニル)アザビシクロ[3.3.1]ノナン
白色結晶, mp = 115-118 ℃
[α]_D ²⁵ = +89.8 (c 1.00, CHCl₃)
IR ν = 2953, 2358, 1734 cm^-1
1H NMR (300MHz, CDCl₃) δ = 4.96-4.87 (m, 1H), 4.82 及び 4.69 (2br s, 1H), 4.56 及び 4.45 (2br s, 1H), 3.87-3.77 (m, 4H), 2.50 (dd, J = 3.8, 6.6 Hz, 1H), 2.35-2.32 (m, 1H), 2.25-2.11 (m, 2H), 2.07-1.92 (m, 3H), 1.88-1.83 (m, 1H).
¹³C-NMR (400MHz, CDCl₃) δ 190.3 及び 190.1 (1C), 154.4 及び154.1 (1C), 96.3, 52.9 及び52.5 (1C), 50.3 及び50.0 (1C), 47.3 及び 46.7 (1C), 45.0 及び 44.5 (1C), 40.5 及び 40.3 (1C), 37.1 及び 36.8 (1C), 27.8 及び 27.3 (1C), 26.2 及び 26.1 (1C).
[HR-EI]: m/z calcd for C₁₂H₁₅Cl₄NO₃ [M]⁺ 360.9806 : found 360.9805.Synthesis of azabicyclo β-amino acids (Lewis acid catalyzed cyclization)
Synthesis of 6-trichloroacetyl-3-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane
N-methoxycarbonyl- (2S) -allyl-5,6-didehydro-5-trichloroacetylpiperidine (1 mmol; 0.326 g) was dissolved in dichloromethane (10 mL) and cooled to -78 ° C. Thereto, titanium tetrachloride (1.1 mmol; 0.124 ml) was added dropwise over 10 minutes, followed by stirring for 12 hours while naturally heating. After the reaction, saturated aqueous sodium hydrogen carbonate (10 mL) was added, and the mixture was extracted with CHCl ₃ (10 mL × 3). The organic layer was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-Hexane: AcOEt = 10: 1) to give 6S-trichloroacetyl-3S-chloro-9- (N-methoxycarbonyl) azabicyclo. [3.3.1] Nonane was obtained in 58% yield.

(6S) -Trichloroacetyl- (3S) -chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane white crystals, mp = 115-118 ° C
[α] _D ²⁵ = +89.8 (c 1.00, CHCl ₃ )
IR ν = 2953, 2358, 1734 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 4.96-4.87 (m, 1H), 4.82 and 4.69 (2br s, 1H), 4.56 and 4.45 (2br s, 1H), 3.87-3.77 (m, 4H), 2.50 (dd, J = 3.8, 6.6 Hz, 1H), 2.35-2.32 (m, 1H), 2.25-2.11 (m, 2H), 2.07-1.92 (m, 3H), 1.88-1.83 (m, 1H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 190.3 and 190.1 (1C), 154.4 and 154.1 (1C), 96.3, 52.9 and 52.5 (1C), 50.3 and 50.0 (1C), 47.3 and 46.7 (1C), 45.0 and 44.5 (1C), 40.5 and 40.3 (1C), 37.1 and 36.8 (1C), 27.8 and 27.3 (1C), 26.2 and 26.1 (1C).
[HR-EI]: m / z calcd for C ₁₂ H ₁₅ Cl ₄ NO ₃ [M] ⁺ 360.9806: found 360.9805.

  The following compound was produced in the same manner as described above except that the starting compound was changed to the 2R-allyl compound (yield 54%).

(6R)-トリクロロアセチル-(3R)-クロロ-9-(N-メトキシカルボニル)アザビシクロ[3.3.1]ノナン
白色固体, mp = 118 ℃
[α]_D ¹⁹ = −86.9 (c 0.96, CHCl₃)
IR ν = 2953, 1739, 1693 cm^-1
1H NMR (300MHz, CDCl₃) δ = 4.92-4.83 (m, 1H), 4.78 及び 4.64 (2br s, 1H), 4.52 及び 4.40 (2br s, 1H), 3.82-3.73 (m, 4H), 2.45 (dd, J = 3.8, 6.6 Hz, 1H), 2.32-1.80 (m, 1H).
¹³C-NMR (400MHz, CDCl₃) δ 190.4 及び 190.2 (1C), 154.5 及び 154.2 (1C), 96.3, 53.0, 50.4 及び 50.0 (1C), 47.4 及び 46.8 (1C), 45.1 及び 44.6 (1C), 40.6 及び 40.4 (1C), 37.1 及び 36.9 (1C), 27.9 及び 27.4 (1C), 26.3 及び 26.2 (1C).
[HR-EI]: m/z calcd for C₁₂H₁₅Cl₄NO₃ [M]⁺ 360.9806 : found 360.9805.

(6R) -Trichloroacetyl- (3R) -chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane white solid, mp = 118 ° C
[α] _D ¹⁹ = −86.9 (c 0.96, CHCl ₃ )
IR ν = 2953, 1739, 1693 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 4.92-4.83 (m, 1H), 4.78 and 4.64 (2br s, 1H), 4.52 and 4.40 (2br s, 1H), 3.82-3.73 (m, 4H), 2.45 (dd, J = 3.8, 6.6 Hz, 1H), 2.32-1.80 (m, 1H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 190.4 and 190.2 (1C), 154.5 and 154.2 (1C), 96.3, 53.0, 50.4 and 50.0 (1C), 47.4 and 46.8 (1C), 45.1 and 44.6 (1C), 40.6 and 40.4 (1C), 37.1 and 36.9 (1C), 27.9 and 27.4 (1C), 26.3 and 26.2 (1C).
[HR-EI]: m / z calcd for C ₁₂ H ₁₅ Cl ₄ NO ₃ [M] ⁺ 360.9806: found 360.9805.

(6S)-メトキシカルボニル-(3S)-クロロ-9-（N-メトキシカルボニル）アザビシクロ
[3.3.1]ノナン
収率81％
無色油状物
[α]_D ²³ = ＋35.9 (c 1.00, CHCl₃)
IR ν = 2951, 1732 cm^-1
1H NMR (300MHz, CDCl₃) δ = 4.76-4.61 (m, 2H), 4.46 及び 4.34 (2br s, 1H), 3.73-3.68 (m, 6H), 2.86-2.77 (m, 1H), 2.62-1.55 (m, 8H).
¹³C-NMR (400MHz, CDCl₃) δ 172.5 及び 172.4 (1C), 154.2 及び 154.0 (1C), 52.9 及び 52.4(1C), 49.0 及び48.5 (1C), 47.3 及び 46.7 (1C), 44.0 及び 43.3 (1C), 42.8 及び 42.5 (1C), 40.7 及び40.2 (1C), 37.4 及び 37.1 (1C), 27.8 及び 27.4 (1C), 25.4 及び 25.1 (1C), 22.6 及び 21.6 (1C).
[HR-EI]: m/z calcd for C₁₂H₁₈ClNO₄ [M]⁺ 275.0924 : found 275.0910.The following compounds were produced by the same method as described above, except that the starting compounds were changed to the compounds in the left column of Chemical Reaction Formula VI.

(6S) -Methoxycarbonyl- (3S) -chloro-9- (N-methoxycarbonyl) azabicyclo
[3.3.1] Nonane yield 81%
Colorless oil
[α] _D ²³ = +35.9 (c 1.00, CHCl ₃ )
IR ν = 2951, 1732 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 4.76-4.61 (m, 2H), 4.46 and 4.34 (2br s, 1H), 3.73-3.68 (m, 6H), 2.86-2.77 (m, 1H), 2.62- 1.55 (m, 8H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 172.5 and 172.4 (1C), 154.2 and 154.0 (1C), 52.9 and 52.4 (1C), 49.0 and 48.5 (1C), 47.3 and 46.7 (1C), 44.0 and 43.3 ( 1C), 42.8 and 42.5 (1C), 40.7 and 40.2 (1C), 37.4 and 37.1 (1C), 27.8 and 27.4 (1C), 25.4 and 25.1 (1C), 22.6 and 21.6 (1C).
[HR-EI]: m / z calcd for C ₁₂ H ₁₈ ClNO ₄ [M] ⁺ 275.0924: found 275.0910.

(6S)-（N-ベンジルカルバモイル）-(3S)-クロロ-9-（N-メトキシカルボニル）アザビシクロ[3.3.1]ノナン
収率86％
白色固体mp = 44-45℃
[α]_D ¹⁹ = ＋33.5 (c 1.00, CHCl₃)
IR ν = 3307, 2951, 2926, 2360, 1672, 1649 cm^-1
1H NMR (300MHz, CDCl₃) δ = 7.38-7.24 (m, 5H), 6.17-5.87 (m, 1H), 4.85-4.33 (m, 5H), 3.80-3.55 (m, 4H), 2.65-1.56 (m, 8H).
¹³C-NMR (400MHz, CDCl₃) δ 171.8, 154.3, 138.0, 128.3 (2C), 127.2〜127.0 (3C), 53.0, 52.4, 49.5, 47.4, 45.3, 44.7, 43.1, 40.4, 37.0, 27.7, 22.4.
[HR-EI]: m/z calcd for C₁₈H₂₃ClN₂O₃ [M]⁺ 350.1398 : found 350.1417.

(6S)-(N-Benzylcarbamoyl)-(3S) -chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane yield 86%
White solid mp = 44-45 ℃
[α] _D ¹⁹ = +33.5 (c 1.00, CHCl ₃ )
IR ν = 3307, 2951, 2926, 2360, 1672, 1649 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 7.38-7.24 (m, 5H), 6.17-5.87 (m, 1H), 4.85-4.33 (m, 5H), 3.80-3.55 (m, 4H), 2.65-1.56 (m, 8H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 171.8, 154.3, 138.0, 128.3 (2C), 127.2-127.0 (3C), 53.0, 52.4, 49.5, 47.4, 45.3, 44.7, 43.1, 40.4, 37.0, 27.7, 22.4 .
[HR-EI]: m / z calcd for C ₁₈ H ₂₃ ClN ₂ O ₃ [M] ⁺ 350.1398: found 350.1417.

6S-（N-フェニルカルバモイル）-3S-クロロ-9-（N-メトキシカルボニル）アザビシクロ[3.3.1]ノナン
収率74％
無色油状物
[α]_D ²³ = ＋81.3 (c 1.00, CHCl₃)
IR ν = 3309, 2951, 1670 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.60 (s, 1H), 7.54 (d,, J = 5.9, 2H), 7.33-7.27 (m, 2H), 7.12-7.08 (m, 1H), 4.89-4.80 (m, 1H), 4.64-4.36 (m, 2H), 3.74 (s, 3H), 2.85-2.69 (m, 1H), 2.59-2.45 (m, 1H), 2.33-1.80 (m, 7H).
¹³C-NMR (400MHz, CDCl₃) δ 170.4, 154.9 及び154.3 (1C), 138.0 及び 137.6 (1C), 128.9 (2C), 124.6 及び 124.2 (1C), 120.0~119.8 (2C), 53.0, 50.0 及び 49.8 (1C), 47.8 及び 47.1 (1C), 46.9 及び 46.0 (1C), 40.7 及び 40.4 (1C), 37.5 及び 37.4 (1C), 27.9 及び 27.6 (1C), 23.2 及び 22.4 (1C).
[HR-EI]: m/z calcd for C₁₇H₂₁ClN₂O₃ [M]⁺ 336.1241 : found 336.1233.

6S- (N-phenylcarbamoyl) -3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane yield 74%
Colorless oil
[α] _D ²³ = +81.3 (c 1.00, CHCl ₃ )
IR ν = 3309, 2951, 1670 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.60 (s, 1H), 7.54 (d ,, J = 5.9, 2H), 7.33-7.27 (m, 2H), 7.12-7.08 (m, 1H), 4.89- 4.80 (m, 1H), 4.64-4.36 (m, 2H), 3.74 (s, 3H), 2.85-2.69 (m, 1H), 2.59-2.45 (m, 1H), 2.33-1.80 (m, 7H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 170.4, 154.9 and 154.3 (1C), 138.0 and 137.6 (1C), 128.9 (2C), 124.6 and 124.2 (1C), 120.0 to 119.8 (2C), 53.0, 50.0 and 49.8 (1C), 47.8 and 47.1 (1C), 46.9 and 46.0 (1C), 40.7 and 40.4 (1C), 37.5 and 37.4 (1C), 27.9 and 27.6 (1C), 23.2 and 22.4 (1C).
[HR-EI]: m / z calcd for C ₁₇ H ₂₁ ClN ₂ O ₃ [M] ⁺ 336.1241: found 336.1233.

6S-（N-n-ペンチルカルバモイル）-3S-クロロ-9-（N-メトキシカルボニル）アザビシクロ[3.3.1]ノナン
収率71％
無色油状物
[α]_D ¹⁹ = ＋43.2 (c 1.00, CHCl₃)
IR ν = 3311, 2954, 2927, 1683, 1647 cm^-1
1H NMR (300MHz, CDCl₃) δ = 5.73-5.49 (m, 1H), 4.86-4.74 (m, 1H) 4.45-4.32 (m, 2H), 3.73-3.71 (m, 3H), 3.31-3.19 (m, 2H), 2.60-2.39 (m, 2H), 2.25-1.25 (m, 12H), 0.90 (t, J = 6.6 Hz, 3H).
¹³C-NMR (400MHz, CDCl₃) δ 171.7, 154.7, 53.2〜52.7 (2C), 50.1 及び50.0 (1C), 47.7 及び 47.0 (1C), 45.8 及び 45.2 (1C), 40.8 及び 40.4 (1C), 39.4, 37.5 及び 37.2 (1C), 29.0〜28.9 (2C), 27.9 及び 27.6 (1C), 23.1〜22.1 (2C), 13.8.
[HR-EI]: m/z calcd for C₁₆H₂₇ClN₂O₃ [M]⁺ 330.1710 : found 330.1711.

6S- (Nn-pentylcarbamoyl) -3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane yield 71%
Colorless oil
[α] _D ¹⁹ = +43.2 (c 1.00, CHCl ₃ )
IR ν = 3311, 2954, 2927, 1683, 1647 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 5.73-5.49 (m, 1H), 4.86-4.74 (m, 1H) 4.45-4.32 (m, 2H), 3.73-3.71 (m, 3H), 3.31-3.19 ( m, 2H), 2.60-2.39 (m, 2H), 2.25-1.25 (m, 12H), 0.90 (t, J = 6.6 Hz, 3H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 171.7, 154.7, 53.2-52.7 (2C), 50.1 and 50.0 (1C), 47.7 and 47.0 (1C), 45.8 and 45.2 (1C), 40.8 and 40.4 (1C), 39.4, 37.5 and 37.2 (1C), 29.0 to 28.9 (2C), 27.9 and 27.6 (1C), 23.1 to 22.1 (2C), 13.8.
[HR-EI]: m / z calcd for C ₁₆ H ₂₇ ClN ₂ O ₃ [M] ⁺ 330.1710: found 330.1711.

6-トリクロロアセチル-3-クロロ-8-（N-メトキシカルボニル）アザビシクロ[3.2.1]オクタン
収率45％
黄色油状物
IR ν = 2954, 1745, 1701 cm^-1
1H NMR (300MHz, CDCl₃) δ = 4.92-4.83 (m, 1H), 4.66-4.43 (m, 2H), 4.02-3.94 (m, 1H), 3.75 (s, 3H), 2.50-2.40 (m, 1H), 2.32-2.25 (m, 1H), 2.23-2.05 (m, 4H).
¹³C-NMR (400MHz, CDCl₃) δ 189.4, 153.3, 96.1, 58.8, 53.4, 52.7, 50.0, 46.0〜45.6 (1C), 41.6〜41.1 (1C), 38.3〜38.0 (1C), 33.8〜33.3 (1C).
[HR-EI]: m/z calcd for C₁₁H₁₃Cl₄NO₃ [M]⁺ 346.9650 : found 346.9617.

6-Trichloroacetyl-3-chloro-8- (N-methoxycarbonyl) azabicyclo [3.2.1] octane yield 45%
Yellow oil
IR ν = 2954, 1745, 1701 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 4.92-4.83 (m, 1H), 4.66-4.43 (m, 2H), 4.02-3.94 (m, 1H), 3.75 (s, 3H), 2.50-2.40 (m , 1H), 2.32-2.25 (m, 1H), 2.23-2.05 (m, 4H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 189.4, 153.3, 96.1, 58.8, 53.4, 52.7, 50.0, 46.0 to 45.6 (1C), 41.6 to 41.1 (1C), 38.3 to 38.0 (1C), 33.8 to 33.3 ( 1C).
[HR-EI]: m / z calcd for C ₁₁ H ₁₃ Cl ₄ NO ₃ [M] ⁺ 346.9650: found 346.9617.

Conversion of azabicyclotrichloroacetyl form to amide
Synthesis of 6S- (N-benzylcarbamoyl) -3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane
(6S) -Trichloroacetyl- (3S) -chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane (1 mmol; 361 mg) was dissolved in CH ₃ CN (3 ml). BnNH ₂ (1.5 mmol; 0.163 ml) and NEt ₃ (2 mmol; 0.279 ml) were added thereto, and the mixture was stirred at room temperature for 6 hours. CH ₃ CN was distilled off under reduced pressure, 3% aqueous HCl (10 ml) was added, and the mixture was extracted with CHCl ₃ (3 × 10 ml). The collected organic layer was dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give 6S- (N-benzylcarbamoyl) -3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1]. Nonane was obtained quantitatively.

3S-クロロ-9-(N-メトキシカルボニル)アザビシクロ[3.3.1]ノナン-6S-カルボン酸
白色シロップ
[α]_D ¹⁹ = ＋33.4 (c 1.00, CHCl₃)
IR ν = 2956, 1730, 1697 cm^-1
1H NMR (300MHz, CDCl₃) δ = 11.13 (br s, 1H), 4.77-4.67 (m, 2H), 4.48-4.36 (m, 1H) 3.76-3.72 (m, 3H), 2.91-2.82 (m, 1H), 2.44-2.37 (m, 1H), 2.26-2.19 (m, 1H), 2.11-1.80 (m, 6H).
¹³C-NMR (400MHz, CDCl₃) δ 177.3, 154.7, 53.0, 49.0 及び 48.5 (1C), 47.5 及び 47.0 (1C), 44.0 及び43.5 (1C), 40.7 及び 40.4 (1C), 37.4 及び 37.1 (1C), 27.9 及び 27.5 (1C), 22.6.
[HR-EI]: m/z calcd for C₁₁H₁₆ClNO₄ [M]⁺ 261.0768 : found 261.0760.Hydrolysis of trichloroacetyl group
Synthesis of 3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane-6S-carboxylic acid
1M NaOH aqueous solution (2 ml) was added to (6S)-(trichloroacetyl)-(3S) -chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane (1 mmol; 361 mg). After stirring for 6 hours, the aqueous layer was washed with Et ₂ O (5 ml). Thereafter, the solution was acidified with 3% aqueous HCl (pH = 2) and extracted with AcOEt (3 × 5 ml). The collected organic layer was then dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to yield 3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane-6S-carboxylic acid. Obtained at 98%.

3S-Chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane-6S-carboxylic acid white syrup
[α] _D ¹⁹ = +33.4 (c 1.00, CHCl ₃ )
IR ν = 2956, 1730, 1697 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 11.13 (br s, 1H), 4.77-4.67 (m, 2H), 4.48-4.36 (m, 1H) 3.76-3.72 (m, 3H), 2.91-2.82 (m , 1H), 2.44-2.37 (m, 1H), 2.26-2.19 (m, 1H), 2.11-1.80 (m, 6H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 177.3, 154.7, 53.0, 49.0 and 48.5 (1C), 47.5 and 47.0 (1C), 44.0 and 43.5 (1C), 40.7 and 40.4 (1C), 37.4 and 37.1 (1C ), 27.9 and 27.5 (1C), 22.6.
[HR-EI]: m / z calcd for C ₁₁ H ₁₆ ClNO ₄ [M] ⁺ 261.0768: found 261.0760.

6S-(N-1-ナフチルカルバモイル)-3S-クロロ-9-(N-メトキシカルボニル)アザビシクロ[3.3.1]ノナン
白色固体, mp = 51℃
IR ν = 3265, 2953, 1654 cm^-1
1H NMR (400MHz, CDCl₃) δ = 8.61 (s, 1H), 7.94-7.68 (m, 4H), 7.49-7.42 (m, 3H), 4.87-4.37 (m, 3H), 3.75-3.68 (m, 3H), 3.14-1.73 (m, 8H).
¹³C-NMR (400MHz, CDCl₃) δ 175.4, 171.1, 155.0, 134.0, 132.0, 128.5, 127.7, 126.1 (2C), 125.9, 125.5, 121.8, 121.1, 53.1, 52.8, 50.1, 47.8, 45.8, 40.7, 37.4, 27.9, 22.5.
[HR-EI]: m/z calcd for C₂₁H₂₃ClN₂O₃ [M]⁺ 386.1397 : found 386.1392.Amide condensation of azabicyclocarboxylic acid
Synthesis of 6S- (N-1-naphthylcarbamoyl) -3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane
3S-Chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane-6S-carboxylic acid (1.26 mmol; 330 mg) was dissolved in CH ₃ CN, EDC (1.5 mmol; 290 mg), HOBt (1.5 mmol; 205 mg), NEt ₃ (1.89 mmol; 0.264 ml), 1-naphthylamine (2.52 mmol; 361 mg) were added. After stirring at room temperature for 24 hours, CH ₃ CN was concentrated under reduced pressure and dissolved in AcOEt (50 ml). The organic layer collected after washing with 3% aqueous HCl (20 ml), saturated aqueous NaHCO ₃ (20 ml), H ₂ O (10 ml) and saturated brine (10 ml) was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 6S- (N-1-naphthylcarbamoyl) -3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane in a yield of 31%.

6S- (N-1-naphthylcarbamoyl) -3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane white solid, mp = 51 ° C
IR ν = 3265, 2953, 1654 cm ^-1
1 H NMR (400MHz, CDCl ₃ ) δ = 8.61 (s, 1H), 7.94-7.68 (m, 4H), 7.49-7.42 (m, 3H), 4.87-4.37 (m, 3H), 3.75-3.68 (m , 3H), 3.14-1.73 (m, 8H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 175.4, 171.1, 155.0, 134.0, 132.0, 128.5, 127.7, 126.1 (2C), 125.9, 125.5, 121.8, 121.1, 53.1, 52.8, 50.1, 47.8, 45.8, 40.7, 37.4, 27.9, 22.5.
[HR-EI]: m / z calcd for C ₂₁ H ₂₃ ClN ₂ O ₃ [M] ⁺ 386.1397: found 386.1392.

無色油状物
IR ν = 3414, 2939, 2873, 1674, 1454 cm^-1
1H NMR (300MHz, CDCl₃) δ = 4.60-4.56 (m, 1H), 4.46-4.35 (m, 2H) 3.72(s, 3H), 3.63-3.45 (m, 2H), 2.43-1.29 (m, 9H).
¹³C-NMR (400MHz, CDCl₃) δ 154.7, 64.8, 64.7, 53.9〜49.3 (1C), 49.0〜47.2 (1C), 41.4〜40.6 (1C), 36.6 及び 36.3 (1C), 28.5 及び 28.1 (1C), 25.2, 24.1, 21.8.
[HR-EI]: m/z calcd for C₁₁H₁₈ClNO₃ [M]⁺ 247.0975 : found 247.0975.Ester reduction
Synthesis of 6S-hydroxymethyl-3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane
6S- (methoxycarbonyl) -3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane (1.13 mmol; 0.312 g) was dissolved in toluene (5 mL) and the solution was heated to -40 ° C. Cooled down. Thereto was added dropwise 1M DIBAL-H (3.3 mmol) in toluene over 10 minutes, and then the mixture was stirred for 12 hours while naturally heating. After the reaction, 3% HCl aq. (10 mL) was added, and the mixture was extracted with CHCl ₃ (10 mL × 3). The organic layer was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-Hexane: AcOEt = 2: 1) to give 6S-hydroxymethyl-3S-chloro-9- (N-methoxycarbonyl) azabicyclo. [3.3.1] Nonane was obtained in 87% yield.

Colorless oil
IR ν = 3414, 2939, 2873, 1674, 1454 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 4.60-4.56 (m, 1H), 4.46-4.35 (m, 2H) 3.72 (s, 3H), 3.63-3.45 (m, 2H), 2.43-1.29 (m, 9H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 154.7, 64.8, 64.7, 53.9-49.3 (1C), 49.0-47.2 (1C), 41.4-40.6 (1C), 36.6 and 36.3 (1C), 28.5 and 28.1 (1C ), 25.2, 24.1, 21.8.
[HR-EI]: m / z calcd for C ₁₁ H ₁₈ ClNO ₃ [M] ⁺ 247.0975: found 247.0975.

黄色油状物
IR ν = 3329, 2931, 1726 cm^-1
1H NMR (300MHz, CDCl₃) δ = 4.92-4.79 (m, 1H), 3.89-3.82 (m, 1H), 3.59 (s, 1H), 3.34 (s, 1H), 2.45-1.81 (m, 9H).
¹³C-NMR (400MHz, CDCl₃) δ 190.1, 96.6, 53.7, 51.6, 47.6, 46.6, 42.2, 38.7, 28.9, 26.4。
[HR-FAB(+)]: m/z calcd for C₁₀H₁₄Cl₄NO [M+H]⁺ 303.9752 : found 303.9753.Derivation to NO radical 1) Deprotection of N-methoxycarbonyl group
Synthesis of 6S-trichloroacetyl-3S-chloro-9-azabicyclo [3.3.1] nonane 6S-trichloroacetyl-3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane (0.68) under nitrogen atmosphere mmol; 0.206 g) in dichloromethane (2 mL) was added iodotrimethylsilane (2.04 mmol; 0.290 mL) and stirred at room temperature for 12 hours. After the reaction, saturated aqueous sodium hydrogen carbonate (10 mL) and saturated aqueous sodium thiosulfate solution (10 mL) were added, and the mixture was extracted with chloroform (10 mL × 3). The organic layer was dried and concentrated under reduced pressure to obtain 6S-trichloroacetyl-3S-chloro-9-azabicyclo [3.3.1] nonane.

Yellow oil
IR ν = 3329, 2931, 1726 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 4.92-4.79 (m, 1H), 3.89-3.82 (m, 1H), 3.59 (s, 1H), 3.34 (s, 1H), 2.45-1.81 (m, 9H ).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 190.1, 96.6, 53.7, 51.6, 47.6, 46.6, 42.2, 38.7, 28.9, 26.4.
[HR-FAB (+)]: m / z calcd for C ₁₀ H ₁₄ Cl ₄ NO [M + H] ⁺ 303.9752: found 303.9753.

  The following compounds were produced by the same method as described above except that the azabicyclo compounds shown in the center row of the chemical reaction formula VI were used as raw materials.

6S-メトキシカルボニル-3S-クロロ-9-アザビシクロ[3.3.1]ノナン
無色油状物
IR ν = 2927, 2852, 1724 cm^-1
1H NMR (300MHz, CDCl₃) δ = 4.68-4.56 (m, 1H), 3.64 (s, 3H), 3.51-3.48 (t, J = 3.6, 1H), 3.22 (brs, 1H), 2.84-2.77 (m, 1H), 2.24-2.16 (m, 2H), 2.04-1.68 (m, 6H).
¹³C-NMR (400MHz, CDCl₃) δ 173.7, 54.3, 51.7, 50.2, 47.9, 45.1, 42.4, 39.1, 28.9, 22.9.
[HR-EI]: m/z calcd for C₁₀H₁₆ClNO₂ [M]⁺ 217.0870 : found 217.0865.

6S-methoxycarbonyl-3S-chloro-9-azabicyclo [3.3.1] nonane colorless oil
IR ν = 2927, 2852, 1724 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 4.68-4.56 (m, 1H), 3.64 (s, 3H), 3.51-3.48 (t, J = 3.6, 1H), 3.22 (brs, 1H), 2.84-2.77 (m, 1H), 2.24-2.16 (m, 2H), 2.04-1.68 (m, 6H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 173.7, 54.3, 51.7, 50.2, 47.9, 45.1, 42.4, 39.1, 28.9, 22.9.
[HR-EI]: m / z calcd for C ₁₀ H ₁₆ ClNO ₂ [M] ⁺ 217.0870: found 217.0865.

6S-（N-ベンジルカルバモイル）-3S-クロロ-9-アザビシクロ[3.3.1]ノナン
黄色固体, mp = 54-58 ℃
IR ν = 3284, 2924, 1708, 1647 cm^-1
1H NMR (300MHz, CDCl₃) δ = 7.38-7.24 (m, 5H), 5.89-5.80 (m, 1H), 4.83-4.71 (m, 1H), 4.51-4.38 (m, 2H), 3.48-3.29 (m, 2H), 2.76-1.47 (m, 8H).
¹³C-NMR (400MHz, CDCl₃) δ 172.7, 138.6, 128.4 (2C), 127.2〜127.0 (3C), 53.9, 51.0, 47.9, 46.1, 43.1, 38.6, 28.5, 22.7, 1.8.
[HR-EI]: m/z calcd for C₁₆H₂₁ClN₂O [M]⁺ 292.1342 : found 292.1353.

6S- (N-benzylcarbamoyl) -3S-chloro-9-azabicyclo [3.3.1] nonane yellow solid, mp = 54-58 ° C
IR ν = 3284, 2924, 1708, 1647 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 7.38-7.24 (m, 5H), 5.89-5.80 (m, 1H), 4.83-4.71 (m, 1H), 4.51-4.38 (m, 2H), 3.48-3.29 (m, 2H), 2.76-1.47 (m, 8H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 172.7, 138.6, 128.4 (2C), 127.2-127.0 (3C), 53.9, 51.0, 47.9, 46.1, 43.1, 38.6, 28.5, 22.7, 1.8.
[HR-EI]: m / z calcd for C ₁₆ H ₂₁ ClN ₂ O [M] ⁺ 292.1342: found 292.1353.

6S-（N-フェニルカルバモイル）-3S-クロロ-9-アザビシクロ[3.3.1]ノナン
白色固体、mp = 84〜87℃
IR ν = 3255, 2926, 2360, 1662 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.61-8.53 (m, 1H), 7.57 (d, J = 8.1 Hz 2H), 7.30-7.25 (m, 2H), 7.10-7.06 (m, 1H), 5.98-5.86 (m, 1H), 4.83-4.71 (m, 1H), 3.90 (s, 1H), 3.48 (s, 1H), 3.23-3.19 (m, 1H), 2.56-2.52 (m, 1H), 2.28-1.83 (m, 7H).
¹³C-NMR (400MHz, CDCl₃) δ 170.3, 137.6, 129.0 (2C), 124.6, 120.2 (2C), 52.0, 50.7, 48.1, 45.7, 40.7, 37.4, 27.5, 22.1.
[HR-EI]: m/z calcd for C₁₅H₁₉ClN₂O [M]⁺ 278.1186 : found 278.1160.

6S- (N-phenylcarbamoyl) -3S-chloro-9-azabicyclo [3.3.1] nonane white solid, mp = 84-87 ° C.
IR ν = 3255, 2926, 2360, 1662 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.61-8.53 (m, 1H), 7.57 (d, J = 8.1 Hz 2H), 7.30-7.25 (m, 2H), 7.10-7.06 (m, 1H), 5.98 -5.86 (m, 1H), 4.83-4.71 (m, 1H), 3.90 (s, 1H), 3.48 (s, 1H), 3.23-3.19 (m, 1H), 2.56-2.52 (m, 1H), 2.28 -1.83 (m, 7H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 170.3, 137.6, 129.0 (2C), 124.6, 120.2 (2C), 52.0, 50.7, 48.1, 45.7, 40.7, 37.4, 27.5, 22.1.
[HR-EI]: m / z calcd for C ₁₅ H ₁₉ ClN ₂ O [M] ⁺ 278.1186: found 278.1160.

6S-（N-n-ペンチルカルバモイル）-3S-クロロ-9-アザビシクロ[3.3.1]ノナン
黄色油状物
IR ν = 3277, 2953, 2927, 2362, 1641 cm^-1
1H NMR (300MHz, CDCl₃) δ = 6.11, 5.91 (2t, J = 5.4 Hz, 1H), 4.78-4.66 (m, 1H), 3.36-3.09 (m, 4H), 2.69-2.61 (m, 1H), 2.47-1.19 (m, 14H), 0.83 (t, J = 6.9 Hz, 3H).
¹³C-NMR (300MHz, CDCl₃) δ 172.7, 54.2, 51.2, 48.0, 46.6, 42.3, 39.3, 39.0, 29.1, 28.9, 22.9, 22.1, 13.7.
[HR-EI]: m/z calcd for C₁₄H₂₅ClN₂O [M]⁺ 272.1656 : found 272.1644.

6S- (Nn-pentylcarbamoyl) -3S-chloro-9-azabicyclo [3.3.1] nonane yellow oil
IR ν = 3277, 2953, 2927, 2362, 1641 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 6.11, 5.91 (2t, J = 5.4 Hz, 1H), 4.78-4.66 (m, 1H), 3.36-3.09 (m, 4H), 2.69-2.61 (m, 1H ), 2.47-1.19 (m, 14H), 0.83 (t, J = 6.9 Hz, 3H).
¹³ C-NMR (300 MHz, CDCl ₃ ) δ 172.7, 54.2, 51.2, 48.0, 46.6, 42.3, 39.3, 39.0, 29.1, 28.9, 22.9, 22.1, 13.7.
[HR-EI]: m / z calcd for C ₁₄ H ₂₅ ClN ₂ O [M] ⁺ 272.1656: found 272.1644.

6-（トリクロロアセチル）-3-クロロ-8-アザビシクロ[3.2.1] オクタン
黄色固体, mp = 50-54℃
IR ν = 2954, 2929, 1735 cm^-1
1H NMR (300MHz, CDCl₃) δ = 4.30-4.03 (m, 1H), 3.78-3.67 (m, 3H), 2.50-1.99 (m, 7H).
¹³C-NMR (400MHz, CDCl₃) δ 194.0, 63.7, 56.9, 51.7, 47.2, 42.4, 42.0, 38.1.
[HR-EI]: m/z calcd for C₉H₁₁Cl₄NO [M+H]⁺ 288.9594 : found 288.9597.

6- (Trichloroacetyl) -3-chloro-8-azabicyclo [3.2.1] octane yellow solid, mp = 50-54 ° C
IR ν = 2954, 2929, 1735 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 4.30-4.03 (m, 1H), 3.78-3.67 (m, 3H), 2.50-1.99 (m, 7H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 194.0, 63.7, 56.9, 51.7, 47.2, 42.4, 42.0, 38.1.
[HR-EI]: m / z calcd for C ₉ H ₁₁ Cl ₄ NO [M + H] ⁺ 288.9594: found 288.9597.

6S-ヒドロキシメチル-3S-クロロ-9-アザビシクロ[3.3.1]ノナン
定量的に得られた
黄色油状物
IR ν = 2922, 2358, 2343 cm^-1
1H NMR (300MHz, CDCl₃) δ = 5.14-5.07 (m, 1H), 4.64-4.52 (m, 1H), 3.60-3.30 (m, 4H), 2.65-1.26 (m, 9H). ¹³C-NMR (400MHz, CDCl₃) δ 65.3, 57.1, 50.0, 48.7, 42.6, 41.6, 38.0, 29.2, 24.4.
[HR-EI]: m/z calcd for C₉H₁₆ClNO [M]⁺ 189.0920 : found 189.0904The following compounds were prepared in the same manner as described above except that 6S-hydroxymethyl-3S-chloro-9- (N-methoxycarbonyl) azabicyclo [3.3.1] nonane was used as a raw material.

6S-hydroxymethyl-3S-chloro-9-azabicyclo [3.3.1] nonane quantitatively obtained yellow oil
IR ν = 2922, 2358, 2343 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 5.14-5.07 (m, 1H), 4.64-4.52 (m, 1H), 3.60-3.30 (m, 4H), 2.65-1.26 (m, 9H). ¹³ C- NMR (400MHz, CDCl ₃ ) δ 65.3, 57.1, 50.0, 48.7, 42.6, 41.6, 38.0, 29.2, 24.4.
[HR-EI]: m / z calcd for C ₉ H ₁₆ ClNO [M] ⁺ 189.0920: found 189.0904

収率90％
赤色油状物
[α]_D ²³ = −20.4 (c 1.00, CHCl₃)
IR ν = 2927, 2854, 1739, 1697 cm^-1
[HR-FAB(+)]: m/z calcd for C₁₀H₁₃Cl₄NO₂ [M+H]⁺ 318.9622 : found 318.9595.2) Conversion reaction to N-oxyl
Synthesis of 6S-trichloroacetyl-3S-chloro-9-azabicyclo [3.3.1] nonane N-oxyl
To a solution of 6S-trichloroacetyl-3S-chloro-9-azabicyclo [3.3.1] nonane (0.63 mmol; 191 mg) in dichloromethane (2 mL) was added metachloroperbenzoic acid (0.75 mmol; 187 mg) and stirred for 1 hour. After the reaction, saturated aqueous sodium hydrogen carbonate (5 mL) was added, and the mixture was extracted with CHCl ₃ (10 mL × 3). The organic layer was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 6S- (trichloroacetyl) -3S-chloro-9-azabicyclo [3.3.1] nonane N-oxyl.

Yield 90%
Red oil
[α] _D ²³ = −20.4 (c 1.00, CHCl ₃ )
IR ν = 2927, 2854, 1739, 1697 cm ^-1
[HR-FAB (+)]: m / z calcd for C ₁₀ H ₁₃ Cl ₄ NO ₂ [M + H] ⁺ 318.9622: found 318.9595.

  1) The following compound was produced by the same method as above except that the deprotected product obtained in the deprotection reaction of N-methoxycarbonyl group was used as a raw material.

6S-メトキシカルボニル-3S-クロロ-9-アザビシクロ[3.3.1]ノナンN-オキシル
収率71％
黄色固体, mp = 95-99℃
[α]_D ²³ = −74.0 (c 1.00, CHCl₃)
IR ν = 2951, 1732 cm^-1
[HR-EI]: m/z calcd for C₁₀H₁₅ClNO₃ [M]⁺ 232.0741 : found 232.0729.

6S-methoxycarbonyl-3S-chloro-9-azabicyclo [3.3.1] nonane N-oxyl yield 71%
Yellow solid, mp = 95-99 ℃
[α] _D ²³ = −74.0 (c 1.00, CHCl ₃ )
IR ν = 2951, 1732 cm ^-1
[HR-EI]: m / z calcd for C ₁₀ H ₁₅ ClNO ₃ [M] ⁺ 232.0741: found 232.0729.

6S-(N-フェニルカルバモイル)-3S-クロロ-9-アザビシクロ[3.3.1]ノナン N-オキシル
収率62％
赤色固体, 68-71 ℃
[α]_D ²³ = −3.3 (c 1.00, CHCl₃)
IR ν = 3311, 2949, 2360, 1739, 1683 cm^-1
[HR-EI]: m/z calcd for C₁₅H₁₈ClN₂O₂ [M]⁺ 293.1057 : found 293.1071.

6S- (N-phenylcarbamoyl) -3S-chloro-9-azabicyclo [3.3.1] nonane N-oxyl yield 62%
Red solid, 68-71 ° C
[α] _D ²³ = −3.3 (c 1.00, CHCl ₃ )
IR ν = 3311, 2949, 2360, 1739, 1683 cm ^-1
[HR-EI]: m / z calcd for C ₁₅ H ₁₈ ClN ₂ O ₂ [M] ⁺ 293.1057: found 293.1071.

6S-（N-n-ペンチルカルバモイル）-3S-クロロ-9-アザビシクロ[3.3.1]ノナンN-オキシル
収率75％
赤色油状物
[α]_D ²³ = −2.4 (c 1.00, CHCl₃)
IR ν = 3298, 2953, 2929, 2858, 1643, 1541 cm^-1
[HR-EI]: m/z calcd for C₁₄H₂₄ClN₂O₂ [M]⁺ 287.1526 : found 287.1531.

6S- (Nn-pentylcarbamoyl) -3S-chloro-9-azabicyclo [3.3.1] nonane N-oxyl yield 75%
Red oil
[α] _D ²³ = −2.4 (c 1.00, CHCl ₃ )
IR ν = 3298, 2953, 2929, 2858, 1643, 1541 cm ^-1
[HR-EI]: m / z calcd for C ₁₄ H ₂₄ ClN ₂ O ₂ [M] ⁺ 287.1526: found 287.1531.

6S-（N-ベンジルカルバモイル）-3S-クロロ-9-アザビシクロ[3.3.1]ノナンN-オキシル
収率79％
赤色油状物
[α]_D ²³ = −23.6 (c 1.00, CHCl₃)
IR ν = 3288, 2926, 2854, 1647, 1533 cm^-1
[HR-EI]: m/z calcd for C₁₆H₂₀ClN₂O₃ [M]⁺ 307.1213 : found 307.1191.

6S- (N-benzylcarbamoyl) -3S-chloro-9-azabicyclo [3.3.1] nonane N-oxyl yield 79%
Red oil
[α] _D ²³ = −23.6 (c 1.00, CHCl ₃ )
IR ν = 3288, 2926, 2854, 1647, 1533 cm ^-1
[HR-EI]: m / z calcd for C ₁₆ H ₂₀ ClN ₂ O ₃ [M] ⁺ 307.1213: found 307.1191.

6-（トリクロロアセチル）-3-クロロ-8-アザビシクロ[3.2.1] オクタン N-オキシル
収率79％
赤色固体, mp = 45℃
IR ν = 2958, 2935, 1747, 1710 cm^-1
[HR-FAB(+)]: m/z calcd for C₉H₁₀Cl₄NO₂ [M+H]⁺ 303.9466 : found 303.9499.

6- (Trichloroacetyl) -3-chloro-8-azabicyclo [3.2.1] octane N-oxyl yield 79%
Red solid, mp = 45 ℃
IR ν = 2958, 2935, 1747, 1710 cm ^-1
[HR-FAB (+)]: m / z calcd for C ₉ H ₁₀ Cl ₄ NO ₂ [M + H] ⁺ 303.9466: found 303.9499.

Introduction of trifluoroacetyl group into cyclic amine skeleton
Synthesis of Nt-butoxycarbonyl-2,3-didehydro-3-trifluoroacetylpiperidine
Nt-butoxycarbonyl-2-methoxypiperidine (1 mmol) was dissolved in THF (5 ml). Trifluoroacetic anhydride (2.2 mmol) was added, stirred at room temperature for 6 hours, saturated aqueous NaHCO ₃ (10 ml) was added, and the mixture was extracted with Et ₂ O (3 × 10 mL). Thereafter, the collected organic layer was dried over anhydrous MgSO ₄ and filtered, and the filtrate was distilled off under reduced pressure. The obtained compound was purified by silica gel column chromatography (n-Hexane: AcOEt = 10: 1) to quantitatively obtain Nt-butoxycarbonyl-2,3-didehydro-3-trifluoroacetylpiperidine.

N-t-ブトキシカルボニル-2,3-ジデヒドロ-3-トリフルオロアセチルピペリジン
黄色油状物
IR ν = 2980, 1728, 1676 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.76 (s, 1H), 3.62 (t, J = 4.8 Hz, 2H), 2.45 (t, J = 4.8 Hz, 2H), 1.94-1.88 (m, 2H), 1.54 (s, 9H).
¹³C-NMR (400MHz, CDCl₃) δ 178.3, 142.3, 118.4, 115.5, 110.9, 83.8, 42.5, 27.7(3C), 19.9, 19.4.
[HR-EI]: m/z calcd for C₁₂H₁₆F₃NO₃ [M]⁺ 279.1082 : found 279.1083.

Nt-butoxycarbonyl-2,3-didehydro-3-trifluoroacetylpiperidine yellow oil
IR ν = 2980, 1728, 1676 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.76 (s, 1H), 3.62 (t, J = 4.8 Hz, 2H), 2.45 (t, J = 4.8 Hz, 2H), 1.94-1.88 (m, 2H) , 1.54 (s, 9H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 178.3, 142.3, 118.4, 115.5, 110.9, 83.8, 42.5, 27.7 (3C), 19.9, 19.4.
[HR-EI]: m / z calcd for C ₁₂ H ₁₆ F ₃ NO ₃ [M] ⁺ 279.1082: found 279.1083.

  The following compounds were produced in the same manner as described above except that the protecting group of the raw material compound was replaced with an N-methoxycarbonyl group.

N-メトキシカルボニル-2,3-ジデヒドロ-3-トリフルオロアセチルピペリジン
定量的に得られた
無色油状物
IR ν = 2960, 1735, 1680 cm^-1
1H NMR (300MHz, CDCl₃) δ = 8.30 (s, 1H), 3.91 (s, 3H), 3.71 (t, J = 4.2 Hz, 2H), 2.38 (t, J = 4.6 Hz, 2H), 1.95-1.89 (m, 2H).
¹³C-NMR (400MHz, CDCl₃) δ 178.7, 153.3, 142.2, 118.3, 115.4, 111.7, 54.1, 42.7, 19.7, 19.3.
[HR-EI]: m/z calcd for C₉H₁₀F₃NO₃ [M]⁺ 237.0613 : found 237.0597.

N-methoxycarbonyl-2,3-didehydro-3-trifluoroacetylpiperidine quantitatively obtained colorless oil
IR ν = 2960, 1735, 1680 cm ^-1
1 H NMR (300MHz, CDCl ₃ ) δ = 8.30 (s, 1H), 3.91 (s, 3H), 3.71 (t, J = 4.2 Hz, 2H), 2.38 (t, J = 4.6 Hz, 2H), 1.95 -1.89 (m, 2H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ 178.7, 153.3, 142.2, 118.3, 115.4, 111.7, 54.1, 42.7, 19.7, 19.3.
[HR-EI]: m / z calcd for C ₉ H ₁₀ F ₃ NO ₃ [M] ⁺ 237.0613: found 237.0597.

  According to the present invention, a nitrogen-containing heterocycle having a carbonyl derivative introduced at the β-position can be efficiently and economically produced by an easy operation using a specific compound. Furthermore, these nitrogen-containing heterocycles are useful as synthetic intermediates for various compounds such as pharmaceuticals, agricultural chemicals, and redox catalysts.

Claims (16)

Formula (II)

(Wherein R ₁ represents an amino-protecting group, R ₂ , R ₃ , and R ₄ each represent H, OH, an optionally substituted alkenyl group, or an alkoxy group, and R ₅ represents OH means an alkylcarbonyloxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. A carbonyl derivative represented by the general formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , and X are as defined above, and R _{5 ′} is H)
The manufacturing method of the compound represented by these, or its salt. A: General formula (II)

(Wherein R ₁ represents an amino-protecting group, R ₂ represents an optionally substituted alkenyl group, and R ₃ and R ₄ each represent H, OH, or an optionally substituted alkenyl group. Or an alkoxy group, and R ₅ represents OH, an alkylcarbonyloxy group, or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. Introducing a carbonyl derivative represented by
Formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , and X are as defined above, and R _{5 ′} is H)
A compound represented by the formula:
B-1: In the presence of a base, the compound represented by the general formula (I) or a salt thereof and an alcohol are reacted with each other to esterify the compound represented by the general formula (I) or a salt thereof. Formula (V)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R _{5 ′} are as defined above, and Y is an alkyl group, an aralkyl group, or an aryl group)
B-2: A compound represented by the general formula (I) or a salt thereof, and an amine compound are reacted to represent the compound represented by the general formula (I). Or a salt thereof may be amidated to give a general formula (VI)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R _{5 ′} are as defined above, and are R ₆ and R ₇ each an H, an aryl group, an aralkyl group, or an alkyl group? , Or both combine to form a ring structure with the nitrogen atom)
A compound represented by the formula:
C: The compound represented by the above general formula (I), (V) or (VI) or a salt thereof and an acid are reacted with each other to represent the above general formula (I), (V) or (VI). A compound of the formula (VII)

(In the formula, R ₁ is an amino-protecting group, A is a halogen atom, OH or formyloxy group, and W is X, OY or NR ₆ R ₇ )
Or a compound represented by the general formula (VII), an enantiomer thereof, a mixture thereof or a salt thereof. General formula (VIII) characterized in that it comprises removing the protecting group of the amino group and oxidizing the resulting compound

(In the formula, A is a halogen atom, OH or formyloxy group, W is X, O—Y or NR ₆ R ₇ , and • represents a free radical)
Or a enantiomer thereof, a mixture thereof or a salt thereof. The method according to claim 1 or 2 wherein the organic group substituted with halogen is chloro or fluoro _(C 1 -C ₆₎ alkyl or chloro and fluoro _(C 1 -C ₆₎ alkyl.   The production method according to claim 1, wherein the reactive derivative is an acid halide, an active ester, or an acid anhydride.   The production according to any one of claims 2 to 4, comprising reacting the compound represented by the general formula (VII) or a salt thereof with a base to hydrolyze the trichloroalkyl group in the general formula (VII). Method.   The manufacturing method in any one of Claims 2-4 including reducing the ester group in general formula (VII) by making the compound or its salt represented with general formula (VII), and a reducing agent react. .   6. A compound obtained by hydrolyzing a trichloroalkyl group or a salt thereof obtained in the course of the production method according to claim 5 is reacted with an amine to amidate a carboxyl group of the compound. The manufacturing method as described. Formula (IV)

(Wherein R ₁ represents an amino-protecting group, R ₂ and R ₃ each represent H, OH, an alkenyl group which may be substituted, or an alkoxy group; R ₅ represents OH, alkylcarbonyl; (It means an oxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. General formula (III) characterized by introducing a carbonyl derivative represented by the formula (III)

(Wherein R ₁ , R ₂ , R ₃ and X are as defined above, and R _{5 ′} is H)
The manufacturing method of the compound represented by these, or its salt. A ': General formula (IV)

(Wherein R ₁ represents an amino-protecting group, R ₂ represents an optionally substituted alkenyl group, R ₃ represents H, OH, an optionally substituted alkenyl group, or an alkoxy group. And R ₅ represents OH, an alkylcarbonyloxy group or an alkoxy group.)
And XCOOH (X represents an organic group substituted with halogen) or a reactive derivative thereof, and XCO (X is as defined above) at the β position of the compound. Introducing a carbonyl derivative represented by
General formula (III)

(Wherein R ₁ , R ₂ , R ₃ and X are as defined above, and R _{5 ′} is H)
A compound represented by the formula:
B′-1: In the presence of a base, the compound represented by the general formula (III) or a salt thereof is reacted with an alcohol to esterify the compound represented by the general formula (III) or a salt thereof. General formula (IX)

Wherein R ₁ , R ₂ , R ₃ and R _{5 ′} are as defined above, and Y is an alkyl group, an aralkyl group or an aryl group.
B'-2: A compound represented by the general formula (III) or a salt thereof and an amine compound are reacted with each other to obtain a compound represented by the general formula (III). The compound or its salt is amidated to give a general formula (X)

Wherein R ₁ , R ₂ , R ₃ and R _{5 ′} are as defined above, and R ₆ and R ₇ are each H, an aryl group, an aralkyl group, an alkyl group, or both are To form a ring structure with nitrogen atom)
A compound represented by the formula:
C ′: The compound represented by the general formula (III), (IX) or (X) or a salt thereof and an acid are reacted with each other to represent the compound represented by the general formula (III), (IX) or (X). A compound of the formula (XI)

(In the formula, R ₁ is an amino-protecting group, A is a halogen atom, OH or formyloxy group, and W is X, OY or NR ₆ R ₇ )
And a compound represented by the formula (XI), an enantiomer thereof, a mixture thereof, or a salt thereof. General formula (XII) characterized in that it comprises removing the protecting group of the amino group and oxidizing the resulting compound

(In the formula, A is a halogen atom, OH or formyloxy group, W is X, O—Y or NR ₆ R ₇ , and • represents a free radical)
Or a enantiomer thereof, a mixture thereof or a salt thereof. Method of manufacturing an organic group substituted with a halogen is chloro or fluoro _(C 1 -C ₆₎ alkyl or chloro and fluoro _(C 1 -C ₆₎ according to claim 8 or 9 wherein the alkyl.   The method according to any one of claims 8 to 10, wherein the reactive derivative is an acid halide, an active ester, or an acid anhydride.   The production according to any one of claims 9 to 11, comprising hydrolyzing a trichloroalkyl group in the general formula (XI) by reacting the compound represented by the general formula (XI) or a salt thereof with a base. Method.   The manufacturing method in any one of Claims 9-11 including reducing the ester group in general formula (XI) by making the compound or its salt represented with general formula (XI), and a reducing agent react. .   13. A compound obtained by hydrolyzing a trichloroalkyl group or a salt thereof obtained in the course of the production method according to claim 12 is reacted with an amine to amidate a carboxyl group of the compound. The manufacturing method as described. A compound represented by the general formula (I), (III), (V), (VI), (VII), (VIII), (XI) or (XII) selected from the group consisting of the following compounds: Its salt.

  16. The compound represented by the general formula (I), (III), (V), (VI), (VII), (VIII), (XI) or (XII) according to claim 15, or an enantiomer thereof, or them Or a salt thereof as a redox catalyst or intermediate for the preparation of a medicament having a β-amino acid structure.