JPH06312989A - Production of (1rs, 2rs, 4rs)-2-(6-chloro-3-pyridyl)-7-azabicyclo(2.2.1)heptane - Google Patents

Production of (1rs, 2rs, 4rs)-2-(6-chloro-3-pyridyl)-7-azabicyclo(2.2.1)heptane

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Publication number
JPH06312989A
JPH06312989A JP5128161A JP12816193A JPH06312989A JP H06312989 A JPH06312989 A JP H06312989A JP 5128161 A JP5128161 A JP 5128161A JP 12816193 A JP12816193 A JP 12816193A JP H06312989 A JPH06312989 A JP H06312989A
Authority
JP
Japan
Prior art keywords
group
carbon atoms
pyridyl
alkyl group
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
JP5128161A
Other languages
Japanese (ja)
Inventor
Masao Yamamoto
雅夫 山本
Kazuhiko Saigo
和彦 西郷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Chemiphar Co Ltd
Original Assignee
Nippon Chemiphar Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Chemiphar Co Ltd filed Critical Nippon Chemiphar Co Ltd
Priority to JP5128161A priority Critical patent/JPH06312989A/en
Publication of JPH06312989A publication Critical patent/JPH06312989A/en
Withdrawn legal-status Critical Current

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Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

PURPOSE:To obtain a new intermediate compound, composed of (1RS, 2RS, 4RS)-4-amino-2-(3-pyridyl)-1-cyclohexanols and derivatives thereof and useful as a synthetic intermediate, etc., for epibatidine useful as an analgesic agent. CONSTITUTION:3-Bromo-6-methoxypyridine is treated with t-butyl-lithium in dry THF at -78 deg.C and the resultant compound then reacts with 4-acetoxy-2- cyclohexenone in the presence of copper iodide and boron trifluoride-diethyl ether to provide a cvclohexanone derivative of formula 1 (R<1> is 1-4C alkyl or benzyl; R<3> is 1-4C alkyl, 2-5C aliphatic acyl, etc.), which is further treated with sodium cyanoborohydride. The produced amino group is protected to afford a new compound of formula II (Y is protecting group), which is then hydrolyzed to provide a new cyclohexanol compound of formula III. Furthermore, the resultant compound is then sulfonylated to afford a new compound of formula IV, which reacts with phosphorus oxychloride or phosgene to provide the objective intermediate compound of formula V.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は、鎮痛作用を有するエキ
ソ−２−（６−クロロ−３−ピリジル）−７−アザビシ
クロ［２．２．１］ヘプタンの新規な製造方法、及びこ
の製造方法で使用する原料又はこの原料を製造するため
の中間体である新規なピリジン誘導体に関する。FIELD OF THE INVENTION The present invention relates to a novel method for producing exo-2- (6-chloro-3-pyridyl) -7-azabicyclo [2.2.1] heptane having an analgesic action, and this production method. And a novel pyridine derivative which is an intermediate for producing the raw material or the raw material used in 1.

【０００２】[0002]

【従来の技術】従来、種々の鎮痛剤、例えば、モルヒネ
のような強作用麻薬性鎮痛剤、コデインのような弱作用
麻薬性鎮痛剤、ブプレノルフィンのような強作用麻薬拮
抗性鎮痛剤、ペンタゾシンのような弱作用麻薬拮抗性鎮
痛剤が使用されている。麻薬性鎮痛剤は強い鎮痛作用を
有するが、副作用として連用による主に中枢神経抑制作
用（鎮痛、鎮静、鎮咳、呼吸抑制等）に対して耐性を生
じ、更に精神的及び身体的依存性を形成し、投薬中止に
より強い禁断症状が現れるという問題がある。麻薬拮抗
性鎮痛剤についても同様の問題がある。アスピリンのよ
うな非麻薬性鎮痛剤（非オピオイド鎮痛剤）は、消化管
障害、腎障害等の副作用はあるものの、麻薬性鎮痛剤の
作用と比較して軽度であるが、鎮痛効果が弱い。従っ
て、耐性や依存性がなく、モルヒネと同等又はそれ以上
の鎮痛作用を有する鎮痛剤が求められている。2. Description of the Related Art Conventionally, various analgesics, for example, a strong narcotic analgesic such as morphine, a weak narcotic analgesic such as codeine, a strong narcotic analgesic such as buprenorphine, pentazocine Such weak-acting opiate antagonistic analgesics have been used. Narcotic analgesics have a strong analgesic effect, but as a side effect, they develop resistance to the central nervous system depressant effect (analgesia, sedation, antitussive, respiratory depression, etc.) by continuous use, and further form psychological and physical dependence. However, there is a problem that withdrawal of medication causes strong withdrawal symptoms. There are similar problems with narcotic antagonistic analgesics. Although non-narcotic analgesics such as aspirin (non-opioid analgesics) have side effects such as gastrointestinal disorders and renal disorders, they are milder than the actions of narcotic analgesics, but have a weak analgesic effect. Therefore, there is a need for an analgesic drug that has neither tolerance nor dependence and has an analgesic action equivalent to or higher than that of morphine.

【０００３】Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．Ｖｏｌ．１
１４，Ｎｏ．９，１９９２，３４７５〜３４７８頁に
は、エクアドル産のカエル(Epipedobates tricolor) の
皮膚からモルヒネの約２００倍の鎮痛作用を有するアル
カロイド物質が単離され、エピバチジン(epibatidine)
と命名され、この物質の効果はナロキソン(naloxone)に
より拮抗されず、μ受容体との結合がなく、非オピオイ
ド鎮痛剤ではないかと報告されている。上記文献によれ
は、エピバチジンは下記式（Ｅｐ）：J. Am. Chem. Soc. Vol. 1
14, No. 9, 1992, pages 3475 to 3478, an alkaloid substance having an analgesic action about 200 times higher than that of morphine was isolated from the skin of a frog (Epipedobates tricolor) from Ecuador, and epibatidine was isolated.
It is reported that the effect of this substance is not antagonized by naloxone, does not bind to the μ receptor, and is a non-opioid analgesic. According to the above literature, epibatidine is represented by the following formula (Ep):

【０００４】[0004]

【化９】 [Chemical 9]

【０００５】で表されるエキソ−２−（６−クロロ−３
−ピリジル）−７−アザビシクロ［２．２．１］ヘプタ
ンであると記載されている。Exo-2- (6-chloro-3 represented by
-Pyridyl) -7-azabicyclo [2.2.1] heptane.

【０００６】[0006]

【発明が解決しようとする課題】上記文献にはエピバチ
ジンの合成方法については記載されておらず、本発明の
目的は、鎮痛剤として有用なエピバチジンの合成方法を
提供することにある。本発明の他の目的は、エピバチジ
ンの合成の原料として使用する新規な化合物及びこの化
合物を合成するための中間体として有用な新規な化合物
を提供することにある。The above literature does not describe a method for synthesizing epibatidine, and an object of the present invention is to provide a method for synthesizing epibatidine useful as an analgesic. Another object of the present invention is to provide a novel compound used as a raw material for the synthesis of epibatidine and a novel compound useful as an intermediate for synthesizing this compound.

【０００７】[0007]

【課題を解決するための手段】本発明は、下記の一般式
（１）：The present invention provides the following general formula (1):

【０００８】[0008]

【化１０】 [Chemical 10]

【０００９】（式中、Ｒ1 は炭素数１〜４のアルキル基
又はベンジル基を表し、Ｙは保護基を表す）で表される
（１ＲＳ，２ＲＳ，４ＳＲ）−２−（３−ピリジル）−
７−アザビシクロ［２．２．１］ヘプタン誘導体を、オ
キシ塩化燐又はホスゲンと反応させることを特徴とする
（１ＲＳ，２ＲＳ，４ＳＲ）−２−（６−クロロ−３−
ピリジル）−７−アザビシクロ［２．２．１］ヘプタン
の製造方法である。(Wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group and Y represents a protecting group) (1RS, 2RS, 4SR) -2- (3-pyridyl) −
A 7-azabicyclo [2.2.1] heptane derivative is reacted with phosphorus oxychloride or phosgene (1RS, 2RS, 4SR) -2- (6-chloro-3-).
Pyridyl) -7-azabicyclo [2.2.1] heptane.

【００１０】他の本発明は、下記の一般式（１）：Another aspect of the present invention is the following general formula (1):

【００１１】[0011]

【化１１】 [Chemical 11]

【００１２】（式中、Ｒ1 は炭素数１〜４のアルキル基
又はベンジル基を表し、Ｙは保護基を表す）で表される
（１ＲＳ，２ＲＳ，４ＳＲ）−２−（３−ピリジル）−
７−アザビシクロ［２．２．１］ヘプタン誘導体であ
る。(Wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and Y represents a protecting group) (1RS, 2RS, 4SR) -2- (3-pyridyl) −
It is a 7-azabicyclo [2.2.1] heptane derivative.

【００１３】他の本発明は、下記の一般式（２）：Another aspect of the present invention is the following general formula (2):

【００１４】[0014]

【化１２】 [Chemical 12]

【００１５】（式中、Ｒ1 は炭素数１〜４のアルキル基
又はベンジル基を表す）で表される（１ＲＳ，２ＲＳ，
４ＳＲ）−２−（３−ピリジル）−７−アザビシクロ
［２．２．１］ヘプタン誘導体である。(Wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group) (1RS, 2RS,
4SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative.

【００１６】他の本発明は、下記の一般式（３）：Another aspect of the present invention is the following general formula (3):

【００１７】[0017]

【化１３】 [Chemical 13]

【００１８】（式中、Ｒ1 は炭素数１〜４のアルキル基
又はベンジル基を表し、Ｒ2 は炭素数１〜４のアルキル
基、フェニル基又はトリル基を表し、Ｗは水素原子又は
保護基を表す）で表される（１ＲＳ，２ＳＲ，４ＲＳ）
−４−アミノ−２−（３−ピリジル）−１−シクロヘキ
サノール誘導体である。(In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 2 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group or a tolyl group, and W represents a hydrogen atom or a protective group. Represents a group) (1RS, 2SR, 4RS)
It is a -4-amino-2- (3-pyridyl) -1-cyclohexanol derivative.

【００１９】他の本発明は、下記の一般式（４）：Another aspect of the present invention is the following general formula (4):

【００２０】[0020]

【化１４】 [Chemical 14]

【００２１】（式中、Ｒ1 は炭素数１〜４のアルキル基
又はベンジル基を表し、Ｗは水素原子又は保護基を表
す）で表される（１ＲＳ，２ＳＲ，４ＲＳ）−４−アミ
ノ−２−（３−ピリジル）−１−シクロヘキサノール誘
導体である。(Wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and W represents a hydrogen atom or a protecting group) (1RS, 2SR, 4RS) -4-amino- It is a 2- (3-pyridyl) -1-cyclohexanol derivative.

【００２２】他の本発明は、下記の一般式（５）：Another aspect of the present invention is the following general formula (5):

【００２３】[0023]

【化１５】 [Chemical 15]

【００２４】（式中、Ｒ1 は炭素数１〜４のアルキル基
又はベンジル基を表し、Ｒ3 は炭素数１〜４のアルキル
基、炭素数２〜５の脂肪族アシル基、環置換基として炭
素数１〜４のアルキル基を有していてもよいシクロヘキ
シルカルボニル基、環置換基として炭素数１〜４のアル
キル基、ニトロ基若しくはハロゲン原子を有していても
よいベンゾイル基を表し、Ｙは保護基を表す）で表され
る（１ＲＳ，２ＳＲ，４ＲＳ）−４−アミノ−２−（３
−ピリジル）−１−シクロヘキサノール誘導体である。(In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, and a ring substituent. Represents a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a benzoyl group which may have a halogen atom, Y represents a protecting group) (1RS, 2SR, 4RS) -4-amino-2- (3
-Pyridyl) -1-cyclohexanol derivative.

【００２５】他の本発明は、下記の一般式（６）：Another aspect of the present invention is the following general formula (6):

【００２６】[0026]

【化１６】 [Chemical 16]

【００２７】（式中、Ｒ1 は炭素数１〜４のアルキル基
又はベンジル基を表し、Ｒ3 は炭素数１〜４のアルキル
基、炭素数２〜５の脂肪族アシル基、環置換基として炭
素数１〜４のアルキル基を有していてもよいシクロヘキ
シルカルボニル基、環置換基として炭素数１〜４のアル
キル基、ニトロ基若しくはハロゲン原子を有していても
よいベンゾイル基を表す）で表される（１ＲＳ，２Ｓ
Ｒ，４ＲＳ）−４−アミノ−２−（３−ピリジル）−１
−シクロヘキサノール誘導体である。(In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, and a ring substituent. Represents a cyclohexylcarbonyl group optionally having an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a benzoyl group optionally having a halogen atom) Represented by (1RS, 2S
R, 4RS) -4-Amino-2- (3-pyridyl) -1
A cyclohexanol derivative.

【００２８】他の本発明は、下記の一般式（７）：Another aspect of the present invention is the following general formula (7):

【００２９】[0029]

【化１７】 [Chemical 17]

【００３０】（式中、Ｒ1 は炭素数１〜４のアルキル基
又はベンジル基を表し、Ｒ3 は炭素数１〜４のアルキル
基、炭素数２〜５の脂肪族アシル基、環置換基として炭
素数１〜４のアルキル基を有していてもよいシクロヘキ
シルカルボニル基、環置換基として炭素数１〜４のアル
キル基、ニトロ基若しくはハロゲン原子を有していても
よいベンゾイル基を表す）で表される（３ＲＳ，４Ｓ
Ｒ）−４−置換オキシ−３−（３−ピリジル）シクロヘ
キサノン誘導体である。(Wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, a ring substituent) Represents a cyclohexylcarbonyl group optionally having an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a benzoyl group optionally having a halogen atom) Represented by (3RS, 4S
R) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative.

【００３１】本発明の（１ＲＳ，２ＲＳ，４ＳＲ）−２
−（６−クロロ−３−ピリジル）−７−アザビシクロ
［２．２．１］ヘプタン（以下、「エピバチジン」と言
うことがある）の製造方法は、前記一般式（１）で表さ
れる（１ＲＳ，２ＲＳ，４ＳＲ）−２−（３−ピリジ
ル）−７−アザビシクロ［２．２．１］ヘプタン誘導体
（１）をオキシ塩化燐又はホスゲンと反応させることに
より製造することができる。(1RS, 2RS, 4SR) -2 of the present invention
A method for producing-(6-chloro-3-pyridyl) -7-azabicyclo [2.2.1] heptane (hereinafter sometimes referred to as "epibatidine") is represented by the general formula (1) ( It can be produced by reacting 1RS, 2RS, 4SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) with phosphorus oxychloride or phosgene.

【００３２】（１ＲＳ，２ＲＳ，４ＳＲ）−２−（３−
ピリジル）−７−アザビシクロ［２．２．１］ヘプタン
誘導体（１）は新規な化合物であり、既知の化合物から
（１ＲＳ，２ＲＳ，４ＳＲ）−２−（３−ピリジル）−
７−アザビシクロ［２．２．１］ヘプタン誘導体（１）
を合成し、更にこの（１ＲＳ，２ＲＳ，４ＳＲ）−２−
（３−ピリジル）−７−アザビシクロ［２．２．１］ヘ
プタン誘導体（１）からエピバチジンを合成する経路を
下記に示す。(1RS, 2RS, 4SR) -2- (3-
Pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) is a novel compound, and from known compounds, (1RS, 2RS, 4SR) -2- (3-pyridyl)-
7-azabicyclo [2.2.1] heptane derivative (1)
Is synthesized, and this (1RS, 2RS, 4SR) -2-
A route for synthesizing epibatidine from (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) is shown below.

【００３３】[0033]

【化１８】 [Chemical 18]

【００３４】[0034]

【化１９】 [Chemical 19]

【００３５】[0035]

【化２０】 [Chemical 20]

【００３６】上記の合成経路の式に於て、Ｒ1 は炭素数
１〜４のアルキル基又はベンジル基を表し、Ｒ2 は炭素
数１〜４のアルキル基、フェニル基、又はトリル基を表
し、Ｒ3 は炭素数１〜４のアルキル基、炭素数２〜５の
脂肪族アシル基、環置換基として炭素数１〜４のアルキ
ル基を有していてもよいシクロヘキシルカルボニル基、
環置換基として炭素数１〜４のアルキル基、ニトロ基若
しくはハロゲン原子を有していてもよいベンゾイル基を
表し、Ｙは保護基を表し、Ｗは水素原子又は保護基を表
す。In the above formula of the synthetic route, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and R 2 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a tolyl group. , R 3 is an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms as a ring substituent,
It represents an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a benzoyl group which may have a halogen atom, Y represents a protecting group, and W represents a hydrogen atom or a protecting group.

【００３７】即ち、既知化合物であるピリジン誘導体
（１０）を有機リチウム及びヨウ化銅と反応させて得ら
れたピリジン誘導体（９）と、シクロヘキセノン誘導体
（８）とから（３ＲＳ，４ＳＲ）−４−置換オキシ−３
−（３−ピリジル）シクロヘキサノン誘導体（７）を
得、（３ＲＳ，４ＳＲ）−４−置換オキシ−３−（３−
ピリジル）シクロヘキサノン誘導体（７）のカルボニル
基を還元アミノ化によりアミノ基に変えて（１ＲＳ，２
ＳＲ，４ＲＳ）−４−アミノ−２−（３−ピリジル）−
１−シクロヘキサノール誘導体（６）を得、（１ＲＳ，
２ＳＲ，４ＲＳ）−４−アミノ−２−（３−ピリジル）
−１−シクロヘキサノール誘導体（６）のアミノ基に保
護基Ｙを結合させて（１ＲＳ，２ＳＲ，４ＲＳ）−４−
アミノ−２−（３−ピリジル）−１−シクロヘキサノー
ル誘導体（５）を得、（１ＲＳ，２ＳＲ，４ＲＳ）−４
−アミノ−２−（３−ピリジル）−１−シクロヘキサノ
ール誘導体（５）の−ＯＲ3 基を−ＯＨ基に変えて（１
ＲＳ，２ＳＲ，４ＲＳ）−４−アミノ−２−（３−ピリ
ジル）−１−シクロヘキサノール誘導体（４）を得、
（１ＲＳ，２ＳＲ，４ＲＳ）−４−アミノ−２−（３−
ピリジル）−１−シクロヘキサノール誘導体の−ＯＨ基
を−Ｏ−ＳＯ2 −Ｒ2 基に変えてピリジン誘導体（３）
を得、（１ＲＳ，２ＳＲ，４ＲＳ）−４−アミノ−２−
（３−ピリジル）−１−シクロヘキサノール誘導体
（３）を分子内環化して（１ＲＳ，２ＲＳ，４ＳＲ）−
２−（３−ピリジル）−７−アザビシクロ［２．２．
１］ヘプタン誘導体（２）を得、（１ＲＳ，２ＲＳ，４
ＳＲ）−２−（３−ピリジル）−７−アザビシクロ
［２．２．１］ヘプタン誘導体（２）から、或はそのア
ミノ基に保護基Ｙを結合させた（１ＲＳ，２ＲＳ，４Ｓ
Ｒ）−２−（３−ピリジル）−７−アザビシクロ［２．
２．１］ヘプタン誘導体（１）から、それらの−ＯＲ1
基を塩素原子に変え、必要に応じて保護基Ｙを脱離させ
てエピバチジンを得る。エピバチジンには光学異性体が
あり、光学活性体を得るためには、上記工程の何れかの
化合物を光学分割すればよい。That is, from a pyridine derivative (9) obtained by reacting a known pyridine derivative (10) with organic lithium and copper iodide and a cyclohexenone derivative (8), (3RS, 4SR) -4 -Substituted oxy-3
A-(3-pyridyl) cyclohexanone derivative (7) was obtained, and (3RS, 4SR) -4-substituted oxy-3- (3-
The carbonyl group of the pyridyl) cyclohexanone derivative (7) is converted to an amino group by reductive amination (1RS, 2
SR, 4RS) -4-Amino-2- (3-pyridyl)-
A 1-cyclohexanol derivative (6) was obtained (1RS,
2SR, 4RS) -4-Amino-2- (3-pyridyl)
A protective group Y is bonded to the amino group of -1-cyclohexanol derivative (6) to obtain (1RS, 2SR, 4RS) -4-
Amino-2- (3-pyridyl) -1-cyclohexanol derivative (5) was obtained, (1RS, 2SR, 4RS) -4.
- amino-2- (3-pyridyl) -1--OR 3 group cyclohexanol derivative (5) by changing the -OH group (1
RS, 2SR, 4RS) -4-Amino-2- (3-pyridyl) -1-cyclohexanol derivative (4) is obtained,
(1RS, 2SR, 4RS) -4-amino-2- (3-
A pyridyl) -1-cyclohexanol derivative in which the —OH group is replaced with an —O—SO 2 —R 2 group to give a pyridine derivative (3)
To obtain (1RS, 2SR, 4RS) -4-amino-2-
Intramolecular cyclization of (3-pyridyl) -1-cyclohexanol derivative (3) to (1RS, 2RS, 4SR)-
2- (3-pyridyl) -7-azabicyclo [2.2.
1] A heptane derivative (2) is obtained, and (1RS, 2RS, 4
SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (2) or a protecting group Y bonded to its amino group (1RS, 2RS, 4S).
R) -2- (3-pyridyl) -7-azabicyclo [2.
2.1] From the heptane derivative (1), their —OR 1
The group is changed to a chlorine atom, and the protecting group Y is eliminated, if necessary, to obtain epibatidine. Epibatidine has optical isomers, and in order to obtain an optically active substance, any compound in the above steps may be optically resolved.

【００３８】上記の各誘導体を表す一般式に於て、Ｒ
1 、Ｒ2 又はＲ3 で表される炭素数１〜４のアルキル基
としては、例えば、メチル、エチル、プロピル、イソプ
ロピル、ｎ−ブチル、イソブチル、ｔ−ブチル等が挙げ
られる。In the general formula representing each of the above derivatives, R
Examples of the alkyl group having 1 to 4 carbon atoms represented by 1 , R 2 or R 3 include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.

【００３９】また、Ｒ3 で表される炭素数２〜５の脂肪
族アシル基としては、例えば、アセチル、プロピオニ
ル、ブチリル、イソブチリル、バレリル、イソバレリ
ル、ピバロイル等が挙げられ、シクロヘキシルカルボニ
ル基又はベンゾイル基の環置換基としての炭素数１〜４
のアルキル基としてはＲ1 について例示したものが挙げ
られ、ハロゲン原子としては塩素、臭素、ヨウ素等が挙
げられる。Examples of the aliphatic acyl group having 2 to 5 carbon atoms represented by R 3 include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like, and cyclohexylcarbonyl group or benzoyl group. 1 to 4 carbon atoms as a ring substituent of
Examples of the alkyl group include those exemplified for R 1 , and examples of the halogen atom include chlorine, bromine, iodine and the like.

【００４０】また、Ｙ又はＷで表される保護基として
は、従来使用されている保護基であってよく、例えば、
下記の一般式（１１）、（１２）、（１３）又は（１
４）：The protecting group represented by Y or W may be a conventionally used protecting group, for example,
The following general formula (11), (12), (13) or (1
4):

【００４１】[0041]

【化２１】 [Chemical 21]

【００４２】で表される基が挙げられる。Examples include groups represented by:

【００４３】上記一般式（１１）に於いて、Ｒ11で表さ
れる基としては、ｔ−ブチル、１−アダマンチル、シク
ロペンチル、ジイソプロピルメチル、２−トリメチルシ
リルエチル、１−メチル−１−アルキルエチル、１，１
−ジメチル−２−ハロエチル、ビニル、ベンジル、置換
ベンジル（例えば、ｐ−メトキシベンジル、ｐ−ニトロ
ベンジル等）、ジフェニルメチル、９−アンスリルメチ
ル、ジ（２−ピリジル）メチル、４−（１，４−ジメチ
ル）ピペリジニル等が挙げられる。In the general formula (11), the group represented by R 11 includes t-butyl, 1-adamantyl, cyclopentyl, diisopropylmethyl, 2-trimethylsilylethyl, 1-methyl-1-alkylethyl, 1,1
-Dimethyl-2-haloethyl, vinyl, benzyl, substituted benzyl (for example, p-methoxybenzyl, p-nitrobenzyl, etc.), diphenylmethyl, 9-anthrylmethyl, di (2-pyridyl) methyl, 4- (1, 4-dimethyl) piperidinyl and the like can be mentioned.

【００４４】上記一般式（１２）に於いて、Ｒ12で表さ
れる基としては、水素原子、メチル、置換メチル（例え
ば、モノクロロメチル、ジクロロメチル、トリフルオロ
メチル等）、フェニル等が挙げられる。In the general formula (12), examples of the group represented by R 12 include a hydrogen atom, methyl, substituted methyl (eg, monochloromethyl, dichloromethyl, trifluoromethyl, etc.), phenyl and the like. .

【００４５】上記一般式（１３）に於いて、Ｒ13で表さ
れる基としては、２−テトラヒドロピラニル、ジ（ｐ−
メトキシフェニル）メチル、トリフェニルメチル、ベン
ジリデン、ベンジル、置換ベンジル（例えば、ｐ−メト
キシベンジル、ｐ−ニトロベンジル等）、サリシリデ
ン、ジフェニルメチレン等が挙げられる。In the above general formula (13), the group represented by R 13 includes 2-tetrahydropyranyl and di (p-
Methoxyphenyl) methyl, triphenylmethyl, benzylidene, benzyl, substituted benzyl (for example, p-methoxybenzyl, p-nitrobenzyl, etc.), salicylidene, diphenylmethylene and the like can be mentioned.

【００４６】上記一般式（１４）に於いて、Ｒ14で表さ
れる基としては、メチル、ｐ−トリル等が挙げられる。In the general formula (14), examples of the group represented by R 14 include methyl and p-tolyl.

【００４７】上記の（１ＲＳ，２ＲＳ，４ＳＲ）−２−
（３−ピリジル）−７−アザビシクロ［２．２．１］ヘ
プタン誘導体（１）〜（３ＲＳ，４ＳＲ）−４−置換オ
キシ−３−（３−ピリジル）シクロヘキサノン誘導体
（７）は何れも新規な化合物であり、エピバチジンを合
成するための中間体としての有用性を有する。各ピリジ
ン誘導体は上記の反応経路から理解できるそれ自体公知
の単位反応を利用して合成することができる。The above (1RS, 2RS, 4SR) -2-
The (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) to (3RS, 4SR) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative (7) are all novel. It is a compound and has utility as an intermediate for the synthesis of epibatidine. Each pyridine derivative can be synthesized by utilizing a unit reaction known per se which can be understood from the above reaction route.

【００４８】上記の反応経路に於て、（３ＲＳ，４Ｓ
Ｒ）−４−置換オキシ−３−（３−ピリジル）シクロヘ
キサノン誘導体（７）として、ピリジン環と−ＯＲ3 と
に関してトランス異性体を示したが、（３ＲＳ，４Ｓ
Ｒ）−４−置換オキシ−３−（３−ピリジル）シクロヘ
キサノン誘導体（７）を合成する際にシス異性体も得ら
れる。エピバチジンを合成するためにはトランス体の
（３ＲＳ，４ＳＲ）−４−置換オキシ−３−（３−ピリ
ジル）シクロヘキサノン誘導体（７）をシス体との混合
物から分離して使用する。In the above reaction route, (3RS, 4S
As the R) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative (7), a trans isomer was shown with respect to the pyridine ring and -OR 3 , but (3RS, 4S
The cis isomer is also obtained when synthesizing the (R) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative (7). In order to synthesize epibatidine, the trans-form (3RS, 4SR) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative (7) is used separately from the mixture with the cis-form.

【００４９】本発明の製造方法は、（１ＲＳ，２ＲＳ，
４ＳＲ）−２−（３−ピリジル）−７−アザビシクロ
［２．２．１］ヘプタン誘導体（１）にオキシ塩化燐又
はホスゲンを反応させてエピバチジンを製造する。オキ
シ塩化燐と共にジメチルホルムアミドを使用してもよ
い。（１ＲＳ，２ＲＳ，４ＳＲ）−２−（３−ピリジ
ル）−７−アザビシクロ［２．２．１］ヘプタン誘導体
（１）に、オキシ塩化燐又はホスゲンを反応させる際の
反応条件は、類似の反応に於けるそれ自体公知の条件を
用いることができる。例えば、（１ＲＳ，２ＲＳ，４Ｓ
Ｒ）−２−（３−ピリジル）−７−アザビシクロ［２．
２．１］ヘプタン誘導体（１）にオキシ塩化燐及びジメ
チルホルムアミドを反応させる場合は、フィルスマイヤ
ー・ハーク反応(Vilsmeier-Haack reaction)の反応条件
を使用することができる。The manufacturing method of the present invention is (1RS, 2RS,
4SR) -2- (3-Pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) is reacted with phosphorus oxychloride or phosgene to produce epibatidine. Dimethylformamide may be used with phosphorus oxychloride. The reaction conditions for reacting (1RS, 2RS, 4SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) with phosphorus oxychloride or phosgene are similar to each other. The conditions known per se in the above can be used. For example, (1RS, 2RS, 4S
R) -2- (3-pyridyl) -7-azabicyclo [2.
2.1] When the heptane derivative (1) is reacted with phosphorus oxychloride and dimethylformamide, the reaction conditions of the Vilsmeier-Haack reaction can be used.

【００５０】エピバチジンは、下記に示すような反応経
路によっても合成することができる。Epibatidine can also be synthesized by the reaction route shown below.

【００５１】[0051]

【化２２】 [Chemical formula 22]

【００５２】[0052]

【化２３】 [Chemical formula 23]

【００５３】上記の反応経路の各式に於て、Ｒ1 、Ｒ3
及びＹは前記の定義と同じであり、Ｒ4 及びＲ5 は炭素
数１〜４のアルキル基を表し、Ｘはハロゲン原子を表
す。In each formula of the above reaction route, R 1 , R 3
And Y are as defined above, R 4 and R 5 represent an alkyl group having 1 to 4 carbon atoms, and X represents a halogen atom.

【００５４】即ち、工程（Ａ）又は工程（Ｂ）によりピ
リジン誘導体（１５）を合成し、ピリジン誘導体（５）
からエピバチジンを合成する方法と同様の方法でピリジ
ン誘導体（１５）からエピバチジンを合成することがで
きる。また、工程（Ｃ）、工程（Ｄ）又は工程（Ｅ）に
よりピリジン誘導体（１６）を合成し、ピリジン誘導体
（５）からエピバチジンを合成する方法と同様の方法で
ピリジン誘導体（１６）からエピバチジンを合成するこ
とができる。That is, the pyridine derivative (15) was synthesized by the step (A) or the step (B) to obtain the pyridine derivative (5).
Epibatidine can be synthesized from the pyridine derivative (15) by a method similar to the method of synthesizing epibatidine from. In addition, pyridine derivative (16) is synthesized in step (C), step (D) or step (E), and epibatidine is converted from pyridine derivative (16) by the same method as in the method of synthesizing epibatidine from pyridine derivative (5). Can be synthesized.

【００５５】[0055]

【実施例】次に、実施例により本発明を更に詳細に説明
する。EXAMPLES Next, the present invention will be described in more detail by way of examples.

【００５６】［実施例１］ （３ＲＳ，４ＳＲ）４−アセトキシ−３−（６−メトキ
シ−３−ピリジル）シクロヘキサノン［トランス体］Example 1 (3RS, 4SR) 4-acetoxy-3- (6-methoxy-3-pyridyl) cyclohexanone [trans form]

【００５７】３−ブロモ−６−メトキシピリジン３５．
２ｇ（１８７ミリモル）を、窒素雰囲気下で乾燥テトラ
ヒドロフラン（ＴＨＦ）５８０ｍｌに溶解させ、−７８
℃で攪拌した。この溶液に１．７Ｍ ｔ−ブチルリチウ
ム−ペンタン溶液２２０ｍｌ（３７４ミリモル）を２時
間かけて滴下し、−７８℃で更に１時間攪拌した。この
溶液に９９％ヨウ化銅１８．０ｇ（９３．６ミリモル）
を粉末のまま加えて−７８℃で１．５時間攪拌した。こ
の混合物に更に三フッ化ホウ素−ジエチルエーテル２
３．０ｍｌ（１８５ミリモル）を５分間かけて滴下し
て、−７８℃で３時間攪拌した。得られた混合物に、４
−アセトキシ−２−シクロヘキセノン１２．０ｇ（７
７．８ミリモル）のＴＨＦ（１６ｍｌ）溶液を１０分間
かけて滴下し、−７８℃で一晩攪拌した。この混合物
に、−７８℃で飽和塩化アンモニウム水溶液４０ｍｌを
加えて室温になるまで放置し、不溶物をセライトを用い
て濾別し、濾液をエーテルで抽出した。得られたエーテ
ル抽出層を飽和食塩水で洗浄し、無水硫酸ナトリウムで
乾燥した後、溶媒を減圧留去して、赤色の粗体油状物を
得た。この油状物を中圧シリカゲルクロマトグラフィー
により精製（溶出液、ヘキサン：酢酸エチル＝３：２）
した後、エーテルから再結晶して、標題の化合物３．８
０ｇ（収率１８．５％）を白色結晶として得た。3-Bromo-6-methoxypyridine 35.
2 g (187 mmol) was dissolved in 580 ml of dry tetrahydrofuran (THF) under a nitrogen atmosphere, and -78
Stir at ℃. To this solution, 220 ml (374 mmol) of 1.7 M t-butyllithium-pentane solution was added dropwise over 2 hours, and the mixture was further stirred at -78 ° C for 1 hour. 18.0 g (93.6 mmol) of 99% copper iodide was added to this solution.
Was added as a powder and stirred at -78 ° C for 1.5 hours. To this mixture was further added boron trifluoride-diethyl ether 2
3.0 ml (185 mmol) was added dropwise over 5 minutes, and the mixture was stirred at -78 ° C for 3 hours. To the resulting mixture, 4
-Acetoxy-2-cyclohexenone 12.0 g (7
A solution of 7.8 mmol) in THF (16 ml) was added dropwise over 10 minutes, and the mixture was stirred at -78 ° C overnight. To this mixture, 40 ml of a saturated aqueous solution of ammonium chloride was added at -78 ° C, the mixture was allowed to stand at room temperature, the insoluble matter was filtered off using Celite, and the filtrate was extracted with ether. The obtained ether extraction layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a red crude oily substance. The oil was purified by medium pressure silica gel chromatography (eluent, hexane: ethyl acetate = 3: 2).
After recrystallization from ether, the title compound 3.8 was obtained.
0 g (yield 18.5%) was obtained as white crystals.

【００５８】また、上記のクロマトグラフィー精製に於
いて、別のフラクションから（３ＲＳ，４ＲＳ）４−ア
セトキシ−３−（６−メトキシ−３−ピリジル）シクロ
ヘキサノン［シス体］２．４４ｍｇ（収率１１．９％）
も無色油状物として得た。ＴＬＣによるＲｆ値はトラン
ス体約０．４、シス体約０．３（展開溶媒；ヘキサン／
酢酸エチル＝１／１）であった。なお、上記の赤色の粗
体油状物のガスクロマトグラフィー分析［カラム：Sili
cone ＯＶ−１７；２ｍ、キャリア：窒素；４０ｍｌ／
分、カラム温度：２３０℃、注入温度２５０℃］の結果
は、粗体油状物中のトランス体／シス体の比が２／１で
あったことを示した。In the above chromatographic purification, from another fraction, 2.44 mg of (3RS, 4RS) 4-acetoxy-3- (6-methoxy-3-pyridyl) cyclohexanone [cis form] (yield 11 .9%)
Was also obtained as a colorless oil. The Rf value by TLC is about 0.4 trans form and about 0.3 cis form (developing solvent: hexane /
It was ethyl acetate = 1/1). Gas chromatographic analysis of the above red crude oil [column: Sili
cone OV-17; 2 m, carrier: nitrogen; 40 ml /
Min, column temperature: 230 ° C., injection temperature 250 ° C.] showed that the ratio of trans isomer / cis isomer in the crude oil was 2/1.

【００５９】トランス体1 Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．９３（３Ｈ，
ｓ），１．８−２．０（１Ｈ，ｍ），２．２−２．３
（１Ｈ，ｍ），２．５−２．６（２Ｈ，ｍ），２．６−
２．７（２Ｈ，ｍ），３．２３（１Ｈ，ｄｄ，Ｊ＝９Ｈ
ｚ，１７Ｈｚ），３．９２（３Ｈ，ｓ），５．２６（１
Ｈ，ｄｔ，Ｊ＝４Ｈｚ，９Ｈｚ），６．７２（１Ｈ，
ｄ，Ｊ＝８．５Ｈｚ），７．４５（１Ｈ，ｄｄ，Ｊ＝
２．５Ｈｚ，８．５Ｈｚ），８．００（１Ｈ，ｄ，Ｊ＝
２．５Ｈｚ） ＦＡＢ−ＭＳ（ｍ／ｅ）；２６４（Ｍ＋１） ＩＲ（ＫＢｒ）；２９５６，１７２４，１６０８，１４
９８，１２９８，１２４２，１０３０． 融点；１０２〜１０３℃Trans form 1 H NMR (CDCl 3 ) δ; 1.93 (3H,
s), 1.8-2.0 (1H, m), 2.2-2.3.
(1H, m), 2.5-2.6 (2H, m), 2.6-
2.7 (2H, m), 3.23 (1H, dd, J = 9H
z, 17 Hz), 3.92 (3H, s), 5.26 (1
H, dt, J = 4Hz, 9Hz), 6.72 (1H,
d, J = 8.5 Hz), 7.45 (1H, dd, J =
2.5 Hz, 8.5 Hz, 8.00 (1H, d, J =
2.5 Hz) FAB-MS (m / e); 264 (M + 1) IR (KBr); 2956, 1724, 1608, 14
98, 1298, 1242, 1030. Melting point: 102-103 ° C

【００６０】シス体1 Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；２．０６（３Ｈ，
ｓ），２．０−３．１（６Ｈ，ｍ），３．２７（１Ｈ，
ｄｄｄ，Ｊ＝３Ｈｚ，５Ｈｚ，１４Ｈｚ），３．９２
（３Ｈ，ｓ），５．２３−５．２８（１Ｈ，ｍ），６．
６５−８．０５（３Ｈ，ｍ）， ＦＡＢ−ＭＳ（ｍ／ｅ）；２６４（Ｍ＋１）Cis isomer 1 H NMR (CDCl 3 ) δ; 2.06 (3H,
s), 2.0-3.1 (6H, m), 3.27 (1H,
ddd, J = 3 Hz, 5 Hz, 14 Hz), 3.92
(3H, s), 5.23-5.28 (1H, m), 6.
65-8.05 (3H, m), FAB-MS (m / e); 264 (M + 1).

【００６１】［実施例２］ （１ＲＳ，２ＳＲ，４ＲＳ）−４−アミノ−２−（６−
メトキシ−３−ピリジル）−１−シクロヘキシルアセテ
ートExample 2 (1RS, 2SR, 4RS) -4-amino-2- (6-
Methoxy-3-pyridyl) -1-cyclohexyl acetate

【００６２】酢酸アンモニウム１０．８ｇ（１４０ミリ
モル）を乾燥メタノール３５０ｍｌに溶解し、この溶液
に実施例１に於けるようにして製造した（３ＲＳ，４Ｓ
Ｒ）−４−アセトキシ−３−（６−メトキシ−３−ピリ
ジル）シクロヘキサノン３．７０ｇ（１４．１ミリモ
ル）及び９５％ナトリウムシアノボロハイドライド０．
９４ｇ（１４．２ミリモル）を加え、室温で一晩攪拌し
た。反応混合物からメタノールを減圧留去し、残渣をジ
クロロメタン１００ｍｌに溶解した後、溶液を飽和重曹
水１００ｍｌで洗浄し、水層をジクロロメタンで抽出
（１００ｍｌ×２）し、合わせた有機層を飽和食塩水１
８０ｍｌで洗浄した。有機層を無水硫酸ナトリウムで乾
燥した後、溶媒を減圧留去して、褐色の油状物４．４０
ｇを得た。この油状物を中圧シリカゲルクロマトグラフ
ィーにより精製（溶出液、クロロホルム：メタノール＝
１０：１〜３：１）し、標題化合物１．５９ｇ（収率４
２．６％）を無色油状物として得た。Ammonium acetate 10.8 g (140 mmol) was dissolved in dry methanol 350 ml and this solution was prepared as in Example 1 (3RS, 4S).
R) -4-acetoxy-3- (6-methoxy-3-pyridyl) cyclohexanone 3.70 g (14.1 mmol) and 95% sodium cyanoborohydride.
94 g (14.2 mmol) was added, and the mixture was stirred at room temperature overnight. Methanol was distilled off from the reaction mixture under reduced pressure, the residue was dissolved in 100 ml of dichloromethane, the solution was washed with 100 ml of saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with dichloromethane (100 ml × 2), and the combined organic layers were saturated brine. 1
It was washed with 80 ml. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily substance 4.40.
g was obtained. This oil was purified by medium pressure silica gel chromatography (eluent, chloroform: methanol =
10: 1 to 3: 1) to give 1.59 g of the title compound (yield 4
2.6%) as a colorless oil.

【００６３】また、上記のクロマトグラフィー精製に於
いて、別のフラクションから（１ＲＳ，２ＳＲ，４Ｓ
Ｒ）−４−アミノ−２−（６−メトキシ−３−ピリジ
ル）−１−シクロヘキシルアセテート０．７１ｇ（収率
１９．０％）も無色油状物として得た。ＴＬＣによるＲ
ｆ値；（１ＲＳ，２ＳＲ，４ＲＳ）−体約０．５、（１
ＲＳ，２ＳＲ，４ＳＲ）−体約０．６（展開溶媒；クロ
ロホルム／メタノール／２８％アンモニア水＝５０／１
０／１）。In the above chromatographic purification, from the other fractions (1RS, 2SR, 4S
R) -4-Amino-2- (6-methoxy-3-pyridyl) -1-cyclohexyl acetate (0.71 g, yield 19.0%) was also obtained as a colorless oil. R by TLC
f value; (1RS, 2SR, 4RS) -body about 0.5, (1
RS, 2SR, 4SR) -body about 0.6 (developing solvent; chloroform / methanol / 28% ammonia water = 50/1)
0/1).

【００６４】（１ＲＳ，２ＳＲ，４ＲＳ）−体1 Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．３−１．６（５
Ｈ，ｍ），１．８１（３Ｈ，ｓ），１．９−２．２（３
Ｈ，ｍ），２．７３（１Ｈ，ｔｄ，Ｊ＝３Ｈｚ，１２Ｈ
ｚ，１２Ｈｚ），２．９４（１Ｈ，ｔｔ，Ｊ＝４Ｈｚ，
４Ｈｚ，１１Ｈｚ），３．９１（３Ｈ，ｓ），４．８４
（１Ｈ，ｔｄ，Ｊ＝４．５Ｈｚ，１１Ｈｚ，１１Ｈ
ｚ），６．６８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．４３
（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，８Ｈｚ），７．９６（１
Ｈ，ｄ，Ｊ＝２Ｈｚ） ＦＡＢ−ＭＳ（ｍ／ｅ）；２６５（Ｍ＋１）(1RS, 2SR, 4RS) -form 1 H NMR (CDCl 3 ) δ; 1.3-1.6 (5
H, m), 1.81 (3H, s), 1.9-2.2 (3
H, m), 2.73 (1H, td, J = 3Hz, 12H
z, 12 Hz), 2.94 (1H, tt, J = 4 Hz,
4 Hz, 11 Hz), 3.91 (3H, s), 4.84
(1H, td, J = 4.5Hz, 11Hz, 11H
z), 6.68 (1H, d, J = 8 Hz), 7.43
(1H, dd, J = 2Hz, 8Hz), 7.96 (1
H, d, J = 2 Hz) FAB-MS (m / e); 265 (M + 1)

【００６５】（１ＲＳ，２ＳＲ，４ＳＲ）−体1 Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．３２（２Ｈ，ｂｒ
ｓ），１．６−１．８（４Ｈ，ｍ），１．８３（３Ｈ，
ｓ），１．８５−２．０（２Ｈ，ｍ），３．１４（１
Ｈ，ｔｄ，Ｊ＝５Ｈｚ，５Ｈｚ，１１Ｈｚ），３．３７
（１Ｈ，ｑｕｉｎｔｅｔ，Ｊ＝３Ｈｚ），３．９１（３
Ｈ，ｓ），４．８−４．９３（１Ｈ，ｍ），６．６７
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．４４（１Ｈ，ｄｄ，Ｊ
＝２．５Ｈｚ，８Ｈｚ），８．００（１Ｈ，ｄ，Ｊ＝
２．５Ｈｚ）(1RS, 2SR, 4SR) -body 1 H NMR (CDCl 3 ) δ; 1.32 (2H, br
s), 1.6-1.8 (4H, m), 1.83 (3H,
s), 1.85-2.0 (2H, m), 3.14 (1
H, td, J = 5 Hz, 5 Hz, 11 Hz), 3.37
(1H, quintet, J = 3Hz), 3.91 (3
H, s), 4.8-4.93 (1H, m), 6.67.
(1H, d, J = 8Hz), 7.44 (1H, dd, J
= 2.5 Hz, 8 Hz), 8.00 (1H, d, J =
2.5 Hz)

【００６６】［実施例３］ （１ＲＳ，２ＳＲ，４ＲＳ）−４−ベンジルオキシカル
ボニルアミノ−２−（６−メトキシ−３−ピリジル）−
１−シクロヘキシルアセテートExample 3 (1RS, 2SR, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl)-
1-cyclohexyl acetate

【００６７】実施例２に於けるようにして製造した（１
ＲＳ，２ＲＳ，４ＲＳ）−４−アミノ−２−（６−メト
キシ−３−ピリジル）−１−シクロヘキシルアセテート
１５１ｍｇ（０．５７ミリモル）、炭酸水素ナトリウム
１２４ｍｇ（１．４８ミリモル）及び水０．８ｍｌの混
合物に、室温でカルボベンゾキシクロリド０．０５ｍｌ
（０．３５ミリモル）のクロロホルム０．８ｍｌ溶液を
滴下し、２時間攪拌した。この反応混合物に更にカルボ
ベンゾキシクロリド０．０５ｍｌ（０．３５ミリモル）
及び炭酸水素ナトリウム６２ｍｇ（０．７４ミリモル）
を加え、３０分間攪拌し、クロロホルムで抽出した後、
無水硫酸ナトリウムで乾燥した。抽出液から溶媒を減圧
留去した後、残渣をシリカゲルカラム精製（酢酸エチル
／ヘキサン＝１／１）し、標題化合物２２７ｍｇを定量
的収率で無色油状物として得た。Prepared as in Example 2 (1
RS, 2RS, 4RS) -4-Amino-2- (6-methoxy-3-pyridyl) -1-cyclohexylacetate 151 mg (0.57 mmol), sodium hydrogencarbonate 124 mg (1.48 mmol) and water 0.8 ml. 0.05 ml of carbobenzoxiclide at room temperature
A solution of (0.35 mmol) in 0.8 ml of chloroform was added dropwise, and the mixture was stirred for 2 hours. To this reaction mixture was further added 0.05 ml (0.35 mmol) of carbobenzoxylcolide.
And sodium hydrogen carbonate 62 mg (0.74 mmol)
Was added, stirred for 30 minutes, extracted with chloroform,
It was dried over anhydrous sodium sulfate. The solvent was distilled off from the extract under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / hexane = 1/1) to obtain 227 mg of the title compound as a colorless oily substance in a quantitative yield.

【００６８】1Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．３−
１．６（３Ｈ，ｍ），１．８１（３Ｈ，ｓ），２．０−
２．３（３Ｈ，ｍ），２．７−２．９（１Ｈ，ｍ），
３．６−３．８（１Ｈ，ｍ），３．９０（３Ｈ，ｓ），
４．７−４．９（２Ｈ，ｍ），５．０８（２Ｈ，ｂｒ
ｓ），６．６６（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．２−
７．４（６Ｈ，ｍ），７．９５（１Ｈ，ｄ，Ｊ＝３Ｈ
ｚ） 1 H NMR (CDCl 3 ) δ; 1.3-
1.6 (3H, m), 1.81 (3H, s), 2.0-
2.3 (3H, m), 2.7-2.9 (1H, m),
3.6-3.8 (1H, m), 3.90 (3H, s),
4.7-4.9 (2H, m), 5.08 (2H, br
s), 6.66 (1H, d, J = 9Hz), 7.2-
7.4 (6H, m), 7.95 (1H, d, J = 3H
z)

【００６９】［実施例４］ （１ＲＳ，２ＲＳ，４ＲＳ）−４−ベンジルオキシカル
ボニルアミノ−２−（６−メトキシ−３−ピリジル）−
１−シクロヘキサノールExample 4 (1RS, 2RS, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl)-
1-cyclohexanol

【００７０】実施例３で得た（１ＲＳ，２ＲＳ，４Ｒ
Ｓ）−４−ベンジルオキシカルボニルアミノ−２−（６
−メトキシ−３−ピリジル）−１−シクロヘキシルアセ
テート２１７ｍｇ（０．５５ミリモル）をメタノール
２．３ｍｌに溶解し、この溶液に１規定水酸化ナトリウ
ム水溶液０．７ｍｌを加え、室温で１．５時間攪拌し
た。反応液からメタノールを減圧留去した後、残渣を酢
酸エチルで抽出し、飽和食塩水で洗浄した。抽出液を無
水硫酸ナトリウムで乾燥した後、溶媒を減圧留去して、
標題化合物１９４ｍｇを定量的収率で白色結晶として得
た。Obtained in Example 3 (1RS, 2RS, 4R
S) -4-benzyloxycarbonylamino-2- (6
217 mg (0.55 mmol) of -methoxy-3-pyridyl) -1-cyclohexyl acetate was dissolved in 2.3 ml of methanol, 0.7 ml of 1N aqueous sodium hydroxide solution was added to this solution, and the mixture was stirred at room temperature for 1.5 hours. did. After methanol was distilled off under reduced pressure from the reaction solution, the residue was extracted with ethyl acetate and washed with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,
194 mg of the title compound was obtained as white crystals in quantitative yield.

【００７１】1Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．３−
１．７（３Ｈ，ｍ），２．０−２．２（３Ｈ，ｍ），
２．５−２．６（２Ｈ，ｍ），３．５−３．７（１Ｈ，
ｍ），３．９２（３Ｈ，ｓ），４．５−４．７（１Ｈ，
ｂｒ），５．０８（２Ｈ，ｂｒｓ），６．７３（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），７．３−７．４（５Ｈ，ｍ），７．
４４（１Ｈ，ｄｄ，Ｊ＝８Ｈｚ），８．０３（１Ｈ，
ｄ，Ｊ＝２Ｈｚ）． 1 H NMR (CDCl 3 ) δ; 1.3-
1.7 (3H, m), 2.0-2.2 (3H, m),
2.5-2.6 (2H, m), 3.5-3.7 (1H,
m), 3.92 (3H, s), 4.5-4.7 (1H,
br), 5.08 (2H, brs), 6.73 (1H,
d, J = 8 Hz), 7.3-7.4 (5H, m), 7.
44 (1H, dd, J = 8Hz), 8.03 (1H,
d, J = 2 Hz).

【００７２】［実施例５］ （１ＲＳ，２ＲＳ，４ＲＳ）−４−ベンジルオキシカル
ボニルアミノ−２−（６−メトキシ−３−ピリジル）−
１−シクロヘキシル メタンスルホネートExample 5 (1RS, 2RS, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl)-
1-cyclohexyl methanesulfonate

【００７３】実施例４で得た（１ＲＳ，２ＲＳ，４Ｒ
Ｓ）−４−ベンジルオキシカルボニルアミノ−２−（６
−メトキシ−３−ピリジル）−１−シクロヘキサノール
１９４ｍｇ（０．５５ミリモル）を乾燥ジクロロメタン
３．５ｍｌに溶解し、この溶液に乾燥ピリジン１．４ｍ
ｌを加えて０℃で攪拌した。この溶液にメタンスルホニ
ルクロリド０．７６ｍｌ（０．９８ミリモル）を滴下
し、室温で１７時間攪拌した。反応液から溶媒を減圧留
去した後、残渣をジクロロメタン１０ｍｌに再溶解し、
水２０ｍｌで洗浄した後、無水硫酸ナトリウムで乾燥
し、溶媒を減圧留去して、褐色の油状物２７６ｍｇを得
た。これを中圧シリカゲルクロマトグラフィーにより精
製（溶出液、クロロホルム：メタノール＝２０：１）
し、標題化合物２３７ｍｇを定量的収率で黄色油状物と
して得た。Obtained in Example 4 (1RS, 2RS, 4R
S) -4-benzyloxycarbonylamino-2- (6
-Methoxy-3-pyridyl) -1-cyclohexanol (194 mg, 0.55 mmol) was dissolved in dry dichloromethane (3.5 ml), and dry pyridine (1.4 m) was added to the solution.
1 was added and the mixture was stirred at 0 ° C. 0.76 ml (0.98 mmol) of methanesulfonyl chloride was added dropwise to this solution, and the mixture was stirred at room temperature for 17 hours. After distilling off the solvent from the reaction solution under reduced pressure, the residue was redissolved in 10 ml of dichloromethane,
After washing with 20 ml of water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 276 mg of a brown oily substance. This was purified by medium pressure silica gel chromatography (eluent, chloroform: methanol = 20: 1).
Then, 237 mg of the title compound was obtained as a yellow oily substance in a quantitative yield.

【００７４】1Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．３−
１．６（２Ｈ，ｍ），１．８−１．９（１Ｈ，ｍ），
２．１−２．２（１Ｈ，ｍ），２．２−２．３（１Ｈ，
ｍ），２．３−２．５（１Ｈ，ｍ），２．３７（３Ｈ，
ｓ），２．８４（１Ｈ，ｍ），３．７０（１Ｈ，ｍ），
３．９１（１Ｈ，ｓ），４．５３（１Ｈ，ｄｄｄ，Ｊ＝
４．４Ｈｚ，１１Ｈｚ，１１Ｈｚ），４．７１（１Ｈ，
ｂｓ），５．０８（２Ｈ，ｓ），６．７３（１Ｈ，ｄ，
Ｊ＝８Ｈｚ），７．３５（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，８
Ｈｚ），８．０２（１Ｈ，ｄ，Ｊ＝２Ｈｚ）． ＦＡＢ−ＭＳ（ｍ／ｅ）；４３５（Ｍ＋１） 1 H NMR (CDCl 3 ) δ; 1.3-
1.6 (2H, m), 1.8-1.9 (1H, m),
2.1-2.2 (1H, m), 2.2-2.3 (1H,
m), 2.3-2.5 (1H, m), 2.37 (3H,
s), 2.84 (1H, m), 3.70 (1H, m),
3.91 (1H, s), 4.53 (1H, ddd, J =
4.4Hz, 11Hz, 11Hz), 4.71 (1H,
bs), 5.08 (2H, s), 6.73 (1H, d,
J = 8 Hz), 7.35 (1 H, dd, J = 2 Hz, 8
Hz), 8.02 (1H, d, J = 2 Hz). FAB-MS (m / e); 435 (M + 1)

【００７５】［実施例６］ （１ＲＳ，２ＲＳ，４ＳＲ）−２−（６−メトキシ−３
−ピリジル）−７−アザビシクロ［２．２．１］ヘプタ
ンExample 6 (1RS, 2RS, 4SR) -2- (6-methoxy-3)
-Pyridyl) -7-azabicyclo [2.2.1] heptane

【００７６】実施例５で得た（１ＲＳ，２ＲＳ，４Ｒ
Ｓ）−４−ベンジルオキシカルボニルアミノ−２−（６
−メトキシ−３−ピリジル）−１−シクロヘキシル メ
タンスルホネート１８．０ｍｇ（０．０４２ミリモル）
を酢酸０．１ｍｌに溶解し、この溶液に４７％臭化水素
酸水溶液０．２ｍｌと酢酸０．２ｍｌとを加えて室温で
１時間攪拌した。この反応液から溶媒を留去した後、７
０％エタノール水溶液１．５ｍｌと１Ｎ水酸化ナトリウ
ム水溶液を加えてｐＨを９に調整し、７０℃で３０分間
攪拌した。反応液から溶媒を減圧留去した後、ジクロロ
メタン５ｍｌで抽出して、水５ｍｌで洗浄した。無水硫
酸ナトリウムで乾燥した後、溶媒を減圧留去して、標題
化合物８．０ｍｇ（収率９３．０％）を黄色油状物とし
て得た。Obtained in Example 5 (1RS, 2RS, 4R
S) -4-benzyloxycarbonylamino-2- (6
-Methoxy-3-pyridyl) -1-cyclohexyl methanesulfonate 18.0 mg (0.042 mmol)
Was dissolved in 0.1 ml of acetic acid, 0.2 ml of 47% hydrobromic acid aqueous solution and 0.2 ml of acetic acid were added to this solution, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off from this reaction solution, 7
The pH was adjusted to 9 by adding 1.5 ml of 0% aqueous ethanol solution and 1N aqueous sodium hydroxide solution, and the mixture was stirred at 70 ° C. for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure, followed by extraction with 5 ml of dichloromethane and washing with 5 ml of water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (8.0 mg, yield 93.0%) as a yellow oil.

【００７７】1Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．４−
１．７（６Ｈ，ｍ），１．８−１．９（１Ｈ，ｍ），
２．７６（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，２２Ｈｚ），３．
５３（１Ｈ，ｓ），３．７６（１Ｈ，ｓ），３．９１
（３Ｈ，ｓ，Ｊ＝１Ｈｚ，２２Ｈｚ），６．６８（１
Ｈ，ｄ，Ｊ＝８Ｈｚ），７．６４（１Ｈ，ｄｄ，Ｊ＝２
Ｈｚ，８Ｈｚ），８．０２（１Ｈ，ｄ，Ｊ＝２Ｈｚ）． ＦＡＢ−ＭＳ（ｍ／ｅ）；２０５（Ｍ＋１） 1 H NMR (CDCl 3 ) δ; 1.4-
1.7 (6H, m), 1.8-1.9 (1H, m),
2.76 (1H, dd, J = 1 Hz, 22 Hz), 3.
53 (1H, s), 3.76 (1H, s), 3.91
(3H, s, J = 1Hz, 22Hz), 6.68 (1
H, d, J = 8 Hz), 7.64 (1H, dd, J = 2)
Hz, 8 Hz), 8.02 (1H, d, J = 2 Hz). FAB-MS (m / e); 205 (M + 1)

【００７８】［実施例７］ （１ＲＳ，２ＲＳ，４ＳＲ）−７−ベンジルオキシカル
ボニル−２−（６−メトキシ−３−ピリジル）−７−ア
ザビシクロ［２．２．１］ヘプタンExample 7 (1RS, 2RS, 4SR) -7-Benzyloxycarbonyl-2- (6-methoxy-3-pyridyl) -7-azabicyclo [2.2.1] heptane

【００７９】実施例６に於けるようにして得た（１Ｒ
Ｓ，２ＲＳ，４ＳＲ）−２−（６−メトキシ−３−ピリ
ジル）−７−アザビシクロ［２．２．１］ヘプタン２
１．９ｍｇ（０．１１ミリモル）に、水０．１ｍｌ及び
炭酸水素ナトリウム２４．０ｍｇ（０．２９ミリモル）
を加えて攪拌した。この反応液にカルボベンゾキシクロ
リド０．０１ｍｌ（０．０７ミリモル）をクロロホルム
１ｍｌに溶解させた溶液を添加し、室温で更に１時間攪
拌した。更に、炭酸水素ナトリウム１２．０ｍｇ（０．
１５ミリモル）及びカルボベンゾキシクロリド０．０１
ｍｌ（０．０７ミリモル）をクロロホルム１ｍｌに溶解
させた溶液及び水０．１ｍｌを加え、室温で３０分間攪
拌した。反応液をクロロホルムで抽出し、無水硫酸ナト
リウムで乾燥した後、溶媒を減圧留去して得られる残渣
を薄層シリカゲルクロマトグラフィーにより精製（溶出
液、ヘキサン：酢酸エチル＝１：１）し、標題化合物３
２．５ｍｇ（収率８７．３％）を黄色油状物として得
た。Obtained as in Example 6 (1R
S, 2RS, 4SR) -2- (6-Methoxy-3-pyridyl) -7-azabicyclo [2.2.1] heptane 2
To 1.9 mg (0.11 mmol), 0.1 ml of water and 24.0 mg (0.29 mmol) of sodium hydrogen carbonate.
Was added and stirred. A solution prepared by dissolving 0.01 ml (0.07 mmol) of carbobenzoxylcolide in 1 ml of chloroform was added to this reaction liquid, and the mixture was further stirred at room temperature for 1 hour. Furthermore, sodium bicarbonate 12.0 mg (0.
15 mmol) and carbobenzoxycyclolide 0.01
A solution prepared by dissolving ml (0.07 mmol) in 1 ml of chloroform and 0.1 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with chloroform, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by thin-layer silica gel chromatography (eluent, hexane: ethyl acetate = 1: 1). Compound 3
2.5 mg (yield 87.3%) was obtained as a yellow oil.

【００８０】1Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．５−
１．７（２Ｈ，ｍ），１．７−１．９（３Ｈ，ｍ），
１．９７（１Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，１２．２Ｈ
ｚ），２．８４（１Ｈ，ｄｄ，Ｊ＝４．９Ｈｚ，８．８
Ｈｚ），３．９０（３Ｈ，ｓ），４．２３（１Ｈ，ｂｒ
ｓ），４．４７（１Ｈ，ｂｒｓ），５．１０（２Ｈ，
ｓ），６．６３（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．２
−７．４（５Ｈ，ｍ），７．４９（１Ｈ，ｄｄ，Ｊ＝
２．４Ｈｚ，８．５Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝
２．４Ｈｚ）． 1 H NMR (CDCl 3 ) δ; 1.5-
1.7 (2H, m), 1.7-1.9 (3H, m),
1.97 (1H, dd, J = 8.8Hz, 12.2H
z), 2.84 (1H, dd, J = 4.9 Hz, 8.8)
Hz), 3.90 (3H, s), 4.23 (1H, br
s), 4.47 (1H, brs), 5.10 (2H,
s), 6.63 (1H, d, J = 8.5 Hz), 7.2
-7.4 (5H, m), 7.49 (1H, dd, J =
2.4 Hz, 8.5 Hz), 7.99 (1H, d, J =
2.4 Hz).

【００８１】［実施例８］ （１ＲＳ，２ＲＳ，４ＳＲ）−２−（６−クロロ−３−
ピリジル）−７−アザビシクロ［２．２．１］ヘプタンExample 8 (1RS, 2RS, 4SR) -2- (6-chloro-3-)
Pyridyl) -7-azabicyclo [2.2.1] heptane

【００８２】実施例７で得た（１ＲＳ，２ＲＳ，４Ｓ
Ｒ）−７−ベンジルオキシカルボニル−２−（６−メト
キシ−３−ピリジル）−７−アザビシクロ［２．２．
１］ヘプタン１０．２ｍｇ（０．０３０ミリモル）を乾
燥ジメチルホルムアミド０．２ｍｌに溶解させた。この
溶液に、氷冷下、オキシ塩化燐６μｌ（０．０６４ミリ
モル）を滴下して室温で２時間攪拌し、次いで８０℃で
１２時間攪拌した。反応液を放冷した後、これに水４ｍ
ｌと炭酸水素ナトリウムとを加えてｐＨを７．５に調整
して、クロロホルムで抽出し、無水硫酸ナトリウムで乾
燥した後、溶媒を減圧留去して粗体を得た。この粗体を
シリカゲルクロマトグラフィーにより精製（溶出液、ク
ロロホルム：メタノール＝９：１〜３：１）し、標題化
合物３．０ｍｇ（収率９３．０％）を黄色油状物として
得た。Obtained in Example 7 (1RS, 2RS, 4S
R) -7-Benzyloxycarbonyl-2- (6-methoxy-3-pyridyl) -7-azabicyclo [2.2.
1] 10.2 mg (0.030 mmol) of heptane was dissolved in 0.2 ml of dry dimethylformamide. To this solution, 6 μl (0.064 mmol) of phosphorus oxychloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours and then at 80 ° C. for 12 hours. After allowing the reaction solution to cool, 4 m of water was added to it.
The pH was adjusted to 7.5 by adding 1 and sodium hydrogen carbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent, chloroform: methanol = 9: 1 to 3: 1) to obtain 3.0 mg (yield 93.0%) of the title compound as a yellow oil.

【００８３】1Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；０．８８
−１．９８（７Ｈ，ｍ），２．８１（１Ｈ，ｍ），３．
６４（１Ｈ，ｓ），３．８９（１Ｈ，ｓ），７．２４
（１Ｈ，ｍ），７．８０（１Ｈ，ｓ），８．２８（１
Ｈ，ｄ，Ｊ＝２．４Ｈｚ）， ＦＡＢ−ＭＳ（ｍ／ｅ）；２０９，２１１ 1 H NMR (CDCl 3 ) δ; 0.88
-1.98 (7H, m), 2.81 (1H, m), 3.
64 (1H, s), 3.89 (1H, s), 7.24
(1H, m), 7.80 (1H, s), 8.28 (1
H, d, J = 2.4 Hz), FAB-MS (m / e); 209,211

【００８４】［実施例９］ （１ＲＳ，２ＲＳ，４ＲＳ）−４−ベンジルオキシカル
ボニルアミノ−２−（６−メトキシ−３−ピリジル）−
１−シクロヘキシル ｐ−トルエンスルホネートExample 9 (1RS, 2RS, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl)-
1-cyclohexyl p-toluene sulfonate

【００８５】実施例４に於けるようにして得た（１Ｒ
Ｓ，２ＲＳ，４ＲＳ）−４−ベンジルオキシカルボニル
アミノ−２−（６−メトキシ−３−ピリジル）−１−シ
クロヘキサノール５５．０ｍｇ（０．１５ミリモル）を
乾燥ピリジン０．６ｍｌに溶解し、この溶液に氷冷下で
ｐ−トルエンスルホニルクロリド３５．０ｍｇ（０．１
８ミリモル）を加え、このまま１７時間攪拌した。更
に、ｐ−トルエンスルホニルクロリド２３．０ｍｇ
（０．１２ミリモル）を加え、室温で３時間攪拌を続け
た。反応液から溶媒を減圧留去した後、残渣をクロロホ
ルムに溶解し、水で洗浄した。無水硫酸ナトリウムで乾
燥し、溶媒を減圧留去した後、残渣を分取ＴＬＣ（酢酸
エチル：ヘキサン＝１：１）で精製し、標題化合物７．
５ｍｇ（収率９．８％）を白色結晶として得た。Obtained as in Example 4 (1R
55.0 mg (0.15 mmol) of S, 2RS, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl) -1-cyclohexanol was dissolved in 0.6 ml of dry pyridine. 35.0 mg (0.1%) of p-toluenesulfonyl chloride was added to the solution under ice cooling.
(8 mmol) was added, and the mixture was stirred as it was for 17 hours. Furthermore, p-toluenesulfonyl chloride 23.0 mg
(0.12 mmol) was added and stirring was continued at room temperature for 3 hours. After the solvent was distilled off from the reaction solution under reduced pressure, the residue was dissolved in chloroform and washed with water. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by preparative TLC (ethyl acetate: hexane = 1: 1) to give the title compound 7.
5 mg (yield 9.8%) was obtained as white crystals.

【００８６】1Ｈ ＮＭＲ（ＣＤＣｌ3 ）δ；１．３−
１．９（３Ｈ，ｍ），２．１（２Ｈ，ｍ），２．３９
（３Ｈ，ｓ），２．７−２．８（１Ｈ，ｍ），３．６−
３．８（１Ｈ，ｍ），３．９０（３Ｈ，ｓ），４．５−
４．７（１Ｈ，ｂｒ），４．８−４．９（１Ｈ，ｍ），
５．０６（２Ｈ，ｂｒｓ），６．３４（１Ｈ，ｄ，Ｊ＝
８Ｈｚ），７．０−７．１（１Ｈ，ｍ），７．２−７．
４（９Ｈ，ｍ），７．７４（１Ｈ，ｄ，Ｊ＝３Ｈｚ）． 1 H NMR (CDCl 3 ) δ; 1.3-
1.9 (3H, m), 2.1 (2H, m), 2.39
(3H, s), 2.7-2.8 (1H, m), 3.6-
3.8 (1H, m), 3.90 (3H, s), 4.5-
4.7 (1H, br), 4.8-4.9 (1H, m),
5.06 (2H, brs), 6.34 (1H, d, J =
8 Hz), 7.0-7.1 (1 H, m), 7.2-7.
4 (9H, m), 7.74 (1H, d, J = 3Hz).

【００８７】[0087]

【発明の効果】本発明は、鎮痛剤として有用なエピバチ
ジンを合成法により有利に製造することができるという
効果を奏する。INDUSTRIAL APPLICABILITY The present invention has an effect that epibatidine useful as an analgesic can be advantageously produced by a synthetic method.

Claims (8)

【特許請求の範囲】[Claims] 【請求項１】 下記の一般式（１）： 【化１】 （式中、Ｒ1 は炭素数１〜４のアルキル基又はベンジル
基を表し、Ｙは保護基を表す）で表される（１ＲＳ，２
ＲＳ，４ＳＲ）−２−（３−ピリジル）−７−アザビシ
クロ［２．２．１］ヘプタン誘導体を、オキシ塩化燐又
はホスゲンと反応させることを特徴とする（１ＲＳ，２
ＲＳ，４ＳＲ）−２−（６−クロロ−３−ピリジル）−
７−アザビシクロ［２．２．１］ヘプタンの製造方法。1. The following general formula (1): (Wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and Y represents a protecting group) (1RS, 2
RS, 4SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative is reacted with phosphorus oxychloride or phosgene (1RS, 2
RS, 4SR) -2- (6-chloro-3-pyridyl)-
A method for producing 7-azabicyclo [2.2.1] heptane. 【請求項２】 下記の一般式（１）： 【化２】 （式中、Ｒ1 は炭素数１〜４のアルキル基又はベンジル
基を表し、Ｙは保護基を表す）で表される（１ＲＳ，２
ＲＳ，４ＳＲ）−２−（３−ピリジル）−７−アザビシ
クロ［２．２．１］ヘプタン誘導体。2. The following general formula (1): (Wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and Y represents a protecting group) (1RS, 2
RS, 4SR) -2- (3-Pyridyl) -7-azabicyclo [2.2.1] heptane derivative. 【請求項３】 下記の一般式（２）： 【化３】 （式中、Ｒ1 は炭素数１〜４のアルキル基又はベンジル
基を表す）で表される（１ＲＳ，２ＲＳ，４ＳＲ）−２
−（３−ピリジル）−７−アザビシクロ［２．２．１］
ヘプタン誘導体。3. The following general formula (2): (In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group) (1RS, 2RS, 4SR) -2
-(3-Pyridyl) -7-azabicyclo [2.2.1]
Heptane derivative. 【請求項４】 下記の一般式（３）： 【化４】 （式中、Ｒ1 は炭素数１〜４のアルキル基又はベンジル
基を表し、Ｒ2 は炭素数１〜４のアルキル基、フェニル
基又はトリル基を表し、Ｗは水素原子又は保護基を表
す）で表される（１ＲＳ，２ＳＲ，４ＲＳ）−４−アミ
ノ−２−（３−ピリジル）−１−シクロヘキサノール誘
導体。4. The following general formula (3): (In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 2 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group or a tolyl group, and W represents a hydrogen atom or a protecting group. (1RS, 2SR, 4RS) -4-amino-2- (3-pyridyl) -1-cyclohexanol derivative represented by the formula (1). 【請求項５】 下記の一般式（４）： 【化５】 （式中、Ｒ1 は炭素数１〜４のアルキル基又はベンジル
基を表し、Ｗは水素原子又は保護基を表す）で表される
（１ＲＳ，２ＳＲ，４ＲＳ）−４−アミノ−２−（３−
ピリジル）−１−シクロヘキサノール誘導体。5. The following general formula (4): (In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and W represents a hydrogen atom or a protecting group) (1RS, 2SR, 4RS) -4-amino-2- ( 3-
Pyridyl) -1-cyclohexanol derivative. 【請求項６】 下記の一般式（５）： 【化６】 （式中、Ｒ1 は炭素数１〜４のアルキル基又はベンジル
基を表し、Ｒ3 は炭素数１〜４のアルキル基、炭素数２
〜５の脂肪族アシル基、環置換基として炭素数１〜４の
アルキル基を有していてもよいシクロヘキシルカルボニ
ル基、環置換基として炭素数１〜４のアルキル基、ニト
ロ基若しくはハロゲン原子を有していてもよいベンゾイ
ル基を表し、Ｙは保護基を表す）で表される（１ＲＳ，
２ＳＲ，４ＲＳ）−４−アミノ−２−（３−ピリジル）
−１−シクロヘキサノール誘導体。6. The following general formula (5): (In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, and 2 carbon atoms.
~ 5 aliphatic acyl group, a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms as a ring substituent, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a halogen atom. Represents a benzoyl group which may have and Y represents a protecting group) (1RS,
2SR, 4RS) -4-Amino-2- (3-pyridyl)
-1-Cyclohexanol derivative. 【請求項７】 下記の一般式（６）： 【化７】 （式中、Ｒ1 は炭素数１〜４のアルキル基又はベンジル
基を表し、Ｒ3 は炭素数１〜４のアルキル基、炭素数２
〜５の脂肪族アシル基、環置換基として炭素数１〜４の
アルキル基を有していてもよいシクロヘキシルカルボニ
ル基、環置換基として炭素数１〜４のアルキル基、ニト
ロ基若しくはハロゲン原子を有していてもよいベンゾイ
ル基を表す）で表される（１ＲＳ，２ＳＲ，４ＲＳ）−
４−アミノ−２−（３−ピリジル）−１−シクロヘキサ
ノール誘導体。7. The following general formula (6): (In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, and 2 carbon atoms.
~ 5 aliphatic acyl group, a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms as a ring substituent, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a halogen atom. (Representing a benzoyl group which may be possessed) is represented by (1RS, 2SR, 4RS)-
4-Amino-2- (3-pyridyl) -1-cyclohexanol derivative. 【請求項８】 下記の一般式（７）： 【化８】 （式中、Ｒ1 は炭素数１〜４のアルキル基又はベンジル
基を表し、Ｒ3 は炭素数１〜４のアルキル基、炭素数２
〜５の脂肪族アシル基、環置換基として炭素数１〜４の
アルキル基を有していてもよいシクロヘキシルカルボニ
ル基、環置換基として炭素数１〜４のアルキル基、ニト
ロ基若しくはハロゲン原子を有していてもよいベンゾイ
ル基を表す）で表される（３ＲＳ，４ＳＲ）−４−置換
オキシ−３−（３−ピリジル）シクロヘキサノン誘導
体。8. The following general formula (7): (In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, and 2 carbon atoms.
~ 5 aliphatic acyl group, a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms as a ring substituent, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a halogen atom. A (3RS, 4SR) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative represented by (representing a benzoyl group which may be possessed).
JP5128161A 1993-04-30 1993-04-30 Production of (1rs, 2rs, 4rs)-2-(6-chloro-3-pyridyl)-7-azabicyclo(2.2.1)heptane Withdrawn JPH06312989A (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817679A (en) * 1993-04-01 1998-10-06 University Of Virginia 7-Azabicyclo 2.2.1!-heptane and -heptene derivatives as cholinergic receptor ligands
US6060473A (en) * 1993-04-01 2000-05-09 Ucb S.A. - Dtb 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands
US6077846A (en) * 1993-09-10 2000-06-20 Ucb, S.A. Epibatidine and derivatives thereof as cholinergic receptor agonists and antagonists
US6117889A (en) * 1994-04-01 2000-09-12 University Of Virginia 7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents
KR100685121B1 (en) * 2005-10-14 2007-02-22 동부일렉트로닉스 주식회사 Non volatile memory device and method of manufacturing the same
JP2013505259A (en) * 2009-09-17 2013-02-14 バーテックス ファーマシューティカルズ インコーポレイテッド Process for preparing azabicyclic compounds
RU2591042C1 (en) * 2015-01-23 2016-07-10 Федеральное государственное унитарное предприятие "Государственный завод медицинских препаратов" Method for producing endo- and exo-isomers of 2- (6'-chloro-pyridin-3'-yl) -7-azabicyclo [2.2.1]heptane

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817679A (en) * 1993-04-01 1998-10-06 University Of Virginia 7-Azabicyclo 2.2.1!-heptane and -heptene derivatives as cholinergic receptor ligands
US6060473A (en) * 1993-04-01 2000-05-09 Ucb S.A. - Dtb 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands
US6077846A (en) * 1993-09-10 2000-06-20 Ucb, S.A. Epibatidine and derivatives thereof as cholinergic receptor agonists and antagonists
US6177451B1 (en) 1993-09-10 2001-01-23 Ucb, S.A. Epibatidine and derivatives thereof as nicotine cholinergic receptor agonists
US6117889A (en) * 1994-04-01 2000-09-12 University Of Virginia 7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents
KR100685121B1 (en) * 2005-10-14 2007-02-22 동부일렉트로닉스 주식회사 Non volatile memory device and method of manufacturing the same
JP2013505259A (en) * 2009-09-17 2013-02-14 バーテックス ファーマシューティカルズ インコーポレイテッド Process for preparing azabicyclic compounds
RU2591042C1 (en) * 2015-01-23 2016-07-10 Федеральное государственное унитарное предприятие "Государственный завод медицинских препаратов" Method for producing endo- and exo-isomers of 2- (6'-chloro-pyridin-3'-yl) -7-azabicyclo [2.2.1]heptane

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