JP2003342256A - Method for producing optically active 3-pyrrolidinyl- cyclopropanecarboxylic acid derivative - Google Patents
Method for producing optically active 3-pyrrolidinyl- cyclopropanecarboxylic acid derivativeInfo
- Publication number
- JP2003342256A JP2003342256A JP2002151913A JP2002151913A JP2003342256A JP 2003342256 A JP2003342256 A JP 2003342256A JP 2002151913 A JP2002151913 A JP 2002151913A JP 2002151913 A JP2002151913 A JP 2002151913A JP 2003342256 A JP2003342256 A JP 2003342256A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- compound
- compound represented
- dibenzylamine
- 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.)
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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
Landscapes
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、抗菌剤の合成中間
体として有用な光学活性な３−ピロリジニル−シクロプ
ロパンカルボン酸誘導体の製造法に関する。TECHNICAL FIELD The present invention relates to a method for producing an optically active 3-pyrrolidinyl-cyclopropanecarboxylic acid derivative useful as a synthetic intermediate for an antibacterial agent.
【０００２】[0002]
【従来の技術】式（Ｑ）2. Description of the Related Art Formula (Q)
【０００３】[0003]
【化１９】 [Chemical 19]
【０００４】（式中、Ｘ1はアミノ基又は水素原子を、
Ｘ2はフッ素原子又は水素原子を示す。）で表されるキ
ノロン誘導体は、幅広い抗菌活性を有し、特にグラム陽
性菌、とりわけＭＲＳＡに対して強力な抗菌活性を示
し、良好な体内動態、安全性をも兼ね備えており、抗菌
剤として有用であることが知られている（ＷＯ９７／１
９０７２号）。式（Ｑ）中、Ｘ1はアミノ基が、Ｘ2はフ
ッ素原子が好ましい。この化合物（Ｑ）は式（９）(In the formula, X 1 is an amino group or a hydrogen atom,
X 2 represents a fluorine atom or a hydrogen atom. The quinolone derivative represented by) has a wide range of antibacterial activities, particularly shows strong antibacterial activity against Gram-positive bacteria, especially MRSA, has good pharmacokinetics and safety, and is useful as an antibacterial agent. Is known to be (WO97 / 1
9072). In formula (Q), X 1 is preferably an amino group and X 2 is preferably a fluorine atom. This compound (Q) has the formula (9)
【０００５】[0005]
【化２０】 [Chemical 20]
【０００６】（式中、Ｒ1はアミノ基の保護基であって
不斉炭素を一つ有し、かつ立体配置の特定された基を示
し、３位のシクロプロピル基と４位のフルオロ原子はシ
ス配置である。）で表される光学活性な３−ピロリジニ
ル−シクロプロパンカルボン酸誘導体を用いて製造でき
る。そしてこの化合物（９）の製法としては、次の反応
式で示される方法が知られている（ＷＯ９７／１９０７
２号）。(In the formula, R 1 is a protecting group for an amino group, has one asymmetric carbon atom, and represents a group having a specified steric configuration, and represents a cyclopropyl group at the 3-position and a fluoro atom at the 4-position. Is a cis configuration.) It can be produced using an optically active 3-pyrrolidinyl-cyclopropanecarboxylic acid derivative. As a method for producing this compound (9), a method represented by the following reaction formula is known (WO97 / 1907).
No. 2).
【０００７】[0007]
【化２１】 [Chemical 21]
【０００８】（式中、Ｒ2はカルボキシル基の保護基を
示し、Ｒ1は前記と同じ）(In the formula, R 2 represents a protecting group for a carboxyl group, and R 1 is the same as above)
【０００９】すなわち、式（５）の化合物を白金触媒の
存在下に接触還元して式（１０）の化合物とし、これを
シリカゲルカラムクロマトグラフィー等により光学分割
して光学活性な式（１１）の化合物を得、次いで加水分
解することにより化合物（９）が製造されている。That is, the compound of formula (5) is catalytically reduced in the presence of a platinum catalyst to give a compound of formula (10), which is optically resolved by silica gel column chromatography or the like to obtain an optically active compound of formula (11). The compound (9) is produced by obtaining the compound and then hydrolyzing it.
【００１０】[0010]
【発明が解決しようとする課題】しかし、この方法は高
価な白金触媒を使用し、かつカラムを用いて光学分割す
るため工業的な大量生産には適さなかった。However, this method is not suitable for industrial mass production because it uses an expensive platinum catalyst and carries out optical resolution using a column.
【００１１】従って、本発明の目的は、抗菌剤の合成中
間体として重要な式（９）の化合物の工業的に有利な製
造法を提供することにある。Accordingly, it is an object of the present invention to provide an industrially advantageous method for producing a compound of formula (9) which is important as a synthetic intermediate for antibacterial agents.
【００１２】[0012]
【課題を解決するための手段】そこで本発明者は、種々
検討した結果、上記化合物（１０）のエステル体でなく
カルボン酸体を得、これにジベンジルアミンを反応させ
れば所望の立体配置を有するカルボン酸体のみが塩を形
成するので、この塩を酸で処理すれば光学活性な化合物
（９）が工業的に有利に得られることを見出した。さら
に、上記化合物（５）のカルボン酸体をパラジウム触媒
の存在下に接触還元すれば、所望の立体配置を有するカ
ルボン酸体が効率良く得られることを見出し、本発明を
完成するに至った。Therefore, as a result of various investigations, the present inventor obtained a carboxylic acid compound instead of an ester compound of the compound (10), and reacted with dibenzylamine to obtain a desired steric configuration. It was found that the optically active compound (9) can be industrially advantageously obtained by treating the salt with an acid, since only the carboxylic acid compound having Further, they have found that a carboxylic acid compound having a desired steric configuration can be efficiently obtained by catalytically reducing the carboxylic acid compound of the compound (5) in the presence of a palladium catalyst, and completed the present invention.
【００１３】本発明方法を出発原料から示せば次の反応
式で表される。The starting material of the method of the present invention is represented by the following reaction formula.
【００１４】[0014]
【化２２】 [Chemical formula 22]
【００１５】（式中、Ｒ3はカルボキシル基の保護基を
示し、Ｒ4はホスホン酸残基の保護基を示し、Ｙはハロ
ゲン原子または水素原子を示し、Ｘはハロゲン原子を示
し、Ｂｎ 2ＮＨはジベンジルアミンを示し、Ｒ1及びＲ2
は前記と同じ）(Wherein R3Is a protecting group for the carboxyl group
Show, RFourRepresents a protecting group for a phosphonic acid residue, and Y represents halo.
Represents a gen atom or a hydrogen atom, and X represents a halogen atom.
And then Bn 2NH represents dibenzylamine, R1And R2
Is the same as above)
【００１６】すなわち、本発明は、式（７）で表される
化合物をジベンジルアミンで処理し、式（９）で表され
る化合物のジベンジルアミン塩（すなわち、式（８）の
化合物）次いで酸で処理することを特徴とする式（９）
で表される化合物の製造法を提供するものである。That is, according to the present invention, the compound represented by the formula (7) is treated with dibenzylamine to obtain a dibenzylamine salt of the compound represented by the formula (9) (that is, the compound represented by the formula (8)). Formula (9) characterized by subsequent treatment with acid
The present invention provides a method for producing a compound represented by:
【００１７】また、本発明は、式（６）で表される化合
物をパラジウム触媒の存在下に接触還元して次式（７）
で表される化合物を得、これをジベンジルアミンで処理
し、式（９）で表される化合物のジベンジルアミン塩を
単離し、次いで酸で処理することを特徴とする式（９）
で表される化合物の製造法を提供するものである。In the present invention, the compound represented by the formula (6) is catalytically reduced in the presence of a palladium catalyst to give the following formula (7):
A compound of formula (9), which is treated with dibenzylamine to isolate the dibenzylamine salt of the compound of formula (9) and then treated with acid.
The present invention provides a method for producing a compound represented by:
【００１８】さらに、本発明方法に用いられる式（６）
の化合物は、式（１）で表される化合物に式（２）で表
される化合物を反応させ、Ｙが水素原子である場合はさ
らにハロゲン化剤で処理して式（３）で表される化合物
を得、これに式（４）で表される化合物を反応させて式
（５）で表される化合物を得、これを加水分解すること
により得られる。Further, the formula (6) used in the method of the present invention is used.
The compound of formula (3) is obtained by reacting the compound of formula (1) with the compound of formula (2), and when Y is a hydrogen atom, it is further treated with a halogenating agent. The compound of formula (4) is reacted with the compound of formula (4) to obtain the compound of formula (5), which is hydrolyzed.
【００１９】[0019]
【発明の実施の形態】本発明方法を前記反応式の各工程
〔（Ａ）〜（Ｆ）〕毎に説明する。BEST MODE FOR CARRYING OUT THE INVENTION The method of the present invention will be described for each step [(A) to (F)] of the above reaction scheme.
【００２０】（１）工程（Ａ）
工程（Ａ）は、化合物（１）に式（２）で表される化合
物を反応させ、Ｙが水素原子である場合はさらにハロゲ
ン化剤で処理して式（３）で表される化合物を得る工程
である。(1) Step (A) In step (A), compound (1) is reacted with a compound represented by formula (2), and when Y is a hydrogen atom, it is further treated with a halogenating agent. This is a step of obtaining a compound represented by the formula (3).
【００２１】式（１）中、Ｙのハロゲン原子としては、
塩素原子、臭素原子又はヨウ素原子が挙げられるが、塩
素原子又は臭素原子が好ましい。またＲ2及びＲ3のカル
ボキシル基の保護基並びにＲ4のホスホン酸残基の保護
基としては、エステルを形成する基であればよく、炭素
数１〜６のアルキレン基とフェニル基とから構成される
置換基を有していてもよいフェニルアルキル基（アラル
キル基）、置換基を有していてもよい炭素数１〜６のア
ルキル基、置換基を有していてもよい炭素数２〜７のア
ルコキシメチル基等を挙げることができる。またフェニ
ルアルキル基、アルキル基の置換基としては、炭素数１
〜６のアルキル基、ハロゲン原子、ニトロ基からなる群
から選ばれる１〜３個が挙げられる。これらのうち、フ
ェニルアルキル基、アルキル基が好ましい。ハロゲン化
剤としては塩素、臭素、Ｎ−クロロコハク酸イミド、Ｎ
−ブロモコハク酸イミド等が用いられ、必要に応じてア
ゾビスイソブチロニトリル（ＡＩＢＮ）等のラジカル開
始剤を添加しても良い。In the formula (1), the halogen atom of Y is
A chlorine atom, a bromine atom or an iodine atom can be mentioned, but a chlorine atom or a bromine atom is preferable. The protecting group for the carboxyl group of R 2 and R 3 and the protecting group for the phosphonic acid residue of R 4 may be any group that forms an ester, and is composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group. A phenylalkyl group (aralkyl group) that may have a substituent, an alkyl group having 1 to 6 carbon atoms that may have a substituent, and a carbon number 2 that may have a substituent. The alkoxymethyl group of 7 and the like can be mentioned. The phenylalkyl group and the substituent of the alkyl group have 1 carbon atoms.
1 to 3 selected from the group consisting of an alkyl group of 6 to 6, a halogen atom and a nitro group. Of these, a phenylalkyl group and an alkyl group are preferable. As a halogenating agent, chlorine, bromine, N-chlorosuccinimide, N
-Bromosuccinimide or the like is used, and if necessary, a radical initiator such as azobisisobutyronitrile (AIBN) may be added.
【００２２】工程（Ａ）の反応は、塩基の存在下に行う
のが好ましい。用いられる塩基としては水素化ナトリウ
ム、金属アルコキシド、炭酸カリウム、ブチルリチウ
ム、トリエチルアミン、ピリジンなどが挙げられるが、
好ましくは水素化ナトリウム等の強塩基が好ましい。溶
媒の種類はテトラヒドロフラン、トルエン、クロロホル
ムなど反応に悪影響を与えない溶媒であればよいが、好
ましくはテトラヒドロフランである。The reaction of step (A) is preferably carried out in the presence of a base. Examples of the base used include sodium hydride, metal alkoxide, potassium carbonate, butyllithium, triethylamine, pyridine and the like,
A strong base such as sodium hydride is preferred. The solvent may be any solvent that does not adversely affect the reaction, such as tetrahydrofuran, toluene, chloroform, etc., but is preferably tetrahydrofuran.
【００２３】（２）工程（Ｂ）
工程（Ｂ）は、化合物（３）に式（４）で表される光学
活性なアミンを反応させて化合物（５）を得る工程であ
る。ここでＲ1は、アミノ基の保護基であって不斉炭素
を一つ有し、かつ、立体配置の特定された基を示し、例
えば、（Ｒ）−１−フェニルエチル基、（Ｓ）−１−フ
ェニルエチル基、（Ｒ）−１−フェニルプロピル基、
（Ｓ）−１−フェニルプロピル基、（Ｒ）−１−フェニ
ル−２−（ｐ−トリル）エチル基、（Ｓ）−１−フェニ
ル−２−（ｐ−トリル）エチル基、（Ｒ）−１−（１−
ナフチル）エチル基、（Ｓ）−１−（１−ナフチル）エ
チル基、（Ｒ）−１−（４−メトキシフェニル）エチル
基、（Ｓ）−１−（４−メトキシフェニル）エチル基、
（Ｒ）−１−（４−クロロフェニル）エチル基、（Ｓ）
−１−（４−クロロフェニル）エチル基、（Ｒ）−１−
（４−ニトロフェニル）エチル基、（Ｓ）−１−（４−
ニトロフェニル）エチル基、（Ｒ）−１−（２，４−ジ
クロロフェニル）エチル基、（Ｓ）−１−（２，４−ジ
クロロフェニル）エチル基、（Ｒ）−１−（２，４−ジ
ニトロフェニル）エチル基、（Ｓ）−１−（２，４−ジ
ニトロフェニル）エチル基、（Ｒ）−１−（３，５−ジ
クロロフェニル）エチル基、（Ｓ）−１−（３，５−ジ
クロロフェニル）エチル基、（Ｒ）−１−（３，５−ジ
ニトロフェニル）エチル基及び（Ｓ）−１−（３，５−
ジニトロフェニル）エチル基等が挙げられる。Ｒ1は、
（Ｒ）−１−フェニルエチル基又は（Ｓ）−１−フェニ
ルエチル基であるのが好ましい。工程（Ｂ）の反応は、
塩基の存在下に行うのが好ましい。用いられる塩基とし
ては、炭酸水素ナトリウム、水酸化ナトリウム、水酸化
カリウム、炭酸ナトリウム、炭酸カリウム、トリエチル
アミン、ピリジン等が好ましい。溶媒は用いる塩基によ
り適宜選択すればよく、例えば、酢酸エチル、メタノー
ル、エタノール、イソプロパノール、テトラヒドロフラ
ン、トルエン、ヘキサン、クロロホルム、アセトニトリ
ル等の反応に悪影響を与えない溶媒であれば良い。反応
温度および時間は、−５℃から溶媒の沸点で、３０分間
から５時間程度が好ましい。(2) Step (B) Step (B) is a step in which compound (3) is reacted with an optically active amine represented by formula (4) to obtain compound (5). Here, R 1 is a protecting group for an amino group, has one asymmetric carbon atom, and represents a group having a specified configuration, for example, (R) -1-phenylethyl group, (S) -1-phenylethyl group, (R) -1-phenylpropyl group,
(S) -1-phenylpropyl group, (R) -1-phenyl-2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p-tolyl) ethyl group, (R)- 1- (1-
Naphthyl) ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S) -1- (4-methoxyphenyl) ethyl group,
(R) -1- (4-chlorophenyl) ethyl group, (S)
-1- (4-chlorophenyl) ethyl group, (R) -1-
(4-nitrophenyl) ethyl group, (S) -1- (4-
Nitrophenyl) ethyl group, (R) -1- (2,4-dichlorophenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dinitro) Phenyl) ethyl group, (S) -1- (2,4-dinitrophenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3,5-dichlorophenyl) ) Ethyl group, (R) -1- (3,5-dinitrophenyl) ethyl group and (S) -1- (3,5-
A dinitrophenyl) ethyl group etc. are mentioned. R 1 is
It is preferably (R) -1-phenylethyl group or (S) -1-phenylethyl group. The reaction in step (B) is
It is preferably carried out in the presence of a base. As the base used, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, pyridine and the like are preferable. The solvent may be appropriately selected depending on the base used, and for example, any solvent which does not adversely influence the reaction such as ethyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, hexane, chloroform and acetonitrile may be used. The reaction temperature and time are preferably -5 ° C to the boiling point of the solvent, and about 30 minutes to 5 hours.
【００２４】（３）工程（Ｃ）
工程（Ｃ）は、化合物（５）を加水分解して化合物
（６）を得る工程である。工程（Ｃ）の加水分解反応
は、炭酸水素ナトリウム、水酸化ナトリウム、水酸化カ
リウム、炭酸ナトリウム、炭酸カリウム等の塩基の存在
下で行うのが好ましい。特に、好ましくは水酸化ナトリ
ウム又は水酸化カリウムである。(3) Step (C) Step (C) is a step of hydrolyzing compound (5) to obtain compound (6). The hydrolysis reaction in step (C) is preferably carried out in the presence of a base such as sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. Particularly preferred is sodium hydroxide or potassium hydroxide.
【００２５】（４）工程（Ｄ）
工程（Ｄ）は、化合物（６）をパラジウム触媒の存在下
に接触還元して化合物（７）を得る工程である。用いる
パラジウム触媒としては、パウジウム−黒、パラジウム
−炭素、パラジウム−アルミナ、パラジウム−ゼオライ
ト等が挙げられるがパラジウム−炭素が好ましい。接触
還元反応における水素圧は、常圧であればよい。しかし
ながら常圧といっても水素ガスの供給のために多少の加
圧状態をつけることがある。反応温度は０℃〜溶媒の還
流温度、反応時間は１〜７２時間が好ましい。(4) Step (D) Step (D) is a step of catalytically reducing compound (6) in the presence of a palladium catalyst to obtain compound (7). Examples of the palladium catalyst to be used include palladium-black, palladium-carbon, palladium-alumina, palladium-zeolite and the like, but palladium-carbon is preferable. The hydrogen pressure in the catalytic reduction reaction may be normal pressure. However, even at normal pressure, some pressure may be applied to supply hydrogen gas. The reaction temperature is preferably 0 ° C. to the reflux temperature of the solvent, and the reaction time is preferably 1 to 72 hours.
【００２６】パラジウム触媒を用いた接触還元反応によ
れば、還元体の面選択性が優れている。なお、還元反応
の面選択性をαとβとの比で表すが、ここでα体とは
（３Ｓ，４Ｓ）体（式（９）に相当）を意味し、β体と
は（３Ｒ，４Ｒ）体を意味する。According to the catalytic reduction reaction using a palladium catalyst, the surface selectivity of the reductant is excellent. The surface selectivity of the reduction reaction is represented by the ratio of α to β, where the α-form means the (3S, 4S) -form (corresponding to formula (9)) and the β-form means (3R, 4R) means a body.
【００２７】（５）工程（Ｅ）
工程（Ｅ）は、化合物（７）をジベンジルアミンで処理
して光学活性なジベンジルアミン塩（８）とし、次いで
酸で処理して光学活性な化合物（９）を得る工程であ
る。(5) Step (E) In step (E), compound (7) is treated with dibenzylamine to give an optically active dibenzylamine salt (8), and then treated with acid to give an optically active compound. This is a step of obtaining (9).
【００２８】化合物（７）とジベンジルアミンとの反応
は、酢酸エチル、テトラヒドロフラン、トルエン、イソ
プロパノール、アセトニトリルなどの溶媒中、室温〜溶
媒の沸点までで行えばよい。The reaction of the compound (7) with dibenzylamine may be carried out in a solvent such as ethyl acetate, tetrahydrofuran, toluene, isopropanol and acetonitrile at room temperature to the boiling point of the solvent.
【００２９】得られた光学活性ジベンジルアミン塩
（８）の酸処理は塩酸、硫酸、硝酸などのプロトン酸で
あって、化合物（９）のカルボン酸より強酸であればど
の酸を用いて中和しても良いが、好ましくは硫酸であ
る。The acid treatment of the obtained optically active dibenzylamine salt (8) is a protonic acid such as hydrochloric acid, sulfuric acid or nitric acid, and any acid can be used as long as it is a stronger acid than the carboxylic acid of the compound (9). Although it may be added, sulfuric acid is preferable.
【００３０】前記のジベンジルアミン塩（８）として
は、次式（８ａ）The dibenzylamine salt (8) is represented by the following formula (8a)
【００３１】[0031]
【化２３】 [Chemical formula 23]
【００３２】で表される塩が特に好ましい。Particularly preferred are salts represented by:
【００３３】本発明で製造された式（１２）で表わされ
る光学活性化合物を原料として、例えば式（１５）で表
わされる化合物が次の方法で製造され、この化合物から
式（Ｑ）で表わされるキノロン系合成抗菌剤が製造され
る（ＷＯ９７／１９０７２号公報）。From the optically active compound represented by the formula (12) produced in the present invention as a raw material, a compound represented by the formula (15) is produced by the following method, and the compound represented by the formula (Q) is produced. A quinolone synthetic antibacterial agent is produced (WO97 / 19072).
【００３４】[0034]
【化２４】 [Chemical formula 24]
【００３５】（式中、Ｒ5はＲ2と同様のカルボキシル基
の保護基を示し、Bocはｔ−ブトキシカルボニル基を示
し、Ｘ1及びＸ2は前記と同じ。）(In the formula, R 5 represents a protecting group for a carboxyl group similar to R 2 , Boc represents a t-butoxycarbonyl group, and X 1 and X 2 are the same as above.)
【００３６】すなわち、化合物（１２）をエステル化し
て得た化合物（１３）にローソン試薬を反応させて化合
物（１４）とし、これをラネーニッケル等の金属触媒の
存在下接触還元して化合物（１５）とし、これにクロロ
炭酸ベンジルを反応させて化合物（１６）とし、これを
加水分解して化合物（１７）とし、これをホフマン転位
反応に付して化合物（１８）とし、金属触媒の存在下に
接触還元して化合物（１９）を得る。この化合物（１
９）とキノロン化合物（２０）とを反応させることによ
り化合物（Ｑ）が得られる。That is, compound (13) obtained by esterifying compound (12) is reacted with Lawesson's reagent to give compound (14), which is catalytically reduced in the presence of a metal catalyst such as Raney nickel to give compound (15). Then, this is reacted with benzyl chlorocarbonate to give compound (16), which is hydrolyzed to give compound (17), which is subjected to a Hofmann rearrangement reaction to give compound (18) in the presence of a metal catalyst. Catalytic reduction gives compound (19). This compound (1
Compound (Q) is obtained by reacting 9) with quinolone compound (20).
【００３７】一方、化合物（９）を原料として、例えば
次の方法によっても化合物（Ｑ）を製造することができ
る。On the other hand, using the compound (9) as a starting material, the compound (Q) can also be produced, for example, by the following method.
【００３８】[0038]
【化２５】 [Chemical 25]
【００３９】（式中、Ｘ1、Ｘ2、Ｒ1及びBocは前記と同
じ。）(In the formula, X 1 , X 2 , R 1 and Boc are the same as above.)
【００４０】すなわち、化合物（９）をクルチウス転位
反応に付して化合物（２１）とし、これを例えばボラン
還元により化合物（２２）とし、これを脱保護した後塩
晶析させて化合物（２３）を得、酸で処理すれば化合物
（１９）が得られる。この化合物（１９）とキノロン化
合物（２０）を反応させれば化合物（Ｑ）が得られる
（ＷＯ９８／５２９３９）。That is, the compound (9) is subjected to the Curtius rearrangement reaction to obtain the compound (21), which is, for example, reduced by borane to give the compound (22), which is deprotected and crystallized with salt to give the compound (23). Is obtained and treated with an acid to obtain the compound (19). The compound (Q) can be obtained by reacting the compound (19) with the quinolone compound (20) (WO98 / 52939).
【００４１】[0041]
【実施例】以下実施例を挙げて本発明を説明するが、本
発明はこれら実施例により何ら限定されるものではな
い。The present invention will be described below with reference to examples, but the present invention is not limited to these examples.
【００４２】実施例１エチル ４−ブロモ−３−（１−エトキシカルボニルシ
クロプロピル）−２−フルオロ−２−ブテノアート
エチル １−（２−ブロモアセチル）シクロプロパンカ
ルボキシレート（１ｇ）、トリエチル ２−フルオロ−
２−ホスホノアセテート（１．０８ｇ）のテトラヒドロ
フラン（２mL）溶液を６０％ＮａＨ（０．１８７ｇ）の
テトラヒドロフラン（８mL）懸濁液に５℃で攪拌下に滴
下した。滴下後反応液を室温に昇温し、２時間攪拌反応
した。反応液を５℃まで氷冷し、水５mLを滴下し、攪
拌、分液した。有機層を取り、水層を酢酸エチル（１０
mL）で抽出した。有機層を合わせ、飽和重曹水（１０m
L）、飽和食塩水（１０mL）の順に洗浄し、無水硫酸ナ
トリウムで乾燥した。溶媒を減圧留去し、得られた残渣
（１．３８ｇ）をシリカゲルカラムクロマトグラフィー
に付し、酢酸エチル：ヘキサン＝０：１００→１０：９
０で展開することにより、標題化合物を淡黄色オイルと
して０．６６ｇ得た。Example 1 Ethyl 4-bromo-3- (1-ethoxycarbonyloxy)
Chloropropyl) -2-fluoro-2-butenoate ethyl 1- (2-bromoacetyl) cyclopropanecarboxylate (1 g), triethyl 2-fluoro-
A solution of 2-phosphonoacetate (1.08 g) in tetrahydrofuran (2 mL) was added dropwise to a suspension of 60% NaH (0.187 g) in tetrahydrofuran (8 mL) at 5 ° C with stirring. After the dropping, the reaction solution was heated to room temperature and reacted with stirring for 2 hours. The reaction solution was ice-cooled to 5 ° C., 5 mL of water was added dropwise, and the mixture was stirred and separated. The organic layer is taken and the aqueous layer is washed with ethyl acetate (10
mL). Combine the organic layers and add saturated aqueous sodium hydrogen carbonate (10 m
L) and saturated brine (10 mL) were washed in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained residue (1.38 g) was subjected to silica gel column chromatography, and ethyl acetate: hexane = 0: 100 → 10: 9.
Development at 0 gave 0.66 g of the title compound as a pale yellow oil.
【００４３】実施例２１−［４−フルオロ−５−オキソ−１−［（１Ｒ）−１
−フェニルエチル］−２，５−ジヒドロ−１Ｈ−ピロー
ル−３−イル］シクロプロパンカルボン酸エチル
エチル １−［（１Ｅ）−１−（ブロモメチル）−３−
エトキシ−２−フルオロ−３−オキソ−１−プロペニ
ル］シクロプロパンカルボキシレート（６４．６ｇ）の
エタノール（２００mL）溶液を、炭酸水素ナトリウム
（４２．０ｇ）のエタノール（２００mL）懸濁液に室温
で攪拌下に滴下した。次いで、懸濁液に（Ｒ）−１−フ
ェニルエチルアミン（２６．６５ｇ）のエタノール（２
００mL）溶液を室温下で滴下し、反応液を攪拌下に２時
間加熱還流した。原料消失を確認後、反応液を放冷し、
不溶物を濾去し、濾液を減圧濃縮した。残渣に酢酸エチ
ル（２００mL）を加え、再度不溶物を濾去した。濾液を
１Ｎ塩酸、５％炭酸水素ナトリウム水溶液、飽和食塩水
の順に洗浄し、有機層を減圧濃縮することにより標題化
合物を黒褐色油状物として６５．２ｇ得た。Example 2 1- [4-fluoro-5-oxo-1-[(1R) -1
-Phenylethyl] -2,5-dihydro-1H-pillow
-3-yl] cyclopropanecarboxylic acid ethyl ethyl 1 - [(1E) -1- (bromomethyl) -3-
Ethoxy-2-fluoro-3-oxo-1-propenyl] cyclopropanecarboxylate (64.6 g) in ethanol (200 mL) was added to a solution of sodium hydrogen carbonate (42.0 g) in ethanol (200 mL) at room temperature. It was added dropwise with stirring. Then, (R) -1-phenylethylamine (26.65 g) in ethanol (2
(00 mL) was added dropwise at room temperature, and the reaction solution was heated under reflux with stirring for 2 hours. After confirming the disappearance of the raw materials, let the reaction liquid cool down,
The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (200 mL) was added to the residue, and the insoluble material was filtered off again. The filtrate was washed successively with 1N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was concentrated under reduced pressure to give the title compound (65.2 g) as a dark brown oil.
【００４４】実施例３１−［４−フルオロ−５−オキソ−１−［（１Ｒ）−１
−フェニルエチル］−２，５−ジヒドロ−１Ｈ−ピロー
ル−３−イル］シクロプロパンカルボン酸
１−［４−フルオロ−５−オキソ−１−［（１Ｒ）−１
−フェニルエチル］−２，５−ジヒドロ−１Ｈ−ピロー
ル−３−イル］シクロプロパンカルボン酸 エチル（６
５．２ｇ）のメタノール（６５mL）溶液に２Ｎ水酸化ナ
トリウム水溶液（１６３mL）を４０℃で撹拌下に滴下
し、同温で３時間攪拌した。原料消失を確認後、反応液
を放冷し、不溶物を濾去して濾液を水洗（３３mL）し
た。有機層を減圧濃縮し、残渣にＩＰＥ（６５mL）と水
（２０mL）を加え、抽出を行い、水層を合わせた。水層
を酢酸（９８mL）へ攪拌下、滴下し、さらに水（５２０
mL）を加えた後、６℃まで氷冷し、１時間攪拌した。析
出する結晶を濾取し、ＩＰＥでスラリー洗浄後、減圧乾
燥することにより標題化合物を黄褐色結晶として４４．
０４ｇ得た。Example 3 1- [4-fluoro-5-oxo-1-[(1R) -1
-Phenylethyl] -2,5-dihydro-1H-pillow
Lu-3-yl] cyclopropanecarboxylic acid 1- [4-fluoro-5-oxo-1-[(1R) -1
-Phenylethyl] -2,5-dihydro-1H-pyrrol-3-yl] cyclopropanecarboxylate ethyl (6
A 2N aqueous sodium hydroxide solution (163 mL) was added dropwise to a solution of 5.2 g) in methanol (65 mL) at 40 ° C. with stirring, and the mixture was stirred at the same temperature for 3 hours. After confirming the disappearance of the raw materials, the reaction solution was allowed to cool, the insoluble material was filtered off, and the filtrate was washed with water (33 mL). The organic layer was concentrated under reduced pressure, IPE (65 mL) and water (20 mL) were added to the residue, extraction was performed, and the aqueous layers were combined. The aqueous layer was added dropwise to acetic acid (98 mL) with stirring, and water (520 mL) was added.
(mL) and then ice-cooled to 6 ° C., and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with IPE slurry, and dried under reduced pressure to give the title compound as yellowish brown crystals.
04 g was obtained.
【００４５】実施例４１−［（ｃｉｓ−３，４）−４−フルオロ−５−オキソ
−１−［（１Ｒ）−１−フェニルエチル］ピロリジニ
ル］シクロプロパンカルボン酸
１−［４−フルオロ−５−オキソ−１−［（１Ｒ）−１
−フェニルエチル］−２，５−ジヒドロ−１Ｈ−ピロー
ル−３−イル］シクロプロパンカルボン酸（３０ｇ）の
ＴＨＦ（６００mL）溶液に、５％Ｐｄ−Ｃ（６０ｇ：Ｐ
Ｅタイプ、５５％ｗｅｔ）を添加し、水素雰囲気下、３
０℃で３時間攪拌した。Ｐｄ−Ｃを濾去し、濾液を無水
硫酸ナトリウムで乾燥した。溶媒を減圧留去し、標題化
合物を粘性油状物として３０．８４ｇ（α：β＝１：
４．８）得た。Example 4 1-[(cis-3,4) -4-fluoro-5-oxo
-1-[(1R) -1-phenylethyl] pyrrolidini
L] cyclopropanecarboxylic acid 1- [4-fluoro-5-oxo-1-[(1R) -1
-Phenylethyl] -2,5-dihydro-1H-pyrrol-3-yl] cyclopropanecarboxylic acid (30 g) in THF (600 mL) solution with 5% Pd-C (60 g: P
E type, 55% wet) was added, and under hydrogen atmosphere, 3
The mixture was stirred at 0 ° C for 3 hours. Pd-C was filtered off, and the filtrate was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a viscous oily substance, 30.84 g (α: β = 1:
4.8) obtained.
【００４６】実施例５１−［（３Ｓ，４Ｓ）−４−フルオロ−５−オキソ−１
−［（１Ｒ）−１−フェニルエチル］ピロリジニル］シ
クロプロパンカルボン酸・１／２ジベンジルアミン塩
１−［（３，４−ｃｉｓ）−４−フルオロ−５−オキソ
−１−［（１Ｒ）−１−フェニルエチル］ピロリジニ
ル］シクロプロパンカルボン酸（３０．８４ｇ）の酢酸
エチル（６０mL）懸濁液に、ジベンジルアミン（２０．
５ｇ）の酢酸エチル（６０mL）溶液を５０℃加熱攪拌下
に添加した。５０℃加温撹拌下、反応溶液に温ＩＰＥ
（８４０mL）を滴下し、結晶析出確認後２５℃まで放冷
した。結晶を濾取し、ＩＰＥ（６０mL）で洗浄、減圧乾
燥することにより粗結晶３１．０６ｇ（９３．４％ｄ．
ｅ．）を得た。粗結晶に酢酸エチル（１２４mL）を加
え、加熱溶解し、６０℃〜６５℃で温ＩＰＥ（９３０m
L）を滴下し、結晶析出確認後、攪拌放冷した。内温３
０℃で氷冷を開始し、内温３℃で１時間攪拌した。結晶
を濾取し、ＩＰＥで洗浄し、減圧乾燥することにより標
題化合物を無色結晶として２８．５０ｇ（９８．１％
ｄ．ｅ．）得た。
Anal. Calcd for C16H16FNO3・1/2C14H15N:C,70.84; H,
6.59; N,5.39; F,4.87.Found:C,70.72; H,6.59; N,5.2
7; F,4.92.Example 5 1-[(3S, 4S) -4-fluoro-5-oxo-1
-[(1R) -1-phenylethyl] pyrrolidinyl] si
Clopropanecarboxylic acid 1/2 dibenzylamine salt 1-[(3,4-cis) -4-fluoro-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidinyl] cyclopropanecarboxylic acid ( To a suspension of 30.84 g) in ethyl acetate (60 mL), dibenzylamine (20.
A solution of 5 g) in ethyl acetate (60 mL) was added with heating and stirring at 50 ° C. Warm IPE to the reaction solution under heating and stirring at 50 ° C.
(840 mL) was added dropwise, and after confirmation of crystal precipitation, the mixture was allowed to cool to 25 ° C. The crystals were collected by filtration, washed with IPE (60 mL), and dried under reduced pressure to give 31.06 g of crude crystals (93.4% d.p.).
e. ) Got. Ethyl acetate (124 mL) was added to the crude crystals and dissolved by heating, and warm IPE (930 m) was added at 60 ° C to 65 ° C.
L) was added dropwise, and after confirmation of crystal precipitation, the mixture was allowed to cool with stirring. Inner temperature 3
Ice cooling was started at 0 ° C., and the mixture was stirred at an internal temperature of 3 ° C. for 1 hr. The crystals were collected by filtration, washed with IPE, and dried under reduced pressure to give the title compound as colorless crystals (28.50 g, 98.1%).
d. e. )Obtained. Anal.Calcd for C 16 H 16 FNO 3・ 1 / 2C 14 H 15 N: C, 70.84; H,
6.59; N, 5.39; F, 4.87.Found: C, 70.72; H, 6.59; N, 5.2
7; F, 4.92.
【００４７】実施例６１−［（３Ｓ，４Ｓ）−４−フルオロ−５−オキソ−１
−［（１Ｒ）−１−フェニルエチル］ピロリジニル］シ
クロプロパンカルボン酸
１−［（３Ｓ，４Ｓ）−４−フルオロ−５−オキソ−１
−［（１Ｒ）−１−フェニルエチル］ピロリジニル］シ
クロプロパンカルボン酸・１／２ジベンジルアミン塩
（２７．５０ｇ）をトルエン（２７５mL）に加え、攪拌
した。０．５Ｎ硫酸（２２０mL）を添加し、４０℃で３
０分攪拌した。有機層を分取し、水層をトルエンで抽出
した。全有機層を合わせ、０．０５Ｎ硫酸、水（５５m
L）の順に洗浄し、無水硫酸ナトリウムで乾燥した。溶
媒を減圧留去後、４０℃で減圧乾燥することにより標題
化合物を無色結晶として２０．２８ｇ（９９．７％ｄ．
ｅ．）得た。Example 6 1-[(3S, 4S) -4-fluoro-5-oxo-1
-[(1R) -1-phenylethyl] pyrrolidinyl] si
Clopropanecarboxylic acid 1-[(3S, 4S) -4-fluoro-5-oxo-1
-[(1R) -1-Phenylethyl] pyrrolidinyl] cyclopropanecarboxylic acid.1 / 2 dibenzylamine salt (27.50 g) was added to toluene (275 mL), and the mixture was stirred. Add 0.5 N sulfuric acid (220 mL) and add 3 at 40 ° C.
Stir for 0 minutes. The organic layer was separated and the aqueous layer was extracted with toluene. Combine all organic layers and add 0.05N sulfuric acid and water (55m
L) was washed in this order and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was dried under reduced pressure at 40 ° C. to give 20.28 g (99.7% d.
e. )Obtained.
【００４８】実施例７ｔｅｒｔ−ブチル １−［（３Ｒ，４Ｓ）−４−フルオ
ロ−５−オキソ−１−［（１Ｒ）−１−フェニルエチ
ル］ピロリジニル］シクロプロピルカルバメート
１−［（３Ｓ，４Ｓ）−４−フルオロ−５−オキソ−１
−［（１Ｒ）−１−フェニルエチル］ピロリジニル］シ
クロプロパンカルボン酸（２２．９ｇ）をトルエン（１
８３mL）に加え、反応容器内を窒素置換し、２２℃で懸
濁攪拌した。次いで乾燥トリエチルアミン（１５．９
ｇ）のトルエン（２２．９mL）溶液とジフェニルホスホ
ニックアジド（２２．７ｇ）のトルエン（２２．９mL）
溶液を順次加えた。添加終了後、２．５時間加熱還流
し、ＴＬＣで原料消失を確認後、９０℃まで冷却し、乾
燥ｔｅｒｔ−ブタノール（２２９mL）を滴下し、２０時
間加熱還流した。ＴＬＣにて反応終了を確認後、室温ま
で放冷し、反応液に水（１３７mL）を加え、攪拌した。
有機層を分取し、水、炭酸水素ナトリウム水溶液の順に
洗浄した。すべての水層を合わせ、酢酸エチルで再抽出
した。全有機層を合わせ、減圧濃縮し、残渣にメタノー
ル、活性炭を加え、２０℃で１時間攪した。活性炭を濾
去し、濾液を減圧濃縮し、得られる残渣をシリカゲルカ
ラムクロマトグラフィーに付し、ＡｃＯＥｔ：ｎ−ｈｅ
ｘａｎｅ＝１：１で展開することにより標題化合物を無
色結晶として２６．３６ｇ得た。Example 7 tert-butyl 1-[(3R, 4S) -4-fluor
Ro-5-oxo-1-[(1R) -1-phenylethyl
]] Pyrrolidinyl] cyclopropylcarbamate 1-[(3S, 4S) -4-fluoro-5-oxo-1
-[(1R) -1-phenylethyl] pyrrolidinyl] cyclopropanecarboxylic acid (22.9 g) was added to toluene (1
83 mL), the inside of the reaction vessel was replaced with nitrogen, and the suspension was stirred at 22 ° C. Then dried triethylamine (15.9
g) toluene solution (22.9 mL) and diphenylphosphonic azide (22.7 g) toluene solution (22.9 mL)
The solutions were added sequentially. After the addition was completed, the mixture was heated under reflux for 2.5 hours, and after confirming disappearance of the raw materials by TLC, cooled to 90 ° C., dried tert-butanol (229 mL) was added dropwise, and the mixture was heated under reflux for 20 hours. After confirming the completion of the reaction by TLC, the mixture was allowed to cool to room temperature, water (137 mL) was added to the reaction solution, and the mixture was stirred.
The organic layer was separated and washed with water and an aqueous sodium hydrogen carbonate solution in this order. All aqueous layers were combined and re-extracted with ethyl acetate. All the organic layers were combined, concentrated under reduced pressure, methanol and activated carbon were added to the residue, and the mixture was stirred at 20 ° C. for 1 hr. Activated carbon was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, AcOEt: n-he.
By developing with xane = 1: 1, 26.36 g of the title compound was obtained as colorless crystals.
【００４９】実施例８ｔｅｒｔ−ブチル １−［（３Ｒ，４Ｓ）−４−フルオ
ロ−１−［（１Ｒ）−１−フェニルエチル］ピロリジニ
ル］シクロプロピルカルバメート
ｔｅｒｔ−ブチル １−［（３Ｒ，４Ｓ）−４−フルオ
ロ−５−オキソ−１−［（１Ｒ）−１−フェニルエチ
ル］ピロリジニル］シクロプロピルカルバメート（１
６．０ｇ）を脱水ＴＨＦ（８０mL）に加え、反応容器内
を窒素置換し、攪拌溶解後、内温４℃まで氷冷した。１
Ｍ ＢＨ3−ＴＨＦ（９７．１mL）を１０℃以下で滴下
後、２５℃まで昇温し、１２時間攪拌した。ＴＬＣで原
料消失を確認後、炭酸カリウム水溶液をゆっくり滴下
し、１時間加熱還流する。反応液を室温まで冷却し、有
機層を分取した。水層は酢酸エチルで抽出し、全有機層
を合わせ、溶媒を減圧留去し、残渣を得た。残渣を酢酸
エチルで再溶解し、酢酸水溶液で洗浄した。酢酸水層を
１Ｎ ＮａＯＨ水溶液でpH１０に調整し、酢酸エチルで
抽出し、有機層を酢酸水溶液で洗浄した。すべての有機
層を合わせ、飽和炭酸水素ナトリウム水溶液、水の順に
洗浄し、溶媒を減圧留去することにより標題化合物を白
色固体として１４．２２ｇ得た。Example 8 tert-Butyl 1-[(3R, 4S) -4-fluor
B-1-[(1R) -1-phenylethyl] pyrrolidini
]] Cyclopropylcarbamate tert-butyl 1-[(3R, 4S) -4-fluoro-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidinyl] cyclopropylcarbamate (1
6.0 g) was added to dehydrated THF (80 mL), the inside of the reaction vessel was replaced with nitrogen, and the mixture was dissolved with stirring, and then cooled to an internal temperature of 4 ° C with ice. 1
After dropping M BH 3-THF with (97.1mL) at 10 ° C. or less, the temperature was raised to 25 ° C., and stirred for 12 hours. After confirming the disappearance of the raw materials by TLC, an aqueous potassium carbonate solution was slowly added dropwise, and the mixture was heated under reflux for 1 hour. The reaction solution was cooled to room temperature and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, all the organic layers were combined, and the solvent was evaporated under reduced pressure to give a residue. The residue was redissolved in ethyl acetate and washed with aqueous acetic acid. The acetic acid aqueous layer was adjusted to pH 10 with a 1N NaOH aqueous solution, extracted with ethyl acetate, and the organic layer was washed with an acetic acid aqueous solution. All the organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and water in this order, and the solvent was evaporated under reduced pressure to obtain 14.22 g of the title compound as a white solid.
【００５０】実施例９ｔｅｒｔ−ブチル １−［（３Ｒ，４Ｓ）−４−フルオ
ロ−ピロリジニル］シクロプロピルカルバメート・シュ
ウ酸塩
ｔｅｒｔ−ブチル １−［（３Ｒ，４Ｓ）−４−フルオ
ロ−１−［（１Ｒ）−１−フェニルエチル］ピロリジニ
ル］シクロプロピルカルバメート（１３．２４ｇ）をエ
タノール（１３２mL）に加え、攪拌溶解した。５％Ｐｄ
／Ｃ（６．６２ｇ：ＰＥタイプ、５５．２７％ｗｅｔ）
を添加し、水素雰囲気下、４０℃で５時間攪拌した。Ｔ
ＬＣで反応終了を確認し，放冷後、触媒を濾去し、濾液
を減圧濃縮した。残渣をエタノール（６２mL）に溶解
後、内温２℃まで撹拌冷却し、シュウ酸・二水和物
（４．７９ｇ）のエタノール（３mL）溶液を滴下し、結
晶析出を確認後、内温−５℃まで冷却し、ＩＰＥ（１３
２mL）を滴下した。０℃以下で１時間撹拌後、結晶を濾
取し、ＩＰＥで洗浄後、４０℃減圧乾燥することによ
り、標題化合物を白色結晶として１１．４９ｇ得た。Example 9 tert-Butyl 1-[(3R, 4S) -4-fluor
Lo-pyrrolidinyl] cyclopropylcarbamate
Urate tert-butyl 1-[(3R, 4S) -4-fluoro-1-[(1R) -1-phenylethyl] pyrrolidinyl] cyclopropylcarbamate (13.24 g) was added to ethanol (132 mL) and stirred. Dissolved. 5% Pd
/ C (6.62g: PE type, 55.27% wet)
Was added, and the mixture was stirred under a hydrogen atmosphere at 40 ° C. for 5 hours. T
After completion of the reaction was confirmed by LC, the mixture was allowed to cool, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. After dissolving the residue in ethanol (62 mL), the mixture was stirred and cooled to an internal temperature of 2 ° C., a solution of oxalic acid dihydrate (4.79 g) in ethanol (3 mL) was added dropwise, and after confirming crystal precipitation, the internal temperature- Cool down to 5 ° C and
2 mL) was added dropwise. After stirring at 0 ° C or lower for 1 hour, the crystals were collected by filtration, washed with IPE, and dried under reduced pressure at 40 ° C to give 11.49 g of the title compound as white crystals.
【００５１】[0051]
【発明の効果】抗菌剤の重要な中間体である式（９）で
表される光学活性な３−ピロリジニル−シクロプロパン
カルボン酸誘導体が工業的に有利に得られる。INDUSTRIAL APPLICABILITY The optically active 3-pyrrolidinyl-cyclopropanecarboxylic acid derivative represented by the formula (9), which is an important intermediate of an antibacterial agent, can be industrially advantageously obtained.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 北川 豊 東京都江戸川区北葛西１丁目16番13号 第 一製薬株式会社東京研究開発センーター内 Ｆターム(参考） 4C069 AB13 BB48 BC01 BC12 4H006 AA02 AC11 AC81 BA25 BA55 BB14 BB15 BB17 BE20 4H039 CA42 CB10 CD90 ─────────────────────────────────────────────────── ─── Continued front page (72) Inventor Yutaka Kitagawa 1-16-13 Kitakasai, Edogawa-ku, Tokyo Ichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center F-term (reference) 4C069 AB13 BB48 BC01 BC12 4H006 AA02 AC11 AC81 BA25 BA55 BB14 BB15 BB17 BE20 4H039 CA42 CB10 CD90
Claims (6)
つ有し、かつ、立体配置の特定された基を示し、３位の
シクロプロピル基と４位のフルオロ原子はシス配置であ
る。）で表される化合物をジベンジルアミンで処理し、
式（９） 【化２】 （式中、Ｒ1は前記と同じ。）で表される化合物のジベ
ンジルアミン塩を単離し、次いで酸で処理することを特
徴とする式（９）で表される化合物の製造法。1. A formula (7): (In the formula, R 1 is a protecting group for an amino group, has one asymmetric carbon atom, and represents a group having a specified configuration, and a cyclopropyl group at the 3-position and a fluoro atom at the 4-position are cis groups. The compound represented by the configuration is treated with dibenzylamine,
Formula (9): (In the formula, R 1 is the same as the above.) The dibenzylamine salt of the compound represented by the above is isolated and then treated with an acid, thereby producing the compound represented by the formula (9).
つ有し、かつ、立体配置の特定された基を示す。）で表
される化合物をパラジウム触媒の存在下に接触還元して
次式（７） 【化４】 （式中、Ｒ1はアミノ基の保護基であって不斉炭素を一
つ有し、かつ、立体配置の特定された基を示し、３位の
シクロプロピル基と４位のフルオロ原子はシス配置であ
る。）で表される化合物を得、これをジベンジルアミン
で処理し、式（９） 【化５】 （式中、Ｒ1は前記と同じ。）で表される化合物のジベ
ンジルアミン塩を単離し、次いで酸で処理することを特
徴とする式（９）で表される化合物の製造法。2. A formula (6): (Wherein R 1 is a protecting group for an amino group, has one asymmetric carbon atom, and represents a group having a specified steric configuration.) Is contacted with a compound in the presence of a palladium catalyst. It is reduced to the following formula (7): (In the formula, R 1 is a protecting group for an amino group, has one asymmetric carbon atom, and represents a group having a specified configuration, and a cyclopropyl group at the 3-position and a fluoro atom at the 4-position are cis groups. The compound of formula (9) is obtained by treating the compound with dibenzylamine. (In the formula, R 1 is the same as the above.) The dibenzylamine salt of the compound represented by the above is isolated and then treated with an acid, thereby producing the compound represented by the formula (9).
護基を示し、Ｘはハロゲン原子を示す）で表される化合
物に式（４） R1-NH2 （４） （式中、Ｒ1はアミノ基の保護基であって不斉炭素を一
つ有し、かつ、立体配置の特定された基を示す。）で表
される化合物を反応させて、式（５） 【化７】 （式中、Ｒ1はアミノ基の保護基であって不斉炭素を一
つ有し、かつ、立体配置の特定された基を示し、Ｒ2は
カルボキシル基の保護基を示す。）で表される化合物を
得て、これを加水分解して、式（６） 【化８】 （式中、Ｒ1は前記と同じ。）で表される化合物を得
て、これをパラジウム触媒の存在下に接触還元して式
（７） 【化９】 （式中、Ｒ1はアミノ基の保護基であって不斉炭素を一
つ有し、かつ、立体配置の特定された基を示し、３位の
シクロプロピル基と４位のフルオロ原子はシス配置であ
る。）で表される化合物を得、これをジベンジルアミン
で処理し、式（９） 【化１０】 （式中、Ｒ1は前記と同じ。）で表される化合物のジベ
ンジルアミン塩を単離し、次いで酸で処理することを特
徴とする式（９）で表される化合物の製造法。3. Formula (3): (In the formula, R 2 and R 3 each independently represent a protective group for a carboxyl group, and X represents a halogen atom), and a compound represented by the formula (4) R 1 -NH 2 (4) , R 1 is a protecting group for an amino group and has one asymmetric carbon atom, and represents a group having a specified steric configuration.), And a compound represented by the formula (5) 7] (In the formula, R 1 is a protecting group for an amino group and has one asymmetric carbon atom and has a specified steric configuration, and R 2 is a protecting group for a carboxyl group). A compound of formula (6): (Wherein R 1 is the same as above), and the compound is subjected to catalytic reduction in the presence of a palladium catalyst to give a compound of the formula (7) (In the formula, R 1 is a protecting group for an amino group, has one asymmetric carbon atom, and represents a group having a specified configuration, and a cyclopropyl group at the 3-position and a fluoro atom at the 4-position are cis groups. The compound of formula (9) is obtained by treating the compound with dibenzylamine. (In the formula, R 1 is the same as the above.) The dibenzylamine salt of the compound represented by the above is isolated and then treated with an acid, thereby producing the compound represented by the formula (9).
カルボキシル基の保護基を示す。）で表される化合物に
式（２） 【化１２】 （式中、Ｒ3はカルボキシル基の保護基を示し、Ｒ4はア
ルキル基を示す。）で表される化合物を反応させ、Ｙが
水素原子である場合は更にハロゲン化剤で処理し、式
（３） 【化１３】 （式中、Ｒ2及びＲ3は各々独立してカルボキシル基の保
護基を示し、Ｘはハロゲン原子を示す。）で表される化
合物を得て、これを式（４） R1-NH2 （４） （式中、Ｒ1はアミノ基の保護基であって不斉炭素を一
つ有し、かつ、立体配置の特定された基を示す。）で表
される化合物と反応させて、式（５） 【化１４】 （式中、Ｒ1はアミノ基の保護基であって不斉炭素を一
つ有し、かつ、立体配置の特定された基を示し、Ｒ2は
カルボキシル基の保護基を示す。）で表される化合物を
得て、これを加水分解して、式（６） 【化１５】 （式中、Ｒ1は前記と同じ。）で表される化合物を得
て、これをパラジウム触媒の存在下に接触還元して式
（７） 【化１６】 （式中、Ｒ1はアミノ基の保護基であって不斉炭素を一
つ有し、かつ、立体配置の特定された基を示し、３位の
シクロプロピル基と４位のフルオロ原子はシス配置であ
る。）で表される化合物を得、これをジベンジルアミン
で処理し、式（９） 【化１７】 （式中、Ｒ1は前記と同じ。）で表される化合物のジベ
ンジルアミン塩を単離し、ついで酸で処理することを特
徴とする式（９）で表される化合物の製造法。4. Formula (1): (In the formula, Y represents a halogen atom or a hydrogen atom, and R 2 represents a protective group for a carboxyl group.) The compound represented by the formula (2): (Wherein R 3 represents a carboxyl-protecting group and R 4 represents an alkyl group), and when Y is a hydrogen atom, it is further treated with a halogenating agent, (3) [Chemical 13] (Wherein, R 2 and R 3 each independently represent a protective group for a carboxyl group, and X represents a halogen atom), and a compound represented by the formula (4) R 1 -NH 2 is obtained. (4) (wherein R 1 is a protecting group for an amino group, has one asymmetric carbon atom, and represents a group having a specified steric configuration), Formula (5) (In the formula, R 1 is a protecting group for an amino group and has one asymmetric carbon atom and has a specified steric configuration, and R 2 is a protecting group for a carboxyl group). A compound of formula (6): (Wherein R 1 is the same as above), and the compound is catalytically reduced in the presence of a palladium catalyst to give a compound of the formula (7) (In the formula, R 1 is a protecting group for an amino group, has one asymmetric carbon atom, and represents a group having a specified configuration, and a cyclopropyl group at the 3-position and a fluoro atom at the 4-position are cis groups. The compound of formula (9) is obtained by treating the compound with dibenzylamine. (In the formula, R 1 is the same as the above.) The dibenzylamine salt of the compound represented by the above is isolated, and then treated with an acid, and the method for producing the compound represented by formula (9).
ある請求項１から４のいずれか１項に記載の製造法。5. The production method according to claim 1, wherein R 1 is a (R) -1-phenylethyl group.
アミン塩が式（８ａ） 【化１８】 で表される塩である請求項１から５のいずれか１項に記
載の製造法。6. A dibenzylamine salt of the compound represented by formula (9) is represented by formula (8a): The method according to any one of claims 1 to 5, which is a salt represented by the formula.
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