JPH1180142A - Production of diphenylalkyl compound - Google Patents

Production of diphenylalkyl compound

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Publication number
JPH1180142A
JPH1180142A JP25746397A JP25746397A JPH1180142A JP H1180142 A JPH1180142 A JP H1180142A JP 25746397 A JP25746397 A JP 25746397A JP 25746397 A JP25746397 A JP 25746397A JP H1180142 A JPH1180142 A JP H1180142A
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Prior art keywords
compound
general formula
formula
compound represented
piperazine
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JP25746397A
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Japanese (ja)
Inventor
Yoko Kawakatsu
Makoto Kimura
Takayuki Namiki
Koji Yamada
Masayuki Yanagi
隆之 並木
浩次 山田
庸行 川勝
誠 木村
正行 柳
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Pola Chem Ind Inc
ポーラ化成工業株式会社
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Abstract

PROBLEM TO BE SOLVED: To readily introduce a carbon isotope to a methine carbon of a diphenylbutyl structure and to obtain a diphenylbutylpiperazine by using a new production method through five processes from a diphenyl ketone derivative. SOLUTION: A diphenylalkyl compound of formula I (R<1> and R<2> are each H or a halogen; X is a carbon atom or its isotope; * is an asymmetric carbon atom) is obtained by reacting a diphenyl ketone derivative with a compound of formula II (Y is a halogen) to give a compound of formula III, then reacting the compound with a hydrogen halide or a hydrohalogenic acid to give a compound of formula IV, further hydrogenating the compound to give a compound of formula V and finally condensing the compound with 1-(2-hydroxy-3- phenylaminopropyl)piperazine. Since the compound of the formula I is used as a medicine and/or its marker, the compound is preferably an optically active substance.

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【発明の属する技術分野】本発明は、標識化合物を製造するのに好適なジフェニルアルキル化合物の製造法に関する。 The present invention relates to relates to a process for the preparation of suitable diphenyl alkyl compound to prepare the labeled compound.

【0002】 [0002]

【従来の技術】ジフェニルアルキル化学構造は、例えば、既に市販されているフルナリジン、シンナリジンの様に、種々の医薬品の化学構造中に多く見られる。 BACKGROUND ART diphenyl alkyl chemical structure, e.g., flunarizine already on the market, as cinnarizine, often observed in the chemical structures of various pharmaceuticals. また、そのなかでもジフェニルアルキル部分の2個のフェニル基にハロゲン原子が付加したものが特に多い。 Also, especially many of the halogen atom added to the two phenyl groups of diphenyl alkyl moiety among them. これはこの化学構造が様々な薬理活性の発現に大きく関わっているためである。 This is because the chemical structure is largely responsible for the expression of various pharmacological activities. 更に、アルキル鎖の炭素数が4のものが特に薬理活性が強いことも知られている。 Furthermore, the number of carbon atoms in the alkyl chain is that of 4 is also known especially pharmacologically active strong. これらの化合物の薬理作用や体内動態などを研究する上で、このジフェニルアルキル構造のメチン炭素を、例えば14 C等のような同位体で標識することは、非常に重要である。 In studying the like pharmacological effects or pharmacokinetics of these compounds, the methine carbon of this diphenyl alkyl structure, for example, be labeled in isotopes such as 14 C, is very important.
しかるに、従来に於いてはこの様な化合物は知られておらず、水素原子をトリチウムなどで置換した化合物を用いてこの様な研究が為されてきた。 However, such compounds at the traditionally not known, such studies have been made a hydrogen atom with a compound obtained by substituting such with tritium. これは、上述した化合物の製造法が見いだされていなかった為、製造しやすいが、挙動の信頼性に欠くトリチウム標識体を用いざるを得ないという状況を反映したものであった。 This is because the preparation of the compounds described above has not been found, although easy to manufacture, was a reflection of the situation that not help using a tritiated body lacks reliability behavior. 即ち、ジフェニルアルキル構造を有する化合物のメチン炭素をその同位体に置き換える技術、言い換えればメチン炭素が炭素の同位体であるジフェニルアルキル構造を構築する技術が望まれていた。 In other words, technology to replace the methine carbon of a compound having a diphenyl alkyl structure isotopes thereof, methine carbon in other words it has been desired a technique for constructing a diphenyl alkyl structure which is an isotope of carbon.

【0003】一方、下記一般式(6)で表される化合物又はその塩の製造法に於いて、下記一般式(1)で表される化合物に下記一般式(2)で表される化合物を反応させ、下記一般式(3)で表される化合物と為し、当該一般式(3)で表される化合物にハロゲン化水素又はハロゲン化水素酸を反応させ、下記一般式(4)で表される化合物と為し、当該一般式(4)で表される化合物を水素添加して下記一般式(5)で表される化合物と為し、当該一般式(5)で表される化合物に1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンを縮合させる方法は未だ知られていなかったし、この方法によれば、ジフェニルブチル構造を有する化合物のメチン炭素を容易にその同位体に置き換える事ができることも全く知られていな On the other hand, in the compound or preparation of a salt thereof represented by the following general formula (6), a compound represented by the following general formula (2) to the compound represented by the following general formula (1) is reacted, without the compound represented by the following general formula (3), by reacting a hydrogen halide or a hydrogen halide acid to the compound represented by the general formula (3), the table the following general formula (4) None the compound, without the compound represented by the following general formula (5) with a compound represented by the general formula (4) hydrogenating the compound represented by the general formula (5) 1Method condensing (2-hydroxy-3-phenyl-aminopropyl) piperazine to not yet known, according to this method, replacing easily isotopes thereof a methine carbon of a compound having a diphenyl butyl structure Do not have been known at all may be able to have things った。 Was Tsu.

【0004】 [0004]

【化7】 [Omitted]

【0005】(但し、式中R1、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表す。) [0005] (wherein R1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof.)

【0006】 [0006]

【化8】 [Of 8]

【0007】(但し、式中Yはハロゲン原子を表す。) [0007] (wherein, wherein Y represents a halogen atom.)

【0008】 [0008]

【化9】 [Omitted]

【0009】(但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表す。) [0009] (wherein, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof.)

【0010】 [0010]

【化10】 [Of 10]

【0011】(但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表し、Zはハロゲン原子を表す。) [0011] (wherein, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof, Z is a halogen atom.)

【0012】 [0012]

【化11】 [Of 11]

【0013】(但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表し、Zはハロゲン原子を表す。) [0013] (wherein, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof, Z is a halogen atom.)

【0014】 [0014]

【化12】 [Of 12]

【0015】(但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表し、*は不斉炭素を表す。) [0015] (wherein, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof, * represents an asymmetric carbon.)

【0016】 [0016]

【発明が解決しようとする課題】従って、本発明はジフェニルブチル構造のメチン炭素にその同位体を導入する事のできる製造法及びジフェニルブチルピペラジン類の製造法を提供することを課題とする。 [SUMMARY OF THE INVENTION Accordingly, the present invention aims to provide a manufacturing method of Preparation can be introduced the isotope methine carbon and diphenyl butyl piperazine diphenyl butyl structure.

【0017】 [0017]

【課題を解決するための手段】斯かる実情に鑑み、本発明者は鋭意検討を重ねた結果、一般式(6)で表される化合物又はその塩の製造法に於いて、一般式(1)で表される化合物に一般式(2)で表される化合物を反応させ、一般式(3)で表される化合物と為し、当該一般式(3)で表される化合物にハロゲン化水素又はハロゲン化水素酸を反応させ、一般式(4)で表される化合物と為し、当該一般式(4)で表される化合物を水素添加して一般式(5)で表される化合物と為し、当該一般式(5)で表される化合物に1−(2−ヒドロキシ−3− In view of such circumstances SUMMARY OF THE INVENTION The present inventors have result of intensive studies, the compound represented by the general formula (6) or in the production process of a salt thereof, Formula (1 the compounds represented by) reacting a compound represented by the general formula (2), without the compound represented by the general formula (3), hydrogen halide compound represented by the general formula (3) or hydrohalic acid is reacted, without the compound represented by the general formula (4), a compound represented by the compound represented by general formula in the formula (4) by hydrogenating (5) No, the compound represented by the general formula (5) 1- (2-hydroxy-3-
フェニルアミノプロピル)ピペラジンを縮合させる方法により、ジフェニルブチルピペラジン類のジフェニルブチル基のメチン炭素の位置に炭素の同位体を導入しうることを見いだし発明を完成させるに至った。 By a method of condensing the phenyl aminopropyl) piperazine, and completed the finding invention that can introduce isotopes of carbon in the position of the methine carbon of diphenyl butyl diphenyl butyl piperazine. 以下、本発明について、発明の実施の形態を中心に詳細に説明する。 The present invention will be described in detail focusing on embodiments of the invention.

【0018】 [0018]

【発明の実施の形態】本発明の製造法の出発原料であるジフェニルケトン誘導体は一般式(1)で表される構造を有している。 Diphenyl ketone derivative as the starting material for the process of the present invention DETAILED DESCRIPTION OF THE INVENTION have a structure represented by the general formula (1). 式中、R 1及びR 2は各々独立に水素原子又はハロゲン原子を示す。 In the formula, R 1 and R 2 represents a hydrogen atom or a halogen atom independently. ここでハロゲン原子として具体的には、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 Specific examples where halogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom. この中でフッ素原子が好ましい。 A fluorine atom is preferred in this. また、R 1 、R 2が共にフッ素原子であるのがさらに好ましい。 Further, the R 1, R 2 are both fluorine atoms are more preferred. 1及びR 2はフェニル環上の何れの位置であっても良いが、共に4位にあるのが好ましい。 R 1 and R 2 may be any position on the phenyl ring, but both preferably in the 4-position. これは、4位置換フェニル構造の薬理学的及び生物学的寄与が大きいとされている為である。 This is because the 4-position pharmacological and biological contribution substituted phenyl structure is greater.

【0019】一般式(1)で表される化合物として、具体的には例えば、ベンゾフェノン、4,4'−ジクロロベンゾフェノン、4−クロロベンゾフェノン、4,4' [0019] compound represented by formula (1) include for example, benzophenone, 4,4'-dichlorobenzophenone, 4-chloro benzophenone, 4,4 '
−ジフルオロベンゾフェノン、4−フルオロベンゾフェノン及びこれらのカルボニル炭素をその同位体で標識化したもの等が挙げられる。 - difluorobenzophenone, 4-fluoro benzophenone and the like that labeled with the isotope these carbonyl carbon and the like. これらのうち、4,4'−ジフルオロベンゾフェノンが好ましく、更には、この化合物のXに示されるカルボニル炭素を14 Cで標識化したものが好ましい。 Of these, 4,4'-difluorobenzophenone are preferable, further, it is preferable that labeled with the carbonyl carbon as shown in X of the compound 14 C.

【0020】本発明の製造法のもう一方の原料である、 [0020], which is the other one of the raw materials of the production method of the present invention,
一般式(2)で表される化合物に関して、Yはハロゲン原子を表し、ハロゲン原子としては臭素原子が特に好ましい。 Regard the compound represented by formula (2), Y represents a halogen atom, particularly preferably a bromine atom as a halogen atom. このものをグリニャール反応によって一般式(1)で表される化合物と反応させることにより一般式(3)で表される化合物を得ることができる。 The thing can be obtained a compound represented by the general formula (3) by reaction with the compound represented by Formula (1) by a Grignard reaction. 即ち、シクロプロピルマグネシウムブロミドと一般式(1)で表される化合物の反応により得ることができる。 That can be obtained by reaction of the compound represented by cyclopropyl bromide and the general formula (1). 溶媒としては、グリニャール反応で使用される溶媒を用いれば良く、例えばジエチルエーテルやテトラヒドロフランなどが好ましく例示できる。 The solvent may be used solvents used in Grignard reaction, such as diethyl ether or tetrahydrofuran can be preferably exemplified. 又、反応条件も同様である。 Further, it is also the reaction conditions.

【0021】上記一般式(3)で表される化合物をハロゲン化水素又はハロゲン化水素酸で処理すると一般式(4)で表される化合物が得られる。 The compounds represented by the compound represented by the general formula (3) is treated with a hydrogen halide or hydrohalic acid formula (4) is obtained. ここでこの処理に使用するハロゲン化水素又はハロゲン化水素酸としては塩化水素、臭化水素酸等が挙げられ、臭化水素酸が特に好ましい。 Here hydrogen halide or hydrogen chloride as a hydrohalic acid used in this process, hydrobromic acid and the like, and hydrobromic acid are particularly preferred.

【0022】一般式(4)で表される化合物を還元反応させることにより、一般式(5)で表される化合物が得られる。 [0022] The compound represented by the general formula (4) to cause a reduction reaction, the compound represented by the general formula (5) is obtained. 一般式(4)で表される化合物を還元する方法としては、アルケン部位のみを還元する方法であれば特に限定されないが、例えば、パラジウム−炭素等の触媒を用いた接触還元等が例示できる。 As a method of reducing the compound represented by the general formula (4) it is not particularly limited as long as it is a method for reducing only the alkene moiety, for example, palladium - catalytic reduction can be exemplified using a catalyst such as carbon.

【0023】上記一般式(5)で表される化合物を1− [0023] The compound represented by the general formula (5) 1-
(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンとアルカリ存在下縮合させることにより、一般式(6)で表される化合物を得ることができる。 (2-hydroxy-3-phenyl-aminopropyl) by engaged piperazine and alkali presence contraction, it is possible to obtain a compound represented by the general formula (6). これら一連の反応は一般式(1)で表される化合物のカルボニル炭素がその同位体であるものを用いて行うのが好ましいが、同様に一般式(6)で表される化合物のうち、同位体を含まないものを製造する方法としても使用することができる。 It is preferred that the carbonyl carbon of the compounds represented by these series of reactions general formula (1) is carried out using those that are isotopes, as well as among the compounds represented by formula (6), isotopic it can also be used as a method of manufacturing the free body. しかしながら、ジフェニルブチル構造のメチン炭素をその同位体に変換しうる意味に於いて、この炭素は炭素同位体であることが特に望ましい。 However, in the meaning which can be converted a methine carbon of diphenyl butyl structure isotopes thereof, it is particularly desirable the carbon is carbon isotope.

【0024】一連の反応によって得られる一般式(6) [0024] obtained by a series of reactions the general formula (6)
で表される化合物は、不斉炭素を有する。 Compound represented by have an asymmetric carbon. 一般式(6) The general formula (6)
で表される化合物は一般に医薬及び/又はその標識体として用いられる為、光学活性体であることが好ましい。 Compound represented by the general for use as a medicament and / or its label, it is preferred that an optically active form.
又、一般式(5)で表される化合物に1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンを縮合させる際、1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンの立体は良く保持される。 Further, when causing a compound represented by the general formula (5) 1- (2-hydroxy-3-phenyl-aminopropyl) piperazine condensation, 1- (2-hydroxy-3-phenyl-aminopropyl) piperazine stereoisomers may It is held. 従って、本発明の製造法において1−(2−ヒドロキシ−3 Accordingly, the production method of the present invention 1- (2-hydroxy-3
−フェニルアミノプロピル)ピペラジンは光学活性体であることが好ましい。 - is preferably phenyl aminopropyl) piperazine is an optically active substance.

【0025】一般式(6)で表される化合物は常法に従ってその塩と為すことが出来る。 The compounds represented by the general formula (6) can be made with a salt according to a conventional method. 例えば、極性又は非極性溶媒中で一般式(6)で表される化合物と酸とを混合すればよい。 For example, it may be mixed with a compound with an acid in a polar or non-polar solvents represented by the general formula (6). ここで言う酸としては、生理的に許容されるものであれば特に限定されず、例えば塩酸、硫酸、硝酸、燐酸等の鉱酸、クエン酸、フマール酸、マレイン酸、蟻酸、酢酸、メタンスルホン酸、ベンゼンスルホン酸、パラトルエンスルホン酸等の有機酸、炭酸等が例示でき、このうち塩酸が好ましい。 The acid here is not particularly limited as long as it is physiologically acceptable, such as hydrochloric acid, sulfuric acid, nitric acid, mineral acid such as citric acid, fumaric acid, maleic acid, formic acid, acetic acid, methanesulphonic acid, benzenesulfonic acid, organic acids such as p-toluenesulfonic acid, can carbonate are exemplified, of which hydrochloric acid is preferred.

【0026】 [0026]

【実施例】以下、実施例を挙げて更に詳細に本発明を説明するが、本発明はこれらに限定されるものでない。 BRIEF DESCRIPTION more detail the present invention by way of examples, but the present invention is not limited thereto.

【0027】(参考例1) (S)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)−4−トリフェニルメチルピペラジンの製造: [0027] (Reference Example 1) (S)-1-(2-hydroxy-3-phenyl-aminopropyl) -4-triphenylmethyl piperazine:
(S)−N−(3−クロロ−2−ヒドロキシプロピル) (S) -N- (3- chloro-2-hydroxypropyl)
アニリン 2.40g(12.93mmol)、1−トリフェニルメチルピペラジン 4.46g(13.58 Aniline 2.40g (12.93mmol), 1- triphenylmethyl piperazine 4.46 g (13.58
mmol)、炭酸カリウム 2.16g(15.63m mmol), potassium carbonate 2.16g (15.63m
mol)、粉砕したヨウ化カリウム 1.08g(6. mol), ground potassium iodide 1.08 g (6.
51mmol)に乾燥エタノール 50mlを加え、窒素雰囲気下、室温で191時間攪拌し、更に3時間攪拌しながら還流した。 51 mmol) in dry ethanol 50ml was added, under nitrogen atmosphere, and stirred for 191 hours at room temperature, and refluxed with stirring for further 3 hours. その後、室温まで冷却し、0.5規定水酸化ナトリウム水溶液 150ml、ベンゼン 6 After cooling to room temperature, 0.5 N sodium hydroxide solution 150 ml, benzene 6
0mlの系に注ぎ、分液し、有機層を分離し、水層は更にベンゼン(30ml×2)で抽出した。 Pour the system of 0 ml, the mixture is separated, and the organic layer was separated and the aqueous layer was further extracted with benzene (30ml × 2). 全有機層は合わせて飽和食塩水 50mlで洗い、硫酸ナトリウム乾燥後、減圧下濃縮した。 All organic layers are combined washed with brine 50 ml, after sodium sulfate dried, and concentrated under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィー(クロロホルム)に付し、目的フラクションを濃縮後、ベンゼン 40mlに溶解し、0.5規定水酸化ナトリウム水溶液80mlと共に振とうし、有機層を分離、水層は更にベンゼン(20ml×2)で抽出した。 The residue was subjected to silica gel column chromatography (chloroform), after concentrating the purpose fractions were dissolved in benzene 40 ml, shaken with 0.5 N sodium hydroxide aqueous solution 80 ml, the organic layer was separated and the aqueous layer further benzene ( and extracted with 20ml × 2). 全有機層は合わせて飽和食塩水 40mlで洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮した。 All organic layers are combined, washed with brine 40 ml, dried over sodium sulfate, and concentrated under reduced pressure. 残渣にエタノールを加え、結晶化し、これを濾取し、乾燥し、目的化合物を4.04g(収率65.5%)得た。 Ethanol was added to the residue, crystallized which is filtered off and dried to give the desired compound 4.04 g (65.5% yield).

【0028】m. [0028] m. p. p. :198〜200℃ IR(KBr錠剤,cm -1 ):3402,1602,1 : 198~200 ℃ IR (KBr tablet, cm -1): 3402,1602,1
504,1448,1004,749,714,694 1 H−NMR(CDCl 3 )δ:2.35〜2.70(8 504,1448,1004,749,714,694 1 H-NMR (CDCl 3 ) δ: 2.35~2.70 (8
H,m),2.70〜2.90(2H,m),2.90 H, m), 2.70~2.90 (2H, m), 2.90
〜3.10(1H,m),3.13〜3.28(1H, ~3.10 (1H, m), 3.13~3.28 (1H,
m),3.35(1H,brs),3.82〜3.96 m), 3.35 (1H, brs), 3.82~3.96
(1H,m),4.08(1H,brs),6.60 (1H, m), 4.08 (1H, brs), 6.60
(2H,d,J=7.6Hz),6.70(1H,t, (2H, d, J = 7.6Hz), 6.70 (1H, t,
J=7.4Hz),7.16(5H,t,J=8.0H J = 7.4Hz), 7.16 (5H, t, J = 8.0H
z),7.21〜7.32(7H,m),7.32〜 z), 7.21~7.32 (7H, m), 7.32~
7.60(5H,m) 7.60 (5H, m)

【0029】(参考例2) (S)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩の製造:(S)−1− [0029] (Reference Example 2) (S)-1-(2-hydroxy-3-phenyl-aminopropyl) piperazine 3 preparation of hydrochloride: (S)-1-
(2−ヒドロキシ−3−フェニルアミノプロピル)−4 (2-hydroxy-3-phenyl-aminopropyl) -4
−トリフェニルメチルピペラジン 7.0g(14.6 - triphenylmethyl piperazine 7.0 g (14.6
6mmol)をテトラヒドロフラン 146mlに溶解し、これに室温で攪拌しながら濃塩酸 5.8mlを一度に加え、更に45分間攪拌した。 The 6 mmol) was dissolved in tetrahydrofuran 146 ml, which with stirring was added concentrated hydrochloric acid 5.8ml once at room temperature and stirred for a further 45 minutes. その後反応液を減圧濃縮し、残渣にベンゼン100mlを加え再び減圧濃縮した。 Then the reaction solution was concentrated under reduced pressure, and concentrated again under reduced pressure benzene 100ml added to the residue. 残渣をジエチルエーテルで洗い、エタノール 5 The residue was washed with diethyl ether, ethanol 5
0ml、メタノール 25mlを加え、更にジエチルエーテル 250mlを加えて粉末とし、濾取し、ジエチルエーテルで洗い、乾燥し、目的化合物を5.00g 0 ml, methanol 25ml was added into a powder further by addition of diethyl ether 250 ml, was filtered, washed with diethyl ether, and dried, the desired compound 5.00g
(収率99.0%)得た。 (99.0% yield).

【0030】(参考例3) (R)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)−4−トリフェニルメチルピペラジンの製造: [0030] (Reference Example 3) (R)-1-(2-hydroxy-3-phenyl-aminopropyl) -4-triphenylmethyl piperazine:
参考例1と同様に、(R)−N−(3−クロロ−2−ヒドロキシプロピル)アニリン 5.67g(30.54 In the same manner as in Reference Example 1, (R) -N- (3- chloro-2-hydroxypropyl) aniline 5.67 g (30.54
mmol)、1−トリフェニルメチルピペラジン 1 mmol), 1-triphenylmethyl piperazine 1
0.53g(32.06mmol)、炭酸カリウム 0.53g (32.06mmol), potassium carbonate
5.10g(36.90mmol)、粉砕したヨウ化カリウム 2.55g(15.36mmol)より、目的化合物を10.64g(収率72.9%)得た。 From 5.10g (36.90mmol), ground potassium iodide 2.55 g (15.36 mmol), to give the desired compound 10.64 g (72.9% yield).

【0031】m. [0031] m. p. p. :196〜197.5℃ IR(KBr錠剤,cm -1 ):3402,1601,1 : 196~197.5 ℃ IR (KBr tablet, cm -1): 3402,1601,1
504,1448,1004,741,715,694 1 H−NMR(CDCl 3 )δ:2.35〜2.70(8 504,1448,1004,741,715,694 1 H-NMR (CDCl 3 ) δ: 2.35~2.70 (8
H,m),2.70〜2.90(2H,m),2.90 H, m), 2.70~2.90 (2H, m), 2.90
〜3.10(1H,m),3.13〜3.28(1H, ~3.10 (1H, m), 3.13~3.28 (1H,
m),3.35(1H,brs),3.82〜3.96 m), 3.35 (1H, brs), 3.82~3.96
(1H,m),4.08(1H,brs),6.60 (1H, m), 4.08 (1H, brs), 6.60
(2H,d,J=7.6Hz),6.70(1H,t, (2H, d, J = 7.6Hz), 6.70 (1H, t,
J=7.4Hz),7.16(5H,t,J=8.0H J = 7.4Hz), 7.16 (5H, t, J = 8.0H
z),7.21〜7.32(7H,m),7.32〜 z), 7.21~7.32 (7H, m), 7.32~
7.60(5H,m) [α] 20 D :−9.7゜(C=1.0,CHCl 3 7.60 (5H, m) [α ] 20 D: -9.7 ° (C = 1.0, CHCl 3)

【0032】(参考例4) (R)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩の製造:参考例2と同様に、(R)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)−4−トリフェニルメチルピペラジン [0032] (Reference Example 4) (R)-1-(2-hydroxy-3-phenyl-aminopropyl) piperazine 3 preparation of the hydrochloride salt: in the same manner as in Reference Example 2, (R) -1- (2- hydroxy 3-phenyl-aminopropyl) -4-triphenylmethyl piperazine
7.0g(14.66mmol)より、目的化合物を5.00g(収率99.0%)得た。 From 7.0g (14.66mmol), the desired compound was obtained 5.00 g (99.0% yield).

【0033】(実施例1) 4,4−ビス(4−フルオロフェニル)ブチルブロミドの製造:マグネシウム(削り状) 0.28g(11. [0033] (Example 1) 4,4-bis (4-fluorophenyl) butyl bromide of preparation: Magnesium (turnings) 0.28 g (11.
52mmol)に、テトラヒドロフラン 8mlを加え、これに窒素雰囲気下室温(26℃)で攪拌しながら、シクロプロピルブロミド 1ml(d=1.51, In 52 mmol), in tetrahydrofuran 8 ml, stirring at this room temperature under a nitrogen atmosphere (26 ° C.), cyclopropyl bromide 1ml (d = 1.51,
12.48mmol)のテトラヒドロフラン8ml溶液を30分要し滴下した。 12.48 mmol) in tetrahydrofuran 8ml solution was taken 30 minutes dripping. シクロプロピルブロミドを少量滴下した後にヨウ素片を加えた。 Iodide was added segment after dropping a small amount of cyclopropyl bromide. 反応液が発熱したが、 The reaction solution generates heat,
40℃以下に調整した。 It was adjusted to 40 ℃ below. 同条件下で30分攪拌した後に4,4'−ジフルオロベンゾフェノン 1.20g After stirring for 30 minutes under the same conditions of 4,4'-difluorobenzophenone 1.20g
(5.50mmol)のテトラヒドロフラン8ml溶液を10分要し滴下し、続いて同条件下で2時間攪拌した。 Tetrahydrofuran 8ml solution was added dropwise took 10 minutes (5.50 mmol), followed by stirring for 2 hours under the same conditions. その後、反応液を飽和塩化アンモニウム水溶液 1 Thereafter, the reaction solution of ammonium saturated chloride solution 1
60ml、ベンゼン 80mlの系に氷冷攪拌下注ぎ、 60 ml, poured with stirring under ice-cooling to the system of benzene 80 ml,
少時攪拌した。 Early days and the mixture was stirred. 有機層を分離し、水層はベンゼンで抽出(40ml×2)し、全有機層は合わせて、飽和食塩水(60ml×2)、水(60ml×2)で洗浄し、硫酸ナトリウム乾燥後、溶媒を減圧留去し、ビス(4−フルオロフェニル)シクロプロピルカルビノールを淡黄色透明油状物として定量的に得た。 The organic layer was separated, and the aqueous layer was extracted with benzene (40 ml × 2), organic layers are combined, saturated brine (60 ml × 2), washed with water (60 ml × 2), after sodium sulfate drying, the solvent was distilled off under reduced pressure to quantitatively obtain bis (4-fluorophenyl) cyclopropyl carbinol as a pale yellow clear oil. ビス(4−フルオロフェニル)シクロプロピルカルビノールの物性値を次に示す。 Following bis physical properties of (4-fluorophenyl) cyclopropyl carbinol.

【0034】 1 H−NMR(CDCl 3 )δ:0.40〜 [0034] 1 H-NMR (CDCl 3) δ: 0.40~
0.50(2H,m),0.55〜0.65(2H, 0.50 (2H, m), 0.55~0.65 (2H,
m),1.48〜1.63(1H,m),1.86(1 m), 1.48~1.63 (1H, m), 1.86 (1
H,s),6.90〜7.05(4H,m),7.32 H, s), 6.90~7.05 (4H, m), 7.32
〜7.45(4H,m) ~7.45 (4H, m)

【0035】ビス(4−フルオロフェニル)シクロプロピルカルビノール 1.4g(5.38mmol)をメタノール 4.8mlに溶解し、これに氷冷攪拌下、4 [0035] bis (4-fluorophenyl) cyclopropyl carbinol 1.4g of (5.38 mmol) was dissolved in methanol 4.8 ml, was added with stirring under ice-cooling thereto, 4
7%臭化水素酸 2.4mlを一度に加え(油状物質が現れ、2層となる)、同条件下で1時間10分激しく攪拌した。 It was added 7% hydrobromic acid 2.4ml at once (oil appears, the two layers), and stirred 1 hour 10 minutes vigorously at the same conditions. その後、反応液をベンゼン 20ml、水40 Thereafter, the reaction solution benzene 20 ml, water 40
mlの系に注ぎ、よく振とうした後有機層を分離し、水層はさらにベンゼンで抽出(10ml×2)し、全有機層は合わせて、飽和食塩水(30ml)で洗浄し硫酸ナトリウムで乾燥後、溶媒を減圧留去した。 It poured into ml of the system, separating the organic layer was shaken well, the aqueous layer is further benzene extract (10 ml × 2), and organic layers are combined, with was washed with saturated brine (30ml), sodium sulfate after drying, the solvent was evaporated under reduced pressure. 1,1−ビス(4−フルオロフェニル)−4−ブロモブテンを黄緑色透明油状物として1.65g(収率94.8%)得た。 The 1,1-bis (4-fluorophenyl) -4- bromobutene (94.8% yield) 1.65 g as a yellow-green clear oil was obtained.
1,1−ビス(4−フルオロフェニル)−4−ブロモブテンの物性値を次に示す。 Following a 1,1-bis (4-fluorophenyl) -4-physical properties of the bromobutene.

【0036】 1 H−NMR(CDCl 3 )δ:2.67 [0036] 1 H-NMR (CDCl 3) δ: 2.67
(2H,q,J=7.0Hz),3.43(2H,t, (2H, q, J = 7.0Hz), 3.43 (2H, t,
J=7.0Hz),6.01(1H,t,J=7.0H J = 7.0Hz), 6.01 (1H, t, J = 7.0H
z),6.90〜7.02(2H,m),7.02〜 z), 6.90~7.02 (2H, m), 7.02~
7.23(6H,m) 7.23 (6H, m)

【0037】1,1−ビス(4−フルオロフェニル)− [0037] 1,1-bis (4-fluorophenyl) -
4−ブロモブテン 0.63g(1.95mmol)をメタノール 12mlに溶解し、これに10%パラジウム−炭素 0.16gを加え、室温攪拌下、水素ガス(風船)にて2時間接触還元を行った。 4- bromobutene 0.63g of (1.95 mmol) was dissolved in methanol 12 ml, which 10% palladium - carbon 0.16g was added, under stirring at room temperature, was carried out for 2 hours catalytic reduction under a hydrogen gas (balloon). その後、パラジウム−炭素を濾去し、これをクロロホルムで数回洗い、 Thereafter, palladium - was filtered off carbon, which was washed several times with chloroform,
濾液及び洗液を合わせて減圧濃縮した。 And concentrated under reduced pressure The combined filtrate and washings. 濃縮残渣にベンゼン 10mlを加え、再び減圧濃縮し、淡黄色油状物質 0.64gを得た。 Benzene 10ml was added to the concentrated residue was concentrated again under reduced pressure to give a pale yellow oil 0.64 g. これをシリカゲルカラムクロマトグラフィー(n−ヘキサン)に付し、目的化合物を無色透明油状物として0.51g(収率:81.0%)得た。 This was subjected to silica gel column chromatography (n- hexane), 0.51 g of the desired compound as a colorless transparent oil (yield: 81.0%). 目的化合物の物性値を次に示す。 Following physical properties of the target compound.

【0038】 1 H−NMR(CDCl 3 )δ:1.72〜 [0038] 1 H-NMR (CDCl 3) δ: 1.72~
1.88(2H,m),2.08〜2.22(2H, 1.88 (2H, m), 2.08~2.22 (2H,
m),3.40(2H,t,J=6.6Hz),3.8 m), 3.40 (2H, t, J = 6.6Hz), 3.8
9(1H,t,J=8.0Hz),6.92〜7.03 9 (1H, t, J = 8.0Hz), 6.92~7.03
(4H,m),7.08〜7.22(4H,m) (4H, m), 7.08~7.22 (4H, m)

【0039】(実施例2) 式(3−1)で表される化合物の製造: [0039] (Example 2) (3-1) Preparation of a compound represented by:

【0040】 [0040]

【化13】 [Of 13]

【0041】(但し、式中14 Cは中性子数8の放射性炭素同位体を表す。) [0041] (where, 14 C in the formula represents a radioactive carbon isotope neutron number 8.)

【0042】マグネシウム (0.14g,5.62m [0042] magnesium (0.14g, 5.62m
mol)に、テトラヒドロフラン(4ml)を加え、これに窒素雰囲気下室温(26℃)で攪拌しながら、シクロプロピルブロミド (0.74g,6.10mmo In mol), tetrahydrofuran (4 ml) was added, while stirring at this room temperature under a nitrogen atmosphere (26 ° C.), cyclopropyl bromide (0.74g, 6.10mmo
l)のテトラヒドロフラン(2ml)溶液を30分要し滴下した。 Tetrahydrofuran (2 ml) solution of l) was added dropwise took 30 minutes. シクロプロピルブロミドを少量滴下した後にヨウ素片を加えた。 Iodide was added segment after dropping a small amount of cyclopropyl bromide. 反応液が発熱したが、40℃以下に調整した。 The reaction solution was exothermic but was adjusted to 40 ° C. or less. 一方、4,4'−ジフルオロベンゾフェノンのカルボニル炭素を14 Cで標識した化合物(850MB On the other hand, labeled compounds carbonyl carbon of 4,4'-difluorobenzophenone in 14 C (850MB
q,440μmol)のテトラヒドロフラン (7m q, 440μmol) in tetrahydrofuran (7m
l)溶液を調製し、氷冷攪拌下これに先に調製したグリニャール試薬を滴下した。 l) was prepared and was added dropwise a Grignard reagent prepared above to this with stirring under ice-cooling. 室温に戻し、1時間攪拌した後、飽和塩化アンモニウム水溶液及びベンゼンを加え、 After returning to room temperature and stirred for 1 hour, a saturated aqueous ammonium chloride and benzene was added,
よく振とうし、有機層を分離し、水層はベンゼンで抽出した。 Shaken well, the organic layer was separated and the aqueous layer was extracted with benzene. 全有機層は合わせて、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的化合物を845MBq(放射化学的純度:75.7%)得た。 All organic layers are combined, washed with saturated brine, dried over sodium sulfate, the solvent was distilled off under reduced pressure, the desired compound 845MBq (radiochemical purity: 75.7%) was obtained. 得られた化合物は実施例1において製造したビス(4−フルオロフェニル)シクロプロピルカルビノールとの液体クロマトグラフィーにより同定された。 The resulting compound was identified by liquid chromatography and bis (4-fluorophenyl) cyclopropyl carbinol, prepared in Example 1.

【0043】(実施例3) 式(4−1)で表される化合物の製造: [0043] (Example 3) of a compound represented by the formula (4-1) prepared:

【0044】 [0044]

【化14】 [Of 14]

【0045】(但し、式中14 Cは中性子数8の放射性炭素同位体を表す。) [0045] (where, 14 C in the formula represents a radioactive carbon isotope neutron number 8.)

【0046】式(3−1)で表される化合物 845M The compounds represented by formula (3-1) 845M
Bqにメタノール 2.5ml及び47%臭化水素酸 Methanol 2.5ml and 47% hydrobromic acid in Bq
1.2mlを加え、1時間激しく攪拌した。 1.2ml was added and stirred vigorously for 1 h. その後、水 20mlを加え、ベンゼンで3回抽出した後、全有機層を合わせ、飽和食塩水で洗浄した。 Thereafter, 20ml of water was added, was extracted three times with benzene and the combined organic layers were washed with saturated brine. 硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的化合物を 830MB After drying over sodium sulfate, the solvent was distilled off under reduced pressure, the desired compound 830MB
q(放射化学的純度:76.0%)得た。 q (radiochemical purity: 76.0%) was obtained. 得られた化合物は実施例1において製造した1,1−ビス(4−フルオロフェニル)−4−ブロモブテンとの液体クロマトグラフィーにより同定された。 The resulting compound was identified by liquid chromatography and 1,1-bis (4-fluorophenyl) -4-bromobutene produced in Example 1.

【0047】(実施例4) 式(5−1)で表される化合物の製造: [0047] (Example 4) (5-1) Preparation of a compound represented by:

【0048】 [0048]

【化15】 [Of 15]

【0049】(但し、式中14 Cは中性子数8の放射性炭素同位体を表す。) [0049] (where, 14 C in the formula represents a radioactive carbon isotope neutron number 8.)

【0050】式(4−1)で表される化合物 830M The compounds represented by formula (4-1) 830M
Bqをメタノール 10mlに溶解し、これに10%パラジウム−炭素 110mgを加え、室温攪拌下、水素ガス(風船)にて2時間接触還元を行った。 The Bq was dissolved in methanol 10 ml, which 10% palladium - carbon 110mg was added, under stirring at room temperature, was carried out for 2 hours catalytic reduction under a hydrogen gas (balloon). その後、パラジウム−炭素を濾去し、これをクロロホルムで数回洗い、濾液及び洗液を合わせて減圧濃縮した。 Thereafter, palladium - was filtered off carbon, which was washed several times with chloroform, and concentrated under reduced pressure the combined filtrate and washings. 濃縮残渣にベンゼンを加え、再び減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン−酢酸エチル) Benzene was added to the concentrated residue, and concentrated again under reduced pressure, the residue was purified by silica gel column chromatography (n- hexane - ethyl acetate)
に付し、目的化合物を無色透明油状物として564MB Subjected to, 564MB of the desired compound as a colorless clear oil
q(放射化学的純度:99.0%)得た。 q (radiochemical purity: 99.0%) was obtained. 得られた化合物は実施例1において製造した4,4−ビス(4−フルオロフェニル)ブチルブロミドとの液体クロマトグラフィーにより同定された。 The resulting compound was identified by liquid chromatography and 4,4-bis (4-fluorophenyl) butyl bromide produced in Example 1.

【0051】(実施例5) (S)−1−[4,4−ビス(4−フルオロフェニル) [0051] (Example 5) (S) -1- [4,4- bis (4-fluorophenyl)
ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンの製造:4,4−ビス(4−フルオロフェニル)ブチルブロミド 0.60g(1.85 Butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine: Prepared 4,4-bis (4-fluorophenyl) butyl bromide 0.60 g (1.85
mmol)に(S)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩 0.75 In mmol) (S) -1- (2- hydroxy-3-phenyl-aminopropyl) piperazine trihydrochloride 0.75
g(2.18mmol)、粉砕したヨウ化カリウム g (2.18 mmol), potassium iodide was pulverized
0.30g(1.81mmol)、炭酸カリウム 1. 0.30 g (1.81 mmol), potassium carbonate 1.
22g(8.83mmol)を順次加え、これに乾燥エタノール 15mlを加え、窒素雰囲気下8時間攪拌しながら加熱還流した。 22g sequentially added (8.83 mmol), which in dry ethanol 15ml and the mixture was heated under reflux with stirring under a nitrogen atmosphere for 8 hours. 室温にて1晩放置後、ベンゼン After standing overnight at room temperature, benzene
20ml、0.5規定水酸化ナトリウム水溶液 40m 20 ml, 0.5 N sodium hydroxide solution 40m
lの系に注ぎ、分液し、ベンゼン層を分離し、水層はベンゼン(20ml×2)で抽出し、全ベンゼン層は合わせて、飽和食塩水(20ml)で洗い、硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣を0.99g得た。 Pour the system of l, were separated, separating the benzene layer, the aqueous layer was extracted with benzene (20 ml × 2), the total benzene layer is combined, washed with saturated brine (20 ml), dried over sodium sulfate the solvent was evaporated under reduced pressure to obtain 0.99g of residue.
シリカゲルカラムクロマトグラフィー(クロロホルム: Silica gel column chromatography (chloroform:
メタノール=100:0→100:0.5→100: Methanol = 100: 0 → 100: 0.5 → 100:
1)に付し、精製物0.63gを得た。 1) to give a purified product 0.63 g. これをベンゼン 10mlに溶解し、0.5規定水酸化ナトリウム水溶液 20mlと共に振とうし、ベンゼン層を分離し、水層はベンゼン(10ml×2)で抽出し、全ベンゼン層は合わせて、飽和食塩水(10ml)で洗い、硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣を0.63g This was dissolved in benzene 10 ml, shaken with 0.5 N aqueous sodium hydroxide 20 ml, was separated benzene layer, the aqueous layer was extracted with benzene (10 ml × 2), the total benzene layer is combined, saturated sodium chloride washed with water (10 ml), dried over sodium sulfate, the solvent was distilled off under reduced pressure, 0.63 g of the residue
(固化)得た。 (Solidified) was obtained. これを熱エタノールに溶解し、熱濾過し、濾液を減圧濃縮した。 This was dissolved in hot ethanol, filtered hot, and the filtrate was concentrated under reduced pressure. エタノール約3mlで再結晶し、結晶を濾取、風乾し、目的化合物を0.50g(収率56.8%)得た。 Recrystallization from ethanol to about 3 ml, the crystals were filtered off, air dried, the desired compound was obtained 0.50 g (56.8% yield).

【0052】白色結晶 m. [0052] white crystals m. p. p. :100〜101℃ IR(KBr錠剤,cm -1 ):3330,1604,1 : 100~101 ℃ IR (KBr tablet, cm -1): 3330,1604,1
507,1221,1158,828,751 1 H−NMR(CDCl 3 )δ:1.33〜1.50(2 507,1221,1158,828,751 1 H-NMR (CDCl 3 ) δ: 1.33~1.50 (2
H,m),2.00(2H,q,J=7.7Hz), H, m), 2.00 (2H, q, J = 7.7Hz),
2.20〜2.57(10H,m),2.57〜2.7 2.20~2.57 (10H, m), 2.57~2.7
5(2H,m),2.98〜3.11(1H,m), 5 (2H, m), 2.98~3.11 (1H, m),
3.18〜3.32(1H,m),3.53(1H,b 3.18~3.32 (1H, m), 3.53 (1H, b
rs),3.86(1H,t,J=7.6Hz),3. rs), 3.86 (1H, t, J = 7.6Hz), 3.
90〜4.00(1H,m),4.10(1H,br 90~4.00 (1H, m), 4.10 (1H, br
s),6.63(2H,d,J=7.3Hz),6.7 s), 6.63 (2H, d, J = 7.3Hz), 6.7
1(1H,t,J=7.3Hz),6.88〜7.02 1 (1H, t, J = 7.3Hz), 6.88~7.02
(4H,m),7.05〜7.22(6H,m) (4H, m), 7.05~7.22 (6H, m)

【0053】(実施例6) 14 C−(S)−1−[4,4−ビス(4−フルオロフェニル)ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンの製造:式(5−1)で表される化合物 282MBqに(S)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3 [0053] (Example 6) 14 C- (S) -1- [4,4- bis (4-fluorophenyl) butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine: Prepared formula (5-1) a compound represented by 282MBq with (S)-1-(2-hydroxy-3-phenyl-aminopropyl) piperazine 3
塩酸塩 372mg(1.08mmol)、粉砕したヨウ化カリウム 186mg(1.12mmol)、炭酸カリウム 644mg(4.67mmol)を順次加え、これに乾燥エタノール 20mlを加え、窒素雰囲気下9時間攪拌しながら加熱還流した。 Hydrochloride 372 mg (1.08 mmol), ground potassium iodide 186 mg (1.12 mmol), sequentially added potassium carbonate 644 mg (4.67 mmol), which in dry ethanol 20ml was added, heated with stirring under a nitrogen atmosphere for 9 hours and reflux. 減圧下濃縮後、 After concentration under reduced pressure,
残渣に水を加え、クロロホルムで3回抽出した。 Water was added to the residue, and extracted three times with chloroform. 全有機層を合わせ、硫酸ナトリウムで乾燥後、溶媒を減圧留去し、得られた残渣を液体クロマトグラフィー〔シリカゲル,22×100mm,クロロホルム/メタノール(2 The combined organic layers, dried over sodium sulfate, the solvent was distilled off under reduced pressure, the resulting residue liquid chromatography [silica gel, 22 × 100 mm, chloroform / methanol (2
5:1),254nm,4ml/min〕に付した。 5: 1), 254nm, was subjected to 4ml / min]. 目的画分を集め、溶媒を留去し、再び液体クロマトグラフィー〔TSKゲル ODS 120T,20×300m Collect the desired fractions, the solvent was distilled off, again liquid chromatography [TSK gel ODS 120T, 20 × 300 meters
m,アセトニトリル/50mM トリエチルアミン−酢酸溶液(pH 4.0)(55:45),254nm, m, acetonitrile / 50 mM triethylamine - acetate solution (pH 4.0) (55:45), 254nm,
18.9ml/min〕で精製した。 It was purified by 18.9ml / min]. 純度の高い画分を集め、減圧下濃縮し、炭酸カリウムを加えてアルカリ性とし、クロロホルムで3回抽出した。 Collected higher fractions purity, and concentrated under reduced pressure, made alkaline by addition of potassium carbonate and extracted three times with chloroform. 硫酸ナトリウムで乾燥し、溶媒を減圧留去し、目的化合物を 166MB Dried over sodium sulfate, the solvent was distilled off under reduced pressure, 166MB the desired compound
q(放射化学的純度:98.0%)得た。 q (radiochemical purity: 98.0%) was obtained. 得られた化合物は、実施例5で得られた化合物との液体クロマトグラフィーにより同定された。 The obtained compound was identified by liquid chromatography and the compound obtained in Example 5.

【0054】(実施例7) (R)−1−[4,4−ビス(4−フルオロフェニル) [0054] (Example 7) (R) -1- [4,4- bis (4-fluorophenyl)
ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンの製造:4,4−ビス(4−フルオロフェニル)ブチルブロミド 0.72g(2.21 Butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine: Prepared 4,4-bis (4-fluorophenyl) butyl bromide 0.72 g (2.21
mmol)、(R)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩 0.90 mmol), (R) -1- (2- hydroxy-3-phenyl-aminopropyl) piperazine trihydrochloride 0.90
g(2.61mmol)、粉砕したヨウ化カリウム g (2.61 mmol), potassium iodide was pulverized
0.36g(2.17mmol)、炭酸カリウム 1. 0.36 g (2.17 mmol), potassium carbonate 1.
47g(10.64mmol)及び乾燥エタノール 1 47g (10.64mmol) and dry ethanol 1
8mlを用いて、実施例5と同様の操作で目的化合物を0.62g(収率58.5%)得た。 With 8 ml, to obtain 0.62g of the desired compound in the same manner as in Example 5 (58.5% yield).

【0055】白色結晶 m. [0055] white crystals m. p. p. :100〜101℃ IR(KBr錠剤,cm -1 ):3330,1604,1 : 100~101 ℃ IR (KBr tablet, cm -1): 3330,1604,1
507,1221,1158,828,751 1 H−NMR(CDCl 3 )δ:1.33〜1.50(2 507,1221,1158,828,751 1 H-NMR (CDCl 3 ) δ: 1.33~1.50 (2
H,m),2.00(2H,q,J=7.7Hz), H, m), 2.00 (2H, q, J = 7.7Hz),
2.20〜2.57(10H,m),2.57〜2.7 2.20~2.57 (10H, m), 2.57~2.7
5(2H,m),2.98〜3.11(1H,m), 5 (2H, m), 2.98~3.11 (1H, m),
3.18〜3.32(1H,m),3.53(1H,b 3.18~3.32 (1H, m), 3.53 (1H, b
rs),3.86(1H,t,J=7.6Hz),3. rs), 3.86 (1H, t, J = 7.6Hz), 3.
90〜4.00(1H,m),4.10(1H,br 90~4.00 (1H, m), 4.10 (1H, br
s),6.63(2H,d,J=7.3Hz),6.7 s), 6.63 (2H, d, J = 7.3Hz), 6.7
1(1H,t,J=7.3Hz),6.88〜7.02 1 (1H, t, J = 7.3Hz), 6.88~7.02
(4H,m),7.05〜7.22(6H,m) (4H, m), 7.05~7.22 (6H, m)

【0056】(実施例8) 14 C−(R)−1−[4,4−ビス(4−フルオロフェニル)ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンの製造:実施例6と同様に、式(5−1)で表される化合物 282MBq、 [0056] (Example 8) 14 C- (R) -1- [4,4- bis (4-fluorophenyl) butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine Preparation of implementation Similarly to example 6, the compound represented by formula (5-1) 282MBq,
(R)−1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩372mg(1.08m (R) -1- (2- hydroxy-3-phenyl-aminopropyl) piperazine trihydrochloride 372 mg (1.08 m
mol)、粉砕したヨウ化カリウム 186mg(1. mol), ground potassium iodide 186 mg (1.
12mmol)、炭酸カリウム 644mg(4.67 12mmol), potassium carbonate 644mg (4.67
mmol)より、目的化合物を 179MBq(放射化学的純度:98.5%)得た。 Than mmol), the desired compound 179MBq (radiochemical purity: 98.5%) was obtained. 得られた化合物は、実施例7で得られた化合物との液体クロマトグラフィーにより同定された。 The obtained compound was identified by liquid chromatography and the compound obtained in Example 7.

【0057】(実施例9) (S)−1−[4,4−ビス(4−フルオロフェニル) [0057] (Example 9) (S) -1- [4,4- bis (4-fluorophenyl)
ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩の製造:(S)−1− Butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine 3 preparation of hydrochloride: (S)-1-
[4,4−ビス(4−フルオロフェニル)ブチル]−4 [4,4-bis (4-fluorophenyl) butyl] -4
−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン 0.38g(0.79mmol)にエタノール 2mlを加え、窒素雰囲気下攪拌しながら、加熱還流することにより、溶解させた。 - (2-hydroxy-3-phenyl-aminopropyl) ethanol 2ml was added to piperazine 0.38 g (0.79 mmol), with stirring under a nitrogen atmosphere, by heating to reflux and dissolved. その後、ゆっくり攪拌しながら、内温60℃まで冷却し、これに7規定塩化水素−エタノール溶液 0.44ml(3.08mmo Then, with slow stirring, it was cooled to an inner temperature of 60 ° C., this 7 N hydrogen chloride - ethanol solution 0.44ml (3.08mmo
l)を一度に加え、少時攪拌、結晶が析出し始めた時点で攪拌を停止し、そのまま1晩室温で放置した。 Added l) at a time, early days stirring, the stirring was stopped when the crystals began to precipitate, and allowed to stand as it is at room temperature overnight. 結晶を濾取、エタノールで洗い、よく広げて一日風乾し、目的化合物を0.43g(収率91.5%)得た。 Filtered crystals, washed with ethanol, may spread dried day air, to obtain the desired compound 0.43 g (91.5% yield).

【0058】淡黄緑色結晶 m. [0058] pale yellow-green crystals m. p. p. :228〜236℃ IR(KBr錠剤,cm -1 ):3420,3205,3 : 228~236 ℃ IR (KBr tablet, cm -1): 3420,3205,3
154,1601,1505,1221,828,68 154,1601,1505,1221,828,68
6,536 1 H−NMR(DMSO−d 6 )δ:1.48〜1.70 6,536 1 H-NMR (DMSO- d 6) δ: 1.48~1.70
(2H,m),2.06(2H,q,J=7.7H (2H, m), 2.06 (2H, q, J = 7.7H
z),3.00〜3.29(6H,m),3.29〜 z), 3.00~3.29 (6H, m), 3.29~
3.86(8H,m),4.02(1H,t,J=7. 3.86 (8H, m), 4.02 (1H, t, J = 7.
8Hz),4.18〜4.33(1H,m),6.78 8Hz), 4.18~4.33 (1H, m), 6.78
(1H,t,J=7.2Hz),6.87(2H,d, (1H, t, J = 7.2Hz), 6.87 (2H, d,
J=7.8Hz),7.00〜7.27(6H,m), J = 7.8Hz), 7.00~7.27 (6H, m),
7.27〜7.45(4H,m),11.78(1H, 7.27~7.45 (4H, m), 11.78 (1H,
brs) brs)

【0059】(実施例10) 14 C−(S)−1−[4,4−ビス(4−フルオロフェニル)ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩の製造: 14 C− [0059] (Example 10) 14 C- (S) -1- [4,4- bis (4-fluorophenyl) butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine trihydrochloride of production: 14 C-
(S)−1−[4,4−ビス(4−フルオロフェニル) (S)-1-[4,4-bis (4-fluorophenyl)
ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン 166MBqをエーテル−クロロホルムの混合液に溶解し、氷冷下5%塩化水素−メタノール溶液 280μl(383μmol)を加えた。 Butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine 166MBq ether - was dissolved in a mixture of chloroform, under ice-cooling 5% hydrochloric - methanol was added to the solution 280μl (383μmol).
析出した結晶を濾取し、エーテルで洗浄し、目的化合物を74.0MBq得た。 The precipitated crystals were collected by filtration and washed with ether to give 74.0MBq the desired compound. 得られた化合物は、実施例9で得られた化合物との液体クロマトグラフィーにより同定された。 The obtained compound was identified by liquid chromatography and the compound obtained in Example 9.

【0060】(実施例11) (R)−1−[4,4−ビス(4−フルオロフェニル) [0060] (Example 11) (R) -1- [4,4- bis (4-fluorophenyl)
ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩の製造:実施例9と同様に、(R)−1−[4,4−ビス(4−フルオロフェニル)ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン 0.50g(1.04m Butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine 3 preparation of hydrochloride Analogously to Example 9, (R) -1- [4,4- bis (4-fluorophenyl) butyl ] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine 0.50 g (1.04 m
mol)、エタノール 2.5ml、7規定塩化水素− mol), ethanol 2.5 ml, 7 N hydrogen chloride -
エタノール溶液 0.60ml(4.20mmol)を用い、目的化合物を0.59g(収率96.7%)得た。 Using ethanol 0.60 ml (4.20 mmol), to give the desired compound 0.59 g (96.7% yield).

【0061】淡黄緑色結晶 m. [0061] pale yellow-green crystals m. p. p. :231〜237℃ IR(KBr錠剤,cm -1 ):3420,3198,3 : 231~237 ℃ IR (KBr tablet, cm -1): 3420,3198,3
154,1602,1505,1221,828,68 154,1602,1505,1221,828,68
6,536 1 H−NMR(DMSO−d 6 )δ:1.48〜1.70 6,536 1 H-NMR (DMSO- d 6) δ: 1.48~1.70
(2H,m),2.06(2H,q,J=7.7H (2H, m), 2.06 (2H, q, J = 7.7H
z),3.00〜3.29(6H,m),3.29〜 z), 3.00~3.29 (6H, m), 3.29~
3.86(8H,m),4.02(1H,t,J=7. 3.86 (8H, m), 4.02 (1H, t, J = 7.
8Hz),4.18〜4.33(1H,m),6.78 8Hz), 4.18~4.33 (1H, m), 6.78
(1H,t,J=7.2Hz),6.87(2H,d, (1H, t, J = 7.2Hz), 6.87 (2H, d,
J=7.8Hz),7.00〜7.27(6H,m), J = 7.8Hz), 7.00~7.27 (6H, m),
7.27〜7.45(4H,m),11.78(1H, 7.27~7.45 (4H, m), 11.78 (1H,
brs) brs)

【0062】(実施例12) 14 C−(R)−1−[4,4−ビス(4−フルオロフェニル)ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン・3塩酸塩の製造:実施例10と同様に、 14 C−(R)−1−[4,4−ビス(4 [0062] (Example 12) 14 C- (R) -1- [4,4- bis (4-fluorophenyl) butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine trihydrochloride : prepared as in example 10, 14 C- (R) -1- [4,4- bis (4
−フルオロフェニル)ブチル]−4−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン 179M - fluorophenyl) butyl] -4- (2-hydroxy-3-phenyl-aminopropyl) piperazine 179M
Bq及び5%塩化水素−メタノール溶液 302μl Bq and 5% hydrogen chloride - methanol solution 302μl
(413μmol)を用い、目的化合物を74.0MB Using (413μmol), 74.0MB the desired compound
q得た。 It was obtained q. 得られた化合物は、実施例11で得られた化合物との液体クロマトグラフィーにより同定された。 The obtained compound was identified by liquid chromatography and the compound obtained in Example 11.

【0063】 [0063]

【発明の効果】本発明によれば、ジフェニルブチル構造のメチン炭素にその同位体を導入する事のできる製造法及びジフェニルブチルピペラジン類の製造法を提供することができる。 According to the present invention, it is possible to provide a manufacturing method of preparation and diphenyl butyl piperazine can be introduced the isotope methine carbon of diphenyl butyl structure.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl. 6識別記号 FI C07C 33/34 C07C 33/34 A // C07M 5:00 7:00 (72)発明者 川勝 庸行 神奈川県横浜市戸塚区柏尾町560 ポーラ 化成工業株式会社戸塚研究所内 (72)発明者 山田 浩次 神奈川県横浜市戸塚区柏尾町560 ポーラ 化成工業株式会社戸塚研究所内 ────────────────────────────────────────────────── ─── of the front page continued (51) Int.Cl. 6 identification symbol FI C07C 33/34 C07C 33/34 a // C07M 5:00 7:00 (72) inventor Kawakatsu IsaoKo Kanagawa Prefecture, Totsuka-ku, Yokohama-shi Casio town 560 Pola Chemical industry Co., Ltd. Totsuka the laboratory (72) inventor Kanagawa Prefecture Koji Yamada, Totsuka-ku, Yokohama-shi Casio-cho, 560 Pola Chemical industry Co., Ltd. Totsuka the laboratory

Claims (8)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】 下記一般式(1)で表される化合物と一般式(2)で表される化合物を反応させることを特徴とする、一般式(3)で表される化合物の製造法。 [Claim 1], characterized by reacting a compound represented by the following compound represented by the general formula (1) and general formula (2), methods for preparation of the compounds represented by the general formula (3). 【化1】 [Formula 1] (但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表す。) 【化2】 (However, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof.) ## STR2 ## (但し、式中Yはハロゲン原子を表す。) 【化3】 (However, wherein Y represents a halogen atom.) Embedded image (但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表す。) (However, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof.)
  2. 【請求項2】 一般式(3)で表される化合物にハロゲン化水素又はハロゲン化水素酸を反応させることを特徴とする、一般式(4)で表される化合物の製造方法。 2. A production method of general formula characterized by reacting a hydrogen halide or a hydrogen halide acid compound represented by formula (3), the compound represented by formula (4). 【化4】 [Of 4] (但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表し、Zはハロゲン原子を表す。) (However, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof, Z is a halogen atom.)
  3. 【請求項3】 一般式(4)で表される化合物を水素添加する事を特徴とする、一般式(5)で表される化合物の製造方法。 3. The method for producing a general formula and wherein the hydrogenating a compound represented by (4), the compound represented by the general formula (5). 【化5】 [Of 5] (但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表し、Zはハロゲン原子を表す。) (However, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof, Z is a halogen atom.)
  4. 【請求項4】 一般式(5)で表される化合物に1− 4. A compound represented by the general formula (5) 1-
    (2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンを縮合させることを特徴とする、一般式(6)で表される化合物又はその塩の製造方法。 (2-hydroxy-3-phenyl-aminopropyl) piperazine the condensation of and wherein, the compound represented by the general formula (6) or a salt thereof. 【化6】 [Omitted] (但し、式中R 1 、R 2はそれぞれ独立に水素原子又はハロゲン原子を表し、Xは炭素原子又はその同位体を表し、*は不斉炭素を表す。) (However, wherein R 1, R 2 each independently represent a hydrogen atom or a halogen atom, X represents a carbon atom or isotopes thereof, * represents an asymmetric carbon.)
  5. 【請求項5】 1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン及び/又は一般式(6)で表される化合物が光学活性体であることを特徴とする、請求項4に記載の製造法。 A compound represented by wherein 1- (2-hydroxy-3-phenyl-aminopropyl) piperazine and / or the general formula (6) is characterized in that an optically active substance, according to claim 4 production method.
  6. 【請求項6】 一般式(1)で表される化合物に一般式(2)で表される化合物を反応させ、一般式(3)で表される化合物と為し、当該の一般式(3)で表される化合物にハロゲン化水素又はハロゲン化水素酸を反応させ、一般式(4)で表される化合物と為し、当該の一般式(4)で表される化合物を水素添加して一般式(5) 6. reacting a Formula (1) Formula to the compound represented by (2), compounds represented by without a compound represented by the general formula (3), the formula (3 ) in hydrogen halide or hydrohalic acid is reacted to the compound represented, without the compound represented by the general formula (4), with the general formula (4) compounds represented by hydrogenating the general formula (5)
    で表される化合物と為し、当該の一般式(5)で表される化合物に1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジンを縮合させることを特徴とする、 In represented without the compound, and characterized in that the compound represented by the general formula (5) 1- (2-hydroxy-3-phenyl-aminopropyl) piperazine condensation,
    一般式(6)で表される化合物又はその塩の製造方法。 Compound or a salt thereof represented by the general formula (6).
  7. 【請求項7】 1−(2−ヒドロキシ−3−フェニルアミノプロピル)ピペラジン及び/又は一般式(6)で表される化合物が光学活性体であることを特徴とする、請求項6に記載の製造法。 7. A 1-compound represented by formula (2-hydroxy-3-phenyl-aminopropyl) piperazine and / or the general formula (6) is characterized in that an optically active substance, according to claim 6 production method.
  8. 【請求項8】 一般式(1)〜(6)で表される化合物に於いて、Xが14 Cであることを特徴とする、請求項6 8. general formula (1) to In the compound represented by formula (6), characterized in that X is 14 C, according to claim 6
    又は7に記載の製造法。 Or process according to 7.
JP25746397A 1997-09-05 1997-09-05 Production of diphenylalkyl compound Pending JPH1180142A (en)

Priority Applications (1)

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JP25746397A JPH1180142A (en) 1997-09-05 1997-09-05 Production of diphenylalkyl compound

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