JP2002371061A - Method for treating 1-chlorocarbonylpiperidine derivative hydrochloric acid salt - Google Patents
Method for treating 1-chlorocarbonylpiperidine derivative hydrochloric acid saltInfo
- Publication number
- JP2002371061A JP2002371061A JP2001184212A JP2001184212A JP2002371061A JP 2002371061 A JP2002371061 A JP 2002371061A JP 2001184212 A JP2001184212 A JP 2001184212A JP 2001184212 A JP2001184212 A JP 2001184212A JP 2002371061 A JP2002371061 A JP 2002371061A
- Authority
- JP
- Japan
- Prior art keywords
- chlorocarbonylpiperidine
- derivative
- hydrochloride
- solvent
- treating
- 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.)
- Granted
Links
Landscapes
- Hydrogenated Pyridines (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、医薬品等の分野で重要
な中間体である１−クロロカルボニルピペリジン誘導体
の製造における、１−クロロカルボニルピペリジン誘導
体塩酸塩の処理方法に関する。The present invention relates to a method for treating a 1-chlorocarbonylpiperidine derivative hydrochloride in the production of a 1-chlorocarbonylpiperidine derivative which is an important intermediate in the field of pharmaceuticals and the like.
【０００２】[0002]
【従来の技術】１−クロロカルボニルピペリジン誘導体
の製造方法としては、ピペリジン誘導体をベンゼン溶媒
中ホスゲンまたはホスゲンダイマーと反応させ、過剰の
ホスゲンを濾過により除去して１−クロロカルボニルピ
ペリジン誘導体塩酸塩とし、この塩酸塩を多量のジクロ
ロメタンに溶解し、炭酸水素ナトリウム、炭酸カリウム
等の塩基性水溶液で処理する方法（特開平９−１１０８
６５，Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，３９，１４
４６（１９９１））や、ジクロロメタン、ベンゼンまた
はアセトニトリル溶媒中、４−ピペリジノピペリジン
に、ハロゲン化トリアルキルシリルを反応させてシリル
体を得、これに炭酸ガスを反応させ、次いで塩化チオニ
ル等を反応させて１−クロロカルボニル−４−ピペリジ
ノピペリジン塩酸塩を得、濾過により４−ピペリジノピ
ペリジン塩酸塩を除去した濾液を、水酸化ナトリウム、
水酸化カリウム、水酸化カルシウム、水酸化バリウム等
の塩基性水溶液でフリー化する方法（特開平１０−２８
７６５０）が知られている。2. Description of the Related Art As a method for producing a 1-chlorocarbonylpiperidine derivative, a piperidine derivative is reacted with phosgene or a phosgene dimer in a benzene solvent, and excess phosgene is removed by filtration to obtain a 1-chlorocarbonylpiperidine derivative hydrochloride, A method of dissolving this hydrochloride in a large amount of dichloromethane and treating it with a basic aqueous solution such as sodium hydrogen carbonate, potassium carbonate or the like (JP-A 9-1108)
65, Chem. Pharm. Bull. , 39,14
46 (1991)) or 4-piperidinopiperidine in a solvent of dichloromethane, benzene or acetonitrile is reacted with a trialkylsilyl halide to obtain a silyl form, which is then reacted with carbon dioxide gas, and then thionyl chloride or the like. The reaction was performed to obtain 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride, and the filtrate from which 4-piperidinopiperidine hydrochloride was removed by filtration was filtered using sodium hydroxide,
Method for making free with a basic aqueous solution of potassium hydroxide, calcium hydroxide, barium hydroxide or the like (Japanese Patent Laid-Open No. 10-28)
7650) is known.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、上記の
Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，３９，１４４６
（１９９１）記載の方法では、反応液を濾過して得られ
る１−クロロカルボニルピペリジン誘導体塩酸塩を多量
のジクロロメタンに溶解し、濾過工程を挿む事無く塩基
性水溶液で処理するため、反応液を濾過して得られる１
−クロロカルボニルピペリジン誘導体塩酸塩の中には、
ピペリジン誘導体の塩酸塩やビスウレア体の塩酸塩が少
量含有し、濾過されないためこれらの不純物が除去され
ず純度の低下をもたらし、溶媒置換せずジクロロメタン
のまま塩基性水溶液で処理してフリー化させているが、
ジクロロメタンが水にやや親和性を有し、そのため塩基
性水溶液との接触により一部が加水分解して収率が低く
なる。また特開平９−１１０８６５記載の方法では、反
応液を濾過して得られる１−クロロカルボニルピペリジ
ン誘導体塩酸塩からジクロロメタン抽出しているもの
の、溶媒置換せず水にやや親和性を有するジクロロメタ
ンのまま塩基性水溶液で処理してフリー化させているた
め、塩基性水溶液との接触により一部が加水分解して収
率が低くなる。However, the above-mentioned Chem. Pharm. Bull. , 39,1446
In the method described in (1991), the 1-chlorocarbonylpiperidine derivative hydrochloride obtained by filtering the reaction solution is dissolved in a large amount of dichloromethane and treated with a basic aqueous solution without inserting a filtration step. 1 obtained by filtration
-Among the chlorocarbonylpiperidine derivative hydrochloride,
It contains a small amount of a hydrochloride of a piperidine derivative or a hydrochloride of a bisurea compound, and is not filtered, so that these impurities are not removed, resulting in a decrease in purity. But
Dichloromethane has a slight affinity for water, so that it is partially hydrolyzed by contact with a basic aqueous solution to lower the yield. In the method described in JP-A-9-110865, dichloromethane is extracted from a 1-chlorocarbonylpiperidine derivative hydrochloride obtained by filtering a reaction solution. However, the solvent is not replaced and dichloromethane having a slight affinity to water is used as a base. Since it is made free by treatment with a basic aqueous solution, a part thereof is hydrolyzed by contact with a basic aqueous solution to lower the yield.
【０００４】一方、特開平１０−２８７６５０記載の方
法では、４−ピペリジノピペリジンに、ハロゲン化トリ
アルキルシリルを反応させてシリル体を得、これに炭酸
ガスを反応させ、次いで塩化チオニル等を反応させて１
−クロロカルボニル−４−ピペリジノピペリジン塩酸塩
を得、濾過により４−ピペリジノピペリジン塩酸塩を除
去した濾液を、用いられている溶媒のジクロロメタン、
ベンゼンまたはアセトニトリルを置換する事無くそのま
ま水酸化ナトリウム、水酸化カリウム、水酸化カルシウ
ム、水酸化バリウム等の塩基性水溶液でフリー化し、有
機層を水洗、乾燥、濃縮し、１−クロロカルボニル−４
−ピペリジノピペリジンを得ているが、反応工程が多く
長時間を要し、また、得られた１−クロロカルボニル−
４−ピペリジノピペリジンの純度が低く、再度イソプロ
ピルエーテル等に溶解して冷却し、析出物を濾別した濾
液を濃縮後ｎ−ヘキサンを加えて結晶化させる再結晶工
程を必要としている。工程的にはホスゲンまたはホスゲ
ンダイマーを用いてクロロカルボニル化する方法が優れ
ているが、収率、純度の点で満足できず、１−クロロカ
ルボニルピペリジン誘導体が、工程数が少なく経済的
で、しかも高収率、高純度で得られる製造方法の改良が
強く求められていた。On the other hand, according to the method described in JP-A-10-287650, 4-piperidinopiperidine is reacted with a trialkylsilyl halide to obtain a silyl form, which is then reacted with carbon dioxide gas, and then thionyl chloride or the like. React 1
-Chlorocarbonyl-4-piperidinopiperidine hydrochloride was obtained, and the filtrate from which 4-piperidinopiperidine hydrochloride had been removed by filtration was used as a solvent, dichloromethane,
Without substituting benzene or acetonitrile, it is made free with a basic aqueous solution such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc., and the organic layer is washed with water, dried and concentrated to give 1-chlorocarbonyl-4.
-Piperidinopiperidine is obtained, but the reaction steps are long and require a long time, and the obtained 1-chlorocarbonyl-
The purity of 4-piperidinopiperidine is low, and it requires a recrystallization step of dissolving again in isopropyl ether or the like, cooling, and concentrating the filtrate from which the precipitate is separated by filtration, and then adding n-hexane for crystallization. In terms of process, chlorocarbonylation using phosgene or a phosgene dimer is excellent, but the yield and purity are unsatisfactory, and the 1-chlorocarbonylpiperidine derivative is economical with a small number of steps, and There has been a strong demand for an improvement in a production method that can be obtained with high yield and high purity.
【０００５】[0005]
【課題を解決するための手段】本発明者らは、１−クロ
ロカルボニルピペリジン誘導体塩酸塩を、選択した溶媒
で溶解した後濾過し、反応で発生してくるピペリジン誘
導体の塩酸塩やビスウレア体の塩酸塩を除去し、濾液の
溶媒を留去後選択した他の溶媒を加えて溶媒置換した後
フリー化を行うことにより、経済的で高純度、高収率で
１−クロロカルボニルピペリジン誘導体が得られること
を見出した。DISCLOSURE OF THE INVENTION The present inventors dissolve 1-chlorocarbonylpiperidine derivative hydrochloride in a selected solvent, and then filtered to obtain a hydrochloride of a piperidine derivative or a bisurea derivative generated in the reaction. By removing the hydrochloride, distilling off the solvent of the filtrate, adding another selected solvent and replacing the solvent, and freezing, the 1-chlorocarbonylpiperidine derivative is obtained economically, with high purity and high yield. Was found to be.
【０００６】すなわち、ピペリジン誘導体にホスゲンま
たはホスゲンダイマーを反応させた後濾過して得られ
る、下記一般式（１）で示される１−クロロカルボニル
ピペリジン誘導体塩酸塩を、That is, a 1-chlorocarbonylpiperidine derivative hydrochloride represented by the following general formula (1), which is obtained by reacting phosgene or a phosgene dimer with a piperidine derivative and then filtering the same,
【０００７】[0007]
【化４】 （式中置換基Ｒ１、Ｒ２は、おのおの互いに独立して、
炭素数が１〜２０個の直鎖状もしくは分枝鎖状のアルキ
ル基、アルケニル基、アルキニル基もしくは、炭素数３
〜８個のシクロアルキル基または、任意に置換されたア
リール基を表し、またはＲ１、Ｒ２で環を形成してピロ
リジニル、ピペリジニルまたはモルホリニル基となって
いてもよい。） １−クロロカルボニルピペリジン誘導体塩酸塩に対し不
活性なクロロホルム、ジクロロメタン、ジクロロエタ
ン、アセトニトリル、プロピオニトリル、Ｎ，Ｎ−ジメ
チルホルムアミド、１，３−ジメチル−２−イミダゾリ
ジノンおよびＮ−メチルピロリドン等から選ばれた単独
または混合溶媒を用い選択的に溶解した後濾過し、反応
で発生してくるピペリジン誘導体の塩酸塩やビスウレア
体の塩酸塩を除去し、濾液の溶媒を留去後、水と分離可
能であって、かつ、誘電率が９．０以下で、１−クロロ
カルボニルピペリジン誘導体塩酸塩に対し不活性な溶媒
を加えて溶媒置換しフリー化をすることにより、下記一
般式（３）で示される１−クロロカルボニルピペリジン
誘導体を高収率、高純度で得ることができる。Embedded image (Wherein the substituents R 1 and R 2 are each independently
A linear or branched alkyl group, alkenyl group, alkynyl group having 1 to 20 carbon atoms or 3 carbon atoms;
Represents up to 8 cycloalkyl groups or optionally substituted aryl groups, or may form a ring with R 1 and R 2 to form a pyrrolidinyl, piperidinyl or morpholinyl group. 1) Chloroform, dichloromethane, dichloroethane, acetonitrile, propionitrile, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone and the like which are inactive against 1-chlorocarbonylpiperidine derivative hydrochloride After selectively dissolving using a single or mixed solvent selected from the above, filtration is performed to remove the hydrochloride of the piperidine derivative and the hydrochloride of the bisurea body generated in the reaction, and after distilling off the solvent of the filtrate, water and By adding an inert solvent to the 1-chlorocarbonylpiperidine derivative hydrochloride, which is separable and has a dielectric constant of 9.0 or less, and displaces the solvent to make it free, the following general formula (3) Can be obtained in high yield and high purity.
【０００８】[0008]
【化５】 （式中置換基Ｒ１、Ｒ２は、おのおの互いに独立して、
炭素数が１〜２０個の直鎖状もしくは分枝鎖状のアルキ
ル基、アルケニル基、アルキニル基もしくは、炭素数３
〜８個のシクロアルキル基または、任意に置換されたア
リール基を表し、またはＲ１、Ｒ２で環を形成してピロ
リジニル、ピペリジニルまたはモルホリニル基となって
いてもよい。）Embedded image (Wherein the substituents R 1 and R 2 are each independently
A linear or branched alkyl group, alkenyl group, alkynyl group having 1 to 20 carbon atoms or 3 carbon atoms;
Represents up to 8 cycloalkyl groups or optionally substituted aryl groups, or may form a ring with R 1 and R 2 to form a pyrrolidinyl, piperidinyl or morpholinyl group. )
【０００９】本発明において用いる１−クロロカルボニ
ルピペリジン誘導体塩酸塩の粗製品は、例えば、Ｃｈｅ
ｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，３９，１４４６（１９９
１）に記載されているような、４−ジメチルアミノピペ
リジン、４−ジエチルアミノピペリジン、４−ピロリジ
ノピペリジン、４−モルホリノピペリジンなどのピペリ
ジン誘導体とホスゲンまたはホスゲンダイマーとを反応
させ、過剰のホスゲンを濾過により除去して得ることが
出来る。The crude product of the 1-chlorocarbonylpiperidine derivative hydrochloride used in the present invention is, for example, Che
m. Pharm. Bull. , 39, 1446 (199
Reaction of piperidine derivatives such as 4-dimethylaminopiperidine, 4-diethylaminopiperidine, 4-pyrrolidinopiperidine, 4-morpholinopiperidine with phosgene or phosgene dimer as described in 1), and filtration of excess phosgene And can be obtained by removal.
【００１０】本発明において、１−クロロカルボニルピ
ペリジン誘導体塩酸塩の溶解に使用される有機溶媒の具
体例としては、クロロホルム、ジクロロメタン、ジクロ
ロエタンなどのハロゲン化炭化水素系溶媒、アセトニト
リル、プロピオニトリル、Ｎ，Ｎ−ジメチルホルムアミ
ド、１，３−ジメチル−２−イミダゾリジノン、Ｎ−メ
チルピロリドンなどの溶媒が単独または混合溶媒として
用いられるが、アセトニトリル、プロピオニトリルなど
の溶媒の単独または混合溶媒が特に好ましい。In the present invention, specific examples of the organic solvent used for dissolving the hydrochloride of the 1-chlorocarbonylpiperidine derivative include halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, acetonitrile, propionitrile, N , N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone and the like may be used alone or as a mixed solvent. Particularly, a solvent such as acetonitrile and propionitrile may be used alone or a mixed solvent. preferable.
【００１１】１−クロロカルボニルピペリジン誘導体塩
酸塩をフリー化する際に使用する溶媒は、疎水性溶媒の
方がフリー化時の１−クロロカルボニルピペリジン誘導
体の分解が少なく好適であった。したがって、１−クロ
ロカルボニルピペリジン誘導体塩酸塩に対し不活性で水
と分離可能であって、かつ、誘電率が９．０以下の溶媒
である、ペンタン、ヘキサン、ヘプタン、オクタン、シ
クロヘキサン、トルエン、キシレンまたはベンゼンが単
独または混合溶媒として用いられる。As the solvent used for liberating the 1-chlorocarbonylpiperidine derivative hydrochloride, a hydrophobic solvent is preferred because the 1-chlorocarbonylpiperidine derivative is less decomposed during the liberation. Therefore, pentane, hexane, heptane, octane, cyclohexane, toluene, xylene, which is a solvent which is inert to the 1-chlorocarbonylpiperidine derivative hydrochloride, is separable from water, and has a dielectric constant of 9.0 or less. Alternatively, benzene is used alone or as a mixed solvent.
【００１２】１−クロロカルボニルピペリジン誘導体塩
酸塩の溶液もしくは懸濁液をフリー化するときに使用す
る塩基としては、炭酸ナトリウム、炭酸カリウム、水酸
化ナトリウム、水酸化カリウム、水酸化カルシウム、水
酸化バリウム、水酸化マグネシウム、炭酸水素ナトリウ
ム、炭酸水素カリウムが挙げられる。かかる塩基の濃度
は、特に制限されないが、０．５〜５０重量％であるこ
とが好ましく、１〜３０重量％であることが特に好まし
い。使用する塩基量としては、１−クロロカルボニルピ
ペリジン誘導体塩酸塩が分解しなければ、特に限定され
ないが、塩酸塩に対し１〜１０当量が好ましく、フリー
化の温度条件としては、１−クロロカルボニルピペリジ
ン誘導体塩酸塩が分解しなければ、特に限定されない
が、２０℃以下が好ましい。以上の操作により、有機層
中に１−クロロカルボニルピペリジン誘導体を得る。こ
のものを、乾燥、濃縮し、ノルマルヘキサン、ノルマル
ヘプタン、シクロヘキサンなどの飽和炭化水素溶媒で晶
析をすることにより、高純度、高収率で１−クロロカル
ボニルピペリジン誘導体を得ることができる。The base used to make the solution or suspension of the 1-chlorocarbonylpiperidine derivative hydrochloride free is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide. , Magnesium hydroxide, sodium bicarbonate, and potassium bicarbonate. The concentration of the base is not particularly limited, but is preferably 0.5 to 50% by weight, and particularly preferably 1 to 30% by weight. The amount of the base to be used is not particularly limited as long as the 1-chlorocarbonylpiperidine derivative hydrochloride is not decomposed, but is preferably 1 to 10 equivalents to the hydrochloride, and the freezing temperature conditions are 1-chlorocarbonylpiperidine. There is no particular limitation as long as the derivative hydrochloride does not decompose, but preferably 20 ° C. or lower. By the above operation, a 1-chlorocarbonylpiperidine derivative is obtained in the organic layer. This is dried, concentrated, and crystallized with a saturated hydrocarbon solvent such as normal hexane, normal heptane, and cyclohexane to obtain a 1-chlorocarbonylpiperidine derivative with high purity and high yield.
【００１３】[0013]
【発明の実施の形態】以下に、実施例を挙げて本発明を
更に具体的に説明するが、本発明はこれらの実施例に限
定されるものではない。DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
【００１４】［実施例１］テトラヒドロフラン３５０ｍ
ｌに、ホスゲン２６．６ｇ（２６９ｍｍｏｌ）を溶解
し、系内を０℃に冷却し、４−ピペリジノピペリジン３
０ｇ（１７９ｍｍｏｌ）をテトラヒドロフラン１５０ｍ
ｌに溶解し５℃以下で滴下する。同温度で１時間後撹拌
し、その後１０〜２０℃で窒素バッキを行う。脱ホスゲ
ン後の反応液を濾過することで、粗１−クロロカルボニ
ル−４−ピペリジノピペリジン塩酸塩を得、このものを
アセトニトリル６００ｍｌに溶解し、不溶分を濾別す
る。濾液を減圧下濃縮することでアセトニトリルを留去
し、ノルマルヘキサン１５０ｍｌを添加し、ノルマルヘ
キサンの懸濁液とする。この懸濁液に、１０℃以下に冷
却下、２５％炭酸カリウム水溶液３５０ｍｌを添加しフ
リー化をおこなった。有機層を分離し、無水硫酸マグネ
シウムで乾燥し、減圧下濃縮し、氷冷下析出した結晶を
濾過することにより、白色結晶の１−クロロカルボニル
−４−ピペリジノピペリジン２９ｇ（収率；７０％）を
得た。Example 1 350 m of tetrahydrofuran
Then, 26.6 g (269 mmol) of phosgene was dissolved in 1 l, and the system was cooled to 0 ° C., and 4-piperidinopiperidine 3 was added.
0 g (179 mmol) in tetrahydrofuran 150 m
and added dropwise at 5 ° C or less. After stirring for 1 hour at the same temperature, nitrogen backing is performed at 10 to 20 ° C. By filtering the reaction solution after the removal of phosgene, crude 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride is obtained, which is dissolved in 600 ml of acetonitrile, and the insoluble matter is separated by filtration. Acetonitrile is distilled off by concentrating the filtrate under reduced pressure, and 150 ml of normal hexane is added to obtain a suspension of normal hexane. To this suspension, 350 ml of a 25% aqueous potassium carbonate solution was added under cooling to 10 ° C. or lower to make the suspension free. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the crystals precipitated under ice cooling were filtered to obtain 29 g of 1-chlorocarbonyl-4-piperidinopiperidine as white crystals (yield; 70%). %).
【００１５】融点：６４．０〜６４．８℃ 定量純度（電位差滴定）：９９．８％Melting point: 64.0-64.8 ° C. Quantitative purity (potentiometric titration): 99.8%
【００１６】［実施例２］トルエン４５０ｍｌに、ホス
ゲン２６．６ｇ（２６９ｍｍｏｌ）を溶解し、系内を０
℃に冷却し、４−ピペリジノピペリジン３０ｇ（１７９
ｍｍｏｌ）をトルエン１５０ｍｌに溶解し５℃以下で滴
下する。同温度で１時間後撹拌し、その後１０〜２０℃
で窒素バッキを行う。脱ホスゲン後の反応液を濾過する
ことで、粗１−クロロカルボニル−４−ピペリジノピペ
リジン塩酸塩を得、このものをアセトニトリル６００ｍ
ｌに溶解し、不溶分を濾別する。濾液を減圧下濃縮する
ことでアセトニトリルを留去し、ノルマルヘキサン１５
０ｍｌを添加し、ノルマルヘキサンの懸濁液とする。こ
の懸濁液に、１０℃以下に冷却下、２５％炭酸カリウム
水溶液３５０ｍｌを添加しフリー化をおこなった。有機
層を分離し、無水硫酸マグネシウムで乾燥し、減圧下濃
縮し、氷冷下析出した結晶を濾過することにより、白色
結晶の１−クロロカルボニル−４−ピペリジノピペリジ
ン２６．８ｇ（収率；６５％）を得た。Example 2 26.6 g (269 mmol) of phosgene was dissolved in 450 ml of toluene.
C. and cooled to 30 g of 4-piperidinopiperidine (179 g).
(mmol) in 150 ml of toluene and added dropwise at 5 ° C or lower. Stir for 1 hour at the same temperature, then 10-20 ° C
To perform nitrogen backing. By filtering the reaction solution after the removal of phosgene, crude 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride was obtained.
and the insoluble matter is filtered off. Acetonitrile was distilled off by concentrating the filtrate under reduced pressure.
Add 0 ml to make a normal hexane suspension. To this suspension, 350 ml of a 25% aqueous potassium carbonate solution was added under cooling to 10 ° C. or lower to make the suspension free. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the crystals precipitated under ice cooling were filtered to obtain 26.8 g of 1-chlorocarbonyl-4-piperidinopiperidine as white crystals (yield). ; 65%).
【００１７】融点：６３．５〜６４．０℃ 定量純度（電位差滴定）：９９．２％Melting point: 63.5-64.0 ° C. Quantitative purity (potentiometric titration): 99.2%
【００１８】［比較例１］粗１−クロロカルボニル−４
−ピペリジノピペリジン塩酸塩の抽出溶媒にジクロロメ
タンを使用したときの例を示す。テトラヒドロフラン３
５０ｍｌに、ホスゲン２６．６ｇ（２６９ｍｍｏｌ）を
溶解し、系内を０℃に冷却し、４−ピペリジノピペリジ
ン３０ｇ（１７９ｍｍｏｌ）をテトラヒドロフラン１５
０ｍｌに溶解し５℃以下で滴下する。同温度で１時間後
撹拌し、その後１０〜２０℃で窒素バッキを行う。脱ホ
スゲン後の反応液を濾過することで、粗１−クロロカル
ボニル−４−ピペリジノピペリジン塩酸塩を得、このも
のをジクロロメタン１２００ｍｌに溶解し、不溶分を濾
別する。この濾液に、１０℃以下に冷却下、２５％炭酸
カリウム水溶液３５０ｍｌを添加しフリー化をおこなっ
た。有機層を分離し、無水硫酸マグネシウムで乾燥し、
減圧下濃縮し、ノルマルヘキサン４００ｍｌに溶解し、
褐色の不溶物を濾別した。濾液を更に濃縮し、氷冷下、
析出した結晶を濾過することにより、微褐色結晶の１−
クロロカルボニル−４−ピペリジノピペリジン２１ｇ
（収率；５１％）を得た。Comparative Example 1 Crude 1-chlorocarbonyl-4
-The example at the time of using dichloromethane as an extraction solvent of piperidinopiperidine hydrochloride is shown. Tetrahydrofuran 3
26.6 g (269 mmol) of phosgene was dissolved in 50 ml, the system was cooled to 0 ° C, and 30 g (179 mmol) of 4-piperidinopiperidine was added to 15 ml of tetrahydrofuran.
Dissolve in 0 ml and add dropwise at 5 ° C or less. After stirring for 1 hour at the same temperature, nitrogen backing is performed at 10 to 20 ° C. By filtering the reaction solution after the removal of phosgene, crude 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride is obtained, which is dissolved in 1200 ml of dichloromethane, and the insoluble matter is separated by filtration. To the filtrate, 350 ml of a 25% aqueous potassium carbonate solution was added under cooling to 10 ° C. or lower to make the filtrate free. Separate the organic layer, dry over anhydrous magnesium sulfate,
Concentrate under reduced pressure, dissolve in 400 ml of normal hexane,
The brown insolubles were filtered off. The filtrate is further concentrated, and cooled with ice.
The precipitated crystals were filtered to give 1-brown crystals 1-.
Chlorocarbonyl-4-piperidinopiperidine 21 g
(Yield; 51%).
【００１９】融点：６２．３〜６４．０℃ 定量純度（電位差滴定）：９７．７％Melting point: 62.3-64.0 ° C. Quantitative purity (potentiometric titration): 97.7%
【００２０】[0020]
【発明の効果】本発明の方法によれば、効率よく１−ク
ロロカルボニルピペリジン誘導体塩酸塩をフリー化で
き、高純度、高収率で１−クロロカルボニルピペリジン
誘導体を得ることができる。According to the method of the present invention, the 1-chlorocarbonylpiperidine derivative hydrochloride can be efficiently freed, and the 1-chlorocarbonylpiperidine derivative can be obtained with high purity and high yield.
Claims (4)
酸塩を塩基を用いてフリー化し、１−クロロカルボニル
ピペリジン誘導体を得る方法において、ピペリジン誘導
体にホスゲンまたはホスゲンダイマーを反応させて得ら
れる、下記一般式（１）で示される１−クロロカルボニ
ルピペリジン誘導体塩酸塩を、 【化１】 （式中置換基Ｒ１、Ｒ２は、おのおの互いに独立して、
炭素数が１〜２０個の直鎖状もしくは分枝鎖状のアルキ
ル基、アルケニル基、アルキニル基もしくは、炭素数３
〜８個のシクロアルキル基または、任意に置換されたア
リール基を表し、またはＲ１、Ｒ２で環を形成してピロ
リジニル、ピペリジニルまたはモルホリニル基となって
いてもよい。） １−クロロカルボニルピペリジン誘導体塩酸塩に対し不
活性で水と分離可能であって、かつ、誘電率が９．０以
下の溶媒から選ばれた単独または混合溶媒に溶解または
懸濁させフリー化を行うことを特徴とする、１−クロロ
カルボニルピペリジン誘導体塩酸塩の処理方法。1. A method for obtaining a 1-chlorocarbonylpiperidine derivative by liberating a 1-chlorocarbonylpiperidine derivative hydrochloride using a base, wherein the piperidine derivative is reacted with phosgene or a phosgene dimer. The 1-chlorocarbonylpiperidine derivative hydrochloride represented by 1) is converted into (Wherein the substituents R 1 and R 2 are each independently
A linear or branched alkyl group, alkenyl group, alkynyl group having 1 to 20 carbon atoms or 3 carbon atoms;
Represents up to 8 cycloalkyl groups or optionally substituted aryl groups, or may form a ring with R 1 and R 2 to form a pyrrolidinyl, piperidinyl or morpholinyl group. ) Insoluble in 1-chlorocarbonylpiperidine derivative hydrochloride, separable from water and having a dielectric constant of 9.0 or less, dissolved or suspended in a single or mixed solvent selected from solvents, and freed. A method for treating a 1-chlorocarbonylpiperidine derivative hydrochloride, which is carried out.
酸塩に対し不活性で水と分離可能であって、かつ、誘電
率が９．０以下の溶媒が、ペンタン、ヘキサン、ヘプタ
ン、オクタン、シクロヘキサン、トルエン、キシレンま
たはベンゼンである請求項１の１−クロロカルボニルピ
ペリジン誘導体塩酸塩の処理方法。2. A solvent which is inert to 1-chlorocarbonylpiperidine derivative hydrochloride, is separable from water, and has a dielectric constant of 9.0 or less is pentane, hexane, heptane, octane, cyclohexane or toluene. 2. The method for treating a 1-chlorocarbonylpiperidine derivative hydrochloride according to claim 1, which is water, xylene or benzene.
酸塩を塩基を用いてフリー化し、１−クロロカルボニル
ピペリジン誘導体を得る方法において、ピペリジン誘導
体にホスゲンまたはホスゲンダイマーを反応させて得ら
れる、下記一般式（１）で示される１−クロロカルボニ
ルピペリジン誘導体塩酸塩を、 【化２】 （式中置換基Ｒ１、Ｒ２は、おのおの互いに独立して、
炭素数が１〜２０個の直鎖状もしくは分枝鎖状のアルキ
ル基、アルケニル基、アルキニル基もしくは、炭素数３
〜８個のシクロアルキル基または、任意に置換されたア
リール基を表し、またはＲ１、Ｒ２で環を形成してピロ
リジニル、ピペリジニルまたはモルホリニル基となって
いてもよい。） クロロホルム、ジクロロメタン、ジクロロエタン、アセ
トニトリル、プロピオニトリル、Ｎ，Ｎ−ジメチルホル
ムアミド、１，３−ジメチル−２−イミダゾリジノンお
よびＮ−メチルピロリドンから選ばれた単独または混合
溶媒で溶解した後濾過し、濾液の溶媒を留去し、つい
で、ペンタン、ヘキサン、ヘプタン、オクタン、シクロ
ヘキサン、トルエン、キシレンまたはベンゼンから選ば
れた単独または混合溶媒を加えて溶媒置換しフリー化を
行うことを特徴とする、１−クロロカルボニルピペリジ
ン誘導体塩酸塩の処理方法。3. A method for obtaining a 1-chlorocarbonylpiperidine derivative by liberating a 1-chlorocarbonylpiperidine derivative hydrochloride using a base, wherein the piperidine derivative is reacted with phosgene or a phosgene dimer. The 1-chlorocarbonylpiperidine derivative hydrochloride represented by 1) is converted into a compound represented by the following formula: (Wherein the substituents R 1 and R 2 are each independently
A linear or branched alkyl group, alkenyl group, alkynyl group having 1 to 20 carbon atoms or 3 carbon atoms;
Represents up to 8 cycloalkyl groups or optionally substituted aryl groups, or may form a ring with R 1 and R 2 to form a pyrrolidinyl, piperidinyl or morpholinyl group. ) After dissolving in a single solvent or a mixed solvent selected from chloroform, dichloromethane, dichloroethane, acetonitrile, propionitrile, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone and N-methylpyrrolidone, followed by filtration. The solvent of the filtrate is distilled off, and then pentane, hexane, heptane, octane, cyclohexane, toluene, xylene or benzene alone or a mixed solvent is added to perform solvent replacement and freeing. A method for treating a 1-chlorocarbonylpiperidine derivative hydrochloride.
酸塩が、下記化学式（２）で示される、１−クロロカル
ボニル−４−ピペリジノピペリジン塩酸塩である請求項
１または請求項２または請求項３記載の処理方法。 【化３】 4. The 1-chlorocarbonylpiperidine derivative hydrochloride is 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride represented by the following chemical formula (2). The processing method described. Embedded image
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008529991A (en) * | 2005-02-08 | 2008-08-07 | フェルミオン オサケ ユキチュア | [1,4 '] bipiperidinyl-1'-carbonyl chloride or a method for producing the hydrochloride thereof |
| EP2341046A3 (en) * | 2009-11-18 | 2011-08-24 | Cadila Healthcare Limited | Process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate |
| JP2018516743A (en) * | 2015-04-20 | 2018-06-28 | コベストロ・エルエルシー | Process for continuous in-line filtration of process streams |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09110865A (en) * | 1995-08-15 | 1997-04-28 | Masao Oguro | Taxol derivative |
-
2001
- 2001-06-19 JP JP2001184212A patent/JP4986343B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09110865A (en) * | 1995-08-15 | 1997-04-28 | Masao Oguro | Taxol derivative |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008529991A (en) * | 2005-02-08 | 2008-08-07 | フェルミオン オサケ ユキチュア | [1,4 '] bipiperidinyl-1'-carbonyl chloride or a method for producing the hydrochloride thereof |
| EP2341046A3 (en) * | 2009-11-18 | 2011-08-24 | Cadila Healthcare Limited | Process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate |
| EP2399907A1 (en) * | 2009-11-18 | 2011-12-28 | Cadila Healthcare Limited | Solid Form of [1,4']-Bipiperidinyl-1'-Carbonyl Chloride |
| JP2018516743A (en) * | 2015-04-20 | 2018-06-28 | コベストロ・エルエルシー | Process for continuous in-line filtration of process streams |
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