JP3950423B2 - Process for producing cis-2,6-dimethylpiperazine - Google Patents
Process for producing cis-2,6-dimethylpiperazine Download PDFInfo
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- JP3950423B2 JP3950423B2 JP2003032012A JP2003032012A JP3950423B2 JP 3950423 B2 JP3950423 B2 JP 3950423B2 JP 2003032012 A JP2003032012 A JP 2003032012A JP 2003032012 A JP2003032012 A JP 2003032012A JP 3950423 B2 JP3950423 B2 JP 3950423B2
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- dimethylpiperazine
- cis
- trans
- reaction
- catalyst
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- IFNWESYYDINUHV-OLQVQODUSA-N (2s,6r)-2,6-dimethylpiperazine Chemical compound C[C@H]1CNC[C@@H](C)N1 IFNWESYYDINUHV-OLQVQODUSA-N 0.000 title claims description 33
- 238000000034 method Methods 0.000 title claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 24
- IFNWESYYDINUHV-PHDIDXHHSA-N (2r,6r)-2,6-dimethylpiperazine Chemical compound C[C@@H]1CNC[C@@H](C)N1 IFNWESYYDINUHV-PHDIDXHHSA-N 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 16
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 14
- 229910017052 cobalt Inorganic materials 0.000 claims description 6
- 239000010941 cobalt Substances 0.000 claims description 6
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- 239000003960 organic solvent Substances 0.000 description 13
- 229910021529 ammonia Inorganic materials 0.000 description 11
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 11
- 229940043276 diisopropanolamine Drugs 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 238000006317 isomerization reaction Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 5
- IFNWESYYDINUHV-UHFFFAOYSA-N 2,6-dimethylpiperazine Chemical compound CC1CNCC(C)N1 IFNWESYYDINUHV-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 239000003905 agrochemical Substances 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012971 dimethylpiperazine Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、医薬、農薬の原料として有用な、シス−２，６−ジメチルピペラジンの製造法、分離方法に関するものである。
【０００２】
【従来の技術】
従来２，６−ジメチルピペラジンの製造方法としては、ジイソプロパノールアミンとアンモニアをニッケル触媒の存在下、水溶媒又は無溶媒にて反応させて得る方法（英国特許第９０２５７０号明細書、米国特許第2911407号明細書、有機合成化学協会誌第１７巻１号１７〜２８頁(1959) )が知られている。
【０００３】
【発明が解決しようとする課題】
２，６−ジメチルピペラジンは、その構造から立体異性体であるシス−及びトランス−２，６−ジメチルピペラジンが存在する。これらの立体異性体のうちシス体の需要の方が多く、特に医薬、農薬の原料としてはシス体が使用されるため、工業的なシス体の高選択的製造法の開発が望まれている。
【０００４】
上記文献には、その方法によって生成するシス体とトランス体の比が記載されていない。本発明者らが従来の方法に従って反応を行なったところ、生成する２，６−ジメチルピペラジンはシス体の割合が多かったが十分ではなく、さらにシス選択率を向上させる必要があった。
【０００５】
こうして得られた反応生成物を上記文献と同様にして蒸留に付してシス体の分離を試みた。しかし、得られるものはシス体及びトランス体を含む混合物であり、シス体とトランス体との分離は蒸留では困難であった。これまで、この立体異性体の混合物からシス体を高純度で分離する方法は知られていない。
さらに、トランス−２，６−ジメチルピペラジンを異性化してシス−２，６−ジメチルピペラジンを製造する方法も知られていない。
【０００６】
本発明の目的は、シス−２，６−ジメチルピペラジンを高い選択率で製造する方法を提供することにある。
本発明の他の目的は、シス−及びトランス−２，６−ジメチルピペラジンの混合物から、高純度でシス−２，６−ジメチルピペラジンを分離できる方法を提供することにある。
さらに本発明の目的は、トランス−２，６−ジメチルピペラジンを異性化してシス−２，６−ジメチルピペラジンを製造する方法を提供することにある。
【課題を解決するための手段】
【０００７】
そこで本発明者らは鋭意検討した結果、溶媒として有機溶剤を用いて触媒存在下でジイソプロパールアミンとアンモニアとの反応を行うと、シス−２，６−ジメチルピペラジンの選択率が著しく改善されること、有機溶剤中のシス−及びトランス−２，６−ジメチルピペラジンの混合物からシス体が高純度で結晶化すること、並びに触媒の存在下、１８０℃以上の温度でトランス体の異性化が起ることを見出し本発明に至った。
【０００８】
即ち本発明は、溶媒及び触媒の存在下でジイソプロパノールアミンとアンモニアとを反応させてシス−２，６−ジメチルピペラジンを製造するにあたり、溶媒に有機溶剤を使用することを特徴とするシス−２，６−ジメチルピペラジンの製造方法、シス−２，６−ジメチルピペラジン、トランス−２，６−ジメチルピペラジン及び有機溶剤を含有する混合液を結晶化処理することを特徴とするシス−２，６−ジメチルピペラジンの分離方法、及び触媒の存在下、１８０℃以上の反応温度でトランス−２，６−ジメチルピペラジンを異性化することを特徴とするシス−２，６−ジメチルピペラジンの製造方法に係るものである。
【０００９】
【発明の実施の形態】
次に、本発明をさらに詳細に説明する。
本発明のシス−２，６−ジメチルピペラジンの製造方法は、ジイソプロパノールアミンとアンモニアを触媒の存在下で反応させるにあたり、溶媒に有機溶剤を使用することを特徴とするものである。本発明に使用される有機溶剤としては、ベンゼン、トルエン、キシレンのような芳香族系炭化水素が好ましい。有機溶剤の使用量は工業的取扱の観点からジイソプロパノールアミン１重量部に対して０．５〜５重量部が好ましい。
【００１０】
触媒は、ニッケル、コバルト等が好ましく、特にニッケル触媒が好ましい。ニッケル触媒及びコバルト触媒としては、ラネーニッケル、ラネーコバルト及び活性炭、シリカゲル、アルミナ等に担持されたニッケル又はコバルト等が使用できる。触媒の使用量は、ジイソプロパノールアミン１重量部に対して０．０１重量部以上であればよく、経済性の面から０．０１〜０．５重量部の使用が好ましい。触媒量が０．０１重量部より少ないと反応の進行が遅く、長時間を要するため好ましくない。
【００１１】
アンモニアの使用量は、ジイソプロパノールアミン１モルに対して１．０〜２．０モルが好ましく、さらに好ましくは１．２〜１．５モル用いるのが望ましい。アンモニアの使用量が２．０モルを越えると反応の進行が遅くなる。
【００１２】
反応は加圧下で行うのが好ましく、その圧は特に限定はなく広く選択できるが、工業的な取扱の面から１９６１．４〜５８８４．２ｋＰａ（２０〜６０ｋｇ／ｃｍ2）とするのが好ましい。反応温度は１５０℃以上が好ましく、工業的取扱の観点からさらに好ましくは１５０℃以上２００℃で行なわれるのがよい。反応温度が１５０℃より低いと反応が進行しにくくなり、反応に長時間を要するため好ましくない。
【００１３】
次に、シス−２，６−ジメチルピペラジンとトランス−２，６−ジメチルピペラジンとの分離は、両者を含有する有機溶剤との混合物を結晶化処理して行なう。例えば、前述のようにして得られた反応液をろ過して触媒を除去し、次いで共沸脱水を行ない水を除去した後、有機溶剤の量がシス−２，６−ジメチルピペラジンの理論生成量の約２〜３重量倍となるようにさらに有機溶剤を加え、加熱して結晶を完全に溶解し、これを冷却して結晶化を行う。結晶化の温度と時間は種々選択できるが、例えば５℃、２時間で結晶化を行なうことにより、実質的にシス−２，６−ジメチルピペラジンのみを晶出させることができ、高純度のシス−２，６−ジメチルピペラジンが得られる。この有機溶剤としては、ベンゼン、トルエン、キシレン等の芳香族炭化水素、ｎ−ヘキサン、シクロヘキサン等の脂肪族炭化水素、またはメタノール、エタノール、イソプロパノール等のアルコール類が使用される。
【００１４】
また、トランス−２，６−ジメチルピペラジンのシス−２，６−ジメチルピペラジンヘの異性化は、触媒の存在下、１８０℃以上の温度で行う。さらに好ましくは１８０〜２３０℃で行なわれるのがよい。反応温度が１８０℃より低いと反応が進行しにくく、トランス体からシス体への異性化が起りにくい。
【００１５】
異性化の触媒は、ニッケル及びコバルト等が好ましく、特にニッケル触媒が好ましい。異性化触媒の具体例は、前述したジイソプロパノールアミンとアンモニアとの反応の触媒と同様である。触媒の使用量は、トランス−２，６−ジメチルピペラジン１重量部に対して０．０１重量部以上であればよく、経済性の面から０．０１〜０．５重量部の使用が好ましい。
【００１６】
異性化を行うにあたって、有機溶剤を溶媒として使用することができる。使用される有機溶剤としては、ベンゼン、トルエン、キシレンのような芳香族炭化水素が好ましい。溶媒の使用量は特に限定はないが、通常トランス−２，６−ジメチルピペラジン１重量部に対して０．５〜５重量部である。
【００１７】
異性化は、アンモニア及び／又は水素の存在下ないしは雰囲気下で行うことができる。アンモニアの使用量は、トランス−２，６−ジメチルピペラジン１モルに対して１．０〜２．０モルが好ましく、さらに好ましくは１．１〜１．５モルである。反応の水素圧は特に限定はなく広く選択できるが、通常１９６１．４〜５８８４．２ｋＰａ（２０〜６０ｋｇ／ｃｍ2）である。
【００１８】
【実施例】
以下、具体的な実施例によって本発明を説明するが、これらは例示的なものであり、本発明はこれらに限定されるものではない。
【００１９】
実施例１
容量１リットルのオートクレープにジイソプロパノールアミン２２０ｇ(1．６５４モル）、トルエン２２０g、ラネーニッケル（川研ファインケミカル（株）社製 商品名ＮＤＴ−６５）１１０ｇを入れ、ここにアンモニア４２．２ｇ（２．５モル）を加えさらに水素ガスを内圧が４４１．３ｋＰａ（４．５ｋｇ／ｃｍ2）になるように吹き込んだ。これを昇温し１７０℃で６時間反応を行なった。反応終了後４０℃まで冷却し、窒素ガスを吹き込んでアンモニアを除き、容器内に析出した結晶を水１３７．３gを加えて溶解し反応液を取り出した。反応液をろ過して触媒を除いた後、共沸により水を除去した。これにトルエン２８０ｇを加え、７０℃に加熱して結晶を溶解した。温度を５℃まで冷却し、そのまま２時間結晶化を行なった。晶出した結晶をろ過し、トルエンで洗浄し乾燥して、純度９９．９％のシス−２，６−ジメチルピペラジンの結晶１１２．４ｇを得た。ろ液は蒸留を行い、シス−及びトランス−２，６−ジメチルピペラジンの混合物を回収した。結晶及び蒸留分を合わせた反応生成物の組成は、原料ジイソプロパノールアミン１ １ ． ８％、シス−２，６−ジメチルピペラジン７１．７％、トランス−２，６−ジメチルピペラジン５．９%であり、シス−２，６−ジメチルピペラジンの選択率は８１．３%であった。
【００２０】
実施例２
実施例１において反応温度を１９０℃に変更した以外は、実施例１と同様の反応及び後処理を行って、純度９９．２％のシス−２，６−ジメチルピペラジンの結晶１２７．１ｇを得た。結晶及び蒸留分を合わせた反応生成物の組成は、原料ジイソプロパノールアミン５．４％、シス−２，６−ジメチルピペラジン７６．１％、トランス−２，６−ジメチルピペラジン５．４％であり、シス−２，６−ジメチルビペラジンの選択率は８２．１％であった。
【００２１】
比較例１
実施例１においてトルエンに代えて水２２０ｇを溶媒として使用した以外は、実施例１と同様の反応及び後処理を行った。その結果、純度９９．８％のシス−２，６−ジメチルピペラジンの結晶１１０．１ｇを得た。結晶及び蒸留分を合わせた反応生成物の組成は、原料ジイソプロパノールアミン４．９％、シス−２，６−ジメチルピペラジン６８．２％、トランス−２，６−ジメチルピペラジン１１．０％であり、シス−２，６−ジメチルピペラジンの選択率は７１．８％であった。
【００２２】
実施例３
容量１００ミリリットルのオートクレープに、シス体９．９％、トランス体９０．１％の組成の２，６−ジメチルピペラジン２０ｇ、ラネーニッケル（川研ファインケミカル（株）社製 商品名ＮＤＨＴ−９０）１ｇ及びトルエン２０ｇを入れ、ここにアンモニア３ｇを加えさらに水素ガスを内圧が５３９．４ｋＰａ（５．５ｋｇ／ｃｍ2）になるように吹き込んだ。これを昇温し２００℃で４時間反応を行った。冷却後ガスクロマトグラフィーにより分析したところ、シス−２，６−ジメチルピペラジンは１０．８ｇ、トランス−２，６−ジメチルピペラジンは７．４ｇであった。
【００２３】
比較例２
実施例３において、反応温度を１７０℃にした以外は実施例３と同様にして反応を行った。ガスクロマトグラフィーにより分析したところ、シス−２，６−ジメチルピペラジンは２．７ｇ、トランス−２，６−ジメチルピペラジンは１６．９ｇであった。
【００２４】
【発明の効果】
本発明によれば、立体異性体のうちトランス−２，６−ジメチルピペラジンの生成を抑制し、医薬、農薬の原料として有用なシス−２，６−ジメチルピペラジンを高選択的に製造することができ、また高純度のシス体を単離することができる。さらに、トランス体をシス体へ良好な率で異性化することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing and separating cis-2,6-dimethylpiperazine which is useful as a raw material for pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
As a conventional method for producing 2,6-dimethylpiperazine, a method obtained by reacting diisopropanolamine and ammonia in the presence of a nickel catalyst in an aqueous solvent or in the absence of a solvent (UK Patent No. 902570, US Pat. No. 2,911,407). No. specification, Journal of Synthetic Organic Chemistry, Vol. 17, No. 17, pp. 17-28 (1959)).
[0003]
[Problems to be solved by the invention]
2,6-Dimethylpiperazine has cis- and trans-2,6-dimethylpiperazine which are stereoisomers due to its structure. Of these stereoisomers, there is more demand for cis isomers, and especially cis isomers are used as raw materials for pharmaceuticals and agricultural chemicals, and therefore, development of a highly selective production method for industrial cis isomers is desired. .
[0004]
The above document does not describe the ratio of cis form and trans form produced by the method. When the present inventors performed the reaction according to a conventional method, the produced 2,6-dimethylpiperazine had a large proportion of cis isomer, but it was not sufficient, and it was necessary to further improve the cis selectivity.
[0005]
The reaction product thus obtained was subjected to distillation in the same manner as in the above literature to try to separate the cis isomer. However, what was obtained was a mixture containing a cis isomer and a trans isomer, and separation of the cis isomer from the trans isomer was difficult by distillation. Until now, there is no known method for separating a cis isomer with high purity from this stereoisomer mixture.
Furthermore, there is no known method for isomerizing trans-2,6-dimethylpiperazine to produce cis-2,6-dimethylpiperazine.
[0006]
An object of the present invention is to provide a method for producing cis-2,6-dimethylpiperazine with high selectivity.
Another object of the present invention is to provide a method capable of separating cis-2,6-dimethylpiperazine with high purity from a mixture of cis- and trans-2,6-dimethylpiperazine.
A further object of the present invention is to provide a process for producing cis-2,6-dimethylpiperazine by isomerizing trans-2,6-dimethylpiperazine.
[Means for Solving the Problems]
[0007]
Therefore, as a result of intensive studies, the present inventors have significantly improved the selectivity of cis-2,6-dimethylpiperazine when a reaction between diisoproparamine and ammonia is performed in the presence of a catalyst using an organic solvent as a solvent. The cis isomer crystallizes with high purity from a mixture of cis- and trans-2,6-dimethylpiperazine in an organic solvent, and the trans isomer isomerization occurs at a temperature of 180 ° C. or higher in the presence of a catalyst. It has been found that this has occurred and has led to the present invention.
[0008]
That is, the present invention uses an organic solvent as a solvent in producing cis-2,6-dimethylpiperazine by reacting diisopropanolamine and ammonia in the presence of a solvent and a catalyst. , 6-dimethylpiperazine, cis-2,6-dimethylpiperazine, cis-2,6-dimethylpiperazine, trans-2,6-dimethylpiperazine and a mixed solution containing an organic solvent are crystallized. A method for producing cis-2,6-dimethylpiperazine, characterized by isolating trans-2,6-dimethylpiperazine at a reaction temperature of 180 ° C. or higher in the presence of a catalyst, and a method for separating dimethylpiperazine. It is.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
Next, the present invention will be described in more detail.
The method for producing cis-2,6-dimethylpiperazine of the present invention is characterized in that an organic solvent is used as a solvent when reacting diisopropanolamine and ammonia in the presence of a catalyst. The organic solvent used in the present invention is preferably an aromatic hydrocarbon such as benzene, toluene or xylene. The amount of the organic solvent used is preferably 0.5 to 5 parts by weight with respect to 1 part by weight of diisopropanolamine from the viewpoint of industrial handling.
[0010]
The catalyst is preferably nickel, cobalt or the like, and particularly preferably a nickel catalyst. As the nickel catalyst and the cobalt catalyst, Raney nickel, Raney cobalt, activated carbon, silica gel, alumina supported on nickel, cobalt, or the like can be used. The amount of the catalyst used may be 0.01 parts by weight or more with respect to 1 part by weight of diisopropanolamine, and is preferably used in an amount of 0.01 to 0.5 parts by weight from the economical aspect. If the amount of catalyst is less than 0.01 parts by weight, the reaction proceeds slowly and takes a long time, which is not preferable.
[0011]
The amount of ammonia used is preferably 1.0 to 2.0 moles, more preferably 1.2 to 1.5 moles per mole of diisopropanolamine. When the amount of ammonia used exceeds 2.0 mol, the reaction proceeds slowly.
[0012]
The reaction is preferably carried out under pressure, and the pressure is not particularly limited and can be selected widely. However, from the viewpoint of industrial handling, it is preferably 1961.4 to 5884.2 kPa (20 to 60 kg / cm 2 ). The reaction temperature is preferably 150 ° C. or higher, and more preferably 150 ° C. or higher and 200 ° C. from the viewpoint of industrial handling. When the reaction temperature is lower than 150 ° C., the reaction is difficult to proceed, and it takes a long time for the reaction, which is not preferable.
[0013]
Next, the separation of cis-2,6-dimethylpiperazine and trans-2,6-dimethylpiperazine is carried out by crystallizing a mixture of the organic solvent containing both. For example, the reaction solution obtained as described above is filtered to remove the catalyst, then azeotropically dehydrated to remove water, and then the amount of organic solvent is the theoretical amount of cis-2,6-dimethylpiperazine. Further, an organic solvent is added so as to be about 2 to 3 times by weight, and the crystal is completely dissolved by heating, followed by cooling to crystallize. The temperature and time of crystallization can be selected variously. For example, by performing crystallization at 5 ° C. for 2 hours, substantially only cis-2,6-dimethylpiperazine can be crystallized, and high-purity cis -2,6-dimethylpiperazine is obtained. As the organic solvent, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as n-hexane and cyclohexane, or alcohols such as methanol, ethanol and isopropanol are used.
[0014]
Further, isomerization of trans-2,6-dimethylpiperazine to cis-2,6-dimethylpiperazine is carried out at a temperature of 180 ° C. or higher in the presence of a catalyst. More preferably, it is carried out at 180 to 230 ° C. When the reaction temperature is lower than 180 ° C., the reaction hardly proceeds and isomerization from the trans isomer to the cis isomer hardly occurs.
[0015]
The isomerization catalyst is preferably nickel, cobalt or the like, and particularly preferably a nickel catalyst. Specific examples of the isomerization catalyst are the same as those for the reaction of diisopropanolamine and ammonia described above. The amount of the catalyst used may be 0.01 parts by weight or more with respect to 1 part by weight of trans-2,6-dimethylpiperazine, and the use of 0.01 to 0.5 parts by weight is preferable from the viewpoint of economy.
[0016]
In carrying out the isomerization, an organic solvent can be used as a solvent. As the organic solvent used, aromatic hydrocarbons such as benzene, toluene and xylene are preferable. Although the usage-amount of a solvent does not have limitation in particular, Usually, it is 0.5-5 weight part with respect to 1 weight part of trans-2,6-dimethylpiperazine.
[0017]
Isomerization can be carried out in the presence or atmosphere of ammonia and / or hydrogen. The amount of ammonia used is preferably 1.0 to 2.0 mol, more preferably 1.1 to 1.5 mol, per 1 mol of trans-2,6-dimethylpiperazine. The hydrogen pressure of the reaction is not particularly limited and can be selected widely, but is usually 1961.4 to 5884.2 kPa (20 to 60 kg / cm 2 ).
[0018]
【Example】
Hereinafter, the present invention will be described by way of specific examples, but these are illustrative and the present invention is not limited thereto.
[0019]
Example 1
Into an autoclave with a capacity of 1 liter, 220 g (1.654 mol) of diisopropanolamine, 220 g of toluene, and 110 g of Raney nickel (trade name NDT-65 manufactured by Kawaken Fine Chemicals Co., Ltd.) were added, and 42.2 g (2. 5 mol) and hydrogen gas was blown so that the internal pressure was 441.3 kPa (4.5 kg / cm 2 ). This was heated up and reacted at 170 ° C. for 6 hours. After completion of the reaction, the mixture was cooled to 40 ° C., nitrogen gas was blown in to remove ammonia, and crystals precipitated in the vessel were dissolved by adding 137.3 g of water, and the reaction solution was taken out. The reaction solution was filtered to remove the catalyst, and then water was removed azeotropically. To this was added 280 g of toluene and heated to 70 ° C. to dissolve the crystals. The temperature was cooled to 5 ° C. and crystallization was carried out for 2 hours. The crystallized crystals were filtered, washed with toluene and dried to obtain 112.4 g of cis-2,6-dimethylpiperazine crystals having a purity of 99.9%. The filtrate was distilled to recover a mixture of cis- and trans-2,6-dimethylpiperazine. The composition of the reaction product of the combined crystals and distillate is the raw material diisopropanolamine 1 1. 8%, cis-2,6-dimethylpiperazine was 71.7%, trans-2,6-dimethylpiperazine was 5.9%, and the selectivity of cis-2,6-dimethylpiperazine was 81.3%. .
[0020]
Example 2
Except that the reaction temperature was changed to 190 ° C. in Example 1, the same reaction and post-treatment as in Example 1 were performed to obtain 127.1 g of cis-2,6-dimethylpiperazine crystals having a purity of 99.2%. It was. The composition of the reaction product combined with crystals and distillate was 5.4% of raw material diisopropanolamine, 76.1% of cis-2,6-dimethylpiperazine, and 5.4% of trans-2,6-dimethylpiperazine. The selectivity for cis-2,6-dimethylbiperazine was 82.1%.
[0021]
Comparative Example 1
The same reaction and post-treatment as in Example 1 were performed except that 220 g of water was used as a solvent in place of toluene in Example 1. As a result, 110.1 g of cis-2,6-dimethylpiperazine crystals having a purity of 99.8% was obtained. The composition of the combined reaction product of crystals and distillate was 4.9% of raw material diisopropanolamine, 68.2% of cis-2,6-dimethylpiperazine, and 11.0% of trans-2,6-dimethylpiperazine. The selectivity for cis-2,6-dimethylpiperazine was 71.8%.
[0022]
Example 3
In an autoclave having a capacity of 100 ml, 20 g of 2,6-dimethylpiperazine having a composition of 9.9% cis and 90.1% trans, 1 g of Raney nickel (trade name NDHT-90, manufactured by Kawaken Fine Chemical Co., Ltd.) and 20 g of toluene was added, 3 g of ammonia was added thereto, and hydrogen gas was further blown so that the internal pressure was 539.4 kPa (5.5 kg / cm 2 ). This was heated up and reacted at 200 ° C. for 4 hours. After cooling, analysis by gas chromatography revealed that cis-2,6-dimethylpiperazine was 10.8 g and trans-2,6-dimethylpiperazine was 7.4 g.
[0023]
Comparative Example 2
In Example 3, the reaction was performed in the same manner as in Example 3 except that the reaction temperature was 170 ° C. Analysis by gas chromatography revealed that cis-2,6-dimethylpiperazine was 2.7 g and trans-2,6-dimethylpiperazine was 16.9 g.
[0024]
【The invention's effect】
According to the present invention, production of trans-2,6-dimethylpiperazine among stereoisomers can be suppressed, and cis-2,6-dimethylpiperazine useful as a raw material for pharmaceuticals and agricultural chemicals can be produced with high selectivity. In addition, a highly pure cis isomer can be isolated. Furthermore, the trans isomer can be isomerized to the cis isomer at a good rate.
Claims (1)
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| JP2003032012A JP3950423B2 (en) | 2003-02-10 | 2003-02-10 | Process for producing cis-2,6-dimethylpiperazine |
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| JP28175293A Division JP3443583B2 (en) | 1993-10-14 | 1993-10-14 | Method for producing cis-2,6-dimethylpiperazine |
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