JP3910989B2 - New pyrrolidine compounds - Google Patents
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- JP3910989B2 JP3910989B2 JP2005004531A JP2005004531A JP3910989B2 JP 3910989 B2 JP3910989 B2 JP 3910989B2 JP 2005004531 A JP2005004531 A JP 2005004531A JP 2005004531 A JP2005004531 A JP 2005004531A JP 3910989 B2 JP3910989 B2 JP 3910989B2
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- 150000003235 pyrrolidines Chemical class 0.000 title description 5
- -1 pyrrolidine compound Chemical class 0.000 claims description 24
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- OKCDBZSDRSXFIB-UHFFFAOYSA-N 2-diethoxyphosphoryl-2-methyl-1-oxido-3,4-dihydropyrrol-1-ium Chemical compound CCOP(=O)(OCC)C1(C)CCC=[N+]1[O-] OKCDBZSDRSXFIB-UHFFFAOYSA-N 0.000 description 5
- VCUVETGKTILCLC-UHFFFAOYSA-N 5,5-dimethyl-1-pyrroline N-oxide Chemical compound CC1(C)CCC=[N+]1[O-] VCUVETGKTILCLC-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N Phosphinothricin Natural products CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- IAJOBQBIJHVGMQ-BYPYZUCNSA-N glufosinate-P Chemical compound CP(O)(=O)CC[C@H](N)C(O)=O IAJOBQBIJHVGMQ-BYPYZUCNSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical class ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- XBRCCZCKPZJGEG-UHFFFAOYSA-N 1,3,2lambda5-dioxaphosphinane 2-oxide Chemical compound O=P1OCCCO1 XBRCCZCKPZJGEG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004435 EPR spectroscopy Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000013319 spin trapping Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XVRIEWDDMODMGA-UHFFFAOYSA-N 5-chloropentan-2-one Chemical class CC(=O)CCCCl XVRIEWDDMODMGA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- MJUJXFBTEFXVKU-UHFFFAOYSA-N diethyl phosphonate Chemical compound CCOP(=O)OCC MJUJXFBTEFXVKU-UHFFFAOYSA-N 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- OSKDHDHKPPRBND-UHFFFAOYSA-N phosphinane-2,3-dione Chemical compound O=C1CCCPC1=O OSKDHDHKPPRBND-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003236 pyrrolines Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- ISLWZBTUAHMAND-UHFFFAOYSA-N 1,3,2-dioxaphosphinan-2-ium 2-oxide Chemical compound O=[P+]1OCCCO1 ISLWZBTUAHMAND-UHFFFAOYSA-N 0.000 description 1
- ILWPUFBXBYEUND-UHFFFAOYSA-N 2-(2,4-dimethyl-1-oxido-3,4-dihydropyrrol-1-ium-2-yl)-4-methyl-1,3,2lambda5-dioxaphosphinane 2-oxide Chemical compound CC1CCOP(=O)(O1)C2(CC(C=[N+]2[O-])C)C ILWPUFBXBYEUND-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- CTSZPNIMMLSKDV-UHFFFAOYSA-N 2-methyl-1-pyrroline Chemical compound CC1=NCCC1 CTSZPNIMMLSKDV-UHFFFAOYSA-N 0.000 description 1
- QCHBQBKLOCGNQX-UHFFFAOYSA-N 4-oxopentyl 4-methylbenzenesulfonate Chemical class CC(=O)CCCOS(=O)(=O)C1=CC=C(C)C=C1 QCHBQBKLOCGNQX-UHFFFAOYSA-N 0.000 description 1
- MUUWQYQRBFVTIB-UHFFFAOYSA-N 5-methyl-2,3-dihydro-1h-pyrrole Chemical compound CC1=CCCN1 MUUWQYQRBFVTIB-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- HWSUUGHIDOOOOJ-UHFFFAOYSA-N dioxaphosphinane Chemical compound C1COOPC1 HWSUUGHIDOOOOJ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
本発明は、電子スピン共鳴測定法に使用するスピントラップ剤として用いるニトロン化合物の合成中間体として有用な新規ピロリジン化合物に関する。 The present invention relates to a novel pyrrolidine compound useful as a synthesis intermediate of a nitrone compound used as a spin trap agent used in an electron spin resonance measurement method.
電子スピン共鳴測定法（ＥＳＲ、ＥＰＲとも称する）に用いるスピントラップ剤において、ピロリジン環を有するニトロン化合物としてはＤＭＰＯ（5,5-Dimethyl-1-pyrroline N-oxide）が最も汎用されている。ＤＭＰＯと比較してスピンアダクトの半減期が長いＤＥＰＭＰＯ(5-Diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide：特表平８−５０１８０８、 Frejaville C. et al., Journal of Medicinal Chemistry Vol.38 258-265(1995))は、ジエチル亜リン酸（ Diethylphosphite ）を原料として得られる中間体のピロリジン化合物ＤＥＰＭＰＨ（Diethyl(2-methyl-2-pyrroridin-2-yl)phosphonate :Pietri S. et al., European Journal of Biochemistry Vol.254 254-256(1998) ) を介して合成が行われている。しかしながらＤＥＰＭＰＯはＤＭＰＯに比べ非常に高価格であるためにＤＭＰＯのようには普及していない。 In a spin trap agent used for an electron spin resonance measurement method (also referred to as ESR or EPR), DMPO (5,5-Dimethyl-1-pyrroline N-oxide) is most widely used as a nitrone compound having a pyrrolidine ring. DEPMPO (5-Diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide: Tokuhei Hei 8-501808, Frejavill e C. et al., Journal of Medicinal Chemistry Vol. 38 258-265 (1995)) is an intermediate pyrrolidine compound DEPMPH (Diethyl (2-methyl-2-pyrroridin-2-yl) phosphonate: Pietri S. et al.) Obtained from diethylphosphite. , European Journal of Biochemistry Vol.254 254-2 56 (1998)). However, DEPMPO is not as popular as DMPO because it is much more expensive than DMPO.
従来より、ラジカルを捕捉するスピントラップ剤が具備すべき特性としては、各種のスピンアダクトが安定で半減期が長く測定が容易に出来ること、in vivo L-band ESR 計測などの生体におけるラジカル計測を容易にするために強いシグナル強度と低毒性であることなどが挙げられており、且つ、安価に供給が可能なことが求められている。しかしながら、このような特性を併せ持つスピントラップ剤の製造に供するための合成中間体は知られていない。 Conventionally, the characteristics of spin trapping agents that trap radicals include that various spin adducts are stable, have a long half-life, and can be measured easily. In vivo L-band ESR measurement, etc. In order to make it easy, strong signal intensity and low toxicity are mentioned, and it is demanded that supply is possible at low cost. However, a synthetic intermediate for use in the production of a spin trap agent having such characteristics is not known.
亜リン酸に結合するエチルアルコ−ルのような直鎖型低級アルコ−ル、例えば、ＤＥＰＭＰＯの原料であるジエチル亜リン酸（Diethyl phosphite、Diethyl hydrogen phosphite 或いは Phosphonic acid diethyl ester と称する）は、安定性に欠けることが知られ、例えば、ジオ−ル類と加熱すると交換反応が起き、容易にエチルアルコ−ルが脱離し、より安定な環状フォスファイト構造を形成することが報告されている（Oswald A.A., Canadian of Journal Chemistry Vol.37 1498-1504(1959)、Barbati S. et al., Synthesis Vol.12 2036-2040 (1999)）。 A linear lower alcohol such as ethyl alcohol that binds to phosphorous acid, such as diethyl phosphite (which is called Diethyl phosphite, Diethyl hydrogen phosphite or Phosphonic acid diethyl ester), which is a raw material of DEPMPO, is stable. For example, it has been reported that when heated with diols, an exchange reaction occurs and ethyl alcohol is easily eliminated to form a more stable cyclic phosphite structure (Oswald AA, Canadian of Journal Chemistry Vol.37 1498-150 4 (1959), Barbati S. et al., Synthesis Vol.12 2036-2040 (1999)).
従って、直鎖型ジ低級アルキルフォスファイト構造を有するＤＥＰＭＰＯ関連化合物（Stoize K. et al., Biological Chemistry Vol.384 493-500 (2003)）対して、安定な環状フォスファイト構造を導入したピロリジン化合物類は、in vitro ラジカル計測、および生体組織における in vivo ラジカル計測において半減期が長く安定した計測を可能にするニトロン化合物、即ち、新規スピントラップ剤を合成するための有用な合成中間体として期待される。 Therefore, a pyrrolidine compound in which a stable cyclic phosphite structure is introduced to a DEPMPO-related compound having a linear di-lower alkyl phosphite structure (Stoize K. et al., Biological Chemistry Vol. 384 493-500 (2003)) Is expected to be a useful intermediate for the synthesis of nitrone compounds, that is, novel spin trapping agents, that enable stable measurement with long half-life in in vitro radical measurement and in vivo radical measurement in living tissues. The
本発明者らは、上記の期待に答えるために新規ニトロン化合物の合成中間体として有用なピロリジン化合物を開発すべく、鋭意研究を行った結果、一般式（１）で表される環状フォスファイト、即ち、２−オキソ−［１，３，２］フォスフォリナン（2-oxo-［1,3,2］Dioxaphosphorinane、1,3,2-Dioxaphosphorinan-2-one ）或いは［１，２，３］ジオキサホスフォフィナン−２−オキサイド（ [1,3,2]Dioxaphosphinane-2-oxide ）構造を併せ持つ新規ピロリジン化合物が安定性にすぐれ、且つ、安全性が高いことを見出し、本発明を完成するに至った。 In order to meet the above expectations, the present inventors have conducted extensive research to develop a pyrrolidine compound useful as a synthetic intermediate for a novel nitrone compound. As a result, the cyclic phosphite represented by the general formula (1), That is, 2-oxo - [1,3,2] phosphoryl Nan (2-oxo- [1,3,2] Dioxaphosphorinane , 1,3,2-Dioxaphosphorinan-2-one) or [1,2,3] A novel pyrrolidine compound having a dioxaphosphinane-2-oxide ([1,3,2] Dioxaphosphinane-2-oxide) structure is found to have excellent stability and high safety, and the present invention is completed. It came to.
即ち、本発明は、下記一般式（１）
以下、本発明を詳細に説明する。
That is, the present invention provides the following general formula (1)
Hereinafter, the present invention will be described in detail.
本発明において、一般式（１）における好適な組合せ例としては、低級アルキル基において、通常はメチル基が好ましいが、脂溶性を高めるためには炭素数の多いアルキル基、例えばｔ−ブチル基などを選択することが出来る。水溶性を付加するにはカルボキシル基またはその塩が適している。生体内における代謝を利用してカルボキシル基に変換したい場合にはアルコキシカルボニル基或いはカルバモイル基を選択するのがよい。分子中の水素原子は、用途に応じて原料中間体あるいは目的物の各段階で文献記載の変換法（Pou S.et al., Journal of Organic Chemistry Vol.55 4438-4443 (1990)、Karoui H. et al., Journal of Organic Chemistry Vol.64 1471-1477 (1999)、Clement J.-L. et al., Organic Biomolecular Chemistry Vol.1 1591-1597 (2003) など）に準じて目的の部位に重水素原子の導入を行うことが可能である。 In the present invention, as a suitable combination example in the general formula (1), in the lower alkyl group, a methyl group is usually preferable. Can be selected. A carboxyl group or a salt thereof is suitable for adding water solubility. When it is desired to convert to a carboxyl group by utilizing metabolism in a living body, an alkoxycarbonyl group or a carbamoyl group is preferably selected. The hydrogen atom in the molecule is converted according to the conversion method described in the literature (Pou S. et al., Journal of Organic Chemistry Vol. 55 4438-4443 (1990), Karoui H et al., Journal of Organic Chemistry Vol.64 1471-1477 (1999), Clement J.-L. et al., Organic Biomolecular Chemistry Vol.1 1591-159 7 (2003), etc.) It is possible to introduce deuterium atoms into
本発明に使用する好適な環状フォスファイトは、文献記載の方法（Zwierzak A., Canadian Journal of Chemistry Vol.45 2501-2512 (1967)、Macconnel R.L.et al., Journal of Organic Chemistry Vol.24 630-635 (1959)、Klosinski P.,Tetrahedron Letters Vol.31 2025-2028 (1990)、Maffei M. et al., Tetrahedron Vol.59 8821-8825 (2003) など）に準じて合成できる。 Suitable cyclic phosphites for use in the present invention are described in literature (Zwierzak A., Canadian Journal of Chemistry Vol. 45 2501-2512 (1967), Macconnel RLet al., Journal of Organic Chemistry Vol. 24 630- 635 (1959), Klosinski P., Tetrahedron Letters Vol. 31 2025-2028 (1990), Maffei M. et al., Tetrahedron Vol. 59 8821-8825 (2003), etc.).
以下に本発明の新規ピロリジン誘導体の合成に好適な環状フォスファイトを例示する。
2-oxo-[1,3,2]dioxaphosphorinane
4-methyl-2-oxo-[1,3,2]dioxaphosphorinane
4,6-dimethyl-2-oxo-[1,3,2]dioxaphosphorinane
5-methyl-2-oxo-[1,3,2]dioxaphosphorinane
5,5-dimethyl-2-oxo-[1,3,2]dioxaphosphorinane
5-t-butyl-2-oxo-[1,3,2]dioxaphosphorinane
Examples of cyclic phosphites suitable for the synthesis of the novel pyrrolidine derivatives of the present invention are shown below.
2-oxo- [1,3,2] dioxaphosphorinane
4-methyl-2-oxo- [1,3,2] dioxaphosphorinane
4,6-dimethyl-2-oxo- [1,3,2] dioxaphosphorinane
5-methyl-2-oxo- [1,3,2] dioxaphosphorinane
5,5-dimethyl-2-oxo- [1,3,2] dioxaphosphorinane
5-t-butyl-2-oxo- [1,3,2] dioxaphosphorinane
本発明の新規ピロリジン誘導体の合成に用いる好適なピロリン誘導体は、文献記載の方法（Kloetz M.C. et al., Journal of American Chemisrty Vol.69 2271-2275 (1947)、Evans G.G., Journal of American Chemisrty Vol.73 5230-5234 (1951) 、Bonnett R. et al., Journal of Chemical Society 2087-2093 (1959) 、Gutteridge N.J.A. et al., Journal of Chemical Society (C) 122-125(1971) 、Frejaville C. et al., Journal of Chemical Society Chemical Communications 1793-1794 (1994)、Clement J.L. et al., Organic Biomolecule Chemistry Vol.1 1591-1595(2003)、Dehnel A. et al., Journal of Organic Chemisrty Vol.53 1566-1567(1988) ほか）に準じて合成できる。 Suitable pyrroline derivatives for use in the synthesis of the novel pyrrolidine derivatives of the present invention are described in literature (Kloetz MC et al., Journal of American Chemisrty Vol. 69 2271-2275 (1947), Evans GG, Journal of American Chemisrty Vol. 73 5230-5234 (1951), Bonnett R. et al., Journal of Chemical Society 2087-2093 (1959), Gutteridge NJA et al., Journal of Chemical Society (C) 122-125 (1971), Frejaville C. et al., Journal of Chemical Society Chemical Communications 1793-1 794 (1994), Clement JL et al., Organic Biomolecule Chemistry Vol. 1 1591-1595 (2003), Dehnel A. et al., Journal of Organic Chemisrty Vol. 53 1566-1567 (1988) et al.).
本発明に係る新規ニトロン化合物の中間体となるピロリジン誘導体の合成は、公知の環状フォスファイト（cyclic phosphite）、より具体的には 2-oxo-1,3,2-dioxaphosphorinane （[1,3,2]dioxaphosphinane 2-oxide とも称する）誘導体とピロリン誘導体との反応（反応経路Ａ）或いはアンモニアの存在下に５−クロロ−２−ペンタノン誘導体との反応（反応経路Ｂ）などに関する文献記載の方法（Moigne F.L. et al., Journal of Organic Chemistry Vol.59 3365-3367 (1994)、Frejaville C. et al., Journal of Medicinal Chemistry Vol.38 258-265 (1995)、Karoui H. et al., Journal of Organic Chemistry Vol.64 1417-1477 (1999)、Barbati S. et al., Synthesis Vol.12 2036-2040(1999) など) に準じて下記の反応経路（Ａ）或いは反応経路（Ｂ）を用いて合成できる。前記の反応経路（Ｂ）において、５−クロロ−２−ペンタノン誘導体に代えて５−トシルオキシ−２−ペンタノン誘導体を，アンモニアに代えて炭酸アンモニウムを用いることが出来る。反応は無溶媒でも進行するが、使用するフォスファイトの種類によって反応液が固まることがあるので反応を制御するためには溶媒を使用することが望ましい。 The synthesis of a pyrrolidine derivative as an intermediate of the novel nitrone compound according to the present invention is carried out by known cyclic phosphite, more specifically 2-oxo-1,3,2-dioxaphosphorinane ([1,3, 2] Methods described in the literature on the reaction of a derivative with a pyrroline derivative (also called dioxaphosphinane 2-oxide) (reaction route A) or the reaction with a 5-chloro-2-pentanone derivative in the presence of ammonia (reaction route B) ( Moigne FL et al., Journal of Organic Chemistry Vol. 59 3365-3367 (1994), Frejaville C. et al., Journal of Medicinal Chemistry Vol. 38 258-265 (1995), Karoui H. et al., Journal of Organic Chemistry Vol.64 1417-1477 (1999), Barbati S. et al., Synthesis Vol.12 2036-2040 (1999) etc.) using the following reaction route (A) or reaction route (B) Can be synthesized. In the reaction route (B), a 5-tosyloxy-2-pentanone derivative can be used instead of the 5-chloro-2-pentanone derivative, and ammonium carbonate can be used instead of ammonia. The reaction proceeds even without solvent, but the reaction solution may solidify depending on the type of phosphite used, so it is desirable to use a solvent to control the reaction.
前記の反応溶媒としてクロロホルム、ジクロルメタンなどのハロゲン系溶媒、テトラハイドロフラン、エーテル、ジイソプロピルエーテル、ジメトキエタン、アセトニトリル、メチルアルコール、エチルアルコール、イソプロピルアルコール、ジメチルアセトアミド、ジメチルフォルムアミド、酢酸エチル、ベンゼン、トルエンなどの中から選択して使用し、下記の合成経路により製造することが出来る。 Halogen solvents such as chloroform and dichloromethane, tetrahydrofuran, ether, diisopropyl ether, dimethoxyethane, acetonitrile, methyl alcohol, ethyl alcohol, isopropyl alcohol, dimethylacetamide, dimethylformamide, ethyl acetate, benzene, toluene, etc. It can be selected and used from among the following synthetic routes.
本発明による新規ピロリジン誘導体の好適な化合物例を以下に示すが、用途に応じて適宜選択することができる。本発明の化合物において、ピロリジン環で形成される２級アミン部における塩の例としては、塩酸塩、硫酸塩、リン酸塩、硝酸塩、ブロム水素酸塩、ヨウ化水素酸塩などの無機酸塩、シュウ酸塩、メタンスルホン酸塩、ベンゼンスルホン酸、トルエンスルホン酸、ピクリン酸などの有機酸塩が挙げられ、またカルボキシル基における塩の例としては、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩などが挙げられ、これらは必要に応じて合成工程、精製工程、もしくは保存のために有利な塩を選択して使用することができる。 Examples of suitable compounds of the novel pyrrolidine derivatives according to the present invention are shown below, but can be appropriately selected according to the application. In the compound of the present invention, examples of the salt in the secondary amine moiety formed by the pyrrolidine ring include inorganic acid salts such as hydrochloride, sulfate, phosphate, nitrate, bromide, and hydroiodide. , Oxalate, methanesulfonate, benzenesulfonic acid, toluenesulfonic acid, picric acid, and other organic acid salts. Examples of salts in the carboxyl group include sodium salt, potassium salt, calcium salt, magnesium salt These may be used, and salts that are advantageous for synthesis, purification, or storage can be selected and used as necessary.
2-Methyl-2-(2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine
2-(5,5-Dimethyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-2-methyl-pyrrolidine
2-Methyl-2-(4-methyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine
2-Methyl-2-(5-methyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine
2-(5-tert-Butyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-2-methyl-pyrrolidine
2-(4,6-Dimethyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine
2-Methyl-2- (2- oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -pyrrolidine
2- (5,5-Dimethyl-2- oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -2-methyl-pyrrolidine
2-Methyl-2- (4- methyl-2-oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -pyrrolidine
2-Methyl-2- (5- methyl-2-oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -pyrrolidine
2- (5-tert-Butyl- 2-oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -2-methyl-pyrrolidine
2- (4,6-Dimethyl-2- oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -pyrrolidine
5-Methyl-5-(5-methyl-2-oxo-2λ5-Methyl-5- (5-methyl-2-oxo-2λ
5Five
-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine-2-carboxylic acid-[1,3,2] dioxaphosphinan-2-yl) -pyrrolidine-2-carboxylic acid
5-Methyl-5-(5-methyl-2-oxo-2λ5-Methyl-5- (5-methyl-2-oxo-2λ
5Five
-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine-2-carboxylic acid ethyl ester-[1,3,2] dioxaphosphinan-2-yl) -pyrrolidine-2-carboxylic acid ethyl ester
5-Methyl-5-(5-methyl-2-oxo-2λ5-Methyl-5- (5-methyl-2-oxo-2λ
5Five
-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine-2-carboxamide-[1,3,2] dioxaphosphinan-2-yl) -pyrrolidine-2-carboxamide
5-Methyl-5-(5-methyl-2-oxo-2λ5-Methyl-5- (5-methyl-2-oxo-2λ
5Five
-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine-3-carboxylic acid-[1,3,2] dioxaphosphinan-2-yl) -pyrrolidine-3-carboxylic acid
5-Methyl-5-(5-methyl-2-oxo-2λ5-Methyl-5- (5-methyl-2-oxo-2λ
5Five
-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine-3-carboxylic acid ethyl ester-[1,3,2] dioxaphosphinan-2-yl) -pyrrolidine-3-carboxylic acid ethyl ester
5-Methyl-5-(5-methyl-2-oxo-2λ5-Methyl-5- (5-methyl-2-oxo-2λ
5Five
-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine-3-carboxamide-[1,3,2] dioxaphosphinan-2-yl) -pyrrolidine-3-carboxamide
以下に本発明の環状フォスファイトが付与されたピロリジン誘導体を原料化合物として用いて合成が可能なニトロン誘導体を例示する。新規ニトロン誘導体は、本発明のピロリジン誘導体を用いて文献記載に記載の合成法（Mathieu C. et al., Free Radical Biology & Medicine Vol.22 803-806 (1997)、Frejaville C. et al., Journal of Chemical Society Chemical Communications 1793-1794(1994) 、Clement J.-L. et al., Organic Biomolecular Chemistry Vol.1 1591-1597 (2003) 、Moigne F.L. et al., Journal of Organic Chemistry Vol.59 3365-3367 (1994)、Barbati S. et al., Synthesis Vol.12 2036-2040 (1999)、Janzen E.G. et al., Journal of Organic Chemistry Vol.60 5441-5445 (1995)など) に準じて合成することが可能である。 Examples of nitrone derivatives that can be synthesized using the pyrrolidine derivative provided with the cyclic phosphite of the present invention as a raw material compound are shown below. A novel nitrone derivative can be synthesized using the pyrrolidine derivative of the present invention (Mathieu C. et al., Free Radical Biology & Medicine Vol. 22 803-806 (1997), Frejaville C. et al., Journal of Chemical Society Chemical Communications 1793-1 794 (1994), Clement J.-L. et al., Organic Biomolecular Chemistry Vol. 1 1591-159 7 (2003), Moigne FL et al., Journal of Organic Chemistry Vol. 59 3365-3367 (1994), Barbati S. et al., Synthesis Vol.12 2036-2040 (1999), Janzen EG et al., Journal of Organic Chemistry Vol.60 5441-5445 (1995), etc.) It is possible to synthesize.
以下に本発明の新規ピロリジン化合物を用いて合成が可能なスピントラップ剤として有用な新規ニトロン化合物を例示する。
2-Methyl-2-(2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-3,4-dihydro-2H-pyrrole 1-oxide
2-Methyl-2-(4-methyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-3,4-dihydro-2H-pyrrol 1-oxide
2-Methyl-2-(5-methyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-3,4-dihydro-2H-pyrrole 1-oxide
2-(5,5-Dimethyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-2-methyl-3,4-dihydro-2H-pyrrole 1-oxide
2-(4,6-dimethyl-2-(2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-2-methyl-3,4-dihydro-2H-pyrrole 1-oxide
Examples of novel nitrone compounds useful as spin trapping agents that can be synthesized using the novel pyrrolidine compounds of the present invention are shown below.
2-Methyl-2- (2- oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -3,4-dihydro-2H-pyrrole 1-oxide
2-Methyl-2- (4- methyl-2-oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -3,4-dihydro-2H-pyrrol 1-oxide
2-Methyl-2- (5- methyl-2-oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -3,4-dihydro-2H-pyrrole 1-oxide
2- (5,5-Dimethyl-2- oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -2-methyl-3,4-dihydro-2H-pyrrole 1-oxide
2- (4,6-dimethyl-2- ( 2-oxo-2λ 5 - [1,3,2] dioxaphosphinan-2-yl) -2-methyl-3,4-dihydro-2H-pyrrole 1-oxide
5-Methyl-5-(5,5-dimetyl-2-oxo-2-2λ 5 -[1,3,2]dioxaphosphinan-2-yl)-1-oxy-4,5-dihydro-3H-pyrrole 2-carboxylic acid
5-Methyl-5-(5,5-dimetyl-2-oxo-2-2λ 5 -[1,3,2]dioxaphosphinan-2-yl)-1-oxy-4,5-dihydro-3H-pyrrole 2-carboxylic acid ethyl ester
5-Methyl-5-(5,5-dimetyl-2-oxo-2-2λ 5 -[1,3,2]dioxaphosphinan-2-yl)-1-oxy-4,5-dihydro-3H-pyrrole 2-carboxamide
5-Methyl-5-(5,5-dimetyl-2-oxo-2-2λ 5 -[1,3,2]dioxaphosphinan-2-yl)-1-oxy-4,5-dihydro-3H-pyrrole 3-carboxylic acid
5-Methyl-5-(5,5-dimetyl-2-oxo-2-2λ 5 -[1,3,2]dioxaphosphinan-2-yl)-1-oxy-4,5-dihydro-3H-pyrrole 3-carboxylic acid ethyl ester
5-Methyl-5-(5,5-dimetyl-2-oxo-2-2λ 5 -[1,3,2]dioxaphosphinan-2-yl)-1-oxy-4,5-dihydro-3H-pyrrole 3-carboxamide
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれに限定されるものではない。
5-Methyl-5- (5,5-dimetyl-2-oxo-2-2λ 5- [1,3,2] dioxaphosphinan-2-yl) -1-oxy-4,5-dihydro-3H-pyrrole 2 -carboxylic acid
5-Methyl-5- (5,5-dimetyl-2-oxo-2-2λ 5- [1,3,2] dioxaphosphinan-2-yl) -1-oxy-4,5-dihydro-3H-pyrrole 2 -carboxylic acid ethyl ester
5-Methyl-5- (5,5-dimetyl-2-oxo-2-2λ 5- [1,3,2] dioxaphosphinan-2-yl) -1-oxy-4,5-dihydro-3H-pyrrole 2 -carboxamide
5-Methyl-5- (5,5-dimetyl-2-oxo-2-2λ 5- [1,3,2] dioxaphosphinan-2-yl) -1-oxy-4,5-dihydro-3H-pyrrole 3 -carboxylic acid
5-Methyl-5- (5,5-dimetyl-2-oxo-2-2λ 5- [1,3,2] dioxaphosphinan-2-yl) -1-oxy-4,5-dihydro-3H-pyrrole 3 -carboxylic acid ethyl ester
5-Methyl-5- (5,5-dimetyl-2-oxo-2-2λ 5- [1,3,2] dioxaphosphinan-2-yl) -1-oxy-4,5-dihydro-3H-pyrrole 3 -carboxamide
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this.
〔実施例１〕
２−メチル−２−（２−オキソ−２λ5 −［１，３，２］ジオキサフォスフィナン−２−イル）−ピロリジン（ 2-Methyl-2-(2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-pyrrolidine）の合成；
２−オキソ−[１，３，２]ジオキソフォスフォリナン30 g（0.25 mol) と２−メチルピロリン 20.8 g (0.25 mol)をジクロルメタン 100 ml に溶解し室温で１８時間、次いで 40 ℃で４時間反応した。反応液に塩酸酸性の飽和食塩水 200mlを加えて十分に攪拌した後に水層を分離した。次いで水層に炭酸ナトリウムを加えて塩基性とし、クロロホルム 300 ml で抽出した。クロロホルム層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後に、シリカゲルカラムクロマトグラフィー（展開溶媒；クロロホルム：メチルアルコール＝２０：１）により分離精製を行った。目的とする分画を減圧濃縮して非晶質固体 22.5 g(収率 43.9 %)を得た。
[Example 1]
2-methyl-2- (2-oxo 2 [lambda] 5 - [l, 3,2] di oxa phosphinothricin nan-2-yl) - pyrrolidine (2-Methyl-2- (2 -oxo-2λ 5 - [1, 3,2 ] synthesis of dioxaphosphinan-2-yl) -pyrrolidine);
2- Oxo- [ 1,3,2] dioxophosphorinane (30 g, 0.25 mol) and 2-methylpyrroline (20.8 g, 0.25 mol) were dissolved in 100 ml of dichloromethane and stirred at room temperature for 18 hours and then at 40 ° C. Reacted for hours. To the reaction solution was added 200 ml of hydrochloric acid saturated brine and stirred sufficiently, and then the aqueous layer was separated. Subsequently, sodium carbonate was added to the aqueous layer to make it basic, and extracted with 300 ml of chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then separated and purified by silica gel column chromatography (developing solvent; chloroform: methyl alcohol = 20: 1). The objective fraction was concentrated under reduced pressure to obtain 22.5 g (yield 43.9%) of an amorphous solid.
元素分析 (C8H16NO3P Mol.Wt.: 205.19 )：Calc. C,46.83; H,7.86; N,6.83
Found C,46.70; H,8.02; N,6.74
ＩＲスペクトル (KBr cm-1) : 3284.5, 2962.5, 2868.8, 147.94, 1425.3,
1369.4, 1259.4, 1249.8, 1191.9, 1130.9, 1056.9, 941.2, 879.5, 804.3,
マススペクトル FAB+, m/z (%)： 206 M+ (16),84(100)、411(6)
1HNMR (300 MHz, CDCl3) :δ 1.40-1.43 (3H, D, J=15.7 Hz)、1.65-1.85(3H,m)
、1.86-1.93 (1H,m)、2.02-2.14 (2H,m)、2.25-2.33 (1H,m)、2.89-2.95 (1H,m)
、3.09-3.15 (1H,m)、4.47-4.58 (4H, m, PO-CH2×2)
13C NMR (CDCl3) : δ 24.2 、25.8、26.7、34.7、47.3、67.3、76,9、77,3
Elemental analysis (C 8 H 16 NO 3 P Mol. Wt .: 205.19): Calc. C, 46.83; H, 7.86; N, 6.83
Found C, 46.70; H, 8.02; N, 6.74
IR spectrum (KBr cm-1): 3284.5, 2962.5, 2868.8, 147.94, 1425.3,
1369.4, 1259.4, 1249.8, 1191.9, 1130.9, 1056.9, 941.2, 879.5, 804.3,
Mass spectrum FAB +, m / z (%): 206 M + (16), 84 (100), 411 (6)
1HNMR (300 MHz, CDCl3): δ 1.40-1.43 (3H, D, J = 15.7 Hz), 1.65-1.85 (3H, m)
, 1.86-1.93 (1H, m), 2.02-2.14 (2H, m), 2.25-2.33 (1H, m), 2.89-2.95 (1H, m)
, 3.09-3.15 (1H, m), 4.47-4.58 (4H, m, PO-CH2 × 2)
13C NMR (CDCl3): δ 24.2, 25.8, 26.7, 34.7, 47.3, 67.3, 76, 9, 77, 3
〔実施例２〕
２−（５，５−ジメチル−２−（２−オキソ−２λ5 −［１，３，２］ジオキサフォスフィナン−２−イル）−２−メチル−ピロリジン（2-(5,5-Dimethyl-(2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-2-methyl-pyrrolidine）の合成：
５，５−ジメチル−２−オキソ−[１，３，２]ジオキソフォスフォリナン36 g(0.24 mol)と２−メチル-1-ピロリン 17 g(0.24 mol) をジクロルメタンに溶解し、室温で反応した。シリカゲル薄層クロマトグラフィー（展開溶媒；クロロホルム：エチルアルコール＝１０：１）により反応の終了を確認した後に、シリカゲルカラムクロマトグラフィー（展開溶媒；クロロホルム：エチルアルコール＝２０：１）にて分離精製を行った。目的とする分画を集め、減圧濃縮により溶媒を除去して固形物を得た。これを結晶化して 24.5 g(mp 109-112℃、収率 48,2 %)を得た。
[Example 2]
2- (5,5-dimethyl-2- (2-oxo 2 [lambda] 5 - [l, 3,2] di oxa phosphinothricin nan-2-yl) -2-methyl - pyrrolidine (2- (5,5-Dimethyl - synthesis of - ([1,3,2] dioxaphosphinan-2 -yl 2-oxo-2λ 5) -2-methyl-pyrrolidine):
Dissolve 36 g (0.24 mol) of 5,5-dimethyl-2-oxo- [ 1,3,2] dioxophosphorinane and 17 g (0.24 mol) of 2-methyl-1-pyrroline in dichloromethane. Reacted. After confirming the completion of the reaction by silica gel thin layer chromatography (developing solvent; chloroform: ethyl alcohol = 10: 1), separation and purification are performed by silica gel column chromatography (developing solvent; chloroform: ethyl alcohol = 20: 1). It was. The desired fraction was collected and the solvent was removed by concentration under reduced pressure to obtain a solid. This was crystallized to obtain 24.5 g (mp 109-112 ° C., yield 48,2%).
元素分析（C10H20NO3P Mol.Wt. 233.24）：Calc. C,51.49; H,8.64; N,6.01
Found C,51.37; H,8.90; N,6.09
ＩＲスペクトル (KBr cm-1) : 3296.1, 2962.5, 2868.8, 1475.4, 1454.2,
1253.6, 1234.4, 1191.9, 1136.0, 1062.7, 1018.3, 817.8
マススペクトル FAB+, m/z (%)： 234 M+ (14)、84(100) 、467(7)
1HNMR (300 MHz, CDCl3) :δ 1.40-1.43 (3H, D, J=15.7 Hz)、1.65-1.85(3H,m)
、1.86-1.93 (1H,m)、2.02-2.14 (2H,m)、2.25-2.33 (1H,m)、2.89-2.95 (1H,m)
、3.09-3.15 (1H,m)、4.47-4.58 (4H, m, PO−CH2 ×2)
13C NMR (CDCl3) : δ 22.1 、24.6、26.2、35.1、47.7、77.0、77,4、77.8
Elemental analysis (C 10 H 20 NO 3 P Mol. Wt. 233.24): Calc. C, 51.49; H, 8.64; N, 6.01
Found C, 51.37; H, 8.90; N, 6.09
IR spectrum (KBr cm-1): 3296.1, 2962.5, 2868.8, 1475.4, 1454.2,
1253.6, 1234.4, 1191.9, 1136.0, 1062.7, 1018.3, 817.8
Mass spectrum FAB +, m / z (%): 234 M + (14), 84 (100), 467 (7)
1HNMR (300 MHz, CDCl3): δ 1.40-1.43 (3H, D, J = 15.7 Hz), 1.65-1.85 (3H, m)
, 1.86-1.93 (1H, m), 2.02-2.14 (2H, m), 2.25-2.33 (1H, m), 2.89-2.95 (1H, m)
, 3.09-3.15 (1H, m), 4.47-4.58 (4H, m, PO-CH 2 × 2)
13C NMR (CDCl3): δ 22.1, 24.6, 26.2, 35.1, 47.7, 77.0, 77,4, 77.8
〔動物の行動への影響に関する試験〕
ＳＤラット(300 g) に２−メチル−２−オキソ−２λ5 −［１，３，２］ジオキサフォスフィナン−２−イル）−ピロリジン 20 mgを含む 50 % PEG-400 水溶液 0.25 mlを腹腔内投与した直後から１８時間、行動に対する影響および毒性に係る症状の観察をした結果、記録すべき変化を生じなかった。
前記方法と同様にＳＤラット(300 g) に２−（５，５−ジメチル−２−オキソ−２λ5 −［１，３，２］ジオキサフォスフィナン−２−イル）−２−メチル−ピロリジン 20 mg を投与した結果、記録すべき変化を生じなかった。
[Studies on effects on animal behavior]
SD rats (300 g) in 2-methyl-2-oxo-2 [lambda] 5 - [l, 3,2] di oxa phosphinothricin nan-2-yl) - pyrrolidine 50% PEG-400 aqueous 0.25 ml ip containing 20 mg As a result of observing symptoms related to behavioral effects and toxicity for 18 hours immediately after the internal administration, no change to be recorded occurred.
The method as well as the SD rats (300 g) 2- (5,5- dimethyl-2-oxo 2 [lambda] 5 - [l, 3,2] di oxa phosphinothricin nan-2-yl) -2-methyl - pyrrolidine Administration of 20 mg produced no change to be recorded.
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