JP4173335B2 - Method for producing optically active 2,3-epoxypropane derivative - Google Patents
Method for producing optically active 2,3-epoxypropane derivative Download PDFInfo
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- JP4173335B2 JP4173335B2 JP2002236597A JP2002236597A JP4173335B2 JP 4173335 B2 JP4173335 B2 JP 4173335B2 JP 2002236597 A JP2002236597 A JP 2002236597A JP 2002236597 A JP2002236597 A JP 2002236597A JP 4173335 B2 JP4173335 B2 JP 4173335B2
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- 125000000753 cycloalkyl group Chemical group 0.000 description 10
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003429 antifungal agent Substances 0.000 description 6
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- 239000007858 starting material Substances 0.000 description 6
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- 125000002252 acyl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 125000005587 carbonate group Chemical group 0.000 description 4
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- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- UKZCGMDMXDLAGZ-UHFFFAOYSA-M magnesium;2-methylpropane;bromide Chemical compound [Mg+2].[Br-].C[C-](C)C UKZCGMDMXDLAGZ-UHFFFAOYSA-M 0.000 description 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 description 1
- UODMSBYDFUPQHC-UHFFFAOYSA-M magnesium;di(propan-2-yl)azanide;bromide Chemical compound CC(C)N([Mg]Br)C(C)C UODMSBYDFUPQHC-UHFFFAOYSA-M 0.000 description 1
- RMHOGFJEHWOPLT-UHFFFAOYSA-M magnesium;di(propan-2-yl)azanide;chloride Chemical compound Cl[Mg+].CC(C)[N-]C(C)C RMHOGFJEHWOPLT-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000005911 methyl carbonate group Chemical group 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- AFFLGGQVNFXPEV-UHFFFAOYSA-N n-decene Natural products CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000000109 phenylethoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical class [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- AHIHJODVQGBOND-UHFFFAOYSA-N propan-2-yl hydrogen carbonate Chemical group CC(C)OC(O)=O AHIHJODVQGBOND-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- IZYZVGMQWYKDBW-UHFFFAOYSA-M sodium;2-(1,2,4-triazol-1-yl)acetate Chemical compound [Na+].[O-]C(=O)CN1C=NC=N1 IZYZVGMQWYKDBW-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、医農薬分野をはじめ多方面において製造上の重要な化合物である光学活性２，３−エポキシプロパン誘導体の短工程な新規製造法に関するものである。
【０００２】
【従来の技術】
近年、ＡＩＤＳ等の感染による免疫不全患者の増加や高度医療の進展または高齢者の増加等による免疫力低下患者の増大によって、いわゆる日和見感染症に代表される真菌感染症が問題となっている。特に免疫低下者にとって、カンジタ症やアスペルギルス症などの深在性の真菌感染症は、生命にも拘わる重篤な場合も少なくなく、医療現場においては注意すべき感染症の一つである。 従来、これら感染症にたいしてはフルコナゾールに代表されるアゾール系の抗真菌剤が多用されてきたが、近年、耐性菌の出現や基本的な作用不足が指摘されるようになり、より広範囲な菌種に有効でより強力な治療薬の開発が望まれている（医薬ジャーナル, vol37(7), 115-119）。
【０００３】
一方、近年開発中のアゾール系の抗真菌剤は、構造がより複雑化する傾向にあり、特にアゾールメチル基が結合する不斉炭素およびそれに連続して存在する不斉炭素部位をいかに効率よく構築するかが大きな技術上の問題点となっている（J.Med.Chem., 41, 1869-1882, 1998）。しかし現在に至るまで、工業的な観点から、安価でかつ安定的な製造方法は確立されていない。
【０００４】
従来の製造技術に関して述べる。
連続する不斉部位の構築方法として、いずれの場合もα−ヒドロキシフェニルケトン誘導体を経由して、ケトン基に対するジアステレオ選択的な増炭エポキシ化を行なうことで構築している（Chem.Pharm.Bull., 41(6), 1035-1042, 1993）。しかし従来製造法は、（１）ジアステレオ選択性が約４：１と悪く、（２）目的とする異性体のみ単離しようとすると低収率であり、（３）工程数および単離、精製工程が極めて煩雑である等、工業的に見て極めて問題のある製造方法であった。加えて、α−ヒドロキシフェニルケトン誘導体自体の製造方法も多工程（Bioorg.Med.Chem.Lett., vol1(7), 349-352, 1991）またはD-乳酸などの高価な出発原料（Chem.Pharm.Bull., 41(6), 1035-1042, 1993）ならびに不斉触媒等の高価な反応試薬（Tetrahedron Letters, vol37(36), 6531-6534, 1996）を必要とし、工業的な製造方法としては十分満足するものではなかった。近年、これらの既存法を改良したL-アラニンを出発原料とする新規な製造法も報告されているが（US6300522）、α−ヒドロキシフェニルケトン誘導体を経由する点において根本的な問題の解決には至っておらず、必ずしも工業的に満足する製造方法ではなかった。
【０００５】
このように、より有用な新規アゾール系の抗真菌剤の開発が望まれているにも拘わらず、２つの不斉炭素を有する光学活性な化合物であるため、従来の製造技術では、工業的な観点から安価でかつ安定的な製造方法は確立されておらず、これら中間体化合物に関して、より効率的な新規製造法の早急な開発が望まれている。
【０００６】
【発明が解決しようとする課題】
本発明の課題は、医農薬分野における有用な化合物であり、特に光学活性なアゾール系抗真菌剤の製造過程において極めて重要な中間体となる、光学活性２，３−エポキシプロパン誘導体の製造に関して、工業的な観点から、短工程で安価にかつ安定的に製造する方法を提供することである。
【０００７】
【課題を解決するための手段】
本発明者らは、上記課題を解決する為に鋭意検討を重ねた結果、アミノ酸誘導体を出発原料とし、光学活性なアゾールアルキルケトン誘導体を経由し、高ジアステレオ選択的なアルキル化を行う製造ルートを見出した。また、反応に伴なうラセミ化等の問題も無く、光学純度良く、望む立体配置を有する化合物を選択的に製造できることを見出した。すなわち、光学活性なα−ヒドロキシカルボン酸誘導体として安価な乳酸誘導体を利用することで、光学活性なアゾール系抗真菌剤の製造過程において極めて重要な中間体となる光学活性２，３−エポキシプロパン誘導体の製造に関して、工業的な観点から短工程で安価にかつ安定的に製造する方法を見出し、本発明を完成するに至った。
【０００８】
すなわち、本発明は以下の[1]〜[２]に記載のとおりである。
[１] 一般式（１）[化８]
【０００９】
【化８】
（式中Ｒ１は置換されてもよいアルキル基、置換されてもよいアラルキル基、置換されてもよいアリール基または置換されてもよいヘテロ環を示し、Ｒ２、Ｒ３はそれぞれ独立して、置換されてもよいアルキル基、置換されてもよいアラルキル基、置換されてもよいアリール基を示し、＊は不斉炭素を表す。）で表されるアミノ酸誘導体と、一般式（２）[化９]
【００１１】
【化９】
（式中Ｒ４は水素、低級アルキル基、アルカリ金属を示し、Ｙは炭素原子または窒素原子を示す。）で表されるアゾール酢酸誘導体を塩基性条件下反応させ、一般式（３）[化１０]
【００１３】
【化１０】
（式中Ｒ１、Ｒ２、＊およびＹは前記と同義である。）で表されるアゾールメチルケトン誘導体を合成し、さらに一般式（４）[化１１]
【００１５】
【化１１】
（式中Ｒ５およびＲ６は互いに独立してハロゲン原子、アルキルオキシカルボニル基、アリールオキシカルボニル基、置換されてもよいアミノ基、置換されてもよいアミド基、置換されてもよいアルキル基、置換されてもよいアルキルオキシ基、置換されてもよいアラルキル基、置換されてもよいアラルキルオキシ基、置換されてもよいフェニル基、置換されてもよいフェニルオキシ基、置換されてもよいヘテロ環または置換されてもよいヘテロ環オキシ基を示し、ＡはＬｉ、ＭｇＸ、ＺｎＸ、ＴｉＸ３、Ｔｉ（ＯＲ７）３、ＣｕＸまたはＣｕＬｉを示す。ただし、Ｘはハロゲン原子を示し、Ｒ７は低級アルキル基を示す。）で表されるフェニル金属試薬をジアステレオ選択的に反応させ、一般式（５）[化１２]
【００１７】
【化１２】
（式中Ｒ１、Ｒ２、Ｒ５、Ｒ６、＊およびＹは前記と同義である。）で表されるアゾールメチルアルコールを合成し、さらに環化することで一般式（６）[化１３]
【００１９】
【化１３】
（式中Ｒ１、Ｒ５、Ｒ６、＊およびＹは前記と同義である。）で表される光学活性２，３−エポキシプロパン誘導体を製造する方法であり、
［２］一般式（１）［化１］
【化１】
【化２】
【化３】
【化４】
【化５】
【化７】
【００２２】
［３］一般式（３）で表されるアゾールメチルケトン誘導体である。
【化３】
【００２３】
【発明の実施の形態】
次に本発明の化合物についてさらに詳細に説明する。
【００２４】
一般式（１）（３）（５）（６）及び（７）中に＊で表した不斉炭素は、Ｒ配置あるいはＳ配置のどちらの立体もとることができ、同様に製造を行うことができる。
【００２５】
本発明において「置換されてもよいアルキル基」とは、アルキル基の任意の位置が置換されてもよいアルキル基を意味する。アルキル基としては、メチル基、エチル基、イソプロピル基、tert-ブチル基、ペンチル基、ヘキシル基、オクチル基、デシル基またはアリル基等を挙げることができる。置換基としては、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００２６】
本発明において「置換されてもよいアラルキル基」とは、アラルキル基の任意の位置が置換されてもよいアラルキル基を意味する。アラルキル基としては、ベンジル基、ナフチルメチル基、フェニルエチル基または９−フルオレニルメチル基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００２７】
本発明において「置換されてもよいアリール基」とは、アリール基の任意の位置が置換されてもよいアリール基を意味する。アリール基としては、フェニル基、ナフチル基、アントラセニル基、フルオレニル基またはフェナントレニル基等を挙げることができる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００２８】
本発明において「置換されていてもよいヘテロ環」とは、ヘテロ環の任意の位置が置換されていてもよいヘテロ環を意味する。ヘテロ環としては、テトラヒドロピラニル基、テトラヒドロフラニル基、テトラヒドロチエニル基、ピペリジル基、モルホリニル基、ピペラジニル基、ピロリル基、フリル基、チエニル基、ピリジル基、フルフリル基、テニル基、ピリジルメチル基、ピリミジル基、ピラジル基、イミダゾイル基、イミダゾイルメチル基、インドリル基、インドリルメチル基、イソキノリル基、キノリル基またはチアゾリル基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００２９】
本発明において「置換されていてもよいアシル基」とは、アシル基の任意の位置が置換されていてもよいアシル基を意味する。アシル基としては、ホルミル基、アセチル基、プロピオニル基、ピバロイル基、ベンゾイル基等を挙げることができる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００３０】
本発明において「置換されていてもよいカーボネート基」とは、カーボネート基の任意の位置が置換されていてもよいカーボネート基を意味する。カーボネート基としては、メチルカーボネート基、エチルカーボネート基、イソプロピルカーボネート基、ベンジルカーボネート基等を挙げることができる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００３１】
本発明において「置換されてもよいアルキルオキシ基」とは、アルキルオキシ基の任意の位置が置換されてもよいアルキルオキシ基を意味する。アルキルオキシ基としては、メトキシ基、エトキシ基、イソプロポキシ基、tert-ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、オクチルオキシ基、デシルオキシ基またはアリルオキシ基等を挙げることができる。置換基としては、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００３２】
本発明において「置換されてもよいアラルキルオキシ基」とは、アラルキルオキシ基の任意の位置が置換されてもよいアラルキルオキシ基を意味する。アラルキルオキシ基としては、ベンジルオキシ基、ナフチルメチルオキシ基、フェニルエチルオキシ基または９−フルオレニルメチルオキシ基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００３３】
本発明において「置換されてもよいフェノキシ基」とは、フェノキシ基の任意の位置が置換されてもよいフェノキシ基を意味する。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００３４】
本発明において「アルキルオキシカルボニル基」としては、メトキシカルボニル基、エトキシカルボニル基、tert-ブトキシカルボニル基等を挙げることができる。
【００３５】
本発明において「アリールオキシカルボニル基」としては、フェノキシカルボニル、ナフチルオキシカルボニル基等を挙げることができる。
【００３６】
本発明において「置換されてもよいアミノ基」とは、アミノ基の任意の位置が置換されてもよいアミノ基を意味する。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基等を挙げることができる。
【００３７】
本発明において「置換されてもよいアミド基」とは、アミド基の任意の位置が置換されてもよいアミノ基を意味する。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基等を挙げることができる。
【００３８】
本発明において「置換されていてもよいヘテロ環オキシ基」とは、ヘテロ環オキシ基の任意の位置が置換されていてもよいヘテロ環オキシ基を意味する。ヘテロ環オキシ基としては、テトラヒドロピラニルオキシ基、テトラヒドロフラニルオキシ基、テトラヒドロチエニルオキシ基、ピペリジルオキシ基、モルホリニルオキシ基、ピペラジニルオキシ基、ピロリルオキシ基、フリルオキシ基、チエニルオキシ基、ピリジルオキシ基、フルフリルオキシ基、テニルオキシ基、ピリジルメチルオキシ基、ピリミジルオキシ基、ピラジルオキシ基、イミダゾイルオキシ基、イミダゾイルメチルオキシ基、インドリルオキシ基、インドリルメチルオキシ基、イソキノリルオキシ基、キノリルオキシ基またはチアゾリルオキシ基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【００３９】
以下に一般式（３）および（５）に含まれる化合物を表−１[表１]〜表−２[表２]に例示する。ただし、これは本願発明化合物を制限するものではない。
【００４０】
【表１】
【表２】
以下に、本発明の代表的な製造法について説明する。
[１]一般式（３）で表されるアゾールメチルケトン誘導体の製造法について述べる。
一般式（１）で表されるアミノ酸誘導体に対し、一般式（２）で表されるアゾール酢酸誘導体を塩基性条件下にて反応させることで一般式（３）で表されるアゾールメチルケトン誘導体を製造することができる。本反応は、炭素−炭素結合反応の後に、あるいは同時に脱炭酸反応を進行させることで、効率良くアゾールメチル基を導入することが可能である。また本反応において、出発原料を光学活性体とした場合、反応による光学純度の低下はほとんど観察されない。使用可能な塩基としては特に制限は無いが、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、トリエチルアミン、ピリジン、１，８−ジアザビシクロウンデセン等の有機アミン塩基、水素化リチウム、水素化ナトリウム等の金属水素化物、n-ブチルリチウム、エチルマグネシウムブロマイド、n-ブチルマグネシウムクロライド、tert-ブチルマグネシウムクロライド等の有機金属塩基、またはナトリウムアミド、リチウムジイソプロピルアミド、塩化マグネシウムジイソプロピルアミド等の金属アミド塩基等を挙げることができる。使用可能な溶媒としては、反応の進行を妨げないものであれば特に制限はないが、水、メタノール、エタノール、ブタノール等のアルコール系溶媒、ヘキサン、トルエン、キシレン等の炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル系溶媒、ジエチルエーテル、ジオキサン、エチレングリコールジメチルエーテル、テトラヒドロフラン等のエーテル系溶媒、クロロホルム、ジクロロメタン等のハロゲン系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド等を挙げることができる。またこれら溶媒は単独で、あるいは２種以上の任意の比率での混合溶媒として使用可能である。反応温度に関しては、−７８℃から使用する溶媒の沸点まで実施可能であるが、好ましくは、−２０℃から溶媒の沸点の温度範囲である。反応時間は特に制限は無いが、数分から２４時間、好ましくは３０分から６時間の範囲である。
【００４３】
[２]一般式で表されるアゾールメチルアルコール誘導体の製造法について述べる。
一般式（３）で表されるアゾールメチルケトン誘導体に対し、一般式（４）で表されるフェニル金属試薬を反応させることで一般式（５）で表されるアゾールメチルアルコール誘導体を製造することができる。この反応において、Ｒ２で示される水酸基の保護基とＡで示される金属種の組み合わせにより、高いジアステレオ選択性でｓｙｎあるいはａｎｔｉの立体を作り分けることができる。
すなわち、Ｒ２Ｏ基における酸素原子と反応に関与するカルボニル基が金属の配位により立体が固定された、いわゆるキレーションモデルにしたがってアリル金属試薬が反応することで、高いｓｙｎのジアステレオ選択性で目的物を得ることができる。より具体的には、Ｓ配置の化合物からはＳ−Ｒ配置の化合物を、Ｒ配置の化合物からはＲ−Ｓ配置の化合物を選択的に製造することができる。
また、Ｒ２で示される水酸基の保護基を立体的に大きくし、配位しにくい金属試薬を選択することで、高いａｎｔｉ選択性で目的物を得ることができる。より具体的には、Ｓ配置の化合物からはＳ−Ｓ配置の化合物を、Ｒ配置の化合物からはＲ−Ｒ配置の化合物を選択的に製造することができる。
また、本反応において、出発原料を光学活性体とした場合、反応による光学純度の低下はほとんど観察されない。使用可能なフェニル金属化合物としては、フェニルリチウム誘導体、フェニルマグネシウム誘導体、フェニル亜鉛誘導体、フェニルチタン誘導体、フェニル銅誘導体またはフェニル銅リチウム誘導体等を挙げることができる。使用可能な溶媒としては、反応の進行を妨げないものであれば特に制限はないが、水、メタノール、エタノール、ブタノール等のアルコール系溶媒、ヘキサン、トルエン、キシレン等の炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル系溶媒、ジエチルエーテル、ジオキサン、エチレングリコールジメチルエーテル、テトラヒドロフラン等のエーテル系溶媒、クロロホルム、ジクロロメタン等のハロゲン系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド等を挙げることができる。またこれら溶媒は単独で、あるいは２種以上の任意の比率での混合溶媒として使用可能である。反応温度に関しては、−７８℃から使用する溶媒の沸点まで実施可能であるが、好ましくは、−４０℃から室温の範囲である。反応時間は特に制限は無いが、数分から２４時間、好ましくは３０分から６時間の範囲である。
【００４４】
[３]一般式（６）で表される光学活性２，３−エポキシプロパン誘導体の製造法について述べる。
一般式（５）で表されるアゾールメチルアルコール誘導体のアミノ基を脱離させ、隣接する水酸基部分で環化することにより、一般式（６）で表される光学活性２，３−エポキシプロパン誘導体を製造することができる。アミノ基の脱離方法は、その他の構造に変化を与えない方法であれば特に制限はない。塩酸、硫酸、トリフルオロ酢酸、p-トルエンスルホン酸または酢酸等による酸処理やアルカリ処理、様々な金属、金属塩による処理、熱処理などによって実施可能である。さらに、ハロゲン化アルキルを加え、アミノ基を４級化することで反応性を上げることもできる。使用可能な溶媒としては、反応の進行を妨げないものであれば特に制限はないが、水、メタノール、エタノール、ブタノール等のアルコール系溶媒、ヘキサン、トルエン、キシレン等の炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル系溶媒、ジエチルエーテル、ジオキサン、エチレングリコールジメチルエーテル、テトラヒドロフラン等のエーテル系溶媒、クロロホルム、ジクロロメタン等のハロゲン系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド等を挙げることができる。またこれら溶媒は単独で、あるいは２種以上の任意の比率での混合溶媒として使用可能である。反応温度に関しては、−２０℃から使用する溶媒の沸点まで実施可能である。反応時間は特に制限は無いが、数分から２４時間、好ましくは３０分から６時間の範囲である。
【００４５】
なお、本発明の出発原料である一般式（１）で表されるアミノ酸誘導体は、市販で容易に入手可能であるか、または一般的に広く知られた方法で合成可能である。例えば、アラニンから既知の方法（Ｃｈｅｍ．Ｒｅｖ．１９９９年、９９号、１１２１など）で合成可能である。さらに、一般式（２）で表されるアゾール酢酸誘導体は、既知の方法(Tetrahedron Lett., 2000, 41(8), 1297等)で容易に合成可能である。また、製造方法として特に明記していない試薬および使用原料に関しては一般的に市販されており、いずれも入手は容易である。
【００４６】
【実施例】
以下に、本発明の実施例を記載するが、本発明はこれらによって制限されるものではない。
[実施例１] (3R)-3-(Ｎ，Ｎ−ジベンジルアミノ) -1-（1H-1,2,4-トリアゾール-1-イル）-2-ブタノンの合成
2-（1H-1,2,4-トリアゾール-1-イル）酢酸ナトリウム塩(1.88g)のＴＨＦ懸濁溶液にＤ−（Ｎ，Ｎ−ジベンジル)アラニン ベンジルエステル（2.0ｇ）のＴＨＦ溶液と塩化マグネシウム1.41ｇを加え、室温で２時間撹拌した。ついで、氷冷下にt-ブチルマグネシウムブロマイドとジイソプロピルアミンから調整した臭化マグネシウム ジイソプロピルアミドのＴＨＦ溶液を滴下した。滴下後、加熱還流を２時間行い、反応溶液を氷冷下で硫酸（18.0g）/水（150ml）/酢酸エチル(225ml)の混合溶液に注加し、室温で40分間撹拌した。この溶液を中和後、分液し、有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィーで単離精製し、目的化合物を収率30%で得た。
【００４７】
[実施例２] (2R,3Ｒ)-3-(Ｎ，Ｎ−ジベンジルアミノ)-2-(2,4-ジフルオロフェニル) -1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール
窒素雰囲気化でマグネシウム (1.5ｇ)をテトラヒドロフラン(25ｍｌ)に懸濁し、ヨウ素（50ｍｇ）を加えてから25℃〜30℃で2,4-ジフルオロブロモベンゼン（11.0ｇ）/テトラヒドロフラン（20ｍｌ）溶液を滴下した。室温で1.5時間撹拌しこれを溶液Ａ（49.2ｇ）とした。別の反応容器に実施例１で得られた化合物（例示化合物Ｒ１１１；2.45ｇ)を入れ、テトラヒドロフラン（20ｍｌ）に溶解して-20℃に冷却した。これに溶液Ａ（9.1g）を-5℃以下で滴下し、-10℃〜0℃で1時間、0℃〜10℃で2時間撹拌した。反応液を5℃に冷却し、1N塩酸（9ｍｌ）を加えてpH8に調整した。5℃〜10℃で30分撹拌した後、酢酸エチル、水を加えて抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸マグネシウムにて乾燥した後、溶媒を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで単離精製し、ジアステレオ選択性がａｎｔｉである目的化合物を収率50%で得た。
【００４８】
[実施例３] (2R,3Ｒ)-2,3-エポキシ-2-(2,4-ジフルオロフェニル) -1-(1H-1,2,4-トリアゾール-1-イル)ブタン
上記にて合成の(2R,3Ｒ) -3-(Ｎ，Ｎ−ジベンジルアミノ)-2-(2,4-ジフルオロフェニル) -1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノールとヨウ化メチルをDMF中60℃で加熱撹拌し、冷却後、水酸化ナトリウム水溶液を加えアルカリ性とし、室温で1夜放置した。反応溶液に水を加え酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィーで単離精製し、目的化合物を収率40%で得た。
【００４９】
[実施例４] (2R,3Ｒ)-3-アミノ-2-(2,4-ジフルオロフェニル) -1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール
実施例２で合成した(2R,3Ｒ) -3-(Ｎ，Ｎ−ジベンジルアミノ)-2-(2,4-ジフルオロフェニル) -1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノールをメタノールに溶解し、10%Pd/Cを触媒とし、水素添加を行った。水素の吸収が止まった後、触媒をろ過し、溶媒を減圧濃縮し、残さをシリカゲルカラムで精製し、脱ベンジル化された表記化合物を収率85%で取得した。
【００５０】
【発明の効果】
本発明の製造法によれば、医農薬分野における有用な化合物であり、特に新規アゾール系抗真菌剤の製造過程において極めて重要な中間体と成り得る光学活性２，３−エポキシプロパン誘導体の製造に関して、工業的な観点から短工程で安価にかつ安定的に製造することが可能となった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for producing an optically active 2,3-epoxypropane derivative which is an important compound for production in various fields including medical and agrochemical fields.
[0002]
[Prior art]
In recent years, fungal infections typified by so-called opportunistic infections have become a problem due to an increase in immunodeficiency patients due to infections such as AIDS, an increase in patients with reduced immunity due to advancement of advanced medical care or an increase in the elderly. In particular, for those who are immunocompromised, deep fungal infections such as candidiasis and aspergillosis are often serious and life-threatening, and are one of the infections to be noted in the medical field. Conventionally, azole antifungal agents typified by fluconazole have been frequently used for these infectious diseases, but in recent years, the emergence of resistant bacteria and the lack of basic action have been pointed out, and a wider range of bacterial species The development of more effective and more effective therapeutic agents is desired (Pharmaceutical Journal, vol37 (7), 115-119).
[0003]
On the other hand, the azole antifungal agents currently under development tend to be more complex in structure, especially how to efficiently construct the asymmetric carbon to which the azolemethyl group is bonded and the asymmetric carbon moiety present continuously. This is a major technical problem (J. Med. Chem., 41, 1869-1882, 1998). However, until now, an inexpensive and stable production method has not been established from an industrial viewpoint.
[0004]
The conventional manufacturing technique will be described.
As a method for constructing a continuous asymmetric site, in any case, it is constructed by carrying out diastereoselective carbon increase epoxidation to a ketone group via an α-hydroxyphenyl ketone derivative (Chem. Pharm. Bull., 41 (6), 1035-1042, 1993). However, the conventional production method has (1) poor diastereoselectivity of about 4: 1, (2) low yield when trying to isolate only the target isomer, (3) number of steps and isolation, The production method was extremely problematic from an industrial point of view, for example, the purification process was extremely complicated. In addition, the production method of the α-hydroxyphenyl ketone derivative itself is also multi-step (Bioorg. Med. Chem. Lett., Vol1 (7), 349-352, 1991) or expensive starting materials such as D-lactic acid (Chem. Pharm. Bull., 41 (6), 1035-1042, 1993) and expensive reaction reagents such as asymmetric catalysts (Tetrahedron Letters, vol37 (36), 6531-6534, 1996) I was not satisfied enough. In recent years, a new production method using L-alanine as a starting material improved from these existing methods has been reported (US6300522). However, in order to solve the fundamental problem in terms of passing through an α-hydroxyphenyl ketone derivative, However, it was not always an industrially satisfactory production method.
[0005]
As described above, since it is an optically active compound having two asymmetric carbons even though the development of a more useful novel azole antifungal agent is desired, the conventional production technique is industrially effective. From the viewpoint, an inexpensive and stable production method has not been established, and rapid development of a more efficient new production method is desired for these intermediate compounds.
[0006]
[Problems to be solved by the invention]
The subject of the present invention is a useful compound in the field of medicine and agrochemicals, and particularly for the production of an optically active 2,3-epoxypropane derivative, which is an extremely important intermediate in the process of producing an optically active azole antifungal agent. From an industrial viewpoint, it is to provide a method for stably and inexpensively producing in a short process.
[0007]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained a production route in which an amino acid derivative is used as a starting material and a highly diastereoselective alkylation is performed via an optically active azole alkyl ketone derivative. I found. It was also found that a compound having a desired configuration can be selectively produced with good optical purity without problems such as racemization accompanying the reaction. That is, an optically active 2,3-epoxypropane derivative which is an extremely important intermediate in the production process of an optically active azole antifungal agent by using an inexpensive lactic acid derivative as an optically active α-hydroxycarboxylic acid derivative With respect to the production of the present invention, a method for producing it inexpensively and stably in a short process from an industrial viewpoint has been found, and the present invention has been completed.
[0008]
That is, the present invention is as described in the following [1] to [2].
[1] General formula (1) [Formula 8]
[0009]
[Chemical 8]
(Wherein R1 represents an optionally substituted alkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group or an optionally substituted heterocycle, and R2 and R3 are each independently substituted; An alkyl group which may be substituted, an aralkyl group which may be substituted, and an aryl group which may be substituted, and * represents an asymmetric carbon.) And an amino acid derivative represented by the general formula (2)
[0011]
[Chemical 9]
(Wherein R4 represents hydrogen, a lower alkyl group, or an alkali metal, and Y represents a carbon atom or a nitrogen atom.) The azole acetic acid derivative represented by the general formula (3) ]
[0013]
[Chemical Formula 10]
(Wherein R1, R2, *, and Y are as defined above), an azolemethylketone derivative represented by the general formula (4)
[0015]
Embedded image
(Wherein R5 and R6 are each independently a halogen atom, an alkyloxycarbonyl group, an aryloxycarbonyl group, an amino group that may be substituted, an amide group that may be substituted, an alkyl group that may be substituted, An optionally substituted alkyloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted phenyl group, an optionally substituted phenyloxy group, an optionally substituted heterocycle or substituted A represents a heterocyclic oxy group which may be substituted, and A represents Li, MgX, ZnX, TiX3, Ti (OR7) 3, CuX or CuLi, wherein X represents a halogen atom and R7 represents a lower alkyl group. ) Is reacted diastereoselectively to give a general formula (5)
[0017]
Embedded image
(Wherein R 1, R 2, R 5, R 6, * and Y have the same meanings as described above) are synthesized and further cyclized to generate the general formula (6) [Chem. 13]
[0019]
Embedded image
(Wherein R1, R5, R6, * and Y are as defined above), a method for producing an optically active 2,3-epoxypropane derivative represented by:
[2]General formula (1) [Chemical formula 1]
[Chemical 1]
[Chemical 2]
[Chemical 3]
[Formula 4]
[Chemical formula 5]
[Chemical 7]
[0022]
[3] An azole methyl ketone derivative represented by the general formula (3).
[Chemical 3]
[0023]
DETAILED DESCRIPTION OF THE INVENTION
Next, the compound of the present invention will be described in more detail.
[0024]
The asymmetric carbon represented by * in the general formulas (1), (3), (5), (6), and (7) can take either the R configuration or the S configuration and should be produced in the same manner. Can do.
[0025]
In the present invention, the “alkyl group that may be substituted” means an alkyl group that may be substituted at any position of the alkyl group. Examples of the alkyl group include a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a pentyl group, a hexyl group, an octyl group, a decyl group, and an allyl group. Substituents include alkoxy groups such as hydroxyl group, methoxy group, benzyloxy group or methoxyethoxy group, phenoxy group, nitro group, amino group, amide group, carboxyl group, alkoxycarbonyl group, phenoxycarbonyl group or fluorine atom, chlorine atom And halogen atoms such as bromine atom or iodine atom.
[0026]
In the present invention, the “aralkyl group which may be substituted” means an aralkyl group in which any position of the aralkyl group may be substituted. Examples of the aralkyl group include a benzyl group, a naphthylmethyl group, a phenylethyl group, and a 9-fluorenylmethyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0027]
In the present invention, the “aryl group that may be substituted” means an aryl group that may be substituted at any position of the aryl group. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a fluorenyl group, and a phenanthrenyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0028]
In the present invention, the “optionally substituted heterocycle” means a heterocycle in which any position of the heterocycle may be substituted. Heterocycles include tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, furyl, thienyl, pyridyl, furfuryl, tenenyl, pyridylmethyl, pyrimidyl Group, pyrazyl group, imidazolyl group, imidazolylmethyl group, indolyl group, indolylmethyl group, isoquinolyl group, quinolyl group or thiazolyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0029]
In the present invention, the “optionally substituted acyl group” means an acyl group in which any position of the acyl group may be substituted. Examples of the acyl group include formyl group, acetyl group, propionyl group, pivaloyl group, benzoyl group and the like. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0030]
In the present invention, the “optionally substituted carbonate group” means a carbonate group in which any position of the carbonate group may be substituted. Examples of the carbonate group include a methyl carbonate group, an ethyl carbonate group, an isopropyl carbonate group, and a benzyl carbonate group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0031]
In the present invention, the “optionally substituted alkyloxy group” means an alkyloxy group in which any position of the alkyloxy group may be substituted. Examples of the alkyloxy group include methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, octyloxy group, decyloxy group and allyloxy group. Substituents include alkoxy groups such as hydroxyl group, methoxy group, benzyloxy group or methoxyethoxy group, phenoxy group, nitro group, amino group, amide group, carboxyl group, alkoxycarbonyl group, phenoxycarbonyl group or fluorine atom, chlorine atom And halogen atoms such as bromine atom or iodine atom.
[0032]
In the present invention, “optionally substituted aralkyloxy group” means an aralkyloxy group in which any position of the aralkyloxy group may be substituted. Examples of the aralkyloxy group include a benzyloxy group, a naphthylmethyloxy group, a phenylethyloxy group, and a 9-fluorenylmethyloxy group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0033]
In the present invention, “optionally substituted phenoxy group” means a phenoxy group in which any position of the phenoxy group may be substituted. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0034]
In the present invention, examples of the “alkyloxycarbonyl group” include methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group and the like.
[0035]
In the present invention, examples of the “aryloxycarbonyl group” include phenoxycarbonyl and naphthyloxycarbonyl groups.
[0036]
In the present invention, the “amino group which may be substituted” means an amino group which may be substituted at any position of the amino group. Examples of the substituent include an alkyl group such as a methyl group, a tert-butyl group or a benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, and a phenyl group.
[0037]
In the present invention, the “amide group that may be substituted” means an amino group that may be substituted at any position of the amide group. Examples of the substituent include an alkyl group such as a methyl group, a tert-butyl group or a benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, and a phenyl group.
[0038]
In the present invention, the “optionally substituted heterocyclic oxy group” means a heterocyclic oxy group in which any position of the heterocyclic oxy group may be substituted. Heterocyclic oxy groups include tetrahydropyranyloxy group, tetrahydrofuranyloxy group, tetrahydrothienyloxy group, piperidyloxy group, morpholinyloxy group, piperazinyloxy group, pyrrolyloxy group, furyloxy group, thienyloxy group, Pyridyloxy group, furfuryloxy group, tenyloxy group, pyridylmethyloxy group, pyrimidyloxy group, pyrazyloxy group, imidazolyloxy group, imidazolylmethyloxy group, indolyloxy group, indolylmethyloxy group, isoquinolyloxy group Quinolyloxy group or thiazolyloxy group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0039]
The compounds contained in the general formulas (3) and (5) are exemplified in Table-1 [Table 1] to Table-2 [Table 2]. However, this does not limit the compounds of the present invention.
[0040]
[Table 1]
[Table 2]
Below, the typical manufacturing method of this invention is demonstrated.
[1] A method for producing an azole methyl ketone derivative represented by the general formula (3) will be described.
The azole methyl ketone derivative represented by the general formula (3) by reacting the azole acetic acid derivative represented by the general formula (2) with the amino acid derivative represented by the general formula (1) under basic conditions. Can be manufactured. In this reaction, an azolemethyl group can be efficiently introduced by allowing the decarboxylation reaction to proceed after or simultaneously with the carbon-carbon bond reaction. In this reaction, when the starting material is an optically active substance, a decrease in optical purity due to the reaction is hardly observed. Although there is no restriction | limiting in particular as a base which can be used, Inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, a triethylamine, a pyridine, 1, 8- diazabicycloun Organic amine bases such as decene, metal hydrides such as lithium hydride and sodium hydride, organometallic bases such as n-butyllithium, ethylmagnesium bromide, n-butylmagnesium chloride, tert-butylmagnesium chloride, or sodium amide, Examples thereof include metal amide bases such as lithium diisopropylamide and magnesium chloride diisopropylamide. Solvents that can be used are not particularly limited as long as they do not interfere with the progress of the reaction, but water, alcohol solvents such as methanol, ethanol, and butanol, hydrocarbon solvents such as hexane, toluene, xylene, and ethyl acetate. And ester solvents such as butyl acetate, ether solvents such as diethyl ether, dioxane, ethylene glycol dimethyl ether and tetrahydrofuran, halogen solvents such as chloroform and dichloromethane, acetonitrile, dimethylformamide and dimethyl sulfoxide. These solvents can be used alone or as a mixed solvent in any ratio of two or more. Regarding the reaction temperature, the reaction can be carried out from −78 ° C. to the boiling point of the solvent to be used, but preferably in the temperature range from −20 ° C. to the boiling point of the solvent. The reaction time is not particularly limited, but is in the range of several minutes to 24 hours, preferably 30 minutes to 6 hours.
[0043]
[2] A method for producing an azolemethyl alcohol derivative represented by the general formula will be described.
Producing an azole methyl alcohol derivative represented by general formula (5) by reacting an azole methyl ketone derivative represented by general formula (3) with a phenyl metal reagent represented by general formula (4) Can do. In this reaction, by combining the hydroxyl protecting group represented by R2 and the metal species represented by A, a syn or anti stereo can be created with high diastereoselectivity.
That is, an allyl metal reagent reacts in accordance with a so-called chelation model in which the carbonyl group involved in the reaction with the oxygen atom in the R2O group is fixed by metal coordination, so that the target compound has high syn diastereoselectivity Can be obtained. More specifically, it is possible to selectively produce an S—R configuration compound from an S configuration compound and an R—S configuration compound from an R configuration compound.
Further, the target product can be obtained with high anti-selectivity by sterically increasing the hydroxyl protecting group represented by R2 and selecting a metal reagent that is difficult to coordinate. More specifically, an SS configuration compound can be selectively produced from an S configuration compound, and an RR configuration compound can be selectively produced from an R configuration compound.
In this reaction, when the starting material is an optically active substance, a decrease in optical purity due to the reaction is hardly observed. Examples of phenyl metal compounds that can be used include phenyl lithium derivatives, phenyl magnesium derivatives, phenyl zinc derivatives, phenyl titanium derivatives, phenyl copper derivatives, and phenyl copper lithium derivatives. Solvents that can be used are not particularly limited as long as they do not interfere with the progress of the reaction, but water, alcohol solvents such as methanol, ethanol, and butanol, hydrocarbon solvents such as hexane, toluene, xylene, and ethyl acetate. And ester solvents such as butyl acetate, ether solvents such as diethyl ether, dioxane, ethylene glycol dimethyl ether and tetrahydrofuran, halogen solvents such as chloroform and dichloromethane, acetonitrile, dimethylformamide and dimethyl sulfoxide. These solvents can be used alone or as a mixed solvent in any ratio of two or more. Regarding the reaction temperature, it can be carried out from −78 ° C. to the boiling point of the solvent used, and is preferably in the range of −40 ° C. to room temperature. The reaction time is not particularly limited, but is in the range of several minutes to 24 hours, preferably 30 minutes to 6 hours.
[0044]
[3] A method for producing the optically active 2,3-epoxypropane derivative represented by the general formula (6) will be described.
An optically active 2,3-epoxypropane derivative represented by the general formula (6) is obtained by eliminating the amino group of the azolemethyl alcohol derivative represented by the general formula (5) and cyclizing at the adjacent hydroxyl group. Can be manufactured. The method for removing the amino group is not particularly limited as long as it does not change the other structures. The treatment can be performed by acid treatment with hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid or acetic acid, alkali treatment, treatment with various metals and metal salts, heat treatment, and the like. Furthermore, the reactivity can be increased by adding an alkyl halide and quaternizing the amino group. Solvents that can be used are not particularly limited as long as they do not interfere with the progress of the reaction, but water, alcohol solvents such as methanol, ethanol, and butanol, hydrocarbon solvents such as hexane, toluene, xylene, and ethyl acetate. And ester solvents such as butyl acetate, ether solvents such as diethyl ether, dioxane, ethylene glycol dimethyl ether and tetrahydrofuran, halogen solvents such as chloroform and dichloromethane, acetonitrile, dimethylformamide and dimethyl sulfoxide. These solvents can be used alone or as a mixed solvent in any ratio of two or more. Regarding the reaction temperature, it can be carried out from −20 ° C. to the boiling point of the solvent used. The reaction time is not particularly limited, but is in the range of several minutes to 24 hours, preferably 30 minutes to 6 hours.
[0045]
The amino acid derivative represented by the general formula (1), which is the starting material of the present invention, is easily available commercially or can be synthesized by a generally widely known method. For example, it can be synthesized from alanine by a known method (Chem. Rev. 1999, No. 99, 1121, etc.). Furthermore, the azole acetic acid derivative represented by the general formula (2) can be easily synthesized by a known method (Tetrahedron Lett., 2000, 41 (8), 1297, etc.). In addition, reagents and raw materials used that are not particularly specified as production methods are generally commercially available, and both are easily available.
[0046]
【Example】
Examples of the present invention will be described below, but the present invention is not limited by these.
Example 1 Synthesis of (3R) -3- (N, N-dibenzylamino) -1- (1H-1,2,4-triazol-1-yl) -2-butanone
To a THF suspension of 2- (1H-1,2,4-triazol-1-yl) acetic acid sodium salt (1.88 g) in a THF solution of D- (N, N-dibenzyl) alanine benzyl ester (2.0 g) Magnesium chloride (1.41 g) was added, and the mixture was stirred at room temperature for 2 hours. Then, a THF solution of magnesium bromide diisopropylamide prepared from t-butylmagnesium bromide and diisopropylamine was added dropwise under ice cooling. After dropwise addition, heating under reflux was performed for 2 hours, and the reaction solution was poured into a mixed solution of sulfuric acid (18.0 g) / water (150 ml) / ethyl acetate (225 ml) under ice-cooling and stirred at room temperature for 40 minutes. The solution was neutralized and then separated, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was isolated and purified by silica gel column chromatography to obtain the target compound in a yield of 30%.
[0047]
[Example 2] (2R, 3R) -3- (N, N-dibenzylamino) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl ) -2-Butanol
Magnesium (1.5 g) was suspended in tetrahydrofuran (25 ml) under a nitrogen atmosphere, iodine (50 mg) was added, and a solution of 2,4-difluorobromobenzene (11.0 g) / tetrahydrofuran (20 ml) was added at 25-30 ° C. It was dripped. The mixture was stirred at room temperature for 1.5 hours to obtain a solution A (49.2 g). In a separate reaction vessel, the compound obtained in Example 1 (Exemplary Compound R111; 2.45 g) was placed, dissolved in tetrahydrofuran (20 ml), and cooled to −20 ° C. Solution A (9.1 g) was added dropwise thereto at −5 ° C. or lower and stirred at −10 ° C. to 0 ° C. for 1 hour and at 0 ° C. to 10 ° C. for 2 hours. The reaction solution was cooled to 5 ° C., and adjusted to pH 8 by adding 1N hydrochloric acid (9 ml). After stirring at 5 ° C. to 10 ° C. for 30 minutes, ethyl acetate and water were added for extraction, and the organic layer was washed with a saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent is concentrated under reduced pressure, and the resulting residue is isolated and purified by silica gel column chromatography to obtain the target compound with diastereoselectivity anti in a yield of 50%. It was.
[0048]
Example 3 (2R, 3R) -2,3-Epoxy-2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butane
(2R, 3R) -3- (N, N-dibenzylamino) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) synthesized above ) -2-Butanol and methyl iodide were heated and stirred in DMF at 60 ° C., cooled, made alkaline with an aqueous sodium hydroxide solution, and allowed to stand overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was isolated and purified by silica gel column chromatography to obtain the target compound in a yield of 40%.
[0049]
Example 4 (2R, 3R) -3-Amino-2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol
(2R, 3R) -3- (N, N-dibenzylamino) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1-) synthesized in Example 2 Yl) -2-butanol was dissolved in methanol, and hydrogenation was performed using 10% Pd / C as a catalyst. After the absorption of hydrogen stopped, the catalyst was filtered, the solvent was concentrated under reduced pressure, and the residue was purified by a silica gel column to obtain the debenzylated title compound in a yield of 85%.
[0050]
【The invention's effect】
According to the production method of the present invention, it is a useful compound in the field of medicine and agrochemicals, and particularly for the production of an optically active 2,3-epoxypropane derivative which can be an extremely important intermediate in the production process of a novel azole antifungal agent. From an industrial point of view, it has become possible to manufacture stably and inexpensively in a short process.
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