JP2018525376A - Novel process for producing chromanol derivatives - Google Patents
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- 238000000034 method Methods 0.000 title abstract description 11
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical class O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 title abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000006722 reduction reaction Methods 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 49
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 28
- 239000003054 catalyst Substances 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 14
- 235000019253 formic acid Nutrition 0.000 claims description 14
- 239000000852 hydrogen donor Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 abstract description 14
- 238000000746 purification Methods 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- -1 chromanol derivative compound Chemical class 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- HGTYMLFMXKYIQW-SSDOTTSWSA-N (4r)-5,7-difluoro-3,4-dihydro-2h-chromen-4-ol Chemical compound FC1=CC(F)=C2[C@H](O)CCOC2=C1 HGTYMLFMXKYIQW-SSDOTTSWSA-N 0.000 description 3
- HGTYMLFMXKYIQW-ZETCQYMHSA-N (4s)-5,7-difluoro-3,4-dihydro-2h-chromen-4-ol Chemical compound FC1=CC(F)=C2[C@@H](O)CCOC2=C1 HGTYMLFMXKYIQW-ZETCQYMHSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OJVRCPGUGZXUAP-UHFFFAOYSA-N 5,7-difluoro-2,3-dihydrochromen-4-one Chemical compound O=C1CCOC2=CC(F)=CC(F)=C21 OJVRCPGUGZXUAP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FVOOPOSZDXPIMS-SECBINFHSA-N (2r)-3,4-dihydro-2h-chromen-2-ol Chemical compound C1=CC=C2O[C@@H](O)CCC2=C1 FVOOPOSZDXPIMS-SECBINFHSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HGTYMLFMXKYIQW-UHFFFAOYSA-N 5,7-difluoro-3,4-dihydro-2h-chromen-4-ol Chemical compound FC1=CC(F)=C2C(O)CCOC2=C1 HGTYMLFMXKYIQW-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/46—Ruthenium, rhodium, osmium or iridium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pyrane Compounds (AREA)
- Catalysts (AREA)
Abstract
本発明は、クロマノール誘導体の新規な製造方法に関する。本発明に係る光学活性を有するクロマノール誘導体の製造方法は、従来知られている光学活性還元反応技術とは異なり、製造されるクロマノールが高い光学純度を示し、別途の精製工程を必要とせず、過酷な反応条件を含まず、危険な試薬を用いないため、大量生産に有利であり、製造収率にも優れている。The present invention relates to a novel method for producing a chromanol derivative. Unlike the conventionally known optically active reduction reaction technique, the method for producing an optically active chromanol derivative according to the present invention exhibits high optical purity, requires no separate purification step, and is harsh. The reaction conditions are not included and no dangerous reagents are used, which is advantageous for mass production and excellent production yield.
Description
本明細書は、２０１５年８月４日に韓国特許庁に提出された韓国特許出願第１０−２０１５−０１１０２４８号の出願日の利益を主張し、その内容のすべては本明細書に含まれる。 This specification claims the benefit of the filing date of Korean Patent Application No. 10-2015-0110248 filed with the Korean Patent Office on August 4, 2015, the entire contents of which are included in this specification.
本発明は、光学活性を有するクロマノール誘導体の新規な製造方法に関する。 The present invention relates to a novel method for producing a chromanol derivative having optical activity.
キラルクロマノール（ｃｈｒｏｍａｎｏｌ）誘導体化合物は、医薬及び化学分野で様々な活性を有する物質であって、現在開発中の医薬品などにおいてもキラルクロマノール構造の化合物は数多く存在する。ところで、同じ分子式を有するクロマノール誘導体化合物であっても、いかなる３次元立体構造を有するかによって、その薬効には非常にばらつきがある。したがって、キラルクロマノール誘導体化合物を立体選択的に合成することは、医薬合成及び有機合成において非常に重要である。しかし、キラルクロマノール誘導体化合物の重要性にもかかわらず、キラルクロマノール誘導体化合物を容易に合成する方法はあまり報告されていない。 A chiral chromanol derivative compound is a substance having various activities in the pharmaceutical and chemical fields, and there are many compounds having a chiral chromanol structure in pharmaceuticals currently under development. By the way, even if a chromanol derivative compound having the same molecular formula is used, its medicinal effect varies greatly depending on what three-dimensional structure it has. Therefore, the stereoselective synthesis of chiral chromanol derivative compounds is very important in pharmaceutical synthesis and organic synthesis. However, despite the importance of chiral chromanol derivative compounds, few methods for easily synthesizing chiral chromanol derivative compounds have been reported.
国際公報ＷＯ２００７／０７２１４６には、５，７−ジフルオロクロマン−４−オンを出発物質として用いて５，７−ジフルオロクロマン−４−オールを製造する方法が記載されている。しかし、前記特許に記載の製造方法は、１次結晶化工程で８６％ｅｅ値の低い光学立体選択性を有し、光学立体選択性を増加させるために精製工程が必ず必要であると明記されている。このような理由から、前記特許に記載の方法は、製造コストが高く、さらなる精製工程を必要とするにもかかわらず、５８％という非常に低い収率を有する。また、１次固体化分離のためにシリカゲル相のカラムクロマトグラフィーを行うため、大量生産工程には適していないといった問題がある。 International Publication WO2007 / 072146 describes a process for producing 5,7-difluorochroman-4-ol using 5,7-difluorochroman-4-one as a starting material. However, the manufacturing method described in the above patent has a low optical stereoselectivity of 86% ee in the primary crystallization process, and it is clearly stated that a purification process is absolutely necessary to increase the optical stereoselectivity. ing. For this reason, the process described in said patent has a very low yield of 58% despite the high production costs and the need for further purification steps. In addition, since silica gel column chromatography is performed for primary solid separation, there is a problem that it is not suitable for mass production processes.
よって、医薬及び化学分野において非常に重要なファーマコフォアとして知られている、光学活性を有するクロマノール誘導体を、高純度の光学品質かつ高収率で、産業的に大量生産することができる、新規な製造方法が求められている。 Therefore, a novel optically active chromanol derivative known as a very important pharmacophore in the pharmaceutical and chemical fields can be industrially mass-produced with high optical quality and high yield. New manufacturing methods are required.
国際公開特許第２００７／０７２１４６号 International Patent Publication No. 2007/072146
本発明は、高い光学純度を示し、別途の精製工程を必要とせず、生産工程において危険な試薬を用いず、生産収率に優れた、クロマノール誘導体の製造方法を提供する。 The present invention provides a method for producing a chromanol derivative that exhibits high optical purity, does not require a separate purification step, does not use a dangerous reagent in the production step, and has an excellent production yield.
本発明は、
下記化学式IIで表される化合物を、下記化学式III又は化学式IVで表される触媒下においてキラル還元反応させ、下記化学式Iで表される化合物を製造するステップを含む、化学式Iで表される化合物の製造方法を提供する。
［化学式I］
A compound represented by Formula I, comprising a step of producing a compound represented by Formula I below by subjecting a compound represented by Formula II below to a chiral reduction reaction in the presence of a catalyst represented by Formula III or Formula IV below. A manufacturing method is provided.
[Chemical Formula I]
本発明の前記製造方法は、従来知られている光学活性還元反応技術とは異なり、製造されるクロマノールが高い光学純度を示し、別途の精製工程を必要とせず、過酷な反応条件を含まず、危険な試薬を用いないため、大量生産に有利であり、製造収率にも優れている。 In the production method of the present invention, unlike the conventionally known optically active reduction reaction technique, the produced chromanol exhibits high optical purity, does not require a separate purification step, does not include severe reaction conditions, Since no dangerous reagent is used, it is advantageous for mass production and excellent in production yield.
前記化学式Iで表される化合物を製造するステップは、前記化学式III又はIVの触媒を用いたキラル還元反応（Ｃｈｉｒａｌ ｒｅｄｕｃｔｉｏｎ）として、前記化学式IIで表される化合物と水素供与体とを前記化学式III又は化学式IVで表される触媒下において反応させ、選択的に光学活性を有する前記化学式Ｉで表される化合物を製造する。 The step of preparing the compound represented by the chemical formula I includes, as a chiral reduction reaction using the catalyst of the chemical formula III or IV, the compound represented by the chemical formula II and a hydrogen donor as the chemical formula III. Alternatively, the reaction is carried out in the presence of a catalyst represented by the chemical formula IV to produce a compound represented by the chemical formula I having selective optical activity.
ここで、前記化学式IIで表される化合物と化学式III又は化学式IVで表される触媒との反応モル比は、１：０．０００１〜１：０．１であってもよく、好ましくは、０．００５〜０．００１である。 Here, the reaction molar ratio of the compound represented by Formula II and the catalyst represented by Formula III or Formula IV may be 1: 0.0001 to 1: 0.1, preferably 0. 0.005 to 0.001.
本発明において、前記化学式Iで表される化合物を製造するステップにおける反応溶媒は、業界で広く用いられる有機溶媒を用いてもよい。例えば、ジクロロメタン、クロロホルム、１，２−ジクロロエタンのようなハロゲン化された炭化水素；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、及びジオキサンのようなエーテル；ベンゼン、トルエン、及びニトロベンゼンのような芳香族炭化水素；ジメチルスルホキシドのようなスルホキシド；ジメチルホルムアミドのようなギ酸アミド；メタノール、エタノール、２−プロパノール、及びブタノールのようなアルコール；又はこれらの混合溶媒であってもよいが、必ずしもこれに限定されるものではない。本発明において、前記化学式Iで表される化合物を製造するステップの反応溶媒は、業界で広く用いられる無極性有機溶媒が好ましく、より好ましくは、テトラヒドロフランである。 In the present invention, an organic solvent widely used in the industry may be used as the reaction solvent in the step of producing the compound represented by Formula I. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and nitrobenzene; It may be a sulfoxide such as dimethyl sulfoxide; a formic acid amide such as dimethylformamide; an alcohol such as methanol, ethanol, 2-propanol, and butanol; or a mixed solvent thereof, but is not necessarily limited thereto. Absent. In the present invention, the reaction solvent in the step of producing the compound represented by Formula I is preferably a nonpolar organic solvent widely used in the industry, more preferably tetrahydrofuran.
本発明の水素供与体は、ギ酸、ギ酸の金属塩、ギ酸のアンモニウム塩、及びギ酸とアミンとの混合物の中から選択してもよい。好ましくは、前記水素供与体は、ギ酸とアミンとの混合物であり、より好ましくは、トリエチルアミン（ＴＥＡ）及びギ酸、又はジイソプロピルエチルアミン（ＤＩＰＥＡ）及びギ酸である。 The hydrogen donor of the present invention may be selected from formic acid, metal salts of formic acid, ammonium salts of formic acid, and mixtures of formic acid and amines. Preferably, the hydrogen donor is a mixture of formic acid and amine, more preferably triethylamine (TEA) and formic acid, or diisopropylethylamine (DIPEA) and formic acid.
前記化学式Iで表される化合物を製造するステップにおいて、化学式IIで表される化合物の化学式III又は化学式IVで表される触媒下におけるキラル還元反応は、２５℃〜８０℃で行ってもよく、好ましくは、３０℃〜５０℃で行われる。これより低い温度だと反応時間が長くなり過ぎるし、これより高い温度だと光学純度（ｃｈｉｒａｌ ｐｕｒｉｔｙ）が低くなり過ぎるため、商業的生産には適さない。 In the step of producing the compound represented by the chemical formula I, the chiral reduction reaction of the compound represented by the chemical formula II under the catalyst represented by the chemical formula III or the chemical formula IV may be performed at 25 ° C. to 80 ° C., Preferably, it is performed at 30 ° C to 50 ° C. If the temperature is lower than this, the reaction time becomes too long, and if it is higher than this, the optical purity becomes too low, which is not suitable for commercial production.
前記化学式Iで表される化合物を製造するステップは、結晶化溶媒を用いて結晶化するステップをさらに含んでもよい。前記結晶化溶媒は、化合物を結晶化するためのものであって、ヘキサン、ヘプタンのようなＣ６〜７の脂肪族炭化水素；ジエチルエーテル、ジイソプロピルエーテルのようなエーテル；又はこれらの混合溶媒などが用いられてもよい。好ましくは、ヘキサン、ヘプタンのようなＣ６〜７の脂肪族炭化水素が用いられる。 The step of producing the compound represented by Formula I may further include a step of crystallization using a crystallization solvent. The crystallization solvent is for crystallization of a compound, and is a C 6-7 aliphatic hydrocarbon such as hexane or heptane; an ether such as diethyl ether or diisopropyl ether; or a mixed solvent thereof. May be used. Preferably, C 6-7 aliphatic hydrocarbons such as hexane and heptane are used.
本発明は、
下記化学式IIで表される化合物と水素供与体とを下記化学式III又は化学式IVで表される触媒下において反応させ、下記化学式Iで表される化合物を製造するステップを含む、化学式Iで表される化合物の製造方法を提供する。
［化学式I］
A compound represented by the following chemical formula II and a hydrogen donor are reacted under a catalyst represented by the following chemical formula III or chemical formula IV to produce a compound represented by the following chemical formula I. A method for producing the compound is provided.
[Chemical Formula I]
本発明の一実施態様によると、本発明は、化学式IIで表される化合物を化学式IIIで表される触媒下においてキラル還元反応させ、下記化学式I−１で表される化合物を製造するステップを含む、化学式I−１で表される化合物の製造方法を提供する。
［化学式I−１］（Ｒ）−５，７−ジフルオロクロマン−４−オール
[Chemical Formula I-1] (R) -5,7-difluorochroman-4-ol
本発明の別の実施態様によると、本発明は、化学式IIで表される化合物を化学式IVで表される触媒下においてキラル還元反応させ、下記化学式I−２で表される化合物を製造するステップを含む、化学式I−２で表される化合物の製造方法を提供する。
［化学式I−２］（Ｓ）−５，７−ジフルオロクロマン−４−オール
[Chemical formula I-2] (S) -5,7-difluorochroman-4-ol
前記のように、本発明に係る製造方法によって、化学式IIの化合物を化学式III又は化学式IVの触媒の存在下において水素供与体とキラル還元反応させると、化学式I−１又は化学式I−２の高い光学活性を有するクロマノール化合物を製造することができる。 As described above, when the compound of formula II is subjected to a chiral reduction reaction with a hydrogen donor in the presence of a catalyst of formula III or IV by the production method according to the present invention, a high formula I-1 or formula I-2 is obtained. A chromanol compound having optical activity can be produced.
例えば、本発明に係る化学式Iで表される化合物の製造方法は、下記反応式Ｉで表すことができる。
［反応式I］
[Reaction Formula I]
前記反応式Iのように、化学式III又は化学式IVで表されるルテニウム触媒下において、有機溶媒下の化学式IIの化合物を水素供与体と反応させ、化学式Iの化合物を製造することができる。 Like the above reaction formula I, the compound of the chemical formula II can be produced by reacting the compound of the chemical formula II in an organic solvent with a hydrogen donor under a ruthenium catalyst represented by the chemical formula III or the chemical formula IV.
本発明の一実施態様によると、下記反応式I−１のように、化学式IIIで表されるルテニウム触媒下において、化学式IIの化合物を水素供与体と反応させ、化学式I−１の化合物を製造することができる。
［反応式I−１］
[Reaction Formula I-1]
本発明の別の実施態様によると、下記反応式I−２のように、化学式IVで表される触媒下において、化学式IIの化合物を水素供与体と反応させ、化学式I−２の化合物を製造することができる。
［反応式I−２］
[Reaction Formula I-2]
本発明に係る光学活性を有するクロマノール誘導体の製造方法は、従来知られている光学活性還元反応技術とは異なり、製造されるクロマノールが高い光学純度を示し、別途の精製工程を必要とせず、過酷な反応条件を含まず、危険な試薬を用いないため、大量生産に有利であり、製造収率にも優れているという長所も有する。 Unlike the conventionally known optically active reduction reaction technique, the method for producing an optically active chromanol derivative according to the present invention exhibits high optical purity, requires no separate purification step, and is harsh. This method is advantageous in mass production because it does not include any unfavorable reaction conditions and does not use dangerous reagents, and also has an advantage of excellent production yield.
また、前記製造方法によって製造される最終生成物は、光学活性を有するクロマノール構造を有する他の化合物を製造するのに用いることができ、特に、抗菌剤、抗潰瘍剤、抗炎症薬として使用可能な化合物の製造における中間体として用いることができる。 In addition, the final product produced by the production method can be used to produce other compounds having an optically active chromanol structure, and can be used particularly as an antibacterial agent, antiulcer agent, or anti-inflammatory agent. It can be used as an intermediate in the production of such compounds.
以下、下記実施例及び実験例により、本発明をより詳細に説明する。しかし、下記実施例及び実験例は、本発明を例示するためのものであって、これら実施例及び実験例により本発明の範囲が限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are for illustrating the present invention, and the scope of the present invention is not limited by these examples and experimental examples.
以下に記載の試薬及び溶媒は、特別な言及がない限り、Ｓｉｇｍａ Ａｌｄｒｉｃｈから購入したものであり、１Ｈ−ＮＭＲは、Ｂｒｕｋｅｒ ＮＭＲ ２７０ＭＨｚで測定し、光学活性は、Ｒｕｄｏｌｐｈ ｒｅｓｅａｒｃｈ ａｎａｌｙｔｉｃａｌ ａｕｔｏＶで測定した。 Reagents and solvents described below were purchased from Sigma Aldrich unless otherwise noted, 1 H-NMR was measured with Bruker NMR 270 MHz, and optical activity was measured with Rudolph research analytical autoV.
実施例１：（Ｒ）−５，７−ジフルオロクロマン−４−オールの製造
反応器にトリエチルアミン３０ｇを投入し、−１０℃に冷却した。ここにギ酸２７ｇを１０℃以下でゆっくりと投入した。ルテニウム触媒ＲｕＣｌ（ｐ−ｃｙｍｅｎｅ）［（Ｒ，Ｒ）−Ｔｓ−ＤＰＥＮ］５６ｍｇを投入した。５，７−ジフルオロクロマン−４−オン３３ｇをテトラヒドロフラン８７ｇに溶解し、反応器に１０℃以下で投入した。４０℃に昇温して反応させた。反応が終わった後、室温に冷却し、酢酸エチル２９３ｇと精製水１６３ｇを投入して攪拌した後、有機層を分離した。４０℃以下で減圧濃縮し、ヘプタン２２２ｇを投入して２５℃で攪拌した後、生成された固体をろ過した。４０℃で真空乾燥し、（Ｒ）−５，７−ジフルオロクロマン−４−オール（３０ｇ、９１％、１００％ｅｅ）を得た。
１Ｈ−ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ３）：δ：６．４７−６．３６（ｍ，２Ｈ），５．０５−４．９７（ｍ，１Ｈ），４．３６−４．２０（ｍ，２Ｈ），２．１６−１．９２（ｍ，３Ｈ）ｐｐｍ
光学回転：［α］Ｄ ２４＝＋１４３．６°（ｃ＝１．００，メタノール）
Example 1: Production of (R) -5,7-difluorochroman-4-ol 30 g of triethylamine was charged into a reactor and cooled to -10 ° C. 27 g of formic acid was slowly added thereto at 10 ° C. or lower. Ruthenium catalyst RuCl (p-cymene) [(R, R) -Ts-DPEN] 56 mg was added. 33 g of 5,7-difluorochroman-4-one was dissolved in 87 g of tetrahydrofuran and charged into the reactor at 10 ° C. or lower. The temperature was raised to 40 ° C. to react. After completion of the reaction, the reaction mixture was cooled to room temperature, 293 g of ethyl acetate and 163 g of purified water were added and stirred, and then the organic layer was separated. After concentration under reduced pressure at 40 ° C. or lower, 222 g of heptane was added and stirred at 25 ° C., and then the produced solid was filtered. Vacuum drying at 40 ° C. gave (R) -5,7-difluorochroman-4-ol (30 g, 91%, 100% ee).
1 H-NMR (270 MHz, CDCl 3 ): δ: 6.47-6.36 (m, 2H), 5.05-4.97 (m, 1H), 4.36-4.20 (m, 2H) ), 2.16-1.92 (m, 3H) ppm
Optical rotation: [α] D 24 = + 143.6 ° (c = 1.00, methanol)
実施例２：（Ｓ）−５，７−ジフルオロクロマン−４−オールの製造
反応器にトリエチルアミン３０ｇを投入し、−１０℃に冷却した。ここにギ酸２７ｇを１０℃以下でゆっくりと投入した。ルテニウム触媒ＲｕＣｌ（ｐ−ｃｙｍｅｎｅ）［（Ｓ，Ｓ）−Ｔｓ−ＤＰＥＮ］５６ｍｇを投入した。５，７−ジフルオロクロマン−４−オン３３ｇをテトラヒドロフラン８７ｇに溶解し、反応器に１０℃以下で投入した。４０℃に昇温して反応させた。反応が終わった後、２５℃に冷却し、酢酸エチル２９３ｇと精製水１６３ｇを投入して攪拌した後、有機層を分離した。４０℃以下で減圧濃縮し、ヘプタン２２２ｇを投入して２５℃で攪拌した後、生成された固体をろ過した。４０℃で真空乾燥し、（Ｓ）−５，７−ジフルオロクロマン−４−オール（２８ｇ、８５％、１００％ｅｅ）を得た。
１Ｈ−ＮＭＲ：スペクトルデータは、（Ｒ）−クロマノール（実施例１）のデータと同じであった。
光学回転：［α］Ｄ ２４＝−１４３．６°（ｃ＝１．００，メタノール）
Example 2: Production of (S) -5,7-difluorochroman-4-ol 30 g of triethylamine was charged into a reactor and cooled to -10 ° C. 27 g of formic acid was slowly added thereto at 10 ° C. or lower. Ruthenium catalyst RuCl (p-cymene) [(S, S) -Ts-DPEN] 56 mg was added. 33 g of 5,7-difluorochroman-4-one was dissolved in 87 g of tetrahydrofuran and charged into the reactor at 10 ° C. or lower. The temperature was raised to 40 ° C. to react. After the reaction was completed, the mixture was cooled to 25 ° C., 293 g of ethyl acetate and 163 g of purified water were added and stirred, and then the organic layer was separated. After concentration under reduced pressure at 40 ° C. or lower, 222 g of heptane was added and stirred at 25 ° C., and then the produced solid was filtered. Vacuum drying at 40 ° C. gave (S) -5,7-difluorochroman-4-ol (28 g, 85%, 100% ee).
1 H-NMR: The spectral data were the same as those for (R) -chromanol (Example 1).
Optical rotation: [α] D 24 = −143.6 ° (c = 1.00, methanol)
Claims (9)
［化学式I］
[Chemical Formula I]
［化学式I−１］
[Chemical Formula I-1]
［化学式I−２］
[Chemical formula I-2]
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