WO2017023124A1 - Novel method for preparing chromanol derivative - Google Patents
Novel method for preparing chromanol derivative Download PDFInfo
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- WO2017023124A1 WO2017023124A1 PCT/KR2016/008580 KR2016008580W WO2017023124A1 WO 2017023124 A1 WO2017023124 A1 WO 2017023124A1 KR 2016008580 W KR2016008580 W KR 2016008580W WO 2017023124 A1 WO2017023124 A1 WO 2017023124A1
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 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 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 21
- 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 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000006722 reduction reaction Methods 0.000 claims description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group 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 8
- 239000000203 mixture Substances 0.000 claims description 6
- 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 16
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 11
- 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- -1 chromanol) derivative compound Chemical class 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 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 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 229940079593 drug Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 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 2
- 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 2
- 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
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction 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
- VXXGFSJYTWNBBS-QMMMGPOBSA-N CO[C@@H](CCOc1cc(F)c2)c1c2F Chemical compound CO[C@@H](CCOc1cc(F)c2)c1c2F VXXGFSJYTWNBBS-QMMMGPOBSA-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 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
- 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 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
Definitions
- the present invention relates to a novel process for preparing chromamanol derivatives having optical activity.
- Chiral chromanol (chromanol) derivative compound is a substance having a variety of activities in medicine and chemistry, and there are many chiral chromanol structural compounds in the currently developed medicines.
- the drug efficacy is often very different depending on the three-dimensional conformation. Therefore, stereoselective synthesis of chiral chromanol derivative compounds is of great importance in medicinal and organic synthesis.
- many methods for easily synthesizing chiral chromanol derivative compounds have not been reported.
- the present invention shows a high optical purity, does not require a separate purification process, and provides a method for producing a chromamanol derivative having an excellent production yield without using a dangerous reagent in the production process.
- It provides a method for producing a compound represented by the formula (I) comprising the step of preparing a compound represented by the formula (I) by chiral reduction reaction of the compound represented by the formula (II) under a catalyst represented by the formula (III) or (IV).
- * represents a Chiral center
- the preparation method of the present invention exhibits high optical purity, which does not require a separate purification process, does not include harsh reaction conditions, and does not use dangerous reagents. It is advantageous for mass production and has a good production yield.
- the preparing of the compound represented by Chemical Formula I is a chiral reduction reaction using the catalyst of Chemical Formula III or 4, wherein the compound represented by Chemical Formula II and the hydrogen donor are represented by Chemical Formula III or Chemical IV.
- the reaction is carried out under a catalyst to prepare a compound represented by the above formula (I) having selectively optical activity.
- 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 0.005 to 0.001.
- the reaction solvent in the step of preparing the compound represented by the formula (I) may be used an organic solvent widely used in the industry.
- Halogenated hydrocarbons such as, but not limited to, dichloromethane, chloroform, 1,2-dichloroethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and nitrobenzene; Sulfoxides such as dimethyl sulfoxide; Formic acid amide, such as dimethylformamide; Alcohols such as methanol, ethanol, 2-propanol and butanol; Or a mixed solvent thereof.
- the reaction solvent in the step of preparing the compound represented by the formula (I) may be preferably a non-polar organic solvent widely used in the industry, more preferably, may be tetrahydrofuran.
- 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.
- the hydrogen donor may be a mixture of formic acid and amine, more preferably triethylamine (TEA) and formic acid, or diisopropylethylamine (DIPEA) and formic acid.
- TEA triethylamine
- DIPEA diisopropylethylamine
- the chiral reduction reaction of the compound represented by Chemical Formula II or Chemical Formula IV may be performed at 25 ° C. to 80 ° C., preferably at 30 ° C. to 50 ° C. have.
- a lower temperature is unsuitable for commercial production because the reaction time is too long, and a high temperature results in too low chiral purity.
- the preparing of the compound represented by Chemical Formula I may further include performing crystallization with a crystallization solvent.
- the crystallization solvent is for the crystallization of the compound, hexane, aliphatic hydrocarbons, C 6 ⁇ 7, such as heptane; Ethers such as diethyl ether and diisopropyl ether; Or mixed solvents thereof may be used.
- hexane it may be used aliphatic hydrocarbons, C 6 ⁇ 7, such as heptane.
- It provides a method of preparing a compound represented by the formula (I) comprising the step of reacting a compound represented by the formula (II) and a hydrogen donor under a catalyst represented by the formula (III) or (IV) .
- * represents a Chiral center
- the present invention provides a compound of formula I-1 comprising chiral reduction of a compound represented by formula II under a catalyst represented by formula III to prepare a compound represented by formula I-1. It provides a method for producing the compound represented.
- the present invention provides a compound of formula I-2 comprising chiral reduction of a compound represented by formula II under a catalyst represented by formula IV to produce a compound represented by formula I-2 It provides a method for producing the compound represented.
- a compound of Formula I may be prepared by reacting a compound of Formula II with a hydrogen donor in an organic solvent under a ruthenium catalyst represented by Formula III or Formula IV.
- a compound of formula (I-1) may be prepared by reacting a compound of formula (II) with a hydrogen donor under a ruthenium catalyst represented by formula (III) as in Scheme I-1.
- the compound of formula (II) may be prepared by reacting the compound of formula (II) with a hydrogen donor under the catalyst represented by formula (IV), as in Scheme I-2.
- the method for preparing an optically active chromamanol derivative according to the present invention does not require a separate purification process because it shows high optical purity and does not include harsh reaction conditions. And because it does not use dangerous reagents, it is advantageous for mass production and has a good production yield.
- the final product prepared by the preparation method can be used to prepare other compounds having a chromamanol structure having an optical activity, in particular as an intermediate for the preparation of compounds that can be used as antibacterial, anti-ulcer, anti-inflammatory drugs Can be used.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Pyrane Compounds (AREA)
Abstract
The present invention relates to a novel method for preparing a chromanol derivative. According to the present invention, unlike a conventionally known optically active reduction technique, a method for preparing a chromanol derivative having optical activity has advantages of: not needing an additional purification process since chromanol, to be prepared, exhibits a high optical purity; being favorable for mass production since no severe reaction conditions are contained and no dangerous reagents are used; and having an excellent preparation yield.
Description
본 명세서는 2015년 8월 4일에 한국특허청에 제출된 한국 특허 출원 제 10-2015-0110248호의 출원일의 이익을 주장하며, 그 내용 전부는 본 명세서에 포함된다. This specification claims the benefit of the application date of Korean Patent Application No. 10-2015-0110248 filed with the Korea Intellectual Property Office on August 4, 2015, the entire contents of which are incorporated herein.
본 발명은 광학 활성을 가지는 크로마놀 유도체의 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for preparing chromamanol derivatives having optical activity.
키랄 크로마놀(chromanol) 유도체 화합물은 의약 및 화학 분야에서 다양한 활성을 가지는 물질로써, 현재 개발 중인 의약품 등에서도 키랄 크로마놀 구조 화합물이 많이 존재한다. 그런데, 동일한 분자식을 가진 크로마놀 유도체 화합물이라도 3차원 입체구조에 따라 약효가 매우 다르게 나타나는 경우가 많다. 그러므로 키랄 크로마놀 유도체 화합물을 입체선택적으로 합성하는 것은 의약합성 및 유기합성에서 대단히 중요하다. 그러나, 키랄 크로마놀 유도체 화합물의 중요성에도 불구하고, 키랄 크로마놀 유도체 화합물을 손쉽게 합성하는 방법은 많이 보고되고 있지 않다. Chiral chromanol (chromanol) derivative compound is a substance having a variety of activities in medicine and chemistry, and there are many chiral chromanol structural compounds in the currently developed medicines. However, even in the case of a chromamanol derivative compound having the same molecular formula, the drug efficacy is often very different depending on the three-dimensional conformation. Therefore, stereoselective synthesis of chiral chromanol derivative compounds is of great importance in medicinal and organic synthesis. However, despite the importance of chiral chromanol derivative compounds, many methods for easily synthesizing chiral chromanol derivative compounds have not been reported.
국제공보 WO 2007/072146에는 5,7-디플루오로크로만-4-온을 출발물질로 사용하여 5,7-디플루오로크로만-4-올을 제조하는 방법이 기재되어 있다. 그러나 상기 특허에 기재된 제조방법은 1차 결정화 공정에서 86 %ee 값의 낮은 광학 입체 선택성을 가지며 광학 입체 선택성을 증가 시키기 위해 정제공정이 반드시 필요하다고 명기되어 있다. 이러한 이유로 상기 특허에 기재되어 있는 방법은 제조 단가가 높으며 추가된 정제 공정에도 불구하고 58%의 매우 낮은 수득률을 가진다. 또한 1차 고체화 분리에 실리카겔 상에서의 컬럼 크로마토그래피를 사용함으로 인하여 대량생산의 공정에는 적합하지 않은 문제점이 있다.International publication WO 2007/072146 describes a process for preparing 5,7-difluorochroman-4-ol using 5,7-difluorochroman-4-one as starting material. However, the manufacturing method described in the patent has a low optical stereoselectivity of 86% ee value in the primary crystallization process, it is specified that the purification process is necessary to increase the optical stereoselectivity. For this reason the process described in this patent is expensive to manufacture and has a very low yield of 58% despite the added purification process. In addition, due to the use of column chromatography on silica gel for primary solidification separation, there is a problem that is not suitable for mass production processes.
이에 따라, 의약 및 화학분야에서 매우 중요한 약물 특이 분자단으로 알려진 광학활성을 갖는 크로마놀 유도체를 고순도의 광학품질 및 고수율로 산업적으로 대량생산할 수 있는 신규한 제조방법이 필요한 실정이다.Accordingly, there is a need for a novel manufacturing method capable of industrially mass-producing chromamanol derivatives having optical activity, which are known as drug specific molecular groups, which are very important in medicine and chemical fields, with high optical quality and high yield.
[선행기술문헌][Preceding technical literature]
[특허문헌][Patent Documents]
국제공개특허 제2007/072146호International Publication No. 2007/072146
본 발명은 높은 광학순도를 나타내어 별도의 정제 공정이 필요하지 않으며, 생산공정에 위험한 시약을 사용하지 않고, 생산 수율이 우수한 크로마놀 유도체의 제조방법을 제공한다.The present invention shows a high optical purity, does not require a separate purification process, and provides a method for producing a chromamanol derivative having an excellent production yield without using a dangerous reagent in the production process.
본 발명은, The present invention,
하기 화학식 Ⅱ로 표시되는 화합물을 하기 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법을 제공한다. It provides a method for producing a compound represented by the formula (I) comprising the step of preparing a compound represented by the formula (I) by chiral reduction reaction of the compound represented by the formula (II) under a catalyst represented by the formula (III) or (IV).
[화학식 Ⅰ][Formula I]
[화학식 Ⅱ] [Formula II]
[화학식 Ⅲ][Formula III]
[화학식 Ⅳ][Formula IV]
상기 화학식 Ⅰ에서 *는 Chiral center를 나타낸다.In Formula I, * represents a Chiral center.
본 발명의 상기 제조 방법은 종래 알려진 광학 활성 환원반응 기술과 달리, 제조되는 크로마놀이 높은 광학순도를 나타내어 별도의 정제 공정을 필요로 하지 않으며, 혹독한 반응 조건을 포함하지 않고 위험한 시약을 사용하지 않기 때문에 대량생산에 유리하고 제조수율 또한 우수한 장점을 가진다. Unlike the conventionally known optically active reduction reaction technology, the preparation method of the present invention exhibits high optical purity, which does not require a separate purification process, does not include harsh reaction conditions, and does not use dangerous reagents. It is advantageous for mass production and has a good production yield.
상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계는 상기 화학식 Ⅲ 또는 4의 촉매를 이용한 키랄 환원 반응(Chiral reduction)으로서, 상기 화학식 Ⅱ로 표시되는 화합물과 수소 공여체를 상기 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매하에 반응시켜 선택적으로 광학 활성을 가지는 상기 화학식 Ⅰ로 표시되는 화합물을 제조한다. The preparing of the compound represented by Chemical Formula I is a chiral reduction reaction using the catalyst of Chemical Formula III or 4, wherein the compound represented by Chemical Formula II and the hydrogen donor are represented by Chemical Formula III or Chemical IV. The reaction is carried out under a catalyst to prepare a compound represented by the above formula (I) having selectively optical activity.
이 때 상기 화학식 Ⅱ으로 표시되는 화합물과 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매의 반응 몰비는 1:0.0001 내지 1:0.1일 수 있으며, 바람직하게, 0.005 내지 0.001 일 수 있다. At this time, 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 0.005 to 0.001.
본 발명에 있어서, 상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계의 반응용매는 업계에서 널리 사용되는 유기용매가 사용될 수 있다. 예컨대, 이에 제한되지 않으나, 디클로로메탄, 클로로폼, 1,2-디클로로에탄 같은 할로겐화된 탄화수소; 디에틸에테르, 디이소프로필에테르, 테트라히드로푸란 및 디옥산 같은 에테르; 벤젠, 톨루엔 및 니트로벤젠 같은 방향족 탄화수소; 디메틸 설폭시드 같은 설폭시드; 디메틸포름아미드 같은 포름산아미드; 메탄올, 에탄올, 2-프로판올 및 부탄올 같은 알코올; 또는 이들의 혼합 용매일 수 있다. 본 발명에 있어서, 상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계의 반응용매는 업계에서 널리 사용되는 무극성 유기용매가 바람직할 수 있으며, 더욱 바람직하게, 테트라하이드로푸란일 수 있다. In the present invention, the reaction solvent in the step of preparing the compound represented by the formula (I) may be used an organic solvent widely used in the industry. Halogenated hydrocarbons such as, but not limited to, dichloromethane, chloroform, 1,2-dichloroethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and nitrobenzene; Sulfoxides such as dimethyl sulfoxide; Formic acid amide, such as dimethylformamide; Alcohols such as methanol, ethanol, 2-propanol and butanol; Or a mixed solvent thereof. In the present invention, the reaction solvent in the step of preparing the compound represented by the formula (I) may be preferably a non-polar organic solvent widely used in the industry, more preferably, may be tetrahydrofuran.
본 발명의 수소공여체는 포름산, 포름산의 금속염, 포름산의 암모늄염, 및 포름산과 아민의 혼합물 중에서 선택될 수 있다. 바람직하게 상기 수소 공여체는 포름산과 아민의 혼합물일 수 있으며, 보다 바람직하게 트리에틸아민(TEA) 및 포름산, 또는 디이소프로필에틸아민(DIPEA) 및 포름산 일 수 있다.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 may be a mixture of formic acid and amine, more preferably triethylamine (TEA) and formic acid, or diisopropylethylamine (DIPEA) and formic acid.
상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계에서 화학식 Ⅱ로 표시되는 화합물의 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응은 25 ℃ 내지 80 ℃에서, 바람직하게 30℃ 내지 50℃ 에서 이루어질 수 있다. 이보다 온도가 낮으면 반응시간이 지나치게 길어지고, 온도가 높으면 광학순도(chiral purity)가 지나치게 낮아지므로 상업적 생산에 부적합하다. In the step of preparing the compound represented by Chemical Formula I, the chiral reduction reaction of the compound represented by Chemical Formula II or Chemical Formula IV may be performed at 25 ° C. to 80 ° C., preferably at 30 ° C. to 50 ° C. have. A lower temperature is unsuitable for commercial production because the reaction time is too long, and a high temperature results in too low chiral purity.
상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계는 결정화 용매로 결정화를 수행하는 단계를 더 포함할 수 있다. 상기 결정화 용매는 화합물의 결정화를 위한 것으로, 헥산, 헵탄과 같은 C6~
7 의 지방족 탄화수소; 디에틸에테르, 디이소프로필에테르 같은 에테르; 또는 이들의 혼합 용매등이 사용될 수 있다. 바람직하게는 헥산, 헵탄과 같은 C6~
7 의 지방족 탄화수소를 사용할 수 있다. The preparing of the compound represented by Chemical Formula I may further include performing crystallization with a crystallization solvent. The crystallization solvent is for the crystallization of the compound, hexane, aliphatic hydrocarbons, C 6 ~ 7, such as heptane; Ethers such as diethyl ether and diisopropyl ether; Or mixed solvents thereof may be used. Preferably hexane, it may be used aliphatic hydrocarbons, C 6 ~ 7, such as heptane.
본 발명은, The present invention,
하기 화학식 Ⅱ로 표시되는 화합물과 수소 공여체를 하기 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 반응시켜 하기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법을 제공한다. It provides a method of preparing a compound represented by the formula (I) comprising the step of reacting a compound represented by the formula (II) and a hydrogen donor under a catalyst represented by the formula (III) or (IV) .
[화학식 Ⅰ][Formula I]
[화학식 Ⅱ][Formula II]
[화학식 Ⅲ][Formula III]
[화학식 Ⅳ][Formula IV]
상기 화학식 Ⅰ에서 *는 Chiral center를 나타낸다. In Formula I, * represents a Chiral center.
본 발명의 일 실시양태에 따르면, 본 발명은 Ⅱ로 표시되는 화합물을 화학식 Ⅲ으로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ-1로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ-1로 표시되는 화합물의 제조방법을 제공한다. According to an embodiment of the present invention, the present invention provides a compound of formula I-1 comprising chiral reduction of a compound represented by formula II under a catalyst represented by formula III to prepare a compound represented by formula I-1. It provides a method for producing the compound represented.
[화학식 Ⅰ-1] (R)-5,7-디플루오로크로만-4-올(R) -5,7-difluorochroman-4-ol
본 발명의 다른 실시양태에 따르면, 본 발명은 Ⅱ로 표시되는 화합물을 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ-2로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ-2로 표시되는 화합물의 제조방법을 제공한다. According to another embodiment of the present invention, the present invention provides a compound of formula I-2 comprising chiral reduction of a compound represented by formula II under a catalyst represented by formula IV to produce a compound represented by formula I-2 It provides a method for producing the compound represented.
[화학식 Ⅰ-2] (S)-5,7-디플루오로크로만-4-올(S) -5,7-difluorochroman-4-ol
상기와 같이, 본 발명에 따른 제조방법에 따라 화학식 Ⅱ의 화합물을 화학식 Ⅲ 또는 화학식 Ⅳ의 촉매 존재 하에 수소 공여체와 키랄 환원반응을 시키면 화학식 Ⅰ-1 또는 화학식 Ⅰ-2의 높은 광학활성을 가지는 크로마놀 화합물을 제조할 수 있다. As described above, when the compound of formula (II) is subjected to chiral reduction with a hydrogen donor in the presence of a catalyst of formula (III) or formula (IV) according to the preparation method according to the present invention, it has a high optical activity of formula (I-1) or (I-2) Known compounds may be prepared.
예를 들면, 본 발명에 따른 화학식 Ⅰ로 표시되는 화합물의 제조 방법은 하기 반응식 I로 표시될 수 있다. For example, the method for preparing a compound represented by Formula (I) according to the present invention may be represented by the following Scheme (I).
[반응식 Ⅰ]Scheme I
상기 반응식 Ⅰ과 같이, 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 루테늄 촉매 하에 유기 용매 하의 화학식 Ⅱ의 화합물을 수소 공여체와 반응시켜 화학식 Ⅰ의 화합물을 제조할 수 있다. As in Scheme I, a compound of Formula I may be prepared by reacting a compound of Formula II with a hydrogen donor in an organic solvent under a ruthenium catalyst represented by Formula III or Formula IV.
본 발명의 일 실시양태에 따르면, 하기 반응식 Ⅰ-1과 같이 화학식 Ⅲ 으로 표시되는 루테늄 촉매 하에 화학식 Ⅱ의 화합물을 수소공여체와 반응시켜 화학식 Ⅰ-1의 화합물을 제조할 수 있다. According to one embodiment of the present invention, a compound of formula (I-1) may be prepared by reacting a compound of formula (II) with a hydrogen donor under a ruthenium catalyst represented by formula (III) as in Scheme I-1.
[반응식 Ⅰ-1][Scheme I-1]
본 발명의 또 다른 실시양태에 따르면, 하기 반응식 Ⅰ-2과 같이, 화학식 Ⅳ로 표시되는 촉매 하에 화학식 Ⅱ의 화합물을 수소공여체와 반응시켜 화학식 Ⅰ-2의 화합물을 제조할 수 있다. According to another embodiment of the present invention, the compound of formula (II) may be prepared by reacting the compound of formula (II) with a hydrogen donor under the catalyst represented by formula (IV), as in Scheme I-2.
[반응식 Ⅰ-2][Scheme I-2]
본 발명에 따른 광학 활성을 갖는 크로마놀 유도체의 제조 방법은 종래 알려진 광학 활성 환원반응 기술과 달리, 제조되는 크로마놀이 높은 광학순도를 나타내어 별도의 정제 공정을 필요로 하지 않으며, 혹독한 반응 조건을 포함하지 않고 위험한 시약을 사용하지 않기 때문에 대량생산에 유리하고 제조수율 또한 우수한 장점을 가진다. Unlike the conventionally known optically active reduction technique, the method for preparing an optically active chromamanol derivative according to the present invention does not require a separate purification process because it shows high optical purity and does not include harsh reaction conditions. And because it does not use dangerous reagents, it is advantageous for mass production and has a good production yield.
또한, 상기 제조방법에 의하여 제조되는 최종 생성물은 광학 활성을 갖는 크로마놀 구조를 가지는 다른 화합물을 제조하는데 사용할 수 있으며, 특히 항균제, 항궤양제, 항염증 치료제로 사용 가능한 화합물의 제조를 위한 중간체로 사용할 수 있다.In addition, the final product prepared by the preparation method can be used to prepare other compounds having a chromamanol structure having an optical activity, in particular as an intermediate for the preparation of compounds that can be used as antibacterial, anti-ulcer, anti-inflammatory drugs Can be used.
이하, 하기 실시예 및 실험예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 그러나, 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것으로 이들 실시예 및 실험예에 의하여 본 발명의 범위가 한정되는 것은 아니다. 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 provided to illustrate the present invention, and the scope of the present invention is not limited by these Examples and Experimental Examples.
이하에서 언급된 시약 및 용매는 특별한 언급이 없는 한 Sigma Aldrich로부터 구입한 것이며, 1H-NMR는 Bruker NMR 270MHz 로 측정하였으며, 광학 활성은 Rudolph research analytical autoV 로 측정하였다. The reagents and solvents mentioned below were purchased from Sigma Aldrich unless otherwise noted, 1 H-NMR was measured by Bruker NMR 270 MHz, and optical activity was measured by Rudolph research analytical autoV.
실시예Example
1: (R)-5,7- 1: (R) -5,7-
디플루오로크로만Difluorochroman
-4-올의 제조Preparation of 4-ol
반응기에 트리에틸아민 30 g을 투입하고 -10 ℃로 냉각하였다. 여기에 포름산 27 g을 10℃ 이하에서 천천히 투입하였다. 루테늄 촉매 RuCl(p-cymene)[(R,R)-Ts-DPEN] 56 mg을 투입하였다. 5,7-디플루오로크로만-4-온 33 g을 테트라히드로푸란 87 g에 용해하여 반응기에 10℃ 이하에서 투입하였다. 40℃ 로 승온하고, 반응하였다. 반응이 종결된 후 실온으로 냉각하고, 에틸아세테이트 293 g와 정제수 163 g을 투입하여 교반 후 유기층 분리하였다. 40℃ 이하에서 감압 농축하고, 헵탄 222 g을 투입하여 25℃ 로 교반 후 생성된 고체를 여과하였다. 40℃ 에서 진공 건조하여 (R)-5,7-디플루오로크로만-4-올(30 g, 91%, 100 %ee)을 수득하였다.30 g of triethylamine was added to the reactor and cooled to -10 ° C. 27 g of formic acid was slowly added thereto at 10 ° C or lower. 56 mg of ruthenium catalyst RuCl (p-cymene) [(R, R) -Ts-DPEN] 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. It heated up at 40 degreeC and reacted. After the reaction was completed, the reaction mixture was cooled to room temperature, 293 g of ethyl acetate and 163 g of purified water were added thereto, followed by stirring. The mixture was concentrated under reduced pressure at 40 占 폚 or lower, 222 g of heptane was added thereto, and the resulting solid was filtered after stirring at 25 占 폚. Vacuum drying at 40 ° C. yielded (R) -5,7-difluorochroman-4-ol (30 g, 91%, 100% ee).
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 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
광학 회전: [α]D
24 = +143.6° (c=1.00, 메탄올)Optical rotation: [α] D 24 = + 143.6 ° (c = 1.00, methanol)
실시예Example
2: (S)-5,7- 2: (S) -5,7-
디플루오로크로만Difluorochroman
-4-올의 제조Preparation of 4-ol
반응기에 트리에틸아민 30 g을 투입하고 -10℃ 로 냉각하였다. 여기에 포름산 27 g을 10℃ 이하에서 천천히 투입하였다. 루테늄 촉매 RuCl(p-cymene)[(S,S)-Ts-DPEN] 56 mg을 투입하였다. 5,7-디플루오로크로만-4-온 33 g을 테트라히드로푸란 87 g에 용해하여 반응기에 10℃ 이하에서 투입하였다. 40℃ 로 승온하고, 반응하였다. 반응이 종결된 후 25℃로 냉각하고, 에틸아세테이트 293 g와 정제수 163 g을 투입하여 교반 후 유기층 분리하였다. 40℃ 이하에서 감압 농축하고, 헵탄 222 g을 투입하여 25 로 교반 후 생성된 고체를 여과하였다. 40℃에서 진공 건조하여 (S)-5,7-디플루오로크로만-4-올(28 g, 85%, 100%ee)을 수득하였다.30 g of triethylamine was added to the reactor and cooled to -10 ° C. 27 g of formic acid was slowly added thereto at 10 ° C or lower. 56 mg of ruthenium catalyst RuCl (p-cymene) [(S, S) -Ts-DPEN] 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. It heated up at 40 degreeC and reacted. After the reaction was terminated, the mixture was cooled to 25 ° C., 293 g of ethyl acetate and 163 g of purified water were added thereto, followed by stirring and separation of the organic layer. The mixture was concentrated under reduced pressure at 40 ° C. or lower, 222 g of heptane was added thereto, stirred at 25, and the resulting solid was filtered. Drying in vacuo at 40 ° C. gave (S) -5,7-difluorochroman-4-ol (28 g, 85%, 100% ee).
1H-NMR: 스펙트럼 데이터는 (R)-크로마놀(실시예 1)의 데이터와 동일하였다. 1 H-NMR: The spectral data were the same as the data of (R) -chromanol (Example 1).
광학 회전: [α]D
24 = -143.6° (c=1.00, 메탄올)Optical rotation: [α] D 24 = -143.6 ° (c = 1.00, methanol)
Claims (9)
- 하기 화학식 Ⅱ로 표시되는 화합물을 하기 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법:A method for preparing a compound represented by formula (I) comprising the step of preparing a compound represented by formula (I) by chiral reduction of a compound represented by formula (II) under a catalyst represented by formula (III) or (IV):[화학식 Ⅰ][Formula I][화학식 Ⅱ] [Formula II][화학식 Ⅲ][Formula III][화학식 Ⅳ][Formula IV]상기에서 *는 카이랄 중심임.* Is chiral center in the above.
- 제1항에 있어서, 상기 화학식 Ⅱ로 표시되는 화합물을 화학식 Ⅲ으로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ-1로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법:According to claim 1, wherein the compound represented by the formula (II) comprising the step of preparing a compound represented by the formula (I-1) by chiral reduction reaction of the compound represented by the formula (II) under a catalyst represented by the formula (III) :[화학식 Ⅰ-1][Formula I-1]
- 제1항에 있어서, 화학식 Ⅱ로 표시되는 화합물을 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ-2로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법:The method for preparing a compound represented by Formula (I) according to claim 1, comprising the step of chiral reduction of the compound represented by Formula (II) under a catalyst represented by Formula (IV) to produce a compound represented by Formula (I-2):[화학식 Ⅰ-2][Formula I-2]
- 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 화학식 Ⅱ로 표시되는 화합물과 촉매의 반응 몰비는 1:0.0001 내지 1:0.1인 화학식 Ⅰ로 표시되는 화합물의 제조방법.The method according to any one of claims 1 to 3, wherein the molar ratio of the compound represented by the formula (II) and the catalyst is 1: 0.0001 to 1: 0.1.
- 제1항 내지 제3항 중 어느 한 항에 있어서, C6~ 7 의 지방족 탄화수소; 에테르; 또는 이들의 혼합 용매로 결정화 시키는 단계를 더 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법.Any one of claims 1 to A method according to any one of claim 3, wherein the aliphatic hydrocarbons, C 6 ~ 7; ether; Or crystallizing with a mixed solvent thereof.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 키랄 환원 반응은 수소 공여체를 사용하여 수행되고, 상기 수소 공여체는 포름산, 포름산의 금속염, 포름산의 암모늄염, 및 포름산과 아민의 혼합물 중에서 선택되는 어느 하나인 화학식 Ⅰ로 표시되는 화합물의 제조방법.The method of claim 1, wherein the chiral reduction reaction is carried out using a hydrogen donor, wherein the hydrogen donor is selected from formic acid, a metal salt of formic acid, an ammonium salt of formic acid, and a mixture of formic acid and amines. Method for producing a compound represented by Formula (I) which is any one.
- 제6항에 있어서, 상기 수소 공여체는 포름산 및 트리에틸아민인 화학식 Ⅰ로 표시되는 화합물의 제조방법.The method of claim 6, wherein the hydrogen donor is formic acid and triethylamine.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 화학식 Ⅱ로 표시되는 화합물의 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응은 25℃ 내지 80℃ 에서 수행되는 화학식 Ⅰ로 표시되는 화합물의 제조방법.The chiral reduction reaction according to any one of claims 1 to 3, wherein the chiral reduction reaction under the catalyst represented by formula (III) or (IV) of the compound represented by formula (II) is carried out at 25 ° C. to 80 ° C. Manufacturing method.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 화학식 Ⅱ로 표시되는 화합물의 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응은 유기 용매 하에 수행되는 화학식 Ⅰ로 표시되는 화합물의 제조방법.The process for preparing a compound represented by the formula (I) according to any one of claims 1 to 3, wherein the chiral reduction reaction of the compound represented by the formula (II) is carried out under a catalyst represented by the formula (III) or (IV).
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| KR20080080195A (en) * | 2005-12-19 | 2008-09-02 | 화이자 인코포레이티드 | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
| KR20080108129A (en) * | 2006-03-17 | 2008-12-11 | 라퀄리아 파마 인코포레이티드 | Chromane derivatives |
| WO2008151927A2 (en) * | 2007-06-15 | 2008-12-18 | Nycomed Gmbh | 6-n-substituted benz imidazole derivatives as acid pump antagonists |
| KR101179302B1 (en) * | 2004-06-22 | 2012-09-03 | 노파르티스 아게 | Enantioselektive Preparation of Quinoline Derivative |
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| KR20080080195A (en) * | 2005-12-19 | 2008-09-02 | 화이자 인코포레이티드 | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
| KR20080108129A (en) * | 2006-03-17 | 2008-12-11 | 라퀄리아 파마 인코포레이티드 | Chromane derivatives |
| WO2008059373A1 (en) * | 2006-11-17 | 2008-05-22 | Raqualia Pharma Inc. | Imidazo [1, 2-a] pyrazine derivatives and their use as acid pump antagonists |
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