WO2018097150A1 - Procédé de fabrication de composé époxy - Google Patents

Procédé de fabrication de composé époxy Download PDF

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Publication number
WO2018097150A1
WO2018097150A1 PCT/JP2017/041914 JP2017041914W WO2018097150A1 WO 2018097150 A1 WO2018097150 A1 WO 2018097150A1 JP 2017041914 W JP2017041914 W JP 2017041914W WO 2018097150 A1 WO2018097150 A1 WO 2018097150A1
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group
compound
production method
mmol
cyclopentene
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PCT/JP2017/041914
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English (en)
Japanese (ja)
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英良 土屋
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帝人ファーマ株式会社
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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
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals

Definitions

  • the present invention relates to a method for stereoselectively epoxidizing a double bond of a mono-substituted 3-cyclopentene compound at the 1-position.
  • metachloroperbenzoic acid is known as an epoxidizing agent for olefins, but epoxidation of mono-substituted 3-cyclopentene compounds is not highly stereoselective.
  • mCPBA metachloroperbenzoic acid
  • the ratio is 3: 1 (Non-Patent Document 1)
  • the ratio is 3: 2 (Non-Patent Document 2).
  • the ratio is 8: 1.
  • Non-patent Document 3 Although the stereoselectivity is improved (Non-patent Document 3), in addition to using an expensive silyl compound, the molecular weight of the substrate increases. This increases the amount of waste and is not suitable for an industrial manufacturing method from the viewpoint of process conversion efficiency (Atom Economy).
  • Patent Document 1 a method for epoxidizing a cyclohexene compound using hydrogen peroxide as an oxidizing agent in the presence of a quaternary ammonium hydrogen sulfate salt, a phosphoric acid compound or a phosphonic acid compound, and a Group 6 metal compound is known (Patent Document 1). ).
  • this reaction is a multifunctional substrate in which the steric pathway to the olefin plane of the oxidant is controlled by replacing the two positions at positions 1 and 2 of the cyclohexene ring of the reaction substrate with an allyl ester group in the syn configuration. (Details will be described later).
  • An object of the present invention is to provide a method for producing a corresponding epoxy compound from a mono-substituted 3-cyclopentene compound with high anti / syn stereoselectivity.
  • phase transfer catalyst for example, a quaternary ammonium salt, a phosphoric acid compound and / or a phosphonic acid compound, and a Group 6 metal compound are used as a catalyst, and the 1-position is mono-substituted with a specific substituent. It was found that by reacting the 3-cyclopentene compound with hydrogen peroxide, the corresponding epoxy compound can be produced stereoselectively in a high yield.
  • the inventors of the present invention have continued research based on such knowledge and have completed the present invention.
  • the present invention includes a step of reacting a compound represented by the formula (1) by adding a phosphoric acid compound and / or a phosphonic acid compound, a Group 6 metal compound, a phase transfer catalyst, and hydrogen peroxide, and reacting them. It is a manufacturing method of the compound represented by 2).
  • R in the formula (1) and the formula (2) is a C 1 -C 6 alkoxy group which may be substituted with 1 to 2 (phenyl group and / or halogen atom), 1 to 2 C 1 ⁇ C 4 alkyl optionally benzyloxy group optionally substituted with a group, one to two (phenyl group and / or halogen atom) with optionally substituted C 1 to C 6 alkyl group or 1, Represents a phenyl group which may be substituted by ⁇ 2 C 1 -C 4 alkyl groups;
  • a corresponding epoxy compound can be produced with high anti / syn stereoselectivity and high yield from the reaction of 3-cyclopentene compound monosubstituted with a specific substituent at the 1-position with hydrogen peroxide. .
  • the cyclohexene ring is on the left side of the figure.
  • the cyclopentene ring is on the right side of the figure.
  • the compound represented by the above formula (1) is oxidized using hydrogen peroxide in the presence of a phosphoric acid compound and / or a phosphonic acid compound, a group 6 metal compound, and a phase transfer catalyst, and the above formula (2).
  • This is a method for producing a compound represented by
  • R is a C 1 -C 6 alkoxy group which may be substituted with 1 to 2 (phenyl group and / or halogen atom), 1 to two C 1 ⁇ C 4 alkyl group which may be substituted benzyloxy group, 1-2 (phenyl group and / or a halogen atom) alkyl ⁇ C 6 optionally C 1 optionally substituted with Or a phenyl group optionally substituted by 1 to 2 C 1 -C 4 alkyl groups.
  • R is preferably a C 1 -C 6 alkoxy group, a benzyloxy group, a C 1 -C 6 alkyl group, or a phenyl group, and particularly preferably a C 1 -C 6 alkoxy group.
  • the hydrogen peroxide source in the production method of the present invention for example, urea-hydrogen peroxide and hydrogen peroxide water are used.
  • hydrogen peroxide water is inexpensive and non-corrosive, and the by-product after the reaction is water. Therefore, the environmental load is small and it is excellent for industrial use.
  • the concentration thereof is not limited, but is generally selected from the range of 1 to 80%, preferably 20 to 80%.
  • the amount of hydrogen peroxide used at that time is not limited, but it is generally selected from the range of 0.8 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to the olefins.
  • phase transfer catalyst used in the production method of the present invention a quaternary ammonium salt is suitable.
  • Such quaternary ammonium salts include, for example, methyltri n-octylammonium chloride, tetra n-butylammonium chloride, tetra n-butylammonium bromide, tetra n-butylammonium hydroxide, tetra n-hexylammonium hydrogen sulfate, tetrahydrogen hydrogen sulfate.
  • n-Octylammonium hydrogen, methyltri-n-octylammonium hydrogensulfate, tetra-n-butylammonium hydrogensulfate, and ethyltri-n-octylammonium hydrogensulfate are preferred, for example, tetra-n-butylammonium hydrogensulfate and methyltri-n-octylammonium hydrogensulfate
  • a quaternary ammonium hydrogen sulfate salt such as These quaternary ammonium salts may be used alone or in combination of two or more. The amount used is generally selected from the range of 0.0001 to 10 mol%, preferably 0.01 to 5 mol%, based on the olefins of the substrate.
  • molybdenum or tungsten is preferable.
  • the molybdenum compound used in the production method of the present invention is a compound that generates molybdate anions in water.
  • molybdic acid molybdenum oxide, molybdenum sulfide, molybdenum chloride, phosphomolybdic acid, molybdic acid Ammonium, potassium molybdate, and sodium molybdate.
  • the tungsten compound used in the production method of the present invention is a compound that generates a tungstate anion in water.
  • tungstic acid tungsten oxide, tungsten sulfide, tungsten chloride, phosphotungstic acid, tungstic acid Ammonium, potassium tungstate (including hydrate), and sodium tungstate (including hydrate).
  • molybdic acid, molybdenum oxide, phosphomolybdic acid, molybdate, tungstic acid, tungsten oxide, phosphotungstic acid, and tungstate are preferable.
  • molybdate and tungstate are preferable, and tungstate is more preferable, and sodium tungstate is particularly preferable, but sodium tungstate dihydrate is most preferable.
  • These group 6 metal compounds may be used alone or in combination of two or more.
  • the amount used is generally selected from the range of 0.0001 to 20 mol%, preferably 0.01 to 20 mol%, based on the olefins of the substrate.
  • a phosphoric acid compound and / or a phosphonic acid compound as a cocatalyst in order to improve the catalytic activity.
  • Such phosphoric acid compounds and / or phosphonic acid compounds include phosphoric acid, polyphosphoric acid, pyrophosphoric acid, ⁇ -aminomethylphosphonic acid, ⁇ -aminoethylphosphonic acid, nitrilotris (methylenephosphonic acid), phenylphosphonic acid, and these Sodium salts and potassium salts are mentioned, among which phosphoric acid and phenylphosphonic acid are preferable.
  • the amount of the phosphoric acid compound and / or phosphonic acid compound used is generally selected from the range of 0.0001 to 20 mol%, preferably 0.01 to 20 mol%, based on the olefins of the substrate.
  • sulfates such as sodium sulfate, sodium sulfate decahydrate, lithium sulfate, potassium sulfate, ammonium sulfate, or magnesium sulfate may be used as the additive, such an additive is the stereoselective object of the present invention. There is no particular influence on the properties, and forms without using such additives are also included in the embodiments of the present invention.
  • the solvent used in the production method of the present invention is not particularly limited, and examples thereof include toluene, xylene, chloroform, dichloromethane, 1,2-dichloroethane, acetonitrile, hexane, and heptane.
  • a mixture of these solvents and water can be used, and the reaction can be performed without using a solvent, but a reaction without using a solvent is particularly preferable.
  • the epoxidation reaction is usually performed in the range of 20 to 100 ° C, preferably in the range of 20 to 70 ° C.
  • the range of 40 to 60 ° C. is preferable.
  • Example 1 of Patent Document 1 shows the most stable conformation of the compound (1) which is the starting material described in Example 1 of Patent Document 1 by molecular mechanics calculation.
  • the configuration of the two allyl ester groups in this compound is not specified, the two allyl groups in compound (1) are determined from the three-dimensional structure of product (2) and compound (3). It is clear that the steric configuration of the ester group was a syn configuration.
  • the most stable conformation of compound (1) has two of the same energy level (potential energy: both 23.353 kcal / mol).
  • potential energy both 23.353 kcal / mol.
  • one of the substituents at the 1,2-position of the cyclohexene ring is always in the axial position, and the side on which the substituent exists is present with respect to the ring surface containing the double bond of the cyclohexene ring. Will be crowded in three dimensions. Therefore, it is strongly suggested that the oxidizing agent as an epoxidizing agent is selectively approached from the surface opposite to the substituent, and therefore high anti / syn stereoselectivity can be expected.
  • FIG. 2 shows the most stable conformation of ethyl 3-cyclopentene-1-carboxylate used in Example 1 as an example of the starting material in the present invention by molecular mechanics calculation under the same conditions (potential energy: -31.69 kcal / mol). Since the ethyl ester group, which is the 1-position substituent, is located in parallel with the cyclopentene ring, it strongly suggests that there is almost no steric difference on either side of the ring surface containing the double bond of the cyclopentene ring. Is done.
  • ethyl 3-cyclopentene-1-carboxylate (10.00 g, 71.34 mmol), sodium molybdate dihydrate (174 mg, 0.72 mmol), phenylphosphonic acid (57 mg, 0.36 mmol) ), And tetra n-butylammonium hydrogen sulfate (242 mg, 0.71 mmol).
  • 30% aqueous hydrogen peroxide (9.48 mL, 92.79 mmol) was added over 2.5 hours.
  • isopropyl acetate (30 mL) was added and the aqueous layer was removed.
  • ethyl 3-cyclopentene-1-carboxylate (10.00 g, 71.34 mmol), sodium tungstate dihydrate (471 mg, 1.43 mmol), phosphoric acid (content 85%, 82 mg, 0.71 mmol), methyltri-n-octylammonium hydrogensulfate (665 mg, 1.43 mmol), and sodium sulfate (3.04 g, 21.40 mmol) were added, and 30% aqueous hydrogen peroxide (9.48 mL, 92.79 mmol) was added. Was added at room temperature over 2 hours. After stirring at 20-30 ° C.
  • the method for producing an epoxy compound of the present invention is used, for example, in the chemical industry including the pharmaceutical manufacturing industry.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epoxy Compounds (AREA)

Abstract

L'invention concerne un procédé de fabrication de composé époxy correspondant qui inclut une étape au cours de laquelle un composé acide phosphorique et/ou un composé acide phosphonique, un composé métallique du groupe 6, un catalyseur de transfert de phase et un peroxyde d'hydrogène sont additionnés et ajoutés à un 3-cyclopentène de position 1 substituée par un groupe alcoxycarbonyle en Ｃ１～Ｃ６, un groupe benzyloxycarbonyle, un groupe alkylcarbonyle en Ｃ１～Ｃ６, un groupe benzyloxycarbonyle, un groupe alkyle en Ｃ１～Ｃ６, ou un groupe benzoyle (ces substituants peuvent être à nouveau substitués par un substituant spécifique). Selon l'invention, il est possible de fabriquer un composé époxy correspondant selon une stéréosélectivité élevée à partir d'un 3-cyclopentène de position 1 monosubstituée par un substituant spécifique.
PCT/JP2017/041914 2016-11-24 2017-11-22 Procédé de fabrication de composé époxy WO2018097150A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116375667A (zh) * 2023-06-04 2023-07-04 北京世纪迈劲生物科技有限公司 一种3-环己烯-1-甲酸-3-环己烯-1-基甲酯的环氧化方法

Citations (2)

* Cited by examiner, † Cited by third party
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WO2007081889A2 (fr) * 2006-01-05 2007-07-19 Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság Production du dolasetron
JP2008094741A (ja) * 2006-10-10 2008-04-24 Showa Denko Kk トリオレフィン化合物の選択的酸化による多官能性エポキシ化合物の製造方法

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WO2007081889A2 (fr) * 2006-01-05 2007-07-19 Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság Production du dolasetron
JP2008094741A (ja) * 2006-10-10 2008-04-24 Showa Denko Kk トリオレフィン化合物の選択的酸化による多官能性エポキシ化合物の製造方法

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CRESSWELL, A. J. ET AL.: "Catalytic, stereospecific syn-dichlorination of alkenes", NATURE CHEMISTRY, vol. 7, no. 2, 2015, pages 146 - 152, XP055487923, ISSN: 1755-4330 *
ENKVIST, E. ET AL.: "Carbocyclic 3'-deoxyadenosine-based highly potent bisubstrate-analog inhibitor of basophilic protein kinases", BIORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, 2007, pages 5336 - 5339, XP022249711, ISSN: 0960-894X *
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MARTINEZ, L. E. ET AL.: "Highly Efficient and Enantioselective Synthesis of Carbocyclic Nucleoside Analogs Using Selective Early Transition Metal Catalysis", JOURNAL OF ORGANIC CHEMISTRY, vol. 61, no. 22, 1996, pages 7963 - 7966, XP002041317, ISSN: 0022-3263 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116375667A (zh) * 2023-06-04 2023-07-04 北京世纪迈劲生物科技有限公司 一种3-环己烯-1-甲酸-3-环己烯-1-基甲酯的环氧化方法

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