WO2013047751A1 - Procédé de fabrication de dérivé de 3,4-dihydroisoquinoléine - Google Patents

Procédé de fabrication de dérivé de 3,4-dihydroisoquinoléine Download PDF

Info

Publication number
WO2013047751A1
WO2013047751A1 PCT/JP2012/075086 JP2012075086W WO2013047751A1 WO 2013047751 A1 WO2013047751 A1 WO 2013047751A1 JP 2012075086 W JP2012075086 W JP 2012075086W WO 2013047751 A1 WO2013047751 A1 WO 2013047751A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
general formula
solvent
compound
reaction
Prior art date
Application number
PCT/JP2012/075086
Other languages
English (en)
Japanese (ja)
Inventor
豪毅 梅谷
Original Assignee
三井化学アグロ株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 三井化学アグロ株式会社 filed Critical 三井化学アグロ株式会社
Priority to JP2013536428A priority Critical patent/JP6084570B2/ja
Priority to CN201280045838.1A priority patent/CN103814014B/zh
Publication of WO2013047751A1 publication Critical patent/WO2013047751A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

  • the present invention relates to a method for producing a 3,4-dihydroisoquinoline derivative.
  • 3,4-dihydroisoquinoline derivatives are known to be important production intermediates in various fields.
  • 1,3,3-trimethyl-3,4-dihydroisoquinoline which is one of the derivatives, is disclosed in Patent Document 1 and Patent Document 2 as an intermediate for producing a medical drug, and in Patent Document 3 It is described as a manufacturing intermediate for laundry detergent compositions. Therefore, a method capable of efficiently producing a 3,4-dihydroisoquinoline derivative is very important.
  • Non-patent Document 1 a method in which phenethyl chloride derivative and acetonitrile are reacted in the presence of tin tetrachloride (Non-patent Document 1), (2) phenethyl alcohol derivative is added to acetonitrile charged with sulfuric acid and acetic acid. (3) A method of reacting ethyl cyanoacetate with a phenethyl alcohol derivative in the presence of sulfuric acid in a benzene solvent (Patent Document 1). (4) A method of reacting acetonitrile and a phenethyl alcohol derivative in a benzene solvent in the presence of sulfuric acid (Patent Document 2) and the like are disclosed.
  • the method (1) uses a transition metal that causes a problem in disposal.
  • the method (2) requires a very long reaction time and two steps.
  • the details of method (3) are unknown because the yield is not described, but the atomic efficiency is not good because it is necessary to remove the ethylcarbonyl group of ethyl cyanoacetate.
  • the method (4) is a method in which the target product can be obtained in one step without using a transition metal and the atomic efficiency of the starting material is excellent, but the yield is low.
  • An object of the present invention is to provide an industrially advantageous production method for 3,4-dihydroisoquinoline derivatives.
  • the desired 3,4-dihydroisoquinoline derivative is obtained by reacting a phenethyl alcohol derivative and an alkyl nitrile derivative in the presence of an acid without using a solvent. It was found that it can be produced with good yield. Further investigations have revealed that the target product can be obtained in a higher yield than the reaction using a conventional benzene solvent by carrying out the reaction in a hydrocarbon solvent. The reaction in the presence of a solvent is suitable for production on a large scale because it is easy to control the heat generated during the reaction.
  • the method of the present invention is not only excellent in yield, but also avoids the use of non-environmentally compatible solvents such as benzene and is easy to operate, and is therefore an effective means for solving the above problems. is there.
  • the present invention has been completed.
  • R1 and R2 each independently represents an optionally substituted alkyl group having 1 to 6 carbon atoms
  • X represents a halogen atom
  • an optionally substituted alkyl group having 1 to 6 carbon atoms substituted Which represents an alkoxy group having 1 to 6 carbon atoms
  • n represents an integer of 0 to 4
  • R3 represents an alkyl group having 1 to 3 carbon atoms.
  • the intended 3,4-dihydroisoquinoline derivative can be produced in high yield by a simple operation while avoiding the use of a solvent that is not environmentally compatible. Therefore, the present invention is suitable as an industrial manufacturing method.
  • the substituent in the alkyl group having 1 to 6 carbon atoms which may be substituted in R1 and R2 in the general formula (1) represents a halogen atom and an alkoxy group having 1 to 6 carbon atoms.
  • the halogen atom is fluorine, chlorine, bromine or iodine.
  • the alkoxy group having 1 to 6 carbon atoms is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butyroxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, a pentoxy group, an isopentoxy group, or 2-methylbutyroxy Group, neopentoxy group, 1-ethylpropoxy group, hexyloxy group, 4-methylpentoxy group, 3-methylpentoxy group, 2-methylpentoxy group, 1-methylpentoxy group, 3,3-dimethylbutoxy Group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group, 2-ethyl
  • a linear or branched alkoxy group such as a butyroxy group is represented.
  • alkoxy group having 1 to 4 carbon atoms is preferable, and a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group are more preferable.
  • the number of substituents is not particularly limited, and each substituent may be the same or different.
  • the alkyl group in the alkyl group having 1 to 6 carbon atoms which may be substituted in R1 and R2 in the general formula (1) is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, s -Butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3- A linear or branched alkyl group such as a dimethylbutyl group or a
  • the halogen atom at X in the general formula (1) is fluorine, chlorine, bromine or iodine.
  • the alkyl group having 1 to 6 carbon atoms which may be substituted in X in the general formula (1) is an alkyl group having 1 to 6 carbon atoms which may be substituted in R1 and R2 in the general formula (1). It is synonymous.
  • the substituent in the alkoxy group having 1 to 6 carbon atoms which may be substituted in X in the general formula (1) is a halogen atom, and is fluorine, chlorine, bromine or iodine.
  • the number of substituents is not particularly limited, and each substituent may be the same or different.
  • the alkoxy group in the alkoxy group having 1 to 6 carbon atoms which may be substituted in X in the general formula (1) is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butyroxy group, an isobutyroxy group, or s-butyroxy.
  • the alkyl group having 1 to 3 carbon atoms for R3 in the general formula (1) is a methyl group, an ethyl group, a propyl group, or an isopropyl group.
  • N in the general formula (1) is an integer of 0 to 4.
  • X in the general formula (1) is 2 or more, Xs may be the same or different.
  • R1, R2, X and n in the general formula (2) have the same meanings as the general formula (1).
  • 1,1-dimethyl-2-phenylethanol is commercially available.
  • R3 in the general formula (3) is synonymous with the general formula (1).
  • acetonitrile is available as a commercial product.
  • the compound represented by the general formula (1) is obtained by combining the compound represented by the general formula (2) and the compound represented by the general formula (3) in a hydrocarbon solvent or without solvent in the presence of an acid. It can obtain by making it react.
  • the hydrocarbon solvent used in the reaction is a linear, branched or cyclic solvent composed of carbon and hydrogen such as pentane, hexane, heptane, octane, 2-methylbutane, isohexane, cyclohexane, methylcyclohexane, A solvent composed of chlorine, carbon and hydrogen such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
  • Preferred are linear and cyclic solvents composed of carbon and hydrogen, and solvents composed of chlorine, carbon and hydrogen, and more preferred are hexane, peptane, cyclohexane, methylcyclohexane and dichloroethane. These solvents can be used alone or in combination of two or more at any ratio.
  • This reaction can be carried out without a solvent, but when a hydrocarbon solvent is used, it is usually preferably 20 times by weight or less with respect to the compound represented by the general formula (2).
  • the acid used is not particularly limited as long as the reaction proceeds, but sulfonic acids are preferred.
  • sulfonic acids include trifluoromethanesulfonic acid and sulfuric acid, and sulfuric acid is preferable.
  • sulfuric acid contains about 3-5% water, but any sulfuric acid can be used. As described in the examples, commercially available sulfuric acid can be used in the reaction after the contained water is converted to sulfuric acid with fuming sulfuric acid.
  • the amount of the acid used is not particularly limited as long as the reaction proceeds, but is usually 3 equivalents or more and 30 equivalents or less, preferably 5 equivalents, relative to the compound represented by the general formula (2). Equivalent to 15 equivalents.
  • the reaction temperature is not particularly limited as long as the reaction proceeds, but it is usually 0 ° C. or higher and 80 ° C. or lower than the boiling point of the solvent, preferably 10 ° C. or higher and 50 ° C. or lower or lower than the boiling point of the solvent.
  • a mixture of a compound represented by the general formula (2) and a compound represented by the general formula (3) in a hydrocarbon solvent is used.
  • a method of adding to the acid, a method of adding a compound represented by the general formula (2) and a compound represented by the general formula (3) to a hydrocarbon solvent, and adding the acid to the acid, represented by the general formula (2) A method of adding a compound obtained by mixing a compound represented by formula (3) to an acid charged with a hydrocarbon-based solvent is not limited thereto, and is appropriately set. be able to.
  • the post-reaction treatment is described below.
  • water or an aqueous alkaline solution can be added.
  • a method of neutralizing with an aqueous alkaline solution after adding water is preferable for safety.
  • the alkaline aqueous solution to be used it is possible to use a solution in which ammonia, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like are dissolved in water.
  • salt is precipitated after the neutralization operation, water can be added to dissolve the salt, or the salt can be removed by filtration operation.
  • solvents used here include benzene solvents such as toluene, xylene, benzene, chlorobenzene and dichlorobenzene, ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate, ethers such as diethyl ether, diisopropyl ether and methyl-t-butyl ether.
  • Solvents containing chlorine, chlorohydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform, and hydrocarbon solvents such as hexane, heptane, cyclohexane, and methylcyclohexane are exemplified, and it is possible to add a solvent that is not compatible with water. It is.
  • the number of times of liquid separation is not particularly limited, and can be carried out according to the target purity.
  • the reaction mixture containing the compound (1) obtained above can remove moisture with a desiccant such as sodium sulfate or magnesium sulfate, but this step is not essential.
  • the solvent can be distilled off.
  • the reaction mixture containing the compound (1) obtained by distilling off the solvent can be further purified according to the target purity.
  • the compound represented by the compound (1) is a solid, it may be washed, reprecipitated or recrystallized with an appropriate solvent, and when it is a liquid, distillation can be performed.
  • both solid and liquid can be purified by column chromatography.
  • 3,4-dihydroisoquinoline derivatives can be efficiently produced by a simple operation.
  • compound (I) 2-methyl-1-phenylpropan-2-ol is referred to as compound (I), 1,3,3-trimethyl-3,4-dihydroisoquinoline is referred to as compound (II), and high performance liquid chromatography is referred to as HPLC.
  • the yield could be remarkably improved by using cyclohexane as the solvent.
  • the obtained compound was distilled at 5 torr 82 ° C. for analysis.
  • the analysis value was consistent with International Publication No. 2003/64389.
  • Example 2 Synthesis of Compound (II) Using Cyclohexane as a Solvent 30 ml of cyclohexane was added to 103.09 g of 95% sulfuric acid and cooled to 15 ° C. To this, 30 ml of cyclohexane containing 20.00 g of compound (I) and 9.29 g of acetonitrile was added dropwise at 20 ° C. or lower. After completion of dropping, the mixture was stirred at 20 ° C. for 20 hours. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 87.5%.
  • Example 4 Synthesis of Compound (II) Using Methylcyclohexane as a Solvent The reaction was carried out in the same manner as in Example 3 except that cyclohexane was changed to methylcyclohexane. When the obtained reaction mixture was observed by HPLC, compound (II) was produced in a reaction yield of 78.7%.
  • Example 5 Synthesis of compound (II) using heptane as a solvent The reaction was carried out in the same manner as in Example 3 except that cyclohexane was changed to heptane. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 84.0%.
  • Example 7 Synthesis of Compound (II) Using Dichloroethane as Solvent After 30 ml of dichloroethane charged with 101.0 g of 97% sulfuric acid was cooled to 15 ° C., 20.00 g of Compound (I) and 9.29 g of acetonitrile were contained. 30 ml of dichloroethane was added dropwise at 20 ° C. or lower. After completion of dropping, the mixture was stirred at 20 ° C. for 20 hours. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 79.0%.
  • the present invention it has become possible to provide a 3,4-dihydroisoquinoline derivative in a high yield by a simple operation. Furthermore, since the present invention can avoid solvents that are not environmentally compatible and can be advantageously produced industrially, it has a high industrial utility value.

Abstract

L'invention fournit un procédé destiné à fabriquer à échelle industrielle et de manière avantageuse un dérivé de 3,4-dihydroisoquinoléine. Plus précisément, l'invention concerne le procédé de fabrication du dérivé de 3,4-dihydroisoquinoléine représenté par la formule générale (1), selon lequel procédé, un composé représenté par la formule générale (2) est mis en réaction avec un composé représenté par la formule générale (3) en présence d'un acide, dans un solvant à base d'hydrocarbure ou sans solvant.
PCT/JP2012/075086 2011-09-29 2012-09-28 Procédé de fabrication de dérivé de 3,4-dihydroisoquinoléine WO2013047751A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2013536428A JP6084570B2 (ja) 2011-09-29 2012-09-28 ３，４−ジヒドロイソキノリン誘導体の製造方法
CN201280045838.1A CN103814014B (zh) 2011-09-29 2012-09-28 3，4－二氢异喹啉衍生物的制造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011-213689 2011-09-29
JP2011213689 2011-09-29

Publications (1)

Publication Number Publication Date
WO2013047751A1 true WO2013047751A1 (fr) 2013-04-04

Family

ID=47995776

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/075086 WO2013047751A1 (fr) 2011-09-29 2012-09-28 Procédé de fabrication de dérivé de 3,4-dihydroisoquinoléine

Country Status (4)

Country Link
JP (1) JP6084570B2 (fr)
CN (1) CN103814014B (fr)
TW (1) TWI530485B (fr)
WO (1) WO2013047751A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001016275A1 (fr) * 1999-08-27 2001-03-08 The Procter & Gamble Company Composants de formulation a action rapide, compositions et procedes de nettoyage utilisant ces composants
WO2003064389A1 (fr) * 2002-01-31 2003-08-07 Ono Pharmaceutical Co., Ltd. Composes bicycliques contenant de l'azote et medicaments contenant ces composes en tant qu'ingredient actif
WO2005070917A1 (fr) * 2004-01-23 2005-08-04 Sankyo Agro Company, Limited 3-(dihydro(tetrahydro)isoquinolin-1-yl)quinolines
WO2007011022A1 (fr) * 2005-07-22 2007-01-25 Sankyo Agro Company, Limited Dérivé de 3-(isoquinoline-1-yl)quinoline
WO2008117061A2 (fr) * 2007-03-28 2008-10-02 Sterix Limited Composé

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001016275A1 (fr) * 1999-08-27 2001-03-08 The Procter & Gamble Company Composants de formulation a action rapide, compositions et procedes de nettoyage utilisant ces composants
WO2003064389A1 (fr) * 2002-01-31 2003-08-07 Ono Pharmaceutical Co., Ltd. Composes bicycliques contenant de l'azote et medicaments contenant ces composes en tant qu'ingredient actif
WO2005070917A1 (fr) * 2004-01-23 2005-08-04 Sankyo Agro Company, Limited 3-(dihydro(tetrahydro)isoquinolin-1-yl)quinolines
WO2007011022A1 (fr) * 2005-07-22 2007-01-25 Sankyo Agro Company, Limited Dérivé de 3-(isoquinoline-1-yl)quinoline
WO2008117061A2 (fr) * 2007-03-28 2008-10-02 Sterix Limited Composé

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHKLYAEV,Y.V. ET AL.: "A new approach to synthesis of 3,3-dialkyl-3,4- dihydroisoquinoline derivatives", HETEROATOM CHEMISTRY, vol. 15, no. 7, 2004, pages 486 - 493, XP055064738 *
SHKLYAEV,Y.V. ET AL.: "Three-component synthesis of 3,4-dihydroisoquinoline derivatives", RUSSIAN CHEMICAL BULLETIN(TRANSLATION OF IZVESTIYA AKADEMII NAUK, SERIYA KHIMICHESKAYA), vol. 51, no. 5, 2002, pages 844 - 849, XP009029011 *

Also Published As

Publication number Publication date
TWI530485B (zh) 2016-04-21
CN103814014A (zh) 2014-05-21
JP6084570B2 (ja) 2017-02-22
CN103814014B (zh) 2016-01-13
JPWO2013047751A1 (ja) 2015-03-26
TW201319046A (zh) 2013-05-16

Similar Documents

Publication Publication Date Title
JP5993860B2 (ja) ４，４−ジフルオロ−３，４−ジヒドロイソキノリン誘導体の製造方法
US6949668B2 (en) Process for producing 5-(3-cyanophenyl)-3-formylbenzoic acid compound
EP2285765B1 (fr) Procédé de préparation de dérivés d acide 1-(2-halobiphényl-4-yl)-cyclopropane carboxylique
JP4528123B2 (ja) ナプロキセンのニトロオキシ誘導体の製造法
CN105175346B (zh) 一种合成瑞舒伐他汀钙中间体的方法
JP6084570B2 (ja) ３，４−ジヒドロイソキノリン誘導体の製造方法
JP5663482B2 (ja) ピリミジニルアセトニトリル誘導体の製造方法及びその合成中間体
JP2018505179A (ja) メデトミジンの合成に有用な３−アリールブタナールなどの化合物の調製方法
CA2962186A1 (fr) Procede de production de derive de triphenylbutene
JP4899385B2 (ja) ３−アミノメチルオキセタン化合物の製法
KR100763770B1 (ko) 아토르바스타틴 합성에 유용한 광학활성 중간체의 제조방법
JP5205971B2 (ja) テトラヒドロピラン化合物の製造方法
JP5309680B2 (ja) フッ素化エステル化合物の製造方法及びその中間体
WO2014206897A2 (fr) Cyclopropanation de phénylacétonitriles ou d'acétates de phényle substitués
KR100763771B1 (ko) 알킬2-[3-[3-[(2ｅ)-(7-클로로-퀴놀린-2-일)바이닐]페닐]-3(ｓ)-하이드록시프로필]벤조에이트의 제조방법
ES2666726T3 (es) Procedimiento para la obtención de derivados de 1,1-dióxido de 1,4-benzotiepina
WO2011010524A1 (fr) Procédé de production de chlorures d'alcoxybenzènesulfonyle
JP2002201169A (ja) ４−シアノ−３−オキソブタン酸エステルの製造法
JP2013121923A (ja) ４，４−ジフルオロ−３，４−ジヒドロイソキノリン類の製造法
CA3016545A1 (fr) Procede de production d'un derive de phenoxyethanol
JP2008195697A (ja) ３−アルキル−７，７，９，９−テトラメチル−１，３，８−トリアザスピロ〔４，５〕デカン誘導体の製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12835067

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2013536428

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12835067

Country of ref document: EP

Kind code of ref document: A1