WO2013115595A1 - Procédé de préparation d'un composé par le biais d'une nouvelle réaction d'addition de michael en utilisant de l'eau ou divers acides comme additifs - Google Patents

Procédé de préparation d'un composé par le biais d'une nouvelle réaction d'addition de michael en utilisant de l'eau ou divers acides comme additifs Download PDF

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Publication number
WO2013115595A1
WO2013115595A1 PCT/KR2013/000829 KR2013000829W WO2013115595A1 WO 2013115595 A1 WO2013115595 A1 WO 2013115595A1 KR 2013000829 W KR2013000829 W KR 2013000829W WO 2013115595 A1 WO2013115595 A1 WO 2013115595A1
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WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
formula
compound
acid
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PCT/KR2013/000829
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English (en)
Korean (ko)
Inventor
박애리
김봉찬
안지은
이희봉
Original Assignee
주식회사 엘지생명과학
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.)
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Application filed by 주식회사 엘지생명과학 filed Critical 주식회사 엘지생명과학
Priority to EA201491463A priority Critical patent/EA026411B1/ru
Priority to BR112014018985-4A priority patent/BR112014018985B1/pt
Priority to AU2013215796A priority patent/AU2013215796B2/en
Priority to CN201380007885.1A priority patent/CN104159884B/zh
Priority to SG11201404396TA priority patent/SG11201404396TA/en
Priority to MX2014009309A priority patent/MX355336B/es
Publication of WO2013115595A1 publication Critical patent/WO2013115595A1/fr
Priority to PH12014501704A priority patent/PH12014501704B1/en
Priority to ZA2014/05598A priority patent/ZA201405598B/en
Priority to TNP2014000329A priority patent/TN2014000329A1/fr
Priority to MA37281A priority patent/MA35906B1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/02—Addition
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/64—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/62—Use of additives, e.g. for stabilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a method for preparing a compound of Formula 1, which can be used as an intermediate such as pharmaceuticals, pesticides, electronic materials or liquid crystals, through a new Michael-addition reaction using water or various acids as an additive. will be.
  • Compounds of the general formula (1) have various skeletons and have biological activities, and thus are widely used as intermediates for synthesizing pharmaceuticals, pesticides, electronic materials or liquid crystal materials.
  • A is R 1 -C ( ⁇ O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5-membered to 10-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo ( ⁇ O) group. Or unsaturated C 6 -C 10 cycloalkyl,
  • R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5- to 10-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl,
  • R5 and R6 are each independently hydrogen; Halogen (ie, F, Cl, Br, or I); And substituted or unsubstituted C 1 -C 4 alkyl,
  • P 1 is selected from the group consisting of benzyl, methyl, ethyl, i-propyl and t-butyl groups.
  • Formula 1 has an advantage of being useful in the synthesis of various organic compounds because it has an ester skeleton that can be easily substituted with other substrates. Therefore, the research on the manufacturing method of the formula (1) is extensive, various synthesis methods have been developed by organic synthetic chemists and reported in many documents.
  • A, R2 to R6 and P 1 are the same as defined in Formula 1, and X is halogen (ie F, Cl, Br, or I).
  • the conventional Michael-addition reaction using only copper powder has a problem of requiring a relatively long reaction time, and has a disadvantage in that it is difficult to obtain the compound of Formula 1 in high yield due to the generation of impurities.
  • the present invention provides a new preparation of the compound of formula (I).
  • the present invention in the preparation of the following Chemical Formula 1 compound by the Michael-addition reaction of the following Chemical Formula 2 and the Chemical Formula 3 in the presence of a copper powder, reacting water or an acid or a mixture thereof
  • A is R 1 -C ( ⁇ O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5-membered to 10-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo ( ⁇ O) group. Or unsaturated C 6 -C 10 cycloalkyl,
  • R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5- to 10-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl,
  • R5 and R6 are each independently hydrogen; Halogen (ie, F, Cl, Br, or I); And substituted or unsubstituted C 1 -C 4 alkyl,
  • P 1 is selected from the group consisting of benzyl group, methyl group, ethyl group, i-propyl group and t-butyl group,
  • X is halogen (ie, F, Cl, Br, or I).
  • 'alkyl' refers to a straight or branched carbon chain having 1 to 10 (or 1 to 4) carbon atoms. Specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like can be included.
  • cycloalkyl refers to a saturated or partially unsaturated mono- or poly-carbocyclic ring having 3 to 10 ring carbon atoms. Specifically, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like can be included.
  • Aryl in the present invention refers to an aromatic mono- or poly-carbocyclic ring having 6 to 10 ring carbon atoms. Specifically, phenyl, naphthalenyl, or the like may be included.
  • heteroaryl refers to an aromatic ring composed of 5 to 10 ring constituent atoms including 1 to 2 oxygen, nitrogen or sulfur as a hetero atom.
  • furan, pyran, isobenzofuran, chroman, and the like may be included.
  • 'alkoxy' refers to a group in which linear or branched carbon chain terminal oxygen of 1 to 5 carbon atoms is bonded. Specifically, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, pentoxy, neo-pentoxy and the like are included. Can be.
  • A, and R1 to R6 are substituted groups, it is chloro, iodo, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy, And one or more substituents selected from acetyl.
  • A is R 1 -C ( ⁇ O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 5 alkyl; Substituted or unsubstituted C 3 -C 6 cycloalkyl; Substituted or unsubstituted C 6 -C 8 aryl; Substituted or unsubstituted 5-membered to 8-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or, when A is bonded to R 3, A, R 3 and the carbons to which they are bonded together, together with an oxo ( ⁇ O) group Forms a substituted saturated or unsaturated C 6 -C 10 cycloalkyl,
  • R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 5 alkyl; Substituted or unsubstituted C 3 -C 6 cycloalkyl; Substituted or unsubstituted C 6 -C 8 aryl; Substituted or unsubstituted 5- to 8-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl.
  • the method for preparing the compound of Formula 1 according to the present invention is characterized by using water or various acids as an additive in Michael-addition reaction of the compound of Formula 2 and compound of Formula 3 in the presence of copper powder.
  • the compound of formula 1 may be prepared, for example, via Scheme 1 below.
  • a is copper powder, additives (water or various acids), amine compounds and solvents,
  • R2, R3, R4, R5, R6, P 1 and X are as defined above.
  • the amount of copper powder is not particularly limited, but in consideration of various conditions, it is preferable to use 1.0 to 6.0 equivalents with respect to 1 mole of the compound of formula 2, and 2.0. It is more preferable to use it in the range equivalent or more.
  • water or various acids or mixtures thereof are used as specific additives of the reaction.
  • Acids usable in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Or organic acids such as formic acid, acetic acid, tartaric acid, or the like, may be used alone or in combination of two or more thereof.
  • water or acetic acid as the additive.
  • the amount of water or acid used as the additive is preferably in the range of 0.1 to 6 equivalents, and more preferably in the range of 0.1 to 1 equivalents, based on 1 mol of the compound of Formula 2.
  • Formula 1 compound preparation method of the present invention can be carried out in the presence of an amine compound.
  • N, N, N ', N'- tetramethylethylenediamine (TMEDA; N, N, N ', N '-Tetramethylethylenediamine), N, N, N', N'- tetramethyl-1,3- Propanediamine (TMPDA; N, N, N ', N' -tetramethyl-1,3-propanediamine), N, N, N', N ', N'- pentamethyldiethylenetriamine (PMDTA; N, N, N ', N', N'- Pentamethyldiethylenetriamine), 2- (dimethylamino) ethyl ether, N, N -dimethyl-2- (4-methyl - 1-1 - piperazylyl
  • An amine compound such as ethanamine ( N, N- dimethyl-2- (4-methyl-1-1-piperazylyl) ethanamine)
  • the amount of the amine compound used is preferably in the range of 0.1 to 6 equivalents, and more preferably in the range of 0.1 to 1 equivalents based on 1 mole of the compound of Formula 2 above.
  • TMEDA is typically used.
  • the solvent used in the method for preparing the compound of formula 1 of the present invention is a conventional organic solvent, acetonitrile, aliphatic nitriles, halogenated aliphatic hydrocarbons (eg dichloromethane, dichloroethane, etc.) or cyclized ethers (eg tetrahydrofuran) , 1,4-dioxane, etc.), but is not limited thereto.
  • tetrahydrofuran is typically used.
  • Michael-addition reaction of the compound of Formula 2 and Formula 3 may be carried out at any temperature in the range from 15 °C to reflux temperature.
  • the reaction time of the present invention may vary depending on the conditions of the reactants, the type of solvent, the amount of the solvent, and the like, but the reaction time can be significantly reduced as compared to the conventional method under the same conditions. TLC, 1 H NMR, HPLC, GC, etc. After confirming that the starting compound of the general formula (2) is all consumed, the reaction is terminated. After the reaction is completed, the solvent is distilled off under reduced pressure, and then the compound of Formula 1 may be separated and purified through a conventional method such as column chromatography.
  • the compound of formula 1 may be prepared using water or various acids or mixtures thereof, which have not been tried so far, as an additive, and the reaction time may be significantly shortened and the synthesis yield may be increased as compared with the prior art. . Therefore, by using the manufacturing method of the present invention it is possible to commercially mass-produce the compound of formula (1) useful as intermediates such as pharmaceuticals, pesticides, electronic materials or liquid crystal materials.
  • the yield (23%) and the improvement of the yield of 34% compared to the reaction time (3 hours) of the prior art ( J. Fluorine Chem . 2003 , 121 , 105) and the reaction time of 2 hours can be achieved.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation d'un composé représenté par la formule chimique 1 en utilisant de l'eau ou divers acides comme additifs dans une réaction d'addition de Michael d'un récepteur de Michael représenté par la formule chimique 2 et d'un composé représenté par la formule chimique 3.
PCT/KR2013/000829 2012-02-03 2013-02-01 Procédé de préparation d'un composé par le biais d'une nouvelle réaction d'addition de michael en utilisant de l'eau ou divers acides comme additifs WO2013115595A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EA201491463A EA026411B1 (ru) 2012-02-03 2013-02-01 Способ получения соединения по реакции присоединения михаэля с применением воды или различных кислот в качестве добавки
BR112014018985-4A BR112014018985B1 (pt) 2012-02-03 2013-02-01 método para preparar um composto
AU2013215796A AU2013215796B2 (en) 2012-02-03 2013-02-01 Method for preparing compound by novel Michael addition reaction using water or various acids as additive
CN201380007885.1A CN104159884B (zh) 2012-02-03 2013-02-01 通过使用水或多种酸作为添加剂的新型麦克尔加成反应制备化合物的方法
SG11201404396TA SG11201404396TA (en) 2012-02-03 2013-02-01 Method for preparing compound by novel michael addition reaction using water or various acids as additive
MX2014009309A MX355336B (es) 2012-02-03 2013-02-01 Metodo para preparar un compuesto mediante la reaccion de adicion de michael novedosa usando agua o varios acidos como aditivo.
PH12014501704A PH12014501704B1 (en) 2012-02-03 2014-07-28 Method for preparing compound by novel michael addition reaction using water or various acids as additive
ZA2014/05598A ZA201405598B (en) 2012-02-03 2014-07-29 Method for preparing compound by novel michael addition reaction using water or various acids as additive
TNP2014000329A TN2014000329A1 (en) 2012-02-03 2014-07-31 Method for preparing compound by novel michael addition reaction using water or various acids as additive
MA37281A MA35906B1 (fr) 2012-02-03 2014-08-12 Procédé de préparation d'un composé par le biais d'une nouvelle réaction d'addition de michael en utilisant de l'eau ou divers acides comme additifs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2012-0011317 2012-02-03
KR20120011317 2012-02-03

Publications (1)

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WO2013115595A1 true WO2013115595A1 (fr) 2013-08-08

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KR (1) KR101539761B1 (fr)
CN (1) CN104159884B (fr)
AU (1) AU2013215796B2 (fr)
BR (1) BR112014018985B1 (fr)
CL (1) CL2014002029A1 (fr)
CO (1) CO7030967A2 (fr)
EA (1) EA026411B1 (fr)
MA (1) MA35906B1 (fr)
MX (1) MX355336B (fr)
MY (1) MY168411A (fr)
PE (1) PE20142331A1 (fr)
PH (1) PH12014501704B1 (fr)
SG (1) SG11201404396TA (fr)
TN (1) TN2014000329A1 (fr)
WO (1) WO2013115595A1 (fr)
ZA (1) ZA201405598B (fr)

Families Citing this family (4)

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Publication number Priority date Publication date Assignee Title
US9774740B2 (en) 2008-01-28 2017-09-26 Afiniti Europe Technologies Limited Techniques for benchmarking pairing strategies in a contact center system
CN108191647B (zh) * 2018-02-22 2020-09-29 江苏尚莱特医药化工材料有限公司 2,2-二氟二羧酸二烷基酯的合成方法
CN113149823B (zh) * 2021-03-29 2023-12-08 上海青平药业有限公司 一种2-r1戊酸的制备方法
CN113354495A (zh) * 2021-05-20 2021-09-07 上海应用技术大学 一种二氟酮羰基取代不对称腈类化合物及其制备与应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07103159B2 (ja) * 1985-01-14 1995-11-08 ネオルックス 放射性核種金属キレート

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS573159B2 (fr) * 1973-12-05 1982-01-20
EP1238962B1 (fr) * 2001-03-07 2008-02-27 Firmenich Sa Procédé pour la préparation de produits d'addition de Michael
AU2008341352B2 (en) * 2007-12-21 2013-08-01 Lg Chem, Ltd. Dipeptidyl peptidase-IV inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07103159B2 (ja) * 1985-01-14 1995-11-08 ネオルックス 放射性核種金属キレート

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COMELLES, JOSEP ET AL.: "Ionic and Covalent Copper(II)-Based Catalysts for Michael Additions. The Mechanism", J. ORG. CHEM., vol. 69, no. 20, October 2004 (2004-10-01), pages 6834 - 6842, XP055079825 *
COMELLES, JOSEP ET AL.: "Michael additions catalyzed by transition metals and lanthanide species. A review", ARKIVOC USA, INC., 26 March 2005 (2005-03-26), pages 207 - 238, XP055079823 *
EVANS, DAVID A. ET AL.: "Catalytic Enantioselective Michael Additions to Unsaturated Ester Derivatives Using Chiral Copper(II) Lewis Acid Complexes", ORGANIC LETTERS, vol. 1, no. 6, 1999, pages 865 - 868, XP055079828 *

Also Published As

Publication number Publication date
KR20130090360A (ko) 2013-08-13
PH12014501704A1 (en) 2014-10-13
MA35906B1 (fr) 2014-12-01
EA201491463A1 (ru) 2014-11-28
TN2014000329A1 (en) 2015-12-21
CO7030967A2 (es) 2014-08-21
BR112014018985A8 (pt) 2017-07-11
SG11201404396TA (en) 2015-06-29
ZA201405598B (en) 2015-09-30
AU2013215796A1 (en) 2014-08-21
MY168411A (en) 2018-11-09
AU2013215796B2 (en) 2016-09-15
MX2014009309A (es) 2014-11-10
CN104159884A (zh) 2014-11-19
BR112014018985B1 (pt) 2021-01-19
EA026411B1 (ru) 2017-04-28
KR101539761B1 (ko) 2015-07-28
PE20142331A1 (es) 2015-01-17
CN104159884B (zh) 2016-01-13
MX355336B (es) 2018-04-16
BR112014018985A2 (fr) 2017-06-20
PH12014501704B1 (en) 2014-10-13
CL2014002029A1 (es) 2014-12-26

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