WO2018128390A1 - Procédé de production d'un composé de 5-(3,6-dihydro-2,6-dioxo-4-trifluorométhyl-1(2h)-pyrimidinyl)phénylthiol - Google Patents

Procédé de production d'un composé de 5-(3,6-dihydro-2,6-dioxo-4-trifluorométhyl-1(2h)-pyrimidinyl)phénylthiol Download PDF

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Publication number
WO2018128390A1
WO2018128390A1 PCT/KR2018/000126 KR2018000126W WO2018128390A1 WO 2018128390 A1 WO2018128390 A1 WO 2018128390A1 KR 2018000126 W KR2018000126 W KR 2018000126W WO 2018128390 A1 WO2018128390 A1 WO 2018128390A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
dioxo
dihydro
trifluoromethyl
Prior art date
Application number
PCT/KR2018/000126
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English (en)
Korean (ko)
Inventor
이경재
국진철
안영천
이준원
Original Assignee
주식회사 팜한농
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 팜한농 filed Critical 주식회사 팜한농
Priority to CN201880005989.1A priority Critical patent/CN110167920A/zh
Publication of WO2018128390A1 publication Critical patent/WO2018128390A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals

Definitions

  • the present invention relates to a method for producing 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound represented by the following general formula (IV). It is about.
  • Korean Patent No. 1103840 (2012.01.02) has used the compound represented by Formula IV as an intermediate to synthesize a uracil compound having the following structure having herbicidal activity.
  • Korean Patent No. 1345394 discloses a method of synthesizing the compound represented by Chemical Formula IV by a one-pot reaction.
  • the present inventors have developed an improved manufacturing method capable of synthesizing the compound represented by Chemical Formula IV, which has various industrial uses, in a stable yield without safety problems, thereby completing the present invention.
  • the 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound can be safely produced in a stable yield.
  • a method is provided.
  • a catalyst mixture comprising a reducing agent, a catalyst and a reaction solvent
  • R 1 and R 2 are each independently hydrogen, halogen or alkyl of 1 to 4 carbon atoms; R 3 is hydrogen or alkyl having 1 to 4 carbon atoms.
  • the preparation process according to the invention is carried out by the reaction rate in the synthesis of 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound.
  • preparing a catalyst mixture comprising a reducing agent, a catalyst and a reaction solvent
  • R 1 and R 2 are each independently hydrogen, halogen or alkyl having 1 to 4 carbon atoms, preferably fluoro, chloro, bromo, or iodoyl, more preferably fluoro or chloro;
  • R 3 is hydrogen or alkyl having 1 to 4 carbon atoms, preferably hydrogen, methyl, ethyl, or propyl, more preferably methyl or ethyl.
  • the compound of formula IV has herbicidal activity and can be suitably used as an active substance of the weed removal composition or as an intermediate thereof.
  • the compound of formula (IV) comprises the steps of forming a compound represented by formula (III) by a reduction reaction of the compound represented by formula (I) in a reaction solvent in the presence of a reducing agent and a catalyst (reduction reaction step); And forming a compound represented by Chemical Formula IV by the hydrolysis reaction of the compound represented by Chemical Formula III (hydrolysis reaction step).
  • the reaction proceeds by substantially adding all the raw materials necessary for the reaction such as a reducing agent, a catalyst, and a precursor (the compound of Formula I) in the reduction reaction step, the yield of the target product is not only lowered due to the runaway reaction, but also serious. Safety issues may arise.
  • the above-described problem may be solved by changing the order of adding reactants in the reduction reaction step.
  • the compound of formula (IV) comprises the steps of (i) preparing a catalyst mixture comprising a reducing agent, a catalyst and a reaction solvent; (ii) separately from the catalyst mixture, preparing a solution comprising the compound of formula (I), and dropwise adding it to the catalyst mixture to reduce the reaction; And (iii) hydrolysis reaction by adding hydrochloric acid to the reaction solution of the reduction reaction.
  • the type of reducing agent included in the catalyst mixture is not particularly limited.
  • the reducing agent lithium aluminum hydride (LiAlH 4 ), red phosphorus (Red P), aluminum chloride (AlCl 3 ), tin (IV) chloride (SnCl 4 ), tin (II) chloride (SnCl 2 )
  • the reducing agent lithium aluminum hydride (LiAlH 4 ), red phosphorus (Red P), aluminum chloride (AlCl 3 ), tin (IV) chloride (SnCl 4 ), tin (II) chloride (SnCl 2 )
  • ZnCl 2 zinc metal
  • the reducing agent may be included in the catalyst mixture in a ratio of 1 to 10 mol, or 1 to 6 mol, or 1 to 4 mol based on 1 mol of the compound of Formula (I).
  • the catalyst included in the catalyst mixture may be iodine (I 2 ).
  • the catalyst may be included in the catalyst mixture in an amount of 0.001 to 1 mol, or 0.005 to 1 mol, or 0.005 to 0.5 mol, or 0.005 to 0.1 mol based on 1 mol of the reducing agent.
  • the kind of reaction solvent contained in the catalyst mixture is not particularly limited.
  • the reaction solvent is selected from the group consisting of acetic acid, ethanol, methanol, tetrahydrofuran, 4-dioxane, N, N-dimethylformamide, dimethylsulfoxide, acetone, dichloromethane, and chloroform
  • One or more compounds may be used.
  • the solution containing the compound of formula (I) is a solution in which the compound of formula (I) is completely dissolved in the same type of organic solvent as the reaction solvent included in the catalyst mixture.
  • the reduction reaction is carried out by dropwise addition of a solution comprising the compound of formula I to the catalyst mixture.
  • the dropping rate of the solution containing the compound of formula (I) can be adjusted in a range that can be suppressed runaway reaction according to the concentration change of the compound of formula (II) which is an intermediate of the reaction.
  • the concentration change of the compounds of Formulas (II) and (III) in the reduction reaction step can be confirmed through conventional methods such as HPLC, and if the compound of Formula (II) is not detected, the reduction reaction step is terminated.
  • This reduction reaction step may be advantageous in terms of securing the reaction efficiency is carried out at a temperature of 80 °C or more, or 80 to 200 °C, or 100 to 150 °C.
  • the reduction reaction step may be performed by dropwise adding a solution including the compound of formula I to the catalyst mixture heated to 100 to 150 °C.
  • a hydrolysis reaction step is performed in which hydrochloric acid is added to a solution containing the compound represented by Formula III obtained through the reduction reaction step to form a compound represented by the following Formula IV.
  • the hydrolysis reaction step may be performed by adding hydrochloric acid and stirring the reaction system at 80 to 120 °C.
  • the compound of Formula IV which is produced through the hydrolysis reaction step, may be recovered through a crystallization process. And, if necessary, a high purity compound can be obtained through a conventional separation and purification process, for example, washing with an organic solvent, fractional distillation, column chromatography, and the like.
  • Acetic acid (209.1 g), red phosphorus (30.8 g, 0.993 mol) and iodine (I 2 , 2.5 g, 10 mmol) were mixed and heated to 80-90 ° C. and stirred for 0.5 h.
  • acetic acid (627.4 g) was added to a compound of formula (I ') (2-chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoro) Romethyl-1 (2H) -pyrimidinyl) phenylsulfonyl chloride; 209.1 g, 0.497 mol) was added to prepare a fully dissolved compound solution.
  • the compound solution was added dropwise to the catalyst mixture at a temperature of 105 to 115 ° C. for 4 hours. After completion of the dropwise addition, the mixture was stirred for 2 hours in the temperature range.
  • the production of the compound of formula III ' which is a reaction product
  • the generation and disappearance of the compound of formula II' which is an intermediate thereof
  • the reduction reaction was terminated. It was. At this time, by checking the concentration change of the compound of Formula (II ′) was carried out a reduction reaction while controlling the rate of dropping.
  • the reaction solution of the reduction reaction was cooled to 80 °C and filtered through a celite pad (residue of red phosphorus).
  • 10% HCl (72.4 g, 0.199 mol) was added dropwise at a temperature ranging from 100 to 110 ° C., followed by stirring at 105 to 110 ° C. for 2 hours, followed by hydrolysis.
  • the reaction mixture was added dropwise to water, followed by stirring to precipitate the product as a solid.
  • the precipitated solid was filtered and dried to obtain a compound of formula IV ′ as a white white solid (169.1 g, 96%).
  • reaction solution was filtered through a celite pad, and then the reaction solution was added to water and extracted with ethylene chloride.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de production d'un composé de 5-(3,6-dihydro-2,6-dioxo-4-trifluorométhyl-1(2H)-pyrimidinyl)phénylthiol. Le procédé de production selon la présente invention permet de fournir un rendement et une sécurité stables du processus de production en supprimant la réaction d'emballement en régulant le taux de réaction lors de la synthèse d'un composé 5-(3,6-dihydro-2,6-dioxo-4-trifluorométhyl-1(2H)pyrimidinyl)phénylthiol.
PCT/KR2018/000126 2017-01-06 2018-01-03 Procédé de production d'un composé de 5-(3,6-dihydro-2,6-dioxo-4-trifluorométhyl-1(2h)-pyrimidinyl)phénylthiol WO2018128390A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880005989.1A CN110167920A (zh) 2017-01-06 2018-01-03 制备5-(3,6-二氢-2,6-二氧-4-三氟甲基-1(2h)-嘧啶基)苯硫酚化合物的方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020170002309A KR20180081276A (ko) 2017-01-06 2017-01-06 5-(3,6-다이하이드로-2,6-다이옥소-4-트리플루오로메틸-1(2h)-피리미디닐)페닐싸이올 화합물의 제조 방법
KR10-2017-0002309 2017-01-06

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WO2018128390A1 true WO2018128390A1 (fr) 2018-07-12

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KR (1) KR20180081276A (fr)
CN (1) CN110167920A (fr)
WO (1) WO2018128390A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006962A1 (fr) * 1990-10-18 1992-04-30 Monsanto Company Composes herbicides d'haloalkylpyrazoles aryle substitue
EP1122244A1 (fr) * 2000-02-04 2001-08-08 Sumitomo Chemical Company, Limited Composés d'uracile et leur usage
WO2003029226A1 (fr) * 2001-09-26 2003-04-10 Basf Aktiengesellschaft Phenoxyalkyl-, phenylthioalkyl-, phenylaminoalkyl- et phenylalkyl-sulfamoylcarboxamides a substitution heterocyclyle
KR20100038052A (ko) * 2008-10-02 2010-04-12 한국화학연구원 우라실계 화합물 및 이를 포함하는 제초제
KR101345394B1 (ko) * 2012-07-13 2013-12-24 동부팜한농 주식회사 5-(3,6-다이하이드로-2,6-다이옥소-4-트리플루오로메틸-1(2ｈ)-피리미디닐)페닐싸이올 화합물의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006962A1 (fr) * 1990-10-18 1992-04-30 Monsanto Company Composes herbicides d'haloalkylpyrazoles aryle substitue
EP1122244A1 (fr) * 2000-02-04 2001-08-08 Sumitomo Chemical Company, Limited Composés d'uracile et leur usage
WO2003029226A1 (fr) * 2001-09-26 2003-04-10 Basf Aktiengesellschaft Phenoxyalkyl-, phenylthioalkyl-, phenylaminoalkyl- et phenylalkyl-sulfamoylcarboxamides a substitution heterocyclyle
KR20100038052A (ko) * 2008-10-02 2010-04-12 한국화학연구원 우라실계 화합물 및 이를 포함하는 제초제
KR101345394B1 (ko) * 2012-07-13 2013-12-24 동부팜한농 주식회사 5-(3,6-다이하이드로-2,6-다이옥소-4-트리플루오로메틸-1(2ｈ)-피리미디닐)페닐싸이올 화합물의 제조방법

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CN110167920A (zh) 2019-08-23
KR20180081276A (ko) 2018-07-16

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