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WO2018128387A1 - Procédé de production d'un composé d'uracile 3-aryle - Google Patents

Procédé de production d'un composé d'uracile 3-aryle Download PDF

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Publication number
WO2018128387A1
WO2018128387A1 PCT/KR2018/000122 KR2018000122W WO2018128387A1 WO 2018128387 A1 WO2018128387 A1 WO 2018128387A1 KR 2018000122 W KR2018000122 W KR 2018000122W WO 2018128387 A1 WO2018128387 A1 WO 2018128387A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
reaction
cyclization
solvent
Prior art date
Application number
PCT/KR2018/000122
Other languages
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.)
Filing date
Publication date
Application filed by 주식회사 팜한농 filed Critical 주식회사 팜한농
Priority to CN201880005354.1A priority Critical patent/CN110167919A/zh
Publication of WO2018128387A1 publication Critical patent/WO2018128387A1/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 process for the preparation of 3-aryluracil compounds.
  • the 3-aryluracil compound represented by the following formula (IV) and salts thereof may be used as important intermediates in the field of manufacturing food, medicine, pesticides, etc. by organic synthesis.
  • 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.
  • the present inventors have developed an improved manufacturing method capable of more efficiently synthesizing the 3-aryluracil compound represented by Chemical Formula IV, which has various industrial uses, and completed the present invention.
  • a method for enabling efficient preparation of a 3-aryluracil compound such as reducing the reaction time and reducing the amount of solvent used, is provided.
  • R 1 is hydrogen, halogen or alkyl of 1 to 4 carbon atoms
  • R 2 is alkyl having 1 to 4 carbon atoms or haloalkyl having 1 to 4 carbon atoms
  • R 3 is alkyl having 1 to 4 carbons
  • R 4 is halogen or cyano
  • R 5 is hydrogen or halogen
  • R 6 is alkyl having 1 to 4 carbons
  • R 7 is alkyl having 1 to 4 carbon atoms.
  • the preparation method according to the present invention enables efficient preparation of 3-aryluracil compounds, such as reducing the reaction time for preparing the 3-aryluracil compound and reducing the amount of solvent used.
  • the cyclization step is provided for the process of preparing 3-aryluracils compound, which is performed while continuously removing the reaction by-products alcohol (R 3 OH and R 6 OH) from the reaction system.
  • R 1 may be hydrogen, halogen or alkyl having 1 to 4 carbon atoms, preferably hydrogen;
  • R 2 is alkyl having 1 to 4 carbon atoms or haloalkyl having 1 to 4 carbon atoms, preferably haloalkyl having 1 to 4 carbon atoms;
  • R 3 , R 6 and R 7 are each alkyl having 1 to 4 carbon atoms;
  • R 4 is halogen or cyano, preferably halogen;
  • R 5 is hydrogen or halogen, preferably halogen.
  • the 3-aryluracils compound represented by Formula IV and salts thereof may be used as important intermediates in the field of manufacturing food, medicine, pesticides, etc. by organic synthesis.
  • 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 is (i) forming a compound of formula III by cyclization reaction of the compound of formula I with the compound of formula II; (ii) by alkylation of a compound of formula III to form an N-substituted compound corresponding to formula IV (a compound in which an alkyl group is introduced on an unsubstituted nitrogen atom of the uracil nucleus) Can be.
  • alcohols R 3 OH and R 6 OH
  • the cyclization step comprises: (a) in a polar or nonpolar solvent having a high boiling point of at least 80 ° C., in the presence of a suitable base, (c) alcohols that are reaction byproducts (R) 3 OH and R 6 OH) are carried out continuously from the reaction system.
  • R reaction byproducts
  • R 6 OH reaction byproducts
  • the base in the cyclization step is potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), cesium carbonate (Cs 2 CO 3 ), potassium bicarbonate (KHCO 3 ), Sodium bicarbonate (NaHCO 3 ), and 1,8-diazabicyclo [5.4.0] undec-7-ene (1,8-diazabicyclo [5.4.0] undec-7-ene) It may be one or more compounds.
  • N, N- dimethylformamide (boiling point 152 to 154 °C), N-methyl as the solvent in the cyclization step
  • Polar solvents such as 2-pyrrolidone (boiling point 202-204 ° C.), and dimethyl sulfoxide (boiling point 189 ° C.);
  • nonpolar solvents such as methyl butyl diglycol (boiling point 211.4 ° C.) and ortho-dichlorobenzene (boiling point 180.5 ° C.) may be used.
  • the cyclization step may be performed at a high temperature of 80 ° C. or higher, or 80 to 250 ° C., or 100 to 230 ° C., or 120 to 220 ° C., or 130 to 210 ° C., but is not limited thereto. It doesn't happen.
  • recovery of the solvent may be achieved by separating the polar layer (for example, the water layer) when performing the cyclization reaction. It may be possible to improve the production efficiency by the reuse of the recovered solvent.
  • the solvent in the cyclization step may be added in a weight of 0.5 to 15 times, or 1 to 10 times, or 1 to 6.1 times with respect to the compound of Formula I, but is not limited thereto. It is not.
  • the cyclization step may be performed by cyclization of the compound of Formula I and the compound of Formula II to form the compound of Formula III, and the reaction products thereof include alcohols (R 3 OH and R). 6 OH) is carried out continuously from the reaction system via distillation.
  • This cyclization step can be carried out using a distillation process.
  • the cyclization step in the presence of the inorganic base potassium carbonate (K 2 CO 3 ), N, N- dimethylformamide added in 3.5 times the weight of the compound of Formula I as a solvent, Alcohols which are reaction by-products can be carried out continuously from the reaction system.
  • K 2 CO 3 inorganic base potassium carbonate
  • N, N- dimethylformamide added in 3.5 times the weight of the compound of Formula I as a solvent
  • the cyclization step may be performed by using N, N-dimethylformamide as a solvent in which N, N-dimethylformamide is added at 1.5 times the weight of the compound of Formula I in the presence of inorganic base potassium carbonate (K 2 CO 3 ).
  • the reaction by-product alcohols can be performed while continuously removing from the reaction system.
  • the cyclization step may be performed by using N, N-dimethylformamide, which is added at 1.5 times the weight of the compound of Formula I in the presence of an inorganic base sodium carbonate (Na 2 CO 3 ).
  • the reaction by-product alcohols can be performed while continuously removing from the reaction system.
  • the cyclization step may be performed by using N, N-dimethylformamide in an amount of 1.5 times the weight of the compound of Formula I in the presence of the inorganic base cesium carbonate (Cs 2 CO 3 ).
  • the reaction by-product alcohols can be performed while continuously removing from the reaction system.
  • the cyclization step may be performed by using N, N-dimethylformamide, which is added at 1.5 times the weight of the compound of Formula I, in the presence of an inorganic base, potassium bicarbonate (KHCO 3 ), as a solvent.
  • the alcohol may be performed by continuously removing the reaction by-products from the reaction system.
  • the cyclization step may be performed by using N, N-dimethylformamide added in an amount of 1.5 times the weight of the compound of Formula I in the presence of an inorganic base sodium bicarbonate (NaHCO 3 ) as a solvent.
  • the alcohol may be performed by continuously removing the reaction by-products from the reaction system.
  • the cyclization step may be performed by the organic base of 1,8-diazabicyclo [5.4.0] undec-7-ene (1,8-diazabicyclo [5.4.0] undec-7-ene).
  • N, N-dimethylformamide added at 1.5 times the weight of the compound of the above formula (I) as a solvent, it can be carried out while continuously removing the alcohol by-products from the reaction system.
  • the cyclization step is N-methyl-2-pyrrolidone added in an amount of 1.5 times the weight of the compound of Formula I in the presence of inorganic base potassium carbonate (K 2 CO 3 ).
  • K 2 CO 3 inorganic base potassium carbonate
  • the cyclization step may be carried out by reaction with dimethyl sulfoxide added in an amount of 1.5 times the weight of the compound of Formula I in the presence of an inorganic base, potassium carbonate (K 2 CO 3 ), as a solvent.
  • Phosphorus alcohols can be carried out continuously from the reaction system.
  • the cyclization step may be performed by reaction with methyl butyl diglycol added at a weight of 6.1 times the compound of Formula I in the presence of an inorganic base, potassium carbonate (K 2 CO 3 ), as a solvent. Alcohol by-products can be carried out continuously from the reaction system.
  • the cyclization step may include, in the presence of an inorganic base, potassium carbonate (K 2 CO 3 ), ortho-dichlorobenzene added in an amount of 1.5 times the weight of the compound of Formula I as a solvent, Alcohols which are reaction by-products can be carried out continuously from the reaction system.
  • potassium carbonate K 2 CO 3
  • ortho-dichlorobenzene added in an amount of 1.5 times the weight of the compound of Formula I as a solvent
  • the product may have a form of a metal salt or an organic salt corresponding to Formula III.
  • alkylated means that an alkyl group having 1 to 4 carbon atoms (R 7 ) is introduced on an unsubstituted nitrogen atom of the uracil nucleus in the compound of Formula III.
  • the alkylation step is carried out continuously without changing the solvent in the presence of an alkylating agent such as dialkyl sulfate or alkyl halide having 1 to 4 carbon atoms or dichloromethane, 1,2 It can be carried out by adding a solvent such as dichloroethane and toluene.
  • an alkylating agent such as dialkyl sulfate or alkyl halide having 1 to 4 carbon atoms or dichloromethane, 1,2
  • a solvent such as dichloroethane and toluene.
  • the 3-aryluracil compound of Formula IV can be prepared.
  • N, N-dimethylformamide (400.3 g) to potassium carbonate (227.9 g, 1.649 mol), a compound of formula (I ') (ethyl 3-amino-4,4,4-trifluorocrotonate, 114.4 g, 0.625 mol) and The compound of formula II '(ethyl N- (4-chloro-2-fluorophenyl) carbamate, 149.5 g, 0.687 mol) was added and the temperature was raised and stirred for 4 hours in the temperature range of 130 to 135 °C. The byproduct (EtOH) produced during stirring was continuously removed by distillation to maintain the temperature.
  • EtOH byproduct
  • the compound of Formula III ' was obtained in the same manner as in Example 1, except that N, N-dimethylformamide, which was a reaction solvent in the cyclization, was added at a weight of 1.5 times the compound of Formula I'.
  • the cyclization was complete after about 4 hours.
  • the cyclization was completed after about 6.5 hours.
  • the cyclization was complete after about 4 hours.
  • the cyclization was completed after about 3.5 hours.
  • the cyclization was completed after about 3.5 hours.
  • the cyclization was complete after about 4 hours.
  • the cyclization was complete after about 4 hours.
  • NMP N-methyl-2-pyrrolidone
  • the cyclization was completed after about 2.5 hours.
  • the cyclization was completed after about 2.5 hours.
  • the compound of Formula III ′ was obtained in the same manner as in Example 1, except that distillation for removing the reaction byproduct (ethanol) was not performed in the cyclization.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (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)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé destiné à la production d'un composé d'uracile 3-aryle. Le procédé de production selon la présente invention peut produire efficacement un composé d'uracile 3-aryle par réduction du temps de réaction pour la production du composé d'uracile 3-aryle et d'une quantité d'un solvant utilisé.
PCT/KR2018/000122 2017-01-06 2018-01-03 Procédé de production d'un composé d'uracile 3-aryle WO2018128387A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880005354.1A CN110167919A (zh) 2017-01-06 2018-01-03 3-芳基尿嘧啶化合物的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2017-0002308 2017-01-06
KR1020170002308A KR20180081275A (ko) 2017-01-06 2017-01-06 3-아릴우라실 화합물의 제조 방법

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WO2018128387A1 true WO2018128387A1 (fr) 2018-07-12

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4859229A (en) * 1986-07-31 1989-08-22 Hoffmann-La Roche Inc. 3-Aryluracils having an ether (thio) carbomyloxy or sulphomyloxy substituent on the aromatic moiety
EP0831091A2 (fr) * 1996-09-23 1998-03-25 Novartis AG Procédé de préparation de 3-aryl-uraciles
EP0563384B1 (fr) * 1990-12-17 2001-10-04 Nissan Chemical Industries, Limited Derive d'uracile
US20020010334A1 (en) * 2000-06-30 2002-01-24 Xun Li Processes to prepare pyrimidinediones
KR20060120187A (ko) * 2003-12-03 2006-11-24 바스프 악티엔게젤샤프트 3-페닐(티오)우라실 및 3-페닐디티오우라실의 제조 방법

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19644534C2 (de) * 1996-10-26 2001-03-22 Vaupel Textilmaschinen Gmbh & Vorrichtung zum Längstrennen einer schmelzfähigen Breitbahn in mindestens zwei Bändern, insbesondere in gemusterte Etikettbänder

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4859229A (en) * 1986-07-31 1989-08-22 Hoffmann-La Roche Inc. 3-Aryluracils having an ether (thio) carbomyloxy or sulphomyloxy substituent on the aromatic moiety
EP0563384B1 (fr) * 1990-12-17 2001-10-04 Nissan Chemical Industries, Limited Derive d'uracile
EP0831091A2 (fr) * 1996-09-23 1998-03-25 Novartis AG Procédé de préparation de 3-aryl-uraciles
US20020010334A1 (en) * 2000-06-30 2002-01-24 Xun Li Processes to prepare pyrimidinediones
KR20060120187A (ko) * 2003-12-03 2006-11-24 바스프 악티엔게젤샤프트 3-페닐(티오)우라실 및 3-페닐디티오우라실의 제조 방법

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CN110167919A (zh) 2019-08-23
KR20180081275A (ko) 2018-07-16

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