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WO2003057659A1 - Procede de production d'ester d'acide 6,6,6-trifluoro-3,5-dioxohexanoique et de l'un de ses tautomeres - Google Patents

Procede de production d'ester d'acide 6,6,6-trifluoro-3,5-dioxohexanoique et de l'un de ses tautomeres Download PDF

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Publication number
WO2003057659A1
WO2003057659A1 PCT/JP2003/000012 JP0300012W WO03057659A1 WO 2003057659 A1 WO2003057659 A1 WO 2003057659A1 JP 0300012 W JP0300012 W JP 0300012W WO 03057659 A1 WO03057659 A1 WO 03057659A1
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WO
WIPO (PCT)
Prior art keywords
acid ester
reacting
group
methyl
trifluoro
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2003/000012
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English (en)
Japanese (ja)
Inventor
Kazuya Okano
Takako Takahashi
Hodaka Itou
Naoko Sumitani
Ken Tanaka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nihon Nohyaku Co Ltd
Original Assignee
Nihon Nohyaku Co Ltd
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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Publication date
Application filed by Nihon Nohyaku Co Ltd filed Critical Nihon Nohyaku Co Ltd
Priority to JP2003557977A priority Critical patent/JPWO2003057659A1/ja
Priority to AU2003202470A priority patent/AU2003202470A1/en
Publication of WO2003057659A1 publication Critical patent/WO2003057659A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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

Definitions

  • the present invention relates to a method for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester useful as an agricultural chemical intermediate and a tautomer thereof.
  • 6,6,6-Trifluoro-3,5-dioxohexanoic acid ester and its tautomers are capable of forming pyrazole rings such as 1-methyl-13-trifluoromethylpyrazole-15-ylacetic acid ester compounds. It is a useful intermediate compound.
  • Pyrazole compounds having a trifluoromethyl group at the 3-position are useful as pesticides, and in particular, 1-methyl-3-trifluoromethylpyrazole-5-yl acetate compounds are useful as fungicides and insecticides. It is known to be useful (JP-A-6-32781 and WO01Z20993).
  • JP-A-6-32781 discloses that a methyl group at the 5-position of a 3-trifluoromethyl-5-methylvirazole compound is lithiated, then reacted with carbon dioxide, and then esterified to convert the methyl group to an alkoxy group.
  • a method for producing 1-methyl-13-trifluoromethylpyrazole-5-ylacetic acid ester which is converted into a carboxymethyl group is described.
  • WO01 / 20993 discloses that a 5-methyl group of a pyrazole compound is oxidized and then converted to an alkoxycarbonylmethyl group through several steps. A method for producing trifluoro-3-pyrromethylpyrazole-15-ylacetic acid ester is described. However, this method has a problem that the manufacturing process is long.
  • Example 1 of Japanese Patent Application Laid-Open No. 6-49039 discloses that trifluoroacetylacetoacetate ethyl ester, which is another name for 6,6,6-trifunoleo 3,5-dioxohexanoate (083 No. 1 55994) — 08— 4) is written.
  • this trifluoroacetate ethyl acetate is a typographical error of trifluoroacetoacetate. Therefore, 6,6,6_trifluoro-3,5-dioxohexanoic acid ester and its tautomer are not yet known. Disclosure of the invention
  • An object of the present invention is to provide 6,6-, 3-trifluoro-3,5-dioxohexanoic acid ester which can be used for producing 1-methyl-3-trifluoromethylpyrazole-5-ylacetic acid ester.
  • An object of the present invention is to provide tautomers and methods for producing them.
  • the present invention provides a method for reacting a 3-oxobutanoic acid ester with a base capable of reacting with a methylene group at the 2-position, reacting the resulting reactant with a base capable of reacting with a methyl group at the 4-position, and treating the resulting reactant.
  • FIG. 1 is an IR chart of the compound of the present invention obtained in the examples. BEST MODE FOR CARRYING OUT THE INVENTION
  • the present inventors have made a reaction between 3-oxobutanoic acid ester and a base to produce di-one and then react it with trifluoroacetic acid ester to give 6,6,6-trifluoro-3,5-dioxo. He knew that hexanoic acid esters and tautomers thereof could be produced, and completed the present invention.
  • the lower alkyl group in the lower alkyl group and the lower alkyl ester preferably means an alkyl group having 1 to 4 carbon atoms.
  • the 2-position methylene group of the 3-oxobutanoate which is the raw material, reacts with the salt group to form an anion, and then the 4-position methyl group reacts with a base to form a dianion. It is thought that trifluoroacetate (CF 3 C0 2 R,) reacts with this to form 6,6,6-trifluoro-3,5-dioxohexanoate and its tautomer.
  • any ester can be used.
  • alkyl esters particularly preferably lower alkyl esters, are used. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl esters of 3-oxobutanoic acid. Of these, methyl and ethyl esters are preferred.
  • Bases capable of reacting with the 2-position methylene group of 3-oxobutanoate include alkali metals such as sodium metal and lithium metal; alkali metal hydrides such as sodium hydride and potassium hydride; methyl lithium, butyl lithium, Organic lithiums such as xyllithium and phenyllithium; alkali metal amides such as sodium amide and dimethylisopropyl amide; alkali metal alkoxides such as potassium t-butoxide.
  • alkali metal hydride, organolithium, and alkali metal amide are preferred, and sodium hydride is particularly preferred.
  • the base is preferably used in an amount of at least equimolar to 3-oxobutanoic acid ester, particularly preferably in the range of from equimolar to 1.5-fold molar.
  • Examples of the base capable of reacting with the methyl group at the 4-position of 3-oxobutanoic acid ester include organic lithium and alkali metal amide. Of these, butyllithium and lithium diisopropylamide are preferred.
  • This base is also preferably used in an equimolar amount or more, particularly preferably in an equimolar to triple molar amount, with respect to the 3-oxobutanoic acid ester.
  • trifluoroacetate examples include an alkyl trifluoroacetate.
  • lower alkyl esters such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl are preferred, and methyl or ethyl esters are particularly preferred.
  • the trifluoroacetate is used in an amount of preferably 0.8 to 2 times, particularly preferably 1 to 1.2 times, the moles of the 3-oxobutanoate.
  • 3-oxobutanoic acid ester is dissolved in a solvent that is stable against a base, and then the base is reacted to produce anion.Then, the base is further reacted to produce diuyon. It is preferable to react by adding an ester.
  • the reaction temperature at this time is preferably lower at a temperature of 50 ° C or lower, more preferably 30 ° C or lower, particularly preferably 10 ° C or lower in terms of suppression of by-product formation and the like. C is performed in the following range. However, if the temperature is too low, it is not preferable in terms of equipment cost and reaction rate. Will be
  • the two-step reaction between the 3-oxobutanoate and the base is usually carried out for 0.1 to 10 hours, preferably for 0.2 to 1 hour. It is not preferable to spend too much time on the stability of the generated anion.
  • the reaction between the produced dione and the trifluoroacetate is generally carried out for 1 to 24 hours, preferably for 1 to 5 hours.
  • ethers such as tetrahydrofuran (THF), getyl ether, diisopropyl ether, dioxane, and methyl tert-butyl ether, and THF is particularly preferable.
  • the reaction when the reaction is carried out in a mixed solvent system in which an aliphatic hydrocarbon solvent such as hexane or heptane is used in addition to the above ether solvent, the yield is high even at a relatively high reaction temperature of 120 ° C or higher. This is industrially preferable because a product can be obtained.
  • the mixing ratio with the aliphatic hydrocarbon solvent is preferably at least 10 Vo 1% or more based on the total amount of the solvent, and more preferably not more than 50 Vo 1%. .
  • the solvent is preferably used in an amount of 1 to 100 times by volume, especially 5 to 30 times by volume of 3-oxobutanoic acid ester.
  • the ester portion of the 6,6,6-trifluoro-3,5_dioxohexanoic acid ester and its tautomer produced according to the present invention inherits the ester portion of 3_oxobutanoic acid ester in principle, When the ester part of 3-oxobutanoate and trifluoroacetate are different, 6,6,6_trifluoro-3,5-dioxohexanoate having an ester part derived from the ester part of trifluoroacetate and its Tautomers may also form.
  • a 1 L four-necked flask was charged with 8.80 g (22 Ommo 1) of 60% by weight sodium hydride washed twice with 5 OmL of hexane and 50 OmL of THF. At 4 ° C, 23.29 g (20 Ommo 1) of methyl 3-oxobutanoate was added, and the mixture was stirred at the same temperature for 15 minutes. Then, 1.32 mol (21 Ommo 1) of 1.59 mo 1 ZL of n-butyllithium-hexane solution was added dropwise at ⁇ 50 ° C. over 15 minutes, and the mixture was stirred at the same temperature for 15 minutes.
  • the obtained organic layer was concentrated under reduced pressure to obtain 48.Og of an oily substance.
  • Internal standard method The obtained oil contained 36.20 g of the desired product (yield 85%).
  • the oily product was purified by distillation under reduced pressure to obtain 32.84 g of the desired product as a fraction having a boiling point of 52 ° C at a pressure of 1.05 mmHg (isolation yield: 68%).
  • 6,6,6-Trifluoro-3,5_dioxohexanoic acid ester and its tautomers have four variable structures as described above. 6,6,6-Trifluoro-5-hydroxy oxyhexenoic acid ester, and in addition, at least in the solution, 6,6,6-Trifluoro-5-hydrogen It was found to be droxy-13-oxohexenoate.
  • 6,6,6-trifluoro-3,5-dioxohexanoate and its tautomers useful as pharmaceutical and agricultural chemical intermediates can be obtained easily and in good yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de production d'ester d'acide 6,6,6-trifluoro-3,5-dioxohexanoïque et de l'un de ses tautomères. A cet effet, on fait réagir au moyen d'un réactif basique un ester d'acide 3-oxobutanoïque sur le groupe méthylène de la position 2, puis on fait réagir au moyen d'un réactif basique le produit de réaction sur le groupe méthylène de la position 4. Il ne reste plus qu'à faire réagir sur un ester d'acide trifluoroacétique le produit de réaction ainsi obtenu.
PCT/JP2003/000012 2002-01-08 2003-01-06 Procede de production d'ester d'acide 6,6,6-trifluoro-3,5-dioxohexanoique et de l'un de ses tautomeres Ceased WO2003057659A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2003557977A JPWO2003057659A1 (ja) 2002-09-19 2003-01-06 ６，６，６−トリフルオロ−３，５−ジオキソヘキサン酸エステル及びその互変異性体の製造方法
AU2003202470A AU2003202470A1 (en) 2002-01-08 2003-01-06 Process for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and tautomer thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2002001771 2002-01-08
JP2002-001771 2002-01-08
JP2002272479A JP2005247690A (ja) 2002-01-08 2002-09-19 ６，６，６−トリフルオロ−３，５−ジオキソヘキサン酸エステル及びその互変異性体の製造方法
JP2002-272479 2002-09-19

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WO2003057659A1 true WO2003057659A1 (fr) 2003-07-17

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AU (1) AU2003202470A1 (fr)
WO (1) WO2003057659A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8987456B2 (en) 2011-10-05 2015-03-24 Merck Sharp & Dohme Corp. 3-pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9006444B2 (en) 2011-10-05 2015-04-14 Merck Sharp & Dohme Corp. Phenyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9120785B2 (en) 2011-05-10 2015-09-01 Merck Sharp & Dohme Corp. Pyridyl aminopyridines as Syk inhibitors
US9145391B2 (en) 2011-05-10 2015-09-29 Merck Sharp & Dohme Corp. Bipyridylaminopyridines as Syk inhibitors
US9216173B2 (en) 2011-10-05 2015-12-22 Merck Sharp & Dohme Corp. 2-Pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9242984B2 (en) 2012-06-20 2016-01-26 Merck Sharp & Dohme Corp. Pyrazolyl derivatives as Syk inhibitors
US9290490B2 (en) 2011-05-10 2016-03-22 Merck Sharp & Dohme Corp. Aminopyrimidines as Syk inhibitors
US9487504B2 (en) 2012-06-20 2016-11-08 Merck Sharp & Dohme Corp. Imidazolyl analogs as syk inhibitors
US9499534B2 (en) 2013-04-26 2016-11-22 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors
US9586931B2 (en) 2012-09-28 2017-03-07 Merck Sharp & Dohme Corp. Triazolyl derivatives as Syk inhibitors
US9598405B2 (en) 2012-12-21 2017-03-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors
US9624210B2 (en) 2012-12-12 2017-04-18 Merck Sharp & Dohme Corp. Amino-pyrimidine-containing spleen tyrosine kinase (Syk) inhibitors
US9670196B2 (en) 2013-12-20 2017-06-06 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as Spleen Tyrosine Kinase inhibitors
US9745295B2 (en) 2013-04-26 2017-08-29 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9775839B2 (en) 2014-03-13 2017-10-03 Merck Sharp & Dohme Corp. 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors
US9783531B2 (en) 2013-12-20 2017-10-10 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9822107B2 (en) 2013-12-20 2017-11-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors

Citations (4)

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Publication number Priority date Publication date Assignee Title
JPH0649039A (ja) * 1992-06-04 1994-02-22 Nippon Soda Co Ltd ピリミジン誘導体、除草剤および農園芸用殺菌剤
WO2000036134A1 (fr) * 1998-12-14 2000-06-22 Forschungszentrum Jülich GmbH Procede de reduction enantioselective d'acides 3,5-dioxocarboxyliques, leurs sels et esters
WO2001020993A1 (fr) * 1999-09-24 2001-03-29 Agro-Kanesho Co., Ltd. Agents insecticides et acaricides
WO2002002547A1 (fr) * 2000-06-30 2002-01-10 Merck Frosst Canada & Co. Pyrones utilisées comme inhibiteurs de la cyclooxygénase-2

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0649039A (ja) * 1992-06-04 1994-02-22 Nippon Soda Co Ltd ピリミジン誘導体、除草剤および農園芸用殺菌剤
WO2000036134A1 (fr) * 1998-12-14 2000-06-22 Forschungszentrum Jülich GmbH Procede de reduction enantioselective d'acides 3,5-dioxocarboxyliques, leurs sels et esters
WO2001020993A1 (fr) * 1999-09-24 2001-03-29 Agro-Kanesho Co., Ltd. Agents insecticides et acaricides
WO2002002547A1 (fr) * 2000-06-30 2002-01-10 Merck Frosst Canada & Co. Pyrones utilisées comme inhibiteurs de la cyclooxygénase-2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHAO L. ET AL.: "Asymmetrix hydrogenation of 3,5-dioxoesters catalyzed by Ru-binap complex: A short step asymmetric synthesis of 6-substituted 5,6-dihydro-2-pyrones", TETRAHEDRON, vol. 49, no. 10, 1993, pages 1997 - 2010, XP002928306 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9120785B2 (en) 2011-05-10 2015-09-01 Merck Sharp & Dohme Corp. Pyridyl aminopyridines as Syk inhibitors
US9145391B2 (en) 2011-05-10 2015-09-29 Merck Sharp & Dohme Corp. Bipyridylaminopyridines as Syk inhibitors
US9290490B2 (en) 2011-05-10 2016-03-22 Merck Sharp & Dohme Corp. Aminopyrimidines as Syk inhibitors
US9006444B2 (en) 2011-10-05 2015-04-14 Merck Sharp & Dohme Corp. Phenyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9216173B2 (en) 2011-10-05 2015-12-22 Merck Sharp & Dohme Corp. 2-Pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US8987456B2 (en) 2011-10-05 2015-03-24 Merck Sharp & Dohme Corp. 3-pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
US9242984B2 (en) 2012-06-20 2016-01-26 Merck Sharp & Dohme Corp. Pyrazolyl derivatives as Syk inhibitors
US9487504B2 (en) 2012-06-20 2016-11-08 Merck Sharp & Dohme Corp. Imidazolyl analogs as syk inhibitors
US9586931B2 (en) 2012-09-28 2017-03-07 Merck Sharp & Dohme Corp. Triazolyl derivatives as Syk inhibitors
US9624210B2 (en) 2012-12-12 2017-04-18 Merck Sharp & Dohme Corp. Amino-pyrimidine-containing spleen tyrosine kinase (Syk) inhibitors
US9598405B2 (en) 2012-12-21 2017-03-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors
US9499534B2 (en) 2013-04-26 2016-11-22 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors
US9745295B2 (en) 2013-04-26 2017-08-29 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9670196B2 (en) 2013-12-20 2017-06-06 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as Spleen Tyrosine Kinase inhibitors
US9783531B2 (en) 2013-12-20 2017-10-10 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9822107B2 (en) 2013-12-20 2017-11-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9775839B2 (en) 2014-03-13 2017-10-03 Merck Sharp & Dohme Corp. 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors

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AU2003202470A1 (en) 2003-07-24

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