WO2007000412A1 - Verfahren zur herstellung von substituierten phenylmalonestern, zwischenverbindungen sowie deren verwendung zur herstellung von 5 , 7-dihydr0xy-6- (2,4, 6-trifluorphenyl) -(1,2 , 4) triazolo (1 , 5-a) pyrimidinen - Google Patents
Verfahren zur herstellung von substituierten phenylmalonestern, zwischenverbindungen sowie deren verwendung zur herstellung von 5 , 7-dihydr0xy-6- (2,4, 6-trifluorphenyl) -(1,2 , 4) triazolo (1 , 5-a) pyrimidinen Download PDFInfo
- Publication number
- WO2007000412A1 WO2007000412A1 PCT/EP2006/063487 EP2006063487W WO2007000412A1 WO 2007000412 A1 WO2007000412 A1 WO 2007000412A1 EP 2006063487 W EP2006063487 W EP 2006063487W WO 2007000412 A1 WO2007000412 A1 WO 2007000412A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compounds
- production
- substituted
- triazolo
- Prior art date
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Classifications
-
- 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
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional 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
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to a process for the preparation of substituted phenylmalonic esters of the formula I.
- R is Ci-C 4 alkyl and Q is halo, Ci-C4-alkyl, Ci-C 4 alkoxy, halo-Ci-C4-alkyl is, or Ci-C4 haloalkoxy, and the index m is an is an integer from 1 to 5, where the groups Q may be the same or different when the index m is greater than 1, comprising steps A) and B):
- the invention relates to novel Phenylmalonesterderivate, and their use as intermediates.
- the object of the present invention was to provide an economical and industrially feasible process for the preparation of substituted phenylmalonic esters of the formula I.
- the method according to the invention overcomes the disadvantages of the prior art. It provides an elegant approach to substituted phenylmalonic esters, especially those having one or more fluorine substituents in the phenyl ring.
- the process according to the invention is preferably suitable for the preparation of those compounds I in which the subscript m is 1, 2, 3 or 4 and the group Q is fluorine, chlorine, methyl, methoxy, trifluoromethoxy.
- the process according to the invention is based on hydroxy compounds of the formula II which are readily available, for example, from the coupling of Grignard salts of the formula IV with mesoxalic esters of the formula V.
- the Grignard reaction is usually carried out at low temperatures, preferably at temperatures of -80 ° to -40 ° C.
- Suitable halogenating agents are chlorinating or brominating agents such as phosphorus oxybromide, phosphorus oxychloride, thionyl chloride, thionyl bromide or sulfuryl chloride; preference is given to phosphorus halides, such as POCl 3 , PCI 5 , POBr 3 or PBr 5 , in particular POCl 3 / PCI 5 - or POBr 3 / PBr 5 systems used.
- the reaction may be carried out neat or in the presence of a solvent. Typical reaction temperatures are from 0 to 15O 0 C or preferably from 80 to 125 0 C.
- Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE ), Dioxane, anisole and tetrahydrofuran (THF), ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, particularly preferably in the halogenating agent or halogenated hydrocarbons. It is also possible to use mixtures of the solvents mentioned.
- the starting materials are generally reacted with one another in equimolar amounts. It may be advantageous for the yield to use [HAL] in an excess relative to II.
- the dehalogenation of the compounds of the formula III and conversion into the phenyl malonates is carried out by catalytic hydrogenation. This reaction is usually carried out at temperatures of from 0 C to 15O 0 C, preferably 1O 0 C to 100 0 C, in an inert organic solvent in the presence of a base [cp. JP 04224535].
- Suitable solvents are water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, as well as dimethyl sulfoxide, dimethylformamide and dimethylacetamide or carboxylic acids.
- Preferred solvents are ethers, such as THF, dioxane and alcohols. It is also possible to use mixtures of the solvents mentioned.
- Bases generally include inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides such as lithium oxide, sodium oxide, calcite oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, Alkali metal amides such as lithium amide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates such as lithium carbonate, potassium carbonate and calcium carbonate, and alkali metal hydrogencarbonates such as sodium bicarbonate, and alkali metal and alkaline earth metal alcoholates such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide and dimethoxy magnesium, as well as organic bases , eg tertiary amines such as trimethylamine, triethylamine, di-is
- the bases will generally be equimolar, in excess, or optionally used as a solvent. Preferably, 3-4 molar equivalents, based on the compound of formula IM, are used.
- the reaction preferably takes place in the presence of a catalyst, such as transition metal catalysts, in particular nickel, cobalt, palladium, platinum, ruthenium, rhodium or copper catalysts.
- a catalyst such as transition metal catalysts, in particular nickel, cobalt, palladium, platinum, ruthenium, rhodium or copper catalysts.
- a catalyst such as transition metal catalysts, in particular nickel, cobalt, palladium, platinum, ruthenium, rhodium or copper catalysts.
- a catalyst such as transition metal catalysts, in particular nickel, cobalt, palladium, platinum, ruthenium, rhodium or copper catalysts.
- Pd / C, Pt / C and Raney Ni or mixtures thereof Preference is given to Pd / C, Pt / C and Raney Ni or mixtures thereof.
- the introduction of hydrogen into the reaction mixture is preferably carried out at temperatures between 0 ° and + 50 0 C, without pressure or at overpressure to about 10 bar.
- the workup and purification of the reaction products is preferably carried out by distillation.
- the identification of the individual products can be carried out both with the help of HPLC and GC analysis.
- phenylmalone esters which are readily available by the process according to the invention are suitable as intermediates for the preparation of dyes or active compounds in the pharmaceutical or agrochemical sector.
- [1,2,4] triazolo [1,5-a] pyrimidine drugs they are treated with 3-amino-1,2,4-triazole to give 5,7-dihydroxy-6-phenyl- [5, 1, 2,4] triazolo [1, 5-a] pyrimidines [cf. EP-A 550 113, EP-A 975 634, US 5 808 066, US 6 117 876, WO 98/46607].
- the reaction mixture was added at 0 0 C first with 12.5 ml of water then with 12.5 ml of 10% hydrochloric acid.
- the aqueous phase was saturated with Na 2 SO 4 , the phases were separated, the aqueous phase was extracted with THF, the combined organic phases were freed from the solvent and the residue was distilled at 0.4 mbar. There were obtained 6.7 g of the title compound of bp 158-160 0 C / 7 mbar. This corresponds to a yield of 88% d. Th.
- Raney nickel 5.0 g of Raney nickel were suspended in a solution of 11.8 g of diethyl 2-chloro-2- (2 ', 4', 6'-trifluorophenyl) malonate and 3.5 g of triethylamine in 300 ml of THF. At about 24 ° C 700 ml of hydrogen were introduced into this suspension for 135 min under slight overpressure. The reaction product was filtered through kieselguhr, then the filtrate was freed from the solvent.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/993,926 US20090131708A1 (en) | 2005-06-27 | 2006-06-23 | Method For Production of Substituted Phenylmalonate Esters, Intermediate Compounds and The Use Thereof for production of 5, 7-dihydroxy-6-(2,4,5-trifluorophenyl)-(1,2,4)triazolo(1,5-A)pyrimidines |
BRPI0612676A BRPI0612676A2 (pt) | 2005-06-27 | 2006-06-23 | processo para preparar compostos, compostos, e, uso de compostos |
IL187975A IL187975A0 (en) | 2005-06-27 | 2007-12-06 | Method for production of substituted phenylmalonate esters intermediate compounds and the use thereof for the production of 5,7-dihydroxy-6-(2,4,6-trifluorophenyl)-(1,2,4)triazolo(1,5-a)pyrimidines |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102005030059.6 | 2005-06-27 | ||
DE102005030059 | 2005-06-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007000412A1 true WO2007000412A1 (de) | 2007-01-04 |
Family
ID=37054431
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2006/063487 WO2007000412A1 (de) | 2005-06-27 | 2006-06-23 | Verfahren zur herstellung von substituierten phenylmalonestern, zwischenverbindungen sowie deren verwendung zur herstellung von 5 , 7-dihydr0xy-6- (2,4, 6-trifluorphenyl) -(1,2 , 4) triazolo (1 , 5-a) pyrimidinen |
Country Status (5)
Country | Link |
---|---|
US (1) | US20090131708A1 (de) |
CN (1) | CN101208289A (de) |
BR (1) | BRPI0612676A2 (de) |
IL (1) | IL187975A0 (de) |
WO (1) | WO2007000412A1 (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105777638B (zh) * | 2016-01-06 | 2019-07-30 | 北京修正创新药物研究院有限公司 | 氯卡色林杂质的制备方法 |
WO2020201974A1 (en) * | 2019-04-01 | 2020-10-08 | Bhagiradha Chemicals & Industries Limited | Novel process for preparation of key intermediate of pinoxaden |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0770615A1 (de) * | 1995-10-27 | 1997-05-02 | American Cyanamid Company | Verfahren zur Herstellung von Dihalogenazolopyrimidinen |
EP0989130A1 (de) * | 1998-09-25 | 2000-03-29 | American Cyanamid Company | Optisch aktive fungizide trifluoromethylalkylamino-triazolopyrimidines |
US6117876A (en) * | 1997-04-14 | 2000-09-12 | American Cyanamid Company | Fungicidal trifluorophenyl-triazolopyrimidines |
WO2005030775A1 (en) * | 2003-09-24 | 2005-04-07 | Wyeth Holdings Corporation | 6-[(substituted)phenyl]triazolopyrimidines as anticancer agents |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6156925A (en) * | 1998-09-25 | 2000-12-05 | American Cyanamid Company | Process for the preparation of halogenated phenylmaloates |
-
2006
- 2006-06-23 CN CNA2006800230736A patent/CN101208289A/zh active Pending
- 2006-06-23 WO PCT/EP2006/063487 patent/WO2007000412A1/de active Application Filing
- 2006-06-23 US US11/993,926 patent/US20090131708A1/en not_active Abandoned
- 2006-06-23 BR BRPI0612676A patent/BRPI0612676A2/pt not_active IP Right Cessation
-
2007
- 2007-12-06 IL IL187975A patent/IL187975A0/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0770615A1 (de) * | 1995-10-27 | 1997-05-02 | American Cyanamid Company | Verfahren zur Herstellung von Dihalogenazolopyrimidinen |
US6117876A (en) * | 1997-04-14 | 2000-09-12 | American Cyanamid Company | Fungicidal trifluorophenyl-triazolopyrimidines |
EP0989130A1 (de) * | 1998-09-25 | 2000-03-29 | American Cyanamid Company | Optisch aktive fungizide trifluoromethylalkylamino-triazolopyrimidines |
WO2005030775A1 (en) * | 2003-09-24 | 2005-04-07 | Wyeth Holdings Corporation | 6-[(substituted)phenyl]triazolopyrimidines as anticancer agents |
Non-Patent Citations (2)
Title |
---|
COPE A C ET AL: "SYNTHESIS OF DIETHYL ARYLMALONATES FROM DIETHYL MESOXALATE", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 14, 1949, pages 856 - 861, XP000655091, ISSN: 0022-3263 * |
GHOSH, S. ET AL.: "Ester enolates from alpha-acetoxy esters. Synthesis of aryl malonic and alpha-aryl alkanoic esters from aryl nucleophiles and alpha-keto esters", J. ORG. CHEM., vol. 47, no. 24, 1982, pages 4692 - 4702, XP002402662 * |
Also Published As
Publication number | Publication date |
---|---|
CN101208289A (zh) | 2008-06-25 |
US20090131708A1 (en) | 2009-05-21 |
IL187975A0 (en) | 2008-03-20 |
BRPI0612676A2 (pt) | 2016-11-29 |
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