Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring 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
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
  • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids

Definitions

• the present invention relates to a particularly advantageous process for the preparation of 1-alkyl, in particular 1,3, dialkyl-pyrazole-5-carboxylic acid esters
• 2,4-diketo acid esters and alkyl hydrazines the 2,4-diketo acid esters being able to be used in whole or in part in the form of their enolates and the alkyl hydrazines in part in the form of alkyl hydrazine salts.
• EP-A 029 363 also describes the synthesis of N-alkyl-substituted pyrazole carboxylic acid esters with long alkyl radicals from the diketoesterenolate and alkylhydrazine present.
• the pyrazole isolated in moderate yields is again not desirable since the N-alkyl substituent and the carboxyl group are in the 1,3-position and not in the 1,5-position as desired.
• either the free alkylhydrazines are reacted with the diketo ester provided, or the sodium enolate of the diketo ester and an alkylhydrazinium salt are introduced, and the hydrazine with basic compounds (such as
• l-alkyl-pyrazole-5-carboxylic acid esters are prepared by reacting the enolate of a 2,4-diketocarboxylic acid ester with an alkylhydrazinium salt in the presence of a solvent, for example an alcohol.
• the alkyl hydrazine salt is to be prepared from alkyl hydrazine with an acid in the presence of alcohol.
• R 1 and R 4 independently of one another each for straight-chain or branched, optionally halogen-substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or optionally substituted C 7 -C 1 aralkyl and
• R 2 and R 3 each independently represent hydrogen, straight-chain or branched, optionally substituted by halogen -CC 0 alkyl, optionally substituted by halogen C 3 -C 7 cycloalkyl or optionally substituted C -C j2 aralkyl, which is characterized in that a 2,4-diketo ester of the formula
• R 2 , R 3 and R 4 have the meaning given for formula (I),
• R 1 has the meaning given for formula (I),
• C 7 -Ci 2 aralkyl and the benzyl preferred therefrom and Cg-Cjo-aryl (called later) and the preferred phenyl (named later) therefrom can, for example each contain up to two substituents from the group of halogen atoms and Cj-C4-alkyl radicals.
• Preferred diketo esters of the formula (II) are those in which the radicals R 2 and R 3 are each independently of one another hydrogen, straight-chain or branched
• 2,4-diketo ester of formula (II) in which R 2 and R 4 are each C j ⁇ -C alkyl, and R 3 is H.
• alkylhydrazines of the formula (III) preferred are those in which R 1 represents straight-chain or branched C j -C 4 alkyl or optionally substituted benzyl.
• Diketo esters of the formula (II) can be prepared by a conventional method by condensing a dialkyl ketone of the formula
• R 2 and R 3 have the meanings given for formula (I),
• R 4 has the meaning entered in formula (I),
• the diketo ester of the formula (II), which is obtained as an enolate can be released by acidification and removed in a customary manner, e.g. can be obtained in pure form by extraction with an organic solvent, concentration and distillation (see Organikum, 16th edition, 1976, p. 472).
• Suitable solvents for the reaction of the dialkyl ketones of the formula (IV) with oxal esters of the formula (V) are, for example, alcohols such as methanol, ethanol, n-propanol, i-propanol and n-, i-, s- and t-butanol Question.
• the alcoholate can be made by dissolving an alkali or alkaline earth metal in the alcohol corresponding to the alcoholate.
• the diketo ester of the formula (II) is reacted with the alkylhydrazine of the formula (III) in such a way that free alkylhydrazine of the formula (III) is present during at least 90% of the reaction.
• Free alkylhydrazine is preferably present during 95 to 100% of the reaction.
• "X% of conversion” means that x% of the total diketo ester of the formula (II) used has been converted.
• Alkylhydrazine of the formula (III) is present.
• a small amount of free alkylhydrazine can also be introduced, for example 10 to 20% by weight of the total amount, and the rest of the alkylhydrazine and the diketoester, both optionally in a solvent or water, added simultaneously. It is advantageous to add the alkylhydrazine with a small lead.
• the diketo ester of the formula (II) is preferably used in the form of an enolate of the formula (VI):
• R 2 , R 3 and R 4 have the meaning given for formula (I) and
• M represents an equivalent of an alkali or alkaline earth metal.
• R 1 has the meaning given for formula (I) and
• X stands for the anion of an organic or inorganic acid.
• Anions X- of inorganic acids are, for example, chloride, bromide, fluoride, hydrogen sulfate, dihydrogen phosphate and hydrogen carbonate.
• anions X- those of organic acids are preferred.
• X "then stands for R 5 COO ⁇ , where R 5 is a Ci-Cir j -aliphatic or a C 6 -C ⁇ 2 aromatic residue, which can each be optionally substituted.
• R 5 is preferably formate, acetate, propionate, butyrate or benzoate.
• R 5 together with the COO "part can also represent an anion of a polybasic organic acid.
• examples are anions of oxalic, malonic, amber, glutaric, adipic, maleic, fumaric, apple, wine and citric acid, which may be mono- or polyanions respectively.
• Such anions can have a plurality of parts by COO or ⁇ and optionally additionally also COOH radicals.
• alkylhydrazine can be present in equivalent amounts in relation to the acid, ie in the same number as the number of acid groups.
• free alkylhydrazine of the formula (III) is advantageously added to the alkylhydrazinium salt before the start of the reaction with the diketoester or its enolate.
• the process according to the invention can be carried out, for example, by adding a diketoesterenolate of the formula (VI), for example in the form of a crude reaction mixture of the condensation reaction between a ketone of the formula (IV) and an oxalate ester of the formula (V), to a mixture of an equimolar one Amount of an alkylhydrazinium salt of formula (VII) metered in, which contains a proportion of free alkylhydrazine of formula (III).
• a diketoesterenolate of the formula (VI) for example in the form of a crude reaction mixture of the condensation reaction between a ketone of the formula (IV) and an oxalate ester of the formula (V)
• the diketoesterenolate of the formula (VI) is thereby reacted with the alkylhydrazinium salt of the formula (VII) free diketo esters of formula (II) and free alkyl hydrazine of formula (III) formed in situ, which react spontaneously to the desired pyrazole of formula (I).
• an alkylhydrazinium salt of the formula (VII) in a mixture with free alkylhydrazine of the formula (III), optionally in the presence of a solvent or water can also be added to the initially introduced diketoester of the formula (II) or an enolate thereof of the formula (VI). This ensures that diketo esters released from the enolate always meet free alkyl hydrazine.
• the total amounts of solvent and water used are generally chosen so that stirrable suspensions or solutions are present.
• the total amount of solvent plus water per mole of reaction batch can e.g. are between 100 and 2,000 ml. This amount is preferably 200 to 1000 ml, particularly preferably 250 to 500 ml. Of the total amount of solvent plus water, for example 10 to 60% by weight, preferably 15 to 40% by weight, can be water.
• 200 mol% of free alkylhydrazine of the formula (III) are present (based on the diketo ester used or its enolate). This amount is particularly preferably 1 to 50 mol%, in particular 5 to 20 mol%.
• the amount of alcoholate can fluctuate within wide limits. At least 90 mol% of alcoholate, based on the ketone of the formula (IV), is preferably used.
• the diketoester of the formula (II) is, in a preceding step, as described above, from a dialkyl ketone of the formula (IV) and an oxalic acid ester Formula (V) prepared, so their molar ratios can vary. It is preferred to work with a slight excess of oxalic acid ester, for example with a deficit of 1 to 10 mol% of dialkyl ketone of the formula (IV) and alcoholate of the formula
• R 6 represents C, -C 4 alkyl
• n corresponds to the valence of M.
• dialkyl ketone and the alcoholate are preferably used in approximately equimolar amounts to one another.
• 0.9 to 1.1 moles of dialkyl ketone of the formula (IV) 0.9 to 1.1 moles of oxalic acid ester of the formula (V) and 0.9 to 1.1 moles of alcoholate, for example of the formula (VIII) , deploy.
• alkylhydrazinium salt of the formula (VII) is prepared from an alkylhydrazine of the formula (III) and a carboxylic acid, for example of the formula R 5 COOH, it is expedient to choose the molar ratio of the two starting materials so that, for example, from 1 to 1 after the formation of the alkylhydrazinium salt 200 mol% of free alkyl hydrazine of the formula (III) are present.
• reaction temperatures for the reaction according to the invention can be, for example, between -20 and + 100 ° C. Preferred are 0 to 80 ° C, particularly preferred 0 to 50 ° C. Such temperatures can also be maintained during a possible subsequent stirring time.
• 2,4-diketopentanecarboxylic acid ethyl ester as sodium, lithium, potassium or magnesium enolate salts
• 2,4-diketohexanecarboxylic acid ethyl ester 2,4-diketoheptanecarboxylic acid ethyl ester
• 2,4-diketooctanecarboxylic acid ethyl ester 2,4-diketo-3-ethylpentanecarboxylic acid ethyl ester ( each in the form of their sodium, lithium, potassium or magnesium enolate salts) or methyl, n-propyl, i-propyl and n-, i-, s- and t-butyl esters of the aforementioned diketocarboxylic acids in the form of the enolate salts mentioned .
• Preferred alkyl hydrazines of the formula (III) are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, benzyl and n-pentyl hydrazine.
• the sodium salt of the 2,4-diketoheptanecarboxylic acid ethyl ester is first prepared from 2-pentanone and diethyl oxalate using sodium ethylate as auxiliary base in ethanol according to known regulations (see e.g. Organikum, 19th ed., P. 490 (1993)). In order to prevent the enolate from precipitating, this solution is kept at 50.degree. C. and made into a previously prepared mixture within 1 hour
• Methylhydrazine and acetic acid (molar ratio 1.1: 1) added. You stir The excess ethanol is distilled off, toluene is added and, if appropriate, further water is added.
• a suitable surfactant for example an alkanesulfonate
• a salt for example an alkali metal halide.
• the toluene phase is then separated off and the aqueous phase is extracted twice more with toluene. After the organic phases have been combined, they are re-extracted with water.
• the water may optionally contain an acid and / or a salt.
• the toluene solution of the crude pyrazole is finally concentrated by distillation of the solvent and the residue is fractionally distilled in vacuo. The two isomeric pyrazoles can be isolated in pure form without great separation effort.
• Alkylhydrazine of the formula (III) is present, as is done according to the prior art (see also comparative example), the undesired isomers are obtained in a larger amount than the desired isomers of the formula (I) or the desired isomer in a significantly smaller excess. It is particularly surprising to note that even a small excess of free alkylhydrazine causes the largely reversed isomer distribution shown.
• l-Alkyl-pyrazol-5-carboxylic acid esters of the formula (I) are valuable intermediates for the preparation of pharmaceutical active substances with vasodilating and / or antispasmodic activity (see EP-OS 463 756, EP-OS 526 004, WO 94/28902 and DE-OS 19 27 429) and for the production of pesticides with insecticidal and akarizi - the action (see JP-OS 89-114 466).
• the isomer ratio was therefore approximately 13: 1 in favor of the desired isomer.

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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)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1998
  • 1998-08-17 DE DE19837067A patent/DE19837067A1/de not_active Withdrawn
• 1999
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  • 1999-08-04 CA CA002340704A patent/CA2340704A1/en not_active Abandoned
  • 1999-08-04 IL IL14128199A patent/IL141281A0/xx unknown
  • 1999-08-04 US US09/762,626 patent/US6444828B1/en not_active Expired - Lifetime
  • 1999-08-04 AT AT99940140T patent/ATE310730T1/de not_active IP Right Cessation
  • 1999-08-04 KR KR1020017002014A patent/KR20010072709A/ko not_active Withdrawn
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  • 1999-08-04 EP EP99940140A patent/EP1104406B1/de not_active Expired - Lifetime
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