EP1919876A1 - Procede pour preparer des pyrazols substitues - Google Patents

Procede pour preparer des pyrazols substitues

Info

Publication number
EP1919876A1
EP1919876A1 EP06776956A EP06776956A EP1919876A1 EP 1919876 A1 EP1919876 A1 EP 1919876A1 EP 06776956 A EP06776956 A EP 06776956A EP 06776956 A EP06776956 A EP 06776956A EP 1919876 A1 EP1919876 A1 EP 1919876A1
Authority
EP
European Patent Office
Prior art keywords
group
formula
stage
alkyl
compound
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.)
Withdrawn
Application number
EP06776956A
Other languages
German (de)
English (en)
Inventor
Meinrad Brenner
Hans Williner
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.)
Lonza AG
Original Assignee
Lonza AG
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 Lonza AG filed Critical Lonza AG
Priority to EP06776956A priority Critical patent/EP1919876A1/fr
Publication of EP1919876A1 publication Critical patent/EP1919876A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • the invention relates to an alternative process for the preparation of substituted 5-aminopyrazoles.
  • Azetidines are suitable according to WO-A-2003/077907 and WO-A-2005/026113 as CCR-3 receptor antagonists in the treatment of inflammation and allergic diseases.
  • the object of the invention was to provide an alternative process for the preparation of substituted 5-aminopyrazoles.
  • the substituents R 1 to R 3 should already be introduced into the molecule during ring formation in order to avoid subsequent substitution.
  • R 1 is selected from the group consisting of hydrogen, Ci -6 alkyl,
  • Ci -6- alkoxy, C 3 . 6 cycloalkyl, aryl and heteroaryl, wherein each substituent except hydrogen R 1 may optionally bear one or more substituents selected from the group consisting of Ci -6 alkyl, C 1-6 alkoxy, halogen, nitro, and R 2 is selected from the group consisting of hydrogen, cyano, halogen, Ci -6 alkyl, C 1-6 alkoxy, Ci -6 alkoxycarbonyl, C3-6 cycloalkyl, aryl and heteroaryl, wherein except for hydrogen, cyano, and halogen each substituent R 2 optionally one or more substituents from the group consisting of Ci -6 alkyl, C 1-6 alkoxy, halogen, nitro can carry, or wherein R and R together a - (CH 2 ) n - group with n 3, 4 or 5, which may optionally contain one or more halogen atoms, and wherein R 3 is selected from the group consisting of Ci -6 alky
  • R 1 , R and R 3 are as defined above, which is reacted in a final step in the presence of a strong base to give a compound of formula I.
  • the compounds of formula II may be aldehydes or ketones.
  • Examples of cyclic ketones of the formula II are cyclopentanone, cyclohexanone or cycloheptanone.
  • the compound of formula II is selected from the corresponding column of Table 1.
  • the compound "compound of the formula I" in each case indicates which compound is predominantly formed in the reaction.
  • the radical R 3 results therein from the hydrazine derivative of the formula III used in each case.
  • Table 2 shows further examples of preferred process variants in which the hydrazine derivative of the formula III used and thus the radical R 3 are defined.
  • R 1 is cyclopropyl
  • R 2 is hydrogen
  • R 3 is methyl
  • Ci-n-alkyl means a straight or branched alkyl group having 1 to n carbon atoms. So represents Ci -7 alkyl beispiels- example, groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-Buty ⁇ , tert-butyl, pentyl, hexyl, heptyl or 1,4-dimethyl-pentyl.
  • Ci-n alkoxy means a straight or branched alkoxy group having 1 to n carbon atoms.
  • Ci -7 alkoxy represents, for example, groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec - Butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy or 1,4-dimethyl-pentyloxy.
  • C 3-6 cycloalkyl means a cycloalkyl group of 3 to 6 carbon atoms and represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Aryl is understood here and below to mean in particular an aromatic group having 6 to 10 carbon atoms, such as, for example, phenyl, p-tolyl or naphthyl.
  • Aralkyl is understood here and below as meaning in particular an alkyl group substituted by an aryl group, for example phenylethyl, where the alkyl group contains from 1 to 4 carbon atoms and the aryl group contains from 6 to 10 carbon atoms, as defined above.
  • Heteroaryl is understood here and below to mean in particular a heteroaromatic group having 4 to 8 carbon atoms, for example 2- or 3-furanyl, 2- or 3-thiophenyl or 2-, 3- or 4-pyridinyl.
  • halogen means fluoro, chloro, bromo or iodo.
  • the base used in the second stage is an inorganic base, preferably selected from the group consisting of alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, trisodium phosphate and mixtures thereof.
  • the first stage is carried out at the reflux temperature of the chosen solvent.
  • the progress of the reaction can be easily determined by thin-layer Chromatography or gas chromatography can be determined.
  • the first stage product does not have to be isolated and can be directly further reacted.
  • inorganic bases are suitable for the second stage and may be selected from the group consisting of alkali and alkaline earth hydroxides, alkali and alkaline earth carbonates, trisodium phosphate and mixtures thereof. Particular preference is given to using an alkali carbonate as base and, in particular, potassium carbonate.
  • the cyanogen chloride is used in the second stage as a gas or dissolved in a solvent. In the process according to the invention, it does not matter whether the reaction mixture of the first stage is added to the cyanogen chloride or the cyanogen chloride to the reaction mixture.
  • the second stage is carried out at a temperature from -100 to 0 0 C, more preferably -70 to -20 0 C.
  • solvents for the first and second stage may be selected from the group consisting of cyclohexane, hexane, heptane, petroleum ether, ethanol, diethyl ether, methyl / tert-butyl ether (MTBE), tetrahydrofuran (THF), toluene, xylene, and mixtures thereof.
  • MTBE methyl / tert-butyl ether
  • THF tetrahydrofuran
  • toluene xylene
  • Particularly preferred are MTBE, THF and toluene.
  • Petroleum ethers generally mean technical alkane mixtures having a relatively broad boiling range, but in particular also isomer mixtures of, for example, hexane and heptane.
  • the strong base used in the third step must be able to deprotonate the carbon atom directly attached to the R group.
  • the strong base is selected from the group consisting of metal hydrides, metal amides, metal alkoxides and organometallic compounds.
  • the metal hydrides used are preferably NaH or KH.
  • Metal amides are preferably selected from the group consisting of sodium amide, lithium diisopropylamide (LDA) and the lithium amide of tetramethylpiperidine (Li-TMP).
  • Organometallic compounds are preferably selected from the group consisting of -butyllithium, sec-butyllithium and tert-butyllithium.
  • the base is selected from the group consisting of lithium diisopropylamide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium and tert-butyl lithium.
  • the third step is carried out at a temperature from -100 to 0 0 C, more preferably -70 to -20 0 C.
  • the solvent must be inert to the strong base used.
  • a solvent change is performed, which is not mandatory. In a preferred process variant, no solvent change takes place between the second and third stages.
  • a solvent which is inert to all reagents of the three stages can be used to carry out the reactions of the first, second and third stages as a "one-pot reaction".
  • the solvent is preferably selected from the group consisting of cyclohexane, hexane, heptane, petroleum ether, diethyl ether, MTBE, THF, toluene, xylene and mixtures thereof. Particularly preferred are MTBE, THF and toluene.
  • the solvent is selected from the group consisting of hexane, hexane, heptane, diethyl ether, MTBE, THF, toluene, xylene and mixtures thereof, more preferably are MTBE, THF and toluene.
  • the strong base is quenched, for example by addition of water, and the product can be isolated.
  • a salt such as ammonium chloride is added for phase separation.
  • Example 2 (£ "/ Z) -iV-cyano-iV- (1-cyclopropyl-etilylidene) -N-methylhydrazine (Mixture)
  • the bulk of the reaction mixture of Example 1 was cooled with an aqueous K 2 CO 3 solution (27.6 g, 200 mmol in 55 mL water) Mixture was introduced at 0 ° C. over 90 minutes of cyanogen chloride (14.0 g, 230 mmol). The mixture was subsequently stirred at 0 ° C. for a further 2 hours. After the end of the reaction, the organic phase was separated and toluene evaporated.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé pour préparer des 5-aminopyrazols substitués, dans le cadre duquel un composé de carbonyle est converti avec un dérivé d'hydrazine et du chlorure de cyanogène, en N-cyanohydrazone qui est rendue cyclique en la présence d'une base forte.
EP06776956A 2005-08-18 2006-08-18 Procede pour preparer des pyrazols substitues Withdrawn EP1919876A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06776956A EP1919876A1 (fr) 2005-08-18 2006-08-18 Procede pour preparer des pyrazols substitues

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05017950 2005-08-18
EP06776956A EP1919876A1 (fr) 2005-08-18 2006-08-18 Procede pour preparer des pyrazols substitues
PCT/EP2006/008162 WO2007020098A1 (fr) 2005-08-18 2006-08-18 Procede pour preparer des pyrazols substitues

Publications (1)

Publication Number Publication Date
EP1919876A1 true EP1919876A1 (fr) 2008-05-14

Family

ID=35986636

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06776956A Withdrawn EP1919876A1 (fr) 2005-08-18 2006-08-18 Procede pour preparer des pyrazols substitues

Country Status (11)

Country Link
US (1) US20090221838A1 (fr)
EP (1) EP1919876A1 (fr)
JP (1) JP2009504702A (fr)
CN (1) CN101296905A (fr)
BR (1) BRPI0614355A2 (fr)
CA (1) CA2619780A1 (fr)
EA (1) EA200800487A1 (fr)
IL (1) IL189581A0 (fr)
MX (1) MX2008002301A (fr)
NO (1) NO20080635L (fr)
WO (1) WO2007020098A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262256B (zh) * 2014-08-01 2016-08-17 江苏大学 利用α，β-不饱和羰基化合物制备多取代吡唑类化合物的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH593950A5 (fr) * 1974-06-13 1977-12-30 Ciba Geigy Ag

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007020098A1 *

Also Published As

Publication number Publication date
NO20080635L (no) 2008-03-11
JP2009504702A (ja) 2009-02-05
WO2007020098A8 (fr) 2008-03-20
EA200800487A1 (ru) 2008-08-29
IL189581A0 (en) 2008-08-07
WO2007020098A1 (fr) 2007-02-22
BRPI0614355A2 (pt) 2011-03-22
US20090221838A1 (en) 2009-09-03
CN101296905A (zh) 2008-10-29
MX2008002301A (es) 2008-03-14
CA2619780A1 (fr) 2007-02-22

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