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EP1537125A1 - Procede de fabrication organometallique de produits intermediaires organiques contenant des liaisons carbone-heteroatome par deprotonation d'heteroatomes - Google Patents

Procede de fabrication organometallique de produits intermediaires organiques contenant des liaisons carbone-heteroatome par deprotonation d'heteroatomes

Info

Publication number
EP1537125A1
EP1537125A1 EP03794905A EP03794905A EP1537125A1 EP 1537125 A1 EP1537125 A1 EP 1537125A1 EP 03794905 A EP03794905 A EP 03794905A EP 03794905 A EP03794905 A EP 03794905A EP 1537125 A1 EP1537125 A1 EP 1537125A1
Authority
EP
European Patent Office
Prior art keywords
lithium
compounds
substituted
alkyl
carbon
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Withdrawn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
EP03794905A
Other languages
German (de)
English (en)
Inventor
Andreas Meudt
Bernd Lehnemann
Michael Erbes
Klaus Forstinger
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.)
Euticals GmbH
Original Assignee
Archimica GmbH
Clariant GmbH
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 Archimica GmbH, Clariant GmbH filed Critical Archimica GmbH
Publication of EP1537125A1 publication Critical patent/EP1537125A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/16—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of hydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides

Definitions

  • the invention relates to a process for the preparation of organic compounds having carbon-heteroatom bonds, a lithium compound (II) being first generated by reacting aliphatic or aromatic halogen compounds (I) with lithium metal, which compound is then used to deprotonate the compounds (III) or ( V) is used, and the resulting lithium salts of the formulas (IV) or (VI) are finally reacted with suitable carbon electrophiles to form the lower bond of the heteroatom-carbon bond and form the products (VIII) or (VIII). (EQUATION 1).
  • Step 1 creating the base
  • Step 2 deprotonation of the substrate
  • Step 3 implementation with an electrophile
  • organometallic chemistry especially that of the element lithium
  • the boom in organometallic chemistry, especially that of the element lithium, in the production of compounds for the pharmaceutical and agrochemical industry and for numerous other applications has been almost exponential in recent years, given the number of applications and the quantity of products manufactured accordingly plots against a timeline.
  • the main reasons for this are the increasingly complex structures of the required fine chemicals for the pharmaceutical and agro sectors on the one hand and the almost unlimited synthetic potential of lithium organyls for the construction of complex organic structures on the other.
  • a large part of this development is the use of organolithium compounds and alkali metal hydrides as strong, less nucleophilic bases for the deprotonation of alcohols, phenols, thiols, amines etc., ie the generation of heteroatom anions, for the conversion with electrophiles.
  • the present invention solves all of these problems and relates to a method for forming heteroatom-carbon bonds, a lithium compound (II) being first generated by reacting aliphatic or aromatic halogen compounds (I) with lithium metal, which compound is then used to deprotonate the compounds (III ) or (V) is used, and the resulting lithium salts of the formulas (IV) or (VI) are finally linked with suitable carbon electrophiles to form the heteroatom-carbon bond and form the products (VIII) or (VIII) for the reaction brought (equation I).
  • Step 1 creating the base lithium
  • Step 2 deprotonation of the substrate
  • Step 3 implementation with an electrophile
  • R stands for methyl, primary, secondary or tertiary branched and unbranched alkyl radicals having 1 to 20 carbon atoms, phenyl, aryl and heteroaryl radicals, substituted by a radical from the group ⁇ methyl, primary, secondary or tertiary alkyl, phenyl Phenyl, aryl, heteroaryl, alkoxy, dialkylamino, alkylthio ⁇ substituted alkyl, substituted or unsubstituted cycloalkyl having 3 to 8 C atoms,
  • Xi represents an oxygen or sulfur bound by a single bond to R1 or an sp2-hybridized nitrogen bound by a double bond to R1
  • X 2 represents an sp3-hybridized nitrogen
  • R 1 and R 2 radicals independently of one another represent substituents from the group ⁇ hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl, alkenyl or alkynyl radicals having 1 to 20 C atoms, substituted cyclic or acyclic alkyl groups, acyl groups , Alkoxy, aryloxy, dialkylamino, alkylamino, arylamino, diarylamino, alkylarylamino, imino, sulfone, sulfonyl, phenyl, substituted phenyl, alkylthio, diarylphosphino,
  • Preferred compounds of formula (III) which can be reacted by the process according to the invention are e.g. Alcohols, thiols, phenols, thiophenols, oximes, hydrazones, preferred compounds of formula (V) are e.g. Amines, carboxamides, sulfonamides and hydrazines, to name but a few.
  • the lithium organyls prepared in this way can be reacted with any electrophilic compounds by methods of the prior art.
  • reaction with carbon electrophiles for example, alkylations to ethers, thioethers, secondary and tertiary amines etc. can be carried out or semi-acetals and their secondary products as well as esters, acid amides and carbonyl derivatives can be prepared by carbonyl additions.
  • the carbon electrophiles come in particular from one of the following categories (the product groups in brackets):
  • Aryl or alkyl cyanates, isocyanates (carbonic acid derivatives) Oxirane, substituted oxiranes (2-hydroxyethers, amines, thioethers, etc.) aziridines, substituted aziridines (2-aminoethers, amines, thioethers, etc.) imines, aldehydes, ketones (hemiacetals, aminals, thioacetals, etc.) organic halogen compounds, triflates, other sulfonates, sulfates (substitution products / alkylation products) ketenes (carboxylic acid derivatives) carboxylic acid chlorides (carboxylic acid derivatives) carboxylic acid esters, thioesters and amides (carboxylic acid derivatives) carbonic acid esters and phosgene derivatives (carboxylic acid derivatives)
  • fluorine, chlorine, bromine or iodine compounds can be used as halogen aliphates or aromatics, since lithium metal in ethereal solvents reacts easily and in almost all cases with quantitative yields with all halogen aromatics and aliphates.
  • Chlorine or bromoaliphatics are preferably used here, since iodine compounds are often expensive, fluorine compounds lead to the formation of LiF, which can lead to material problems in later aqueous workups as HF. In special cases, however, such halides can also be used advantageously.
  • alkyl or aryl halides which can be converted to liquid alkanes or aromatics after deprotonation.
  • Chloro- or bromocyclohexane, benzyl chloride, tert-butyl chloride, chlorhexanes, chlorheptanes or chloroctanes as well as chloro- and bromobenzenes, -toluenes and -xylenes are particularly preferably used.
  • reaction is carried out in a suitable organic solvent; ethereal solvents, for example tetrahydrofuran, dioxane, diethyl ether, di-n-butyl ether, diisopropyl ether, glyme, diglyme, dibutyl diglyme or anisole are preferred, tetrahydrofuran is particularly preferably used.
  • ethereal solvents for example tetrahydrofuran, dioxane, diethyl ether, di-n-butyl ether, diisopropyl ether, glyme, diglyme, dibutyl diglyme or anisole are preferred, tetrahydrofuran is particularly preferably used.
  • Another advantage of the method according to the invention is that it is possible to work with organolithium compounds at very high concentrations. Concentrations of the aliphatic or aromatic intermediates of formula (II) of 5 to 30% by weight, in particular 12 to 25% by weight, are preferred.
  • halogen compound (R-Hal) and substrate to be deprotonated (III or IV) are metered in simultaneously or as a mixture to lithium metal in the ether.
  • the organolithium compound first forms, which then immediately deprotonates the substrate.
  • the preferred reaction temperatures are in the range from -100 to +70 ° C, and temperatures from -80 to -25 ° C are particularly preferred when deprotonation not at the same time as the lithiation, but in a second step.
  • the particularly preferred temperature range is between -40 and +40 ° C.
  • the lithium can be used as a dispersion, powder, chips, sand, granules, pieces, bars or in some other form, the size of the lithium particles not being quality-relevant but merely influencing the reaction times. Smaller particle sizes are therefore preferred, for example granules, powders or dispersions.
  • the amount of lithium added is 1.95 to 2.5 mol, preferably 1.98 to 2.15 mol, per mole of halogen to be reacted.
  • organic redox systems by adding, for example biphenyl, 4,4 '-di-tert-butylbiphenyl or anthracene, substantial increases in reaction rates are observed. The addition of such systems proved to be particularly advantageous when the lithiation times were> 12 h without this catalysis.
  • Substrates that can be used for deprotonation are initially all oxygen, sulfur and nitrogen compounds which carry a sufficiently acidic hydrogen atom on the corresponding heteroatom in order to be deprotonated under the reaction conditions.
  • the lithium compounds generated according to the invention can be converted using the methods familiar to the person skilled in the art with electrophilic carbon compounds (electrophilic) to give products with newly formed heteroatom-carbon bonds which are of great interest for the pharmaceutical and agrochemical industry.
  • the workups are generally aqueous, with either water or aqueous mineral acids being metered in or the reaction mixture being metered into water or aqueous mineral acids.
  • the pH of the product to be isolated is adjusted here.
  • the reaction products are obtained, for example, by extraction and evaporation of the organic phases, alternatively the organic solvents can also be distilled off from the hydrolysis mixture and the product which then precipitates can be obtained by filtration.
  • the purities of the products from the processes according to the invention are generally high, but a further purification step, for example by recrystallization with the addition of small amounts of activated carbon, may be required for special applications (pharmaceutical precursors).
  • the yields of the reaction products are between 70 and 99%, typical yields are in particular 80 to 95%.
  • the method according to the invention opens up a very economical method for the transformation of acidic hydrogen into any residues in a highly selective, economical way.
  • Tetrahydrofuran is cooled to -35 ° C and 13.29 g (0.105 mol) of 4-chlorotoluene are slowly added. The mixture is stirred at this temperature until the conversion of the 4-chlorotoluene is at least 97% a / a It. GC (approx. 8 h). 9.81 g (0.100 mol) of 2-furylmethanol are added, the mixture is allowed to warm to room temperature, 14.28 g (0.120 mol) of propargyl bromide are added and the mixture is boiled under reflux for 2 h. To
  • a suspension of 1.45 g (0.210 mol) of lithium granules in 150 ml of tetrahydrofuran and 19.63 g (0.100 mol) of benzaldehyde phenylhydrazone is mixed with 15.61 g (0.105 mol) of octyl chloride at -40 ° C. and at - 30 ° C stirred until the conversion of the octyl chloride It. GC at min. 97% a / a is (approx. 8 h). Then 11.34 g (0.120 mol) of methyl chloroformate are added dropwise and the reaction mixture is stirred at 0 ° C. for 30 minutes.
  • the reaction mixture is hydrolyzed with 100 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml of toluene.
  • the combined organic phases are concentrated and the crude product is recrystallized from ethanol.
  • the product is obtained in the form of colorless, flake-like crystals with a yield of 20.85 g (0.082 mol, 82%) and an HPLC purity of> 98.5% a / a.

Landscapes

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

Abstract

L'invention concerne un procédé de combinaison de liaisons carbone-hétéroatome, consistant d'abord à faire réagir des composés halogènes aliphatiques ou aromatiques (I) avec du métal lithium de manière à produire un composé lithium (II) employé ensuite pour la déprotonation des composés (III) ou (V). Les sels de lithium résultants (V) ou (VI) sont ensuite mis en réaction avec des électrophiles de carbone correspondants par combinaison de la liaison carbone-hétéroatome de manière à produire les produits (VII) ou (VIII).
EP03794905A 2002-08-31 2003-08-21 Procede de fabrication organometallique de produits intermediaires organiques contenant des liaisons carbone-heteroatome par deprotonation d'heteroatomes Withdrawn EP1537125A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10240260A DE10240260A1 (de) 2002-08-31 2002-08-31 Verfahren zur metallorganischen Herstellung organischer Zwischenprodukte mit Kohlenstoff-Heteroatom-Bindungen über die Deprotonierung von Heteroatomen
DE10240260 2002-08-31
PCT/EP2003/009250 WO2004024737A1 (fr) 2002-08-31 2003-08-21 Procede de fabrication organometallique de produits intermediaires organiques contenant des liaisons carbone-heteroatome par deprotonation d'heteroatomes

Publications (1)

Publication Number Publication Date
EP1537125A1 true EP1537125A1 (fr) 2005-06-08

Family

ID=31502217

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03794905A Withdrawn EP1537125A1 (fr) 2002-08-31 2003-08-21 Procede de fabrication organometallique de produits intermediaires organiques contenant des liaisons carbone-heteroatome par deprotonation d'heteroatomes

Country Status (5)

Country Link
US (1) US20050258553A1 (fr)
EP (1) EP1537125A1 (fr)
JP (1) JP2005537331A (fr)
DE (1) DE10240260A1 (fr)
WO (1) WO2004024737A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101432188B (zh) * 2006-05-02 2012-08-15 西门子公司 运行具有废热回收的船舶驱动系统的方法以及具有废热回收的船舶驱动系统

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0739485B2 (ja) * 1987-05-01 1995-05-01 ダイセル化学工業株式会社 新規ブロック・コポリエ−テル・グリコ−ルの製造法
DE10150610A1 (de) * 2001-10-12 2003-04-30 Clariant Gmbh Verfahren zur metallorganischen Herstellung organischer Zwischenprodukte über Amidbasen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004024737A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101432188B (zh) * 2006-05-02 2012-08-15 西门子公司 运行具有废热回收的船舶驱动系统的方法以及具有废热回收的船舶驱动系统

Also Published As

Publication number Publication date
WO2004024737A1 (fr) 2004-03-25
US20050258553A1 (en) 2005-11-24
JP2005537331A (ja) 2005-12-08
DE10240260A1 (de) 2004-03-11

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