EP1590331A1 - Verfahren zur herstellung eines reagens von acylimidazoliumtyp - Google Patents

Verfahren zur herstellung eines reagens von acylimidazoliumtyp

Info

Publication number
EP1590331A1
EP1590331A1 EP04701979A EP04701979A EP1590331A1 EP 1590331 A1 EP1590331 A1 EP 1590331A1 EP 04701979 A EP04701979 A EP 04701979A EP 04701979 A EP04701979 A EP 04701979A EP 1590331 A1 EP1590331 A1 EP 1590331A1
Authority
EP
European Patent Office
Prior art keywords
reagent
formula
group
process according
acid
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Withdrawn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
EP04701979A
Other languages
English (en)
French (fr)
Inventor
Thierry Schlama
Franco Manfre
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.)
Rhodia Chimie SAS
Original Assignee
Rhodia Chimie SAS
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 Rhodia Chimie SAS filed Critical Rhodia Chimie SAS
Publication of EP1590331A1 publication Critical patent/EP1590331A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a process for preparing a reagent of the acylimidazolium type.
  • the invention relates more particularly to an N- (benzyloxycarbonyl) -N'-methylimidazolium salt.
  • Rapoport reagent which can be represented by the following formula:
  • Y is an anion and represents, for example, a tetrafluoroborate or trifluoromethanesulfonate anion.
  • the first consists in reacting imidazole and benzyl chloroformate leading to an imidazolide which is separated by crystallization and then reacted with triethyloxonium tetrafluoroborate making it possible to obtain, after crystallization, N- (benzyloxycarbonyl) -N tetrafluoroborate '- ethylimidazolium which is then used as a reagent to protect an amino group.
  • the drawbacks of the process described reside in the fact that it comprises two stages with separation of the intermediate product.
  • Said method involves an alkylation step which uses triethyloxonium tetrafluoroborate which is an expensive reagent, commercially available in solution diluted in dichloromethane and which moreover has a high toxicity.
  • the objective of the present invention is to provide a process which is more easily implemented on an industrial scale and which does not have the abovementioned drawbacks.
  • - Ri represent an alkyl or phenyl group
  • R represents an alkyl, alkenyl, cycloalkyl, aryl, arylalkyl group,
  • - Z represents a valential bond, an oxygen atom or an NR 2 group; R 2 having the same meaning as R,
  • - Y is an anion from an acid whose pKa is less than 1, characterized in that it is obtained by reacting:
  • - R and Z have the meaning given above, - X represents a bromine or chlorine atom.
  • alkyl means a linear or branched hydrocarbon chain having from 1 to 12 carbon atoms and preferably from 1 to 4 carbon atoms.
  • alkyl groups examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl.
  • alkenyl is meant a hydrocarbon group, linear or branched having from 2 to 12 carbon atoms, comprising one or more double bonds, preferably 1 to 2 double bonds.
  • the allyl group is a preferred example.
  • cycloalkyl is meant a cyclic, monocyclic hydrocarbon group comprising from 3 to 8 carbon atoms, preferably a cyclopentyl or cyclohexyl group.
  • aryl is meant an aromatic mono- or polycyclic group, preferably mono- or bicyclic comprising from 6 to 12 carbon atoms, preferably phenyl or naphthyl.
  • the phenyl group is preferred.
  • arylalkyl is meant a hydrocarbon group, linear or branched carrying a monocyclic aromatic ring and comprising from 7 to 12 carbon atoms, preferably benzyl.
  • the starting reagent of formula (II) comprises a group -CO-X.
  • a first class are those of the chloride or bromide type of carboxylic acids of formula (II) in which Z represents a valential bond.
  • R represents a linear or branched alkyl group having from 1 to 4 carbon atoms, preferably a methyl or ethyl group.
  • acetyl chloride is cited.
  • a second family of compounds are the chloro- or bromoformate type compounds.
  • those of formula (II) are chosen in which Z represents an oxygen atom and R preferably represents a linear or branched alkyl group having from 1 to 4 carbon atoms or a benzyl group.
  • the preferred compounds are the chloroformate or alkyl or benzyl bromoformate.
  • Another class of compounds are those of formula (II) in which Z represents an NR 2 group.
  • the envisaged compounds are of the carbamoyl chloride or bromide type.
  • those of formula (II) are chosen in which R and R 2 are identical and preferably represent a linear or branched alkyl group having from 1 to 4 carbon atoms.
  • dimethylcarbamoyl chloride is mentioned.
  • the imidazole reagent is a nitrogen heterocyclic compound which corresponds to formula (III) and which carries on the ring a group Ri which is a linear or branched alkyl group having from 1 to 12 carbon atoms or a phenyl group.
  • Ri which is a linear or branched alkyl group having from 1 to 12 carbon atoms or a phenyl group.
  • this group is considered to be a leaving group when the reagent of formula (I) is used as a protecting group, in particular for protecting the amino groups, it is advantageous from an economic point of view to be a simple nature, and more particularly represents a linear or branched alkyl group having from 1 to 4 carbon atoms, preferably a methyl group.
  • a preferred reagent is N-methylimidazole.
  • the third reagent involved in the process of the invention is a strong acid HY whose characteristic is to have a pKa in water of less than 1.0.
  • PKa is defined as the ionic dissociation constant of the acid / base couple, when water is used as a solvent.
  • the anion Y ′′ must be non-nucleophilic. More precisely, it must not react in solution with the compound obtained, namely Pacylimidazolium. As more specific examples, we can mention: BF 4 " , PF 6 " ,
  • trifluoromethanesulfonic acid is commonly known as “triflic acid”.
  • a strong concentrated acid, preferably pure, is used to minimize the introduction of water.
  • the three reactants are reacted without carrying out isolation of the intermediate product.
  • reagents are used which are in liquid form and can therefore be transported by pumps. Consequently, they are more easily implemented industrially compared to a solid form.
  • reagents comprising a -COX group of formula (II) and the imidazole type reagent of formula (III).
  • the amount of reagents involved is such that the ratio between the number of moles of the reagent of formula (III) over the number of moles of reagent of formula (II) is advantageously chosen between 1 and 1, 2 and preferably around of 1.
  • a preferred embodiment of the invention consists in carrying out the reaction in an organic solvent.
  • solvent It must be inert under the conditions of the invention, in particular with respect to the strong acid.
  • an organic solvent Preferably, an organic solvent, aprotic and not very polar, is used.
  • solvents suitable for the present invention there may be mentioned in particular aliphatic, cycloaliphatic or aromatic hydrocarbons, halogenated or not.
  • aliphatic hydrocarbons ⁇ may more particularly cite paraffins such as, in particular, hexane, cyclohexane, methylcyclohexane, petroleum ether type petroleum fractions; aromatic hydrocarbons such as in particular benzene, toluene, xylenes, cumene, petroleum fractions consisting of a mixture of alkylbenzenes, in particular cuts of the Solvesso® type.
  • organic solvents mention may be made of halogenated aliphatic hydrocarbons and more particularly, n-chlorobutane, dichloromethane, 1, 2-dichloroethane; halogenated aromatic hydrocarbons, and more particularly, mono- or dichlorobenzene. It is also possible to use a mixture of organic solvents.
  • the preferred solvents are: dichloromethane or toluene.
  • the amount of organic solvent used is such that the concentration of the reagents of formula (II) and (III) in the solvent is between 5% and 30% by weight.
  • the reaction is carried out at a temperature which is advantageously between 0 ° C and 30 ° C, preferably at room temperature.
  • ambient temperature most often means a temperature between 15 ° C and 25 ° C.
  • the reaction is carried out at atmospheric pressure, but lower or higher pressures may also be suitable.
  • the process of the invention is carried out under a controlled atmosphere of inert gases.
  • An atmosphere of rare gases, preferably argon, can be established, but it is more economical to use nitrogen.
  • the reaction is carried out with stirring and protected from moisture.
  • the process can be carried out batchwise or continuously.
  • a suspended product is formed which corresponds to formula (IV):
  • R, Ri, X and Z have the meanings given for formulas (II) and (III).
  • the strong acid is preferably added triflic acid.
  • the amount of acid added is such that the ratio between the number of H + ions and the number of moles of product of formula (IV), product obtained following the reaction of the reactants (II) and (III), varies between 0.9 and 1.5, preferably between 1 and 1.1.
  • the acid is gradually added to the reaction medium.
  • a perfectly clear homogeneous solution comprising the reagent of formula (I).
  • This reagent providing a protective group of RZ-CO- type capable of being used to block functional groups, preferably amino groups can therefore be used in the form of the solution previously obtained. It is also possible to use it in solid form obtained after elimination of the reaction solvent by evaporation.
  • Said reagent is advantageously used to protect the amino or substituted amino groups present in any type of molecule.
  • - R a and R independently of one another represent a hydrogen atom or a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the aforementioned groups, - R a and R b can be linked so as to constitute with the carbon atoms which carry them a heterocyclic group having from 3 to 20 atoms, saturated, unsaturated, or aromatic, monocyclic or polycyclic
  • R a and R can represent, independently of one another, an acyclic aliphatic group, saturated or unsaturated, linear or branched.
  • R a and Rb preferably represent an acyclic saturated linear or branched aliphatic group, preferably in Ci to C ⁇ 2 , and even more preferably in Ci to C 4 .
  • the invention does not exclude the presence of an unsaturation on the hydrocarbon chain such as one or more double bonds which can be conjugated or not.
  • the hydrocarbon chain can optionally be interrupted by a heteroatom (for example, oxygen, sulfur, nitrogen or phosphorus) or by a functional group insofar as the latter does not react and a group such as in particular -CO- can be mentioned in particular.
  • a heteroatom for example, oxygen, sulfur, nitrogen or phosphorus
  • a functional group insofar as the latter does not react and a group such as in particular -CO- can be mentioned in particular.
  • the hydrocarbon chain may optionally carry one or more substituents (for example, halogen, carboxylic, ester, amino or alkyl and / or arylphosphine) insofar as they do not interfere.
  • substituents for example, halogen, carboxylic, ester, amino or alkyl and / or arylphosphine
  • acyclic, saturated or unsaturated, linear or branched aliphatic group may optionally carry a cyclic substituent.
  • cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.
  • the acyclic aliphatic group can be linked to the ring by a valential bond, a heteroatom or a functional group such as oxy, carbonyl, carboxyl, sulfonyl etc.
  • cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents themselves being optionally carriers of any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention. Mention may in particular be made of alkyl and C1 to C alkoxy groups.
  • cycloalkylalkyl groups for example, cyclohexylalkyl or arylkyl groups preferably C 7 to C 2 , in particular benzyl or phenylethyl.
  • the groups R a and R b can also represent, independently of one another, a carbocyclic group saturated or comprising 1 or 2 unsaturations in the ring, generally C 3 to C 8 , preferably to 6 carbon atoms in the ring; said cycle can be substituted.
  • a carbocyclic group saturated or comprising 1 or 2 unsaturations in the ring, generally C 3 to C 8 , preferably to 6 carbon atoms in the ring; said cycle can be substituted.
  • this type of group mention may be made of cyclohexyl groups optionally substituted by linear or branched alkyl groups having from 1 to 4 carbon atoms.
  • the groups R a and Rb may represent, independently of one another, an aromatic, and in particular benzene, hydrocarbon group corresponding to the general formula
  • - Q represents a group selected from a linear or branched alkyl, Ci -C 6 alkoxy linear or branched Ci to C 6 alkylthio group linear or branched Ci -C 6) -NO 2 , a -CN group, a halogen atom, a CF 3 group.
  • R a and Rb can also represent, independently of one another, a polycyclic aromatic hydrocarbon group with the cycles being able to form between them ortho-condensed, ortho- and pericondensed systems. Mention may more particularly be made of a naphthyl group; said cycle can be substituted.
  • R a and R b can also represent, independently of one another, a polycyclic hydrocarbon group constituted by at least 2 saturated and / or unsaturated carbocycles or by at least 2 carbocycles of which only one of them is aromatic and forming between them ortho- or ortho- and pericondensed systems.
  • the cycles are in C 3 to C 8 , preferably in C 6 .
  • R a and Rb can also represent, independently of one another, a heterocyclic group, saturated, unsaturated or aromatic, comprising in particular 5 or 6 atoms in the ring including one or two heteroatoms such as nitrogen atoms (not substituted by a hydrogen atom), sulfur and oxygen; the carbon atoms of this heterocycle can also be substituted.
  • R a and R can also represent a polycyclic heterocyclic group defined as being either a group consisting of at least two aromatic or non-aromatic heterocycles containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri-condensed systems , or either a group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems; the carbon atoms of said rings possibly being substituted.
  • groups R a and Rb of heterocyclic type there may be mentioned, among others, the furyl, thienyl, isoxazolyl, furazanyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrannyl, phosphino and quinolyl, naphthyridinyl, benzopyrannyl groups. , benzofurannyl.
  • R a and R can be linked so as to constitute, with the carbon atoms which carry them, a heterocyclic group having 3 to 20 atoms, saturated, unsaturated, or aromatic, monocyclic or polycyclic as defined above. It can include two or three ortho-condensed rings which means that at least two rings have two carbon atoms in common. In the case of polycyclic compounds, the number of atoms in each cycle preferably varies between 3 and 6. R a and R preferentially form a pyrimidine or purine type cycle.
  • the number of substituents present on each cycle depends on the carbon condensation of the cycle and on the presence or not of unsaturation on the cycle.
  • the reagent of the invention can be used to protect the amino groups present in amino acids.
  • amino acids that may be mentioned include glycine, cysteine, aspartic acid, glutamic acid, histidine.
  • the reagent of the invention is very particularly suitable for protecting weakly nucleophilic nitrogen atoms (deactivated). Thus, it is very advantageous to use it during the synthesis of the nucleic acid monomers to protect the amino groups which are present in natural bases such as those derived from pyrimidine (C 4 N 2 H 4 ), thymine (C 5 N 2 O 2 H 6 ), cytosine
  • the compound comprising the amino or substituted amino group to be protected can be reacted with the reagent of the invention, in a suitable solvent.
  • the solvent is chosen so that it completely or partially dissolves the reagents and the product obtained.
  • the molar ratio between the reagent and the compound comprising the group to be protected can vary widely, for example between 1 and 10, preferably between 1 and 3.
  • nitriles such as acetonitrile, benzonitrile
  • amides such as dimethylformamide, dimethylacetamide
  • aliphatic or aromatic halogenated hydrocarbons mention may be made of partially chlorinated hydrocarbons such as dichloromethane, dichloroethane, aromatic halogenated hydrocarbons such as monochlorobenzene.
  • the reaction temperature is advantageously between 0 and 100 ° C, preferably between 20 and 60 ° C.
  • the product obtained comprising the protected group is recovered in a conventional manner. It will be specified for example that in the case of the use of the dimethylformamide solvent, at the end of the reaction, water is added and the product formed precipitates so that it can be separated, for example by filtration.
  • the group can be deprotected, for example by treatment with a strong acid.
  • strong acid is meant in the present invention, an acid having a pKa in water of less than - 1.0.
  • PKa is defined as the ionic dissociation constant of the acid / base couple, when water is used as a solvent.
  • strong acids mention may in particular be made of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methane sulfonic acid, trifluoromethanesulfonic acid.
  • a concentrated acid solution is used.
  • Commercial solutions are used in particular, especially hydrochloric acid (37%), sulfuric acid (95 - 98%), trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid (100%).
  • the amount of acid expressed by the ratio of the number of proton equivalents to the number of moles of substrate to be deprotected can vary between approximately 2 and 10, preferably between approximately 2 and 5.
  • the temperature of the deprotection reaction is advantageously situated between room temperature and 60 ° C.
  • deprotection under hydrogen pressure for example between 1 and 20 Bar
  • a noble metal preferably deposited on a support.
  • the temperature of the deprotection reaction is within the same temperature range specified above.
  • a white suspension is then formed in the solvent.
  • the solvent is evaporated under reduced pressure of 12 mm of mercury.
  • the medium is left under stirring for 6 days.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP04701979A 2003-01-15 2004-01-14 Verfahren zur herstellung eines reagens von acylimidazoliumtyp Withdrawn EP1590331A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0300390 2003-01-15
FR0300390A FR2849851B1 (fr) 2003-01-15 2003-01-15 Procede de preparation d'un reactif de type acylimidazolium.
PCT/FR2004/000059 WO2004069807A1 (fr) 2003-01-15 2004-01-14 Procede de preparation d'un reactif de type acylimidazolium

Publications (1)

Publication Number Publication Date
EP1590331A1 true EP1590331A1 (de) 2005-11-02

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US (1) US20060149051A1 (de)
EP (1) EP1590331A1 (de)
FR (1) FR2849851B1 (de)
WO (1) WO2004069807A1 (de)

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JP5454458B2 (ja) * 2010-11-25 2014-03-26 信越化学工業株式会社 ポジ型レジスト材料及びパターン形成方法
TWI486335B (zh) * 2011-12-29 2015-06-01 Eternal Materials Co Ltd 鹼產生劑

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US824645A (en) * 1906-02-20 1906-06-26 Baker City Iron & Supply Co Coupling device for aerial tramways and the like.
US2524751A (en) * 1947-02-04 1950-10-10 Armstrong Cork Co Comminuting machine
US3317957A (en) * 1965-06-11 1967-05-09 Nrm Corp Pelletizer
DE1964413C3 (de) * 1969-12-23 1973-10-04 Hermann Berstorff Maschinenbau Gmbh, 3000 Hannover Einrichtung zum Granulieren von thermoplastischen Kunststoffen
JPS5646966B2 (de) * 1974-01-08 1981-11-06
US3991202A (en) * 1974-01-31 1976-11-09 Janssen Pharmaceutica N.V. Imidazolium salts
US4728276A (en) * 1986-01-31 1988-03-01 Gala Industries, Inc. Underwater pelletizer
DE4116933A1 (de) * 1991-05-24 1992-11-26 Werner & Pfleiderer Granuliervorrichtung fuer plastische kunststoffmassen
JPH0784010B2 (ja) * 1991-11-29 1995-09-13 株式会社神戸製鋼所 水中カット造粒装置
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Publication number Publication date
WO2004069807A1 (fr) 2004-08-19
FR2849851A1 (fr) 2004-07-16
FR2849851B1 (fr) 2007-01-26
US20060149051A1 (en) 2006-07-06

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