EP2197882A2 - Procédé de production de dérivés teda - Google Patents

Procédé de production de dérivés teda

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Publication number
EP2197882A2
EP2197882A2 EP08803391A EP08803391A EP2197882A2 EP 2197882 A2 EP2197882 A2 EP 2197882A2 EP 08803391 A EP08803391 A EP 08803391A EP 08803391 A EP08803391 A EP 08803391A EP 2197882 A2 EP2197882 A2 EP 2197882A2
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EP
European Patent Office
Prior art keywords
alkyl
diazabicyclo
alkoxy
aryl
dihydropyrazine
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.)
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Application number
EP08803391A
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German (de)
English (en)
Inventor
Gunther Van Cauwenberge
Johann-Peter Melder
Joachim-Thierry Anders
Christoph Benisch
Rainer Klopsch
Gregor Daun
Christian Dully
Boris Buschhaus
Henning Boeckemeier
Evelyn Pox
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BASF SE
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BASF SE
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Application filed by BASF SE filed Critical BASF SE
Priority to EP08803391A priority Critical patent/EP2197882A2/fr
Publication of EP2197882A2 publication Critical patent/EP2197882A2/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a process for the preparation of triethylenediamine (TEDA) derivatives starting from dihydropyrazines and olefins.
  • TEDA triethylenediamine
  • Exemplary TEDA derivatives which can be prepared by the process according to the invention correspond to the general formula (Ia) or (Ib)
  • the present invention also relates to a selection of novel TEDA derivatives according to the above-defined general formula (Ia) or (Ib) and their use as polyurethane catalysts, preferably as incorporable polyurethane catalysts.
  • TEDA triethylenediamine, also referred to as 1, 4-diazabicyclo [2.2.2] octane (DABCO)
  • DABCO 4-diazabicyclo [2.2.2] octane
  • WO 01/02404 describes a process for the preparation of TEDA using zeolite catalysts.
  • the educts of TEDA production are ethylenediamine (EDA) and piperazine (PIP).
  • TEDA is an important chemical raw material and is used, among other things, in the production of pharmaceuticals and plastics, in particular as a catalyst in the production of polyurethanes (PUR).
  • TEDA derivatives which have functional groups (for example an ester, ether or amino function) proves to be difficult with the processes described above.
  • Such TEDA derivatives with a functional group are only occasionally known.
  • the use of such substituted TEDA derivatives as PUR catalyst has not yet been described.
  • TEDA derivatives are described, for example, by T. Oishi et al., Tetrahedron Letters, Vol. 33 (5), pp. 639-642 (1992).
  • the corresponding TEDA derivatives are synthesized by reaction with 1, 2-dibromoethane in ethanol, which have two benzoxymethyl substituents in position 2 and 3 of TEDA.
  • the corresponding substituents may also have t-butyldimethylsilyl or t-butyldiphenylsilyl-containing ether substituents instead of benzyl.
  • WO 98/24790 relates to the preparation of TEDA derivatives in which TEDA is linked via a methyl ester bridge with a benzene fragment.
  • the compounds used as drugs are prepared by first reacting piperazine with 2,3-dibromopropionic acid ethyl ester to a TEDA derivative having an ethyl ester function in position 2. This TEDA derivative is then reduced with lithium aluminum hydride to 2-hydroxymethyl-TEDA, which is then reacted with the corresponding benzoic acid derivative to the target molecule.
  • DE-A 30 48 031 relates to a process for the preparation of substituted pyrazines.
  • Process dihydropyrazines are reacted with carbonyl derivatives in the presence of a base to substituted pyrazine.
  • Suitable carbonyl compounds include carbonyl compounds which contain a double bond, such as terpene aldehydes, unsaturated aliphatic aldehydes, unsaturated aliphatic ketones or furan aldehydes.
  • strong organic bases such as alkali metal alkoxides (alkoxide)
  • alkali metal hydrides or alkali metal amides no TEDA derivatives are obtained with the method described in DE-A 30 48 031. The reason for this difference in reactivity is to be found in a different reaction mechanism underlying the reaction described in DE-A 30 48 031.
  • the reaction described in DE-A 30 48 031 is based on the following mechanism: First, the strong base used, e.g. an alkoxide, a proton in the saturated position 5 of 5,6-dihydropyrazine, to give the corresponding acid, e.g. the corresponding alcohol. The resulting dihydropyrazine anion then nucleophilically attacks the carbonyl compound to form intermediately a 5- [V-hydroxy-1 '- (substituent) -methyl] -5,6-dihydropyrazine.
  • the strong base used e.g. an alkoxide
  • a proton in the saturated position 5 of 5,6-dihydropyrazine to give the corresponding acid, e.g. the corresponding alcohol.
  • the resulting dihydropyrazine anion then nucleophilically attacks the carbonyl compound to form intermediately a 5- [V-hydroxy-1 '- (substituent) -methyl] -5,6-dihydr
  • TEDA derivative unsubstituted TEDA is also encompassed by the term "TEDA derivative".
  • TEDA and TEDA derivatives By the method according to the invention can be advantageously prepared TEDA and TEDA derivatives, especially those TEDA derivatives containing substituents with functional groups.
  • Substituents with functional groups are to be understood as meaning those substituents which have at least one heteroatom, such as halogen, S, P, O or N.
  • TEDA derivatives with substituents which contain functional groups are particularly advantageously suitable as catalyst for the production of polyurethane (PUR catalyst).
  • PUR catalyst polyurethane
  • the polyurethanes produced in this way, in particular polyurethane foams, are distinguished by the fact that the catalysts used do not outgas from the polyurethane since they are chemically bound into the corresponding polyurethane, in particular in polyurethane foam, or because they have an increased vapor pressure feature.
  • step a the reaction of a dihydropyrazine with an olefin takes place, wherein in each case one carbon atom of the olefin double bond is linked by the reaction with one ring nitrogen atom of the dihydropyrazine.
  • dihydropyrazine and of olefin in principle there are no restrictions, both educts can be both unsubstituted and substituted.
  • These starting materials are commercially available or can be prepared by methods known to those skilled in the art. Details of the synthesis of the dihydropyrazine starting materials are described in more detail below.
  • the educt synthesis starting from (optionally substituted) ethylenediamine (s) and dicarbonyl compounds to the dihydropyrazines can be carried out in various solvents.
  • all organic solvents and water are suitable.
  • protic solvents e.g. 1, 2-propanediol or water
  • the reaction in these solvents leads to poorer dihydropyrazine selectivities and to an increased tendency to biopolymerize of polymers.
  • diethyl ether although chemically useful, but not recommended for safety reasons (low boiling point, auto-oxidizing) on an industrial scale.
  • MTBE tert-butyl methyl ether
  • This solvent has chemical properties similar to those of diethyl ether (solubility, polarity and mixing behavior with organic solvents or water) but with a higher boiling point and no autoxidisability, making it safer to handle.
  • MTBE tert-butyl methyl ether
  • This solvent has chemical properties similar to those of diethyl ether (solubility, polarity and mixing behavior with organic solvents or water) but with a higher boiling point and no autoxidisability, making it safer to handle.
  • MTBE tert-butyl methyl ether
  • Ethylenediamine or an EDA derivative is initially charged in a subset of MTBE and the dicarbonyl compound (equimolar) in MTBE is slowly added dropwise. It forms an insoluble intermediate which decomposes on subsequent heating to ambient temperature or above in product, EDA and water. The intermediate makes the uniform agitation very difficult, therefore, a relatively large amount of solvent is used. If the amount of solvent is too small, the mixture solidifies, forming lumps that still contain dicarbonyl compound. These lumps heat up a great deal and melt into a tough black mass. Therefore, you can not work solvent-free.
  • MTBE Tert-butyl methyl ether
  • the synthesis of Dihydropyrazine can be carried out between -80 0 C and 80 ° C.
  • the reaction between -20 0 C and 60 0 C, more preferably carried out between 0 ° C and 50 ° C.
  • the reaction pressure can be between 0.5 and 250 bar (absolute). Preference is given to working at atmospheric pressure.
  • the synthesis of the dihydropyrazines is particularly preferably carried out without an additionally added catalyst because the reactivity of the dicarbonyl compounds and the ethylenediamine derivatives is very high on its own.
  • Step a Reaction of dihvdropyrazine with the olefin
  • step a) TEDA derivatives are prepared which have a carbon-carbon double bond (unsaturated TEDA derivatives) in the TEDA skeleton.
  • step b) can be carried out, in which the product obtained in step a) is subjected to hydrogenation.
  • the reaction of the dihydropyrazine with the olefin can be carried out in various solvents.
  • solvents are methanol, 1, 2-propanediol, dioxane, tetrahydrofuran or MTBE.
  • a catalyst can be used.
  • step a) is carried out in the absence of bases. It is particularly preferred to work without the addition of a catalyst, since the reaction can also be controlled thermally.
  • the reaction can be carried out at temperatures of -50 0 C to 200 0 C.
  • the reaction is carried out at a reaction temperature between 0 ° C and 150 0 C.
  • the reaction temperature is particularly preferably 60 ° C. to 130 ° C.
  • the reaction pressure can be between 0.5 and 250 bar (absolute). Preference is given to working at atmospheric pressure.
  • the molar ratio of dihydropyrazine to olefin can be varied from 20: 1 to 1:20. Particularly advantageous is the use of equimolar amounts.
  • the reaction can be explained by the mechanism of a cycloaddition between a diene and a dienophile (Diels-Alder reaction) or as a Michael addition.
  • Diels-Alder reaction Diels-Alder reaction
  • the choice of substituents is therefore largely arbitrary, since especially the diene skeleton of dihydropyrazine and the olefinic double bond are involved in the reaction.
  • the rate of reaction and chemoselectivity of cycloadditions often depend on the electronic ratios of the two reactants.
  • the substituents on both reactants can be varied in their properties by introducing protective groups, derivatization and reversal, to achieve the desired reactivity.
  • the introduction of protective groups is known to the person skilled in the art.
  • Step b Hydrogenation of the reaction product from a)
  • step b) The hydrogenation according to step b) is carried out by methods known to those skilled in the art.
  • the hydrogenation can be carried out directly after step a) without isolation of the unsaturated TEDA derivative obtained in step a).
  • the products obtained in steps a) and b) can be purified and isolated by methods known to those skilled in the art.
  • step a If protected starting materials have been used in step a), the corresponding protective groups can be removed again after step a) or optionally following step b) by methods known to the person skilled in the art (deprotection step c)). Optionally, this deprotection can also be carried out together with the hydrogenation in step b).
  • Alkyl (Ci-Ci o alkyl; means this shortcut that the corresponding alkyl group having 1 to 10 carbon atoms) may be unsaturated either linear or branched, acyclic or cyclic and saturated or. This also applies if they are part of another group such as, for example, alkoxy groups (C 1 -C 10 -alkyl-O-), alkoxycarbonyl groups or aminoalkyl groups or if they are substituted. Accordingly, alkyl also includes alkylene radicals (- (CH 2 ) n -, with n, for example, 1 to 10). Thus, for example, alkylamino (C 1 -C 10 -alkoxy) means that a C 1 -C 10 -alkoxy radical is in turn substituted by an alkylamino radical.
  • alkyl groups are: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl.
  • both the n-isomers of these radicals and branched isomers such. Isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neophen tyl, 3,3-dimethylbutyl, 2-ethylhexyl, etc. included.
  • alkyl also includes alkyl radicals which are unsubstituted or optionally substituted by one or more further radicals, for example 1 to 10 identical or different radicals, such as, for example, hydroxyl, amino, alkylamino, dialkylamino, aryl, Heteroaryl, alkoxy or halogen.
  • the additional substituents can occur in any position of the alkyl radical.
  • alkyl also includes cycloalkyl and cycloalkyl-alkyl- (alkyl which in turn is substituted with cycloalkyl) wherein cycloalkyl has at least 3 carbon atoms.
  • cycloalkyl radicals are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. If appropriate, these may also be polycyclic ring systems, such as decalinyl, norbornanyl, bornanyl or adamantanyl.
  • the cycloalkyl radicals may be unsubstituted or optionally substituted by one or more further radicals, as exemplified above for the alkyl radicals.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Aryl is a 5- to 14-membered, aromatic, mono-, bi- or tricycle.
  • the radical aryl is thus derived from mono-, bi- or tricyclic aromatics which contain no ring heteroatoms. Unless they are monocyclic systems, the second or third ring may also be in the saturated or partially unsaturated form, as long as the particular forms are known and stable.
  • aryl may also be at least monosubstituted, for example with halogen, alkyl or alkoxy. Examples of aryl are: phenyl, naphthyl, indanyl, 1, 2-dihydro-naphthenyl or 1,2,3,4-tetrahydronaphthyl.
  • aryl is phenyl.
  • a preferred embodiment of the present invention relates to a process for the preparation of triethylenediamine (TEDA) derivatives of the general formulas (Ia) or (Ib)
  • All carbon atoms may be R- or S- or E- or Z-configured.
  • the representation shown in the structural formulas does not imply a representation of the absolute configuration (eg endo or exo position or an orientation up / down of a particular substituent) on a carbon atom or the absolute configuration of a double bond, the drawing is only to illustrate the To understand connectivity, ie on which C atom which substituents can be situated.
  • R1 to R10 are independently selected from
  • the groups R14 are independent of each other substituted residues R14 can thereby in any position of the (Ci-Ci o alkyl) - fragment is, the upper limit of the residues R14 by the number of hydrogen atoms in the corresponding (Ci-Ci O alkyl) fragment is fixed.
  • R 13 is H, hydroxy, amino, aryl, C 1 -C 10 -alkoxy, amino- (C 1 -C 10 -alkoxy), alkylamino (C 1 -C 10 -alkoxy), dialkylamino (C 1 -C 10 -alkoxy), amino (Ci -Ci 0 -alkyl), aminoaryl, -NH (C 1 -C 10 -alkyl), -N (C 1 -C 10 -alkyl) 2 , -NH-aryl, -N- (aryl) 2 , halogen, hydroxyaryl, -O- aryl or -O- (C r Cio-alkyl) -aryl;
  • R14 is hydroxy, amino, aryl, Ci-Ci 0 alkoxy, amino (Ci-Ci 0 alkoxy), alkylamino (d- Cio-alkoxy), dialkylamino (C r Cio-alkoxy), amino (C r is Cio-alkyl), -NH (C 1 -C 10 -alkyl), -N (C 1 -C 10 -alkyl) 2 , hydroxyaryl, aminoaryl, -NH-aryl, -N (aryl) 2 , halogen, -PH-aryl, -P (Aryl) 2 , -O-aryl or -O- (C 1 -C 10 -alkyl) -aryl,
  • A can be any anion, preferably A is selected from halogen, sulfate,
  • Halogen is especially chlorine.
  • At least one of the substituents R1 to R10 is selected from
  • R 13 and R 14 are each independently of the same hydroxy, C 1 -C 10 -alkoxy, -NH 2 , - NH (Ci-Cio-alkyl), -N (Ci-Ci o alkyl) 2, -O-aryl, or -O- (C r Ci 0 alkyl) -aryl, and u is from 0 to 10 degrees.
  • the dihydropyrazine (II) is particularly preferably selected from 2,3-dihydropyrazine, 2-methyl-5,6-dihydropyrazine, 2-ethyl-5,6-dihydropyrazine, 2-propyl-5,6-dihydropyrazine, 2,3- Dimethyl 5,6-dihydropyrazine, 2,3-diethyl-5,6-dihydropyrazine, 2-ethyl-3-methyl-5,6-dihydropyrazine, 2,5-dimethyl-5,6-dihydropyrazine, 2,6- Dimethyl 5,6-dihydropyrazine, 2,3,5-trimethyl-5,6-dihydropyrazine, 2-hydroxy-5,6-dihydropyrazine, 2-methyl-3-hydroxy-5,6-dihydropyrazine, 2-methyl 5-hydroxy-5,6-dihydropyrazine, 2-methyl-6-hydroxy-5,6-di
  • the olefin (III) is particularly preferably selected from ethylene, propylene, butylene, hydroxypropylene, hydroxybutylene, vinyl methyl ketone, acrylic acid, methyl acrylate, ethyl acrylate, propyl acrylate, vinyl methyl ether, (dimethylaminoethyl) vinyl ether, (2-hydroxyethyl) vinyl ether, (I -Hydroxyethyl) vinyl ethers, allylmethylketone, 3-hydroxybut-1-ene, 3-hydroxypent-1-ene, 3-hydroxyhex-1-ene, 4-hydroxybut-1-ene, 4-hydroxypent-1-ene, 4 Hydroxyhex-1-ene, 5-hydroxypent-1-ene, 5-hydroxyhex-1-ene, 6-hydroxyhex-1-ene, 4-hydroxypent-2-ene, 4-hydroxyhex-2-ene, 2-hydroxybutyl 3-ene, 4-hydroxypent-2-ene, 4-hydroxyhex-2-ene
  • the TEDA derivative (Ia) is a compound according to the formula (Ia1)
  • R 2, R 7 and R 8 independently of one another are H, -OH, - (C r C 3 -alkyl) -OH, (C 1 -C 3 -alkyl) -O- (C 1 -C 3 -alkyl), -CN, -O-phenyl, - (C 1 -C 3 -alkyl) -O-phenyl, C 1 -C 3 -alkoxy, - C (O) (-C 3 -alkoxy), -C (O) OH, -N (CH 3) 2, -NH (CH 3), -NH 2, - (C r C 3 alkyl) -N ( CH 3 ) 2 , - (C 1 -C 3 -alkyl) -NH (CH 3 ), - (C 1 -C 3 -alkyl) -NH 2 , or - (C 1 -C 3 -alkyl) -OC (O) (CrC 3 alkoxy
  • the TEDA derivative (Ib) is a compound according to formula (Ib1),
  • R 2, R 7 and R 8 independently of one another are H, -OH, - (C 1 -C 3 -alkyl) -OH, - (C 1 -C 3 -alkyl) -O- (C 1 -C 3 -alkyl), -CN, - O-phenyl, - (C r C 3 alkyl) -O-phenyl, C r C 3 alkoxy, - C (O) (-C 3 -alkoxy), -C (O) OH, -N (CH 3) 2 , -NH (CH 3 ), -NH 2 , - (C r C 3 -alkyl) -N (CH 3 ) 2 , - (dC 3 -alkyl) -NH (CH 3 ), - (Ci-C 3 -Alkyl) -NH 2 , or - (C 1 -C 3 -alkyl) -OC (O) (C 1 -C 3
  • R5 and R6 are independently H, C r C 3 alkyl, -C (O) OH, -C (O) (-C 3 -alkoxy), or - (Ci-C3 alkyl) -O- (CrC 3 alkyl ) are,
  • the dihydropyrazine (II) is prepared by reacting a dicarbonyl compound with ethylenediamine (EDA) or an EDA derivative.
  • EDA ethylenediamine
  • the carbonyl compound is a diketo compound.
  • Preferred diketo compounds are selected from 2,3-pentanedione, 2,3-butanedione, glyoxal, methylglyoxal.
  • Preferred EDA derivatives are EDA, 1,2-propanediamine, 1,2-butanediamine, 2,3-butanediamine, 1,2-pentanediamine, 2,3-pentanediamine, 1,2-hexanediamine, 2,3-hexanediamine, 3 , 4-hexanediamine.
  • reaction is carried out in organic solvents, for example ethers, esters, alcohols or alkanes.
  • organic solvents for example ethers, esters, alcohols or alkanes.
  • the reaction is carried out in a moderately polar but water-immiscible solvent.
  • Tert-butyl methyl ether (MTBE) is particularly preferably used as the solvent and, in addition, it is worked under N 2 as protective gas.
  • the synthesis of Dihydropyrazine can be carried out between -80 0 C and 80 0 C.
  • the reaction between -20 ° C and 60 0 C, more preferably carried out between 0 ° C and 50 ° C.
  • the reaction pressure can be between 0.5 and 250 bar (abs.). Preference is given to working at atmospheric pressure.
  • Another object of the present invention are novel triethylenediamine derivatives which can be prepared by the process according to the invention.
  • These TEDA derivatives according to the invention contain substituents with functional groups, in particular substituents, which have at least one heteroatom, such as halogen, O, P, S or N, preferably O or N.
  • substituents with functional groups in particular substituents, which have at least one heteroatom, such as halogen, O, P, S or N, preferably O or N.
  • isolated TEDA derivatives are already known.
  • These already known TEDA derivatives are not the subject of the present invention with regard to the TEDA derivatives as such.
  • the TEDA derivatives of the invention thus do not include those disclosed in the aforementioned documents by T. Oishi et al., L. Street et al., E. Shiskhin et al. as well as in WO 98/24790 and DE-A 30 48 031 described TEDA derivatives.
  • the TEDA derivatives according to the invention correspond to the general formula (Ia) or (Ib),
  • radicals R 1 to R 12 have the above meanings and wherein at least one of the substituents R 1 to R 10 contains at least one heteroatom selected from halogen, O, P, S or N, preferably O or N, or at least one of R 1 to R 10 contains -OH or -NH 2 , provided that not one of R 1 to R 12 is -C (O) OH, -C (O) OCH 3 , -C (O) OC 2 H 5 , -CH 2 -OH, -CH 2 -O-benzyl or -CH 2 -OC (O) -CH 3 when the other radicals from R 1 to R 12 are hydrogen, and not two adjacent radicals R 1 to R 12 equals -CH 2 -O-benzyl when the other radicals from R 1 to R 12 are hydrogen.
  • Adjacent remainder is understood to mean that the respective radicals are bonded to 2 different carbon atoms of the TEDA derivatives according to the invention and these
  • Another object of the present invention is the use of the inventive TEDA derivatives for the production of polyurethanes.
  • the TEDA derivatives according to the invention are preferably used as catalyst, in particular in the production of polyurethane foams.
  • Such processes for the preparation of polyurethanes are known to the person skilled in the art.
  • a further subject of the present invention are thus also polyurethanes comprising at least one TEDA derivative according to the invention.
  • Such polyurethanes, preferably polyurethane foams are distinguished by the fact that the TEDA derivatives used do not outgas because they chemically enter the corresponding polyurethanes. are involved. In this way, low-odor or odorless polyurethanes can be produced.
  • the TEDA derivative according to the invention may preferably be used in its capacity as a polyurethane catalyst as a gel catalyst for the crosslinking reaction or as a blowing catalyst for the release of CO 2 with the aid of water.
  • the TEDA derivative according to the invention is particularly preferably used as a gel catalyst which promotes the crosslinking reaction between polyisocyanate and polyol component.
  • Example 2 Butanedione (52.9 g, 615 mmol, 1 eq.) Is initially charged in 1,2-propanediol (50 g) and EDA (73.8 g, 1.23 mol, 2 eq.) Is added with ice-cooling. The temperature rises to about 40 0 C. The solution turns yellow to black.
  • GC analysis on a 30m RTX-5 amine column shows that the product mixture of 14.7% EDA, 81.5% 1, 2-propanediol and 0.61% 2,3-dimethyl-5,6 -dihydropyrazine composed (solvent-free: 79.5% EDA, 3.29% 2,3-dimethyl-5,6-dihydropyrazine).
  • Example 4 EDA (5:58 g, 92 mmol) in MeOH submitted (20 mL) at 0 0 C. Butanedione (4.00 g, 46.4 mmol, 1 eq.) Is dissolved in MeOH (40 ml) and added dropwise very slowly over 2 h to the EDA solution and stirred vigorously. The temperature of the mixture does not rise above 0 ° C. The resulting white solid is filtered off and washed with cold MeOH. The solid is converted on removal of the solvent at 30 0 C in 2,3-dimethyl-5,6-dihydropyrazine (brown oil).
  • Example 6 Work is carried out under N 2 .
  • EDA (2.79 g, 46.4 mmol, 2 eq.) Is initially charged in MTBE (60 mL) at 0 ° C.
  • Butanedione (4.00 g, 46.4 mmol) in MTBE (6 mL) is added dropwise (over 40 min). Due to the white precipitate, the approach is very firm, it is therefore strongly stirred. It is then heated quickly to 50 0 C to dissolve the precipitate. There are two phases. The mixture is then immediately cooled to 0 ° C to avoid polymerization. The organic phase is fractionally distilled. The desired product boils at 28 mbar / 95 ° C and is collected in the cold trap.
  • the product is obtained at 7 mbar / 105 ° C (bottom) / 40 ° C (top).
  • GC analysis on a 30 m RTX-5 amine column shows that the product mixture consists of 83.1% MTBE, 16.5% 2,3-dimethyl-5,6-dihydropyrazine and 0.44% other ( solvent-free: 97.6% 2,3-dimethyl-5,6-dihydropyrazine, 2.60% other).
  • Butanedione (172 g, 2 mol, 1 eq.) Is initially charged in MTBE and EDA (120 g, 2 mol, 1 eq. In 120 ml of MTBE) is slowly added dropwise. The batch is heated to 30 ° C and the aqueous extracted phase with 3 x 100 ml_ MTBE. The combined organic phases are dried with MgSO 4 and MTBE removed on a rotary evaporator at 55 ° C as far as possible. The residue is fractionally distilled via the rotating band column. The temperature rises during the dropping in the flask to about 35 ° C, since the reaction mixture solidified in places. The dropping is stopped immediately and it is waited until the reaction subsides. The solution does not turn dark. Apparent short-term heating above 30 0 C has no further effects on the course of the reaction.
  • 2,3-dihydropyrazine shows a strong tendency to dimerization and polymerization, which is why it should be preferred to work at low temperatures. After the synthesis of dihydropyrazine, the next stage should be started as soon as possible.
  • Glyoxal (5.8 g, 0.1 mol, 1 eq., 14.5 g 40% solution in H 2 O) is so conces- dropwise such that the temperature does not rise above 0 0 C.
  • the heat development of the reaction is much lower than that with the use of methylglyoxal or butanedione.
  • the aqueous phase is almost colorless.
  • the desired product is detected by GC-MS but not isolated. After 1 h at ambient temperature, the discharge becomes rubbery.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) shows the following composition: (in GC fl.%) 74.5% ethylenediamine, 14.6% 2,3-dihydropyrazine, 10.9% unknown compounds, water content not taken into account.
  • the EDA (4.5 g, 75 mmol, 3 eq.) Is dissolved in MTBE (40 mL), cooled to 0 ° C. and methylglyoxal (1.8 g, 25 mmol, 1 eq., 4.5 g 40% solution in H 2 O ) (30 min).
  • the batch is warmed overnight to ambient temperature.
  • the organic phase is colorless, the watery tan colored.
  • the aqueous phase contains mainly 3 main products.
  • the desired product is detected in both phases by GC-MS, but not isolated.
  • Example 20 2-Ethyl-3-methyl-5,6-dihvdropyrazine To a solution consisting of one part of ethylenediamine in part 1, 2-propanediol, a solution of one part of 2,3-pentanedione is dissolved in part 1 , 2-propanediol added slowly. There is an exothermic reaction.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) has the following composition: (in GC-FI%) 25.28% ethylenediamine, 56.76% 1, 2-propanediol, 16.62% 2-ethyl-3-methyl -5,6-dihydropyrazine, 0.77% Other.
  • Example 21 A portion of the discharge from Example 1 (2,3-dimethyl-5,6-dihydropyrazine 77%) is initially charged, 1 g of ethyl acrylate is added. At room temperature, there is no reaction. The reaction vessel is heated to 100 ° C. for a few minutes. GC analysis (30 m RTX-5 amines) of the reaction effluent shows the following composition: 0.17% EDA, 4.24% ethyl acrylate,
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) shows after 90 min the following composition: (in GC-FI%) 69.9% methanol, 1, 59% ethylenediamine, 11, 3% 2,3-dimethyl-5, 6-dihydropyrazine, 3.79% 2-hydroxyethylpiperazine, 2.23% N-acetyl-EDA, 0.71% N, N-bis [2 '- (ethoxycarbonyl) ethyl] ethylenediamine, 10.5% Other.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) shows after 30 min the following composition: (in GC-FI%) 0.94% ethylenediamine, 81, 5% 1, 2-propanediol, 7.10% 2,3- Dimethyl-5,6-dihydropyrazine, 1.18% N-acetyl-EDA, 0.08% 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (product) , 9,20% Other.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) shows after 90 min the following composition: (in GC-FI%) 1, 28% ethylenediamine, 84.9% 1, 2-propanediol, 0.25% piperazine, 4, 12% 2,3-dimethyl-5,6-dihydropyrazine, 0.31% N-acetyl-EDA, 0.04% 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] octane 5-s (product), 9,10% Other.
  • Solvent-free 8.48% ethylenediamine, 1.66% piperazine, 27.3% 2,3-dimethyl-5,6-dihydropyrazine, 2.05% N-acetyl-EDA, 0.26% 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (product), 60.36% Other.
  • Example 24 2,3-dimethyl-5,6-dihydropyrazine (approx. 12 mmol in 20 mL 1, 2-propanediol, 1 eq) and 1, 2- propanediol (30 ml) are heated to 60 0 C. At this temperature, ethyl acrylate (6.0 g, 60 mmol, 0.5 eq. Dissolved in 2.0 ml. 1,2-propanediol) is added dropwise under N 2 (10 min.) And the mixture is subsequently heated rapidly to 100 ° C. The reaction solution is left for 5 min at this temperature. The gas chromatogram of the reaction mixture (30 m RTX 5 amines) showed the following composition: (in GC-FI%)
  • 2,3-Dimethyl-5,6-dihydropyrazine is purified by distillation before the experiment. (Example 9). As a high-boiling, largely inert solvent dioxane is selected. The acrylic acid ester is used only in slight excess (1.2 equivalents).
  • 2,3-Dimethyl-5,6-dihydropyrazine (1.778 g, 16.16 mmol, 1 eq.) Is dissolved under N 2 in dioxane (25 mL) and heated to 80 ° C.
  • Ethyl acrylate (1939 g, 19.39 mmol, 1.2 eq.) Is dissolved in dioxane (8 mL) and slowly added dropwise (15 min).
  • the mixture is brought to reflux for 4 h at 95 ° C, allowed to stand overnight at 20 0 C and heated again for 4 h.
  • the yield of the desired product can be significantly increased.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) shows the following composition: (in GC-FI%)
  • Example 27 EDA (. 6.0 g, 0.1 mol, 1 eq) (10 g) were charged and slowly added dropwise butadione (8.6 g, 0.1 mol, 1 eq.) In dioxane (2.0 g) at 0 0 C in dioxane. There are added 12 g of dioxane and the mixture stirred for 15 min. The apparatus is rendered inert with N 2 and treated with ethyl acrylate (10 g, 0.1 mol, 1 eq.). The solution is heated to boiling (95 ° C) and left at this temperature for 3 h. The desired product can be detected by GC-MS.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) has the following composition: (in GC-FI%) 65.8% dioxane, 11.1% 2,3-dimethyl-5,6-dihydropyrazine, 10.1 % 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (product), 13.0% Other.
  • Solvent-free 32.5% 2,3-dimethyl-5,6-dihydropyrazine, 29.5% 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (Product), 38.0% Other.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) has the following composition: (in GC-FI%) 34.1% dioxane, 11.5% 2,3-dimethyl-5,6-dihydropyrazine, 27.0 % 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (product), 5.40% + 12.2% addition products of the major product plus further equivalents of acrylic acid ester, 9.80 % Other.
  • Solvent-free 2.26% ethyl acrylate, 25.0% 2,3-dimethyl-5,6-dihydropyrazine, 48.0% 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct -5-ene (product), 7.60% + 16.5% addition products of the major product plus further equivalents of acrylic acid ester, 0.69% Other.
  • This result corresponds to a conversion of 50.3% with respect to dimethyldihydropyrazine or 95.4% with respect to ethyl acrylate and a selectivity of dimethyldihydropyrazine to the desired product of about 90%.
  • 2,3-Dimethyldihydropyrazine (141 g, 1.28 mol, 1 eq. 196 g of a ca. 72% solution in MTBE) and ethyl acrylate (128 g, 1, 28 mol, 1 eq.) are heated together to 82 ° C and stirred at this temperature for a total of 11.5 h until no acrylic acid ester can be detected in the GC.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) has the following composition: (in GC-FI%) 7.70% MTBE, 16.9% 2,3-dimethyl-5,6-dihydropyrazine, 46.2% 2 -Ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (product), 8.92% + 17.3% addition products of the major product plus further equivalents of acrylic acid ester, 2.98% Other , Solvent-free: 18.3% 2,3-dimethyl-5,6-dihydropyrazine, 50.1% 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (product ), 9.67% + 18.7% addition products of the major product plus further equivalents of acrylic acid ester, 3.23% other.
  • This result corresponds to a conversion of 65.1% with respect to dimethyldi- hydropyrazine or 100% with respect to ethyl acrylate and a selectivity of the dimethyldihydropyrazine to the desired product of 76.1%.
  • Solvent-free 10.0% ethyl acrylate, 24.8% 2,3-dimethyl-5,6-dihydropyrazine, 42.6% 2-ethoxycarbonyl-5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct -5-ene (product), 7.79% + 12.5% addition products of the main product plus further equivalents of acrylic esters, 2.26% others.
  • This result corresponds to a conversion of 52.6% with respect to dimethyldihydropyrazine and 79% with respect to ethyl acrylate and a selectivity of dimethyldihydropyrazine to the desired product of 81.0%.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) shows the following composition: (in GC-FI%) 3.40% MeOH, 19.1% acetone, 8.46% 2,3-dimethyl-5,6-dihydropyrazine , 1, 51% diethyl maleate, 40.26% 2,3-bis (ethoxycarbonyl) -5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (product), 19 , 5% other.
  • Solvent-free 10.95% 2,3-dimethyl-5,6-dihydropyrazine, 1.95% diethyl maleate, 52.13% 2,3-bis (ethoxycarbonyl) -5,6-dimethyl-1, 4- diazabicyclo [2.2.2] oct-5-ene (product), 25.25% Other.
  • 2,3-Dimethyldihydropyrazin (. 5.5 g, 50 mmol, 1 eq) is dissolved in MTBE (30 ml_) and at about - 30 0 C cooled (ice, dry ice and NaCl).
  • Dimethyl maleate (7.2 g, 50 mmol, 1 eq.) Is slowly added dropwise so that the temperature does not change significantly. The batch is stirred overnight and slowly warmed to ambient temperature. It is allowed to stand for 10 days at ambient temperature, the contents becoming increasingly dark brown but not tenacious as in Example 31.
  • the gas chromatogram of the reaction mixture (30 m RTX 5 amines) shows the following composition: (in GC-FI%) 0.31% MeOH, 70.1% MTBE, 3.84% 2,3-dimethyl-5,6-dihydropyrazine , 11.1% diethyl maleate, 11.6% 2,3-bis (ethoxycarbonyl) -5,6-dimethyl-1,4-diazabicyclo [2.2.2] oct-5-ene (product), 3 , 05% Other.
  • 2,3-dihydropyrazine from Example 16 is mixed with ethyl acrylate and heated to 80 0 C for a few minutes. There is little product formed (3.4%), which is detected by GC-MS.
  • the reaction conditions are not yet optimized and therefore not yet adapted to the high reactivity of 2,3-dihydropyrazine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de production de dérivés de triéthylènediamine (TEDA), caractérisé en ce qu'il comprend les étapes suivantes : a) réaction d'une dihydropyrazine avec une oléfine, b) éventuellement, hydrogénation à la suite de l'étape a). L'invention concerne en outre de nouveaux dérivés TEDA en tant que tels, ainsi que leur utilisation en tant que catalyseurs d'incorporation pour la production de polyuréthannes.
EP08803391A 2007-09-03 2008-08-29 Procédé de production de dérivés teda Withdrawn EP2197882A2 (fr)

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EP08803391A EP2197882A2 (fr) 2007-09-03 2008-08-29 Procédé de production de dérivés teda

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CN103265677B (zh) 2008-05-30 2016-06-08 东曹株式会社 羟基烷基三亚乙基二胺类化合物的制造方法及使用其的聚氨酯树脂制造用催化剂组合物
US8466323B2 (en) 2008-12-19 2013-06-18 Basf Se Process for preparing pure triethanolamine (TEOA)
SG11201507371RA (en) 2013-03-14 2015-10-29 Alkermes Pharma Ireland Ltd Prodrugs of fumarates and their use in treating various deseases
US8669281B1 (en) 2013-03-14 2014-03-11 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
CA2940845C (fr) 2014-02-24 2019-09-24 Alkermes Pharma Ireland Limited Sulfonamide et promedicaments de fumarates de sulfinamide et leur utilisation dans le traitement de diverses maladies

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DE3048031A1 (de) * 1979-12-21 1981-09-17 Firmenich S.A., 1211 Genève Verfahren zur herstellung substituierter pyrazine
FR2756563B1 (fr) * 1996-12-04 1998-12-24 Synthelabo Derives de benzoate de 1,4-diazabicyclo[2.2.2]oct-2-yl- methyle, leur preparation et leur application en therapeutique
DE19930736C2 (de) * 1999-07-05 2001-07-05 Performance Chemicals Handels Verfahren zur Herstellung von Triethylendiamin unter Einsatz von Ethylendiamin
US6147185A (en) * 1999-07-23 2000-11-14 Air Products And Chemicals, Inc. 1,4-diazabicyclo[2.2.2]octane compounds and their use for the production of polyurethanes
DE10132499A1 (de) * 2001-07-05 2003-01-23 Basf Ag Verfahren zur selektiven Synthese von Triethylendiamin
DE10321565B4 (de) * 2003-05-14 2013-09-26 Symrise Ag Verfahren zur Herstellung von Alkyldihydro-1,4-diazinen und Alkyl-1,4-diazinen

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