Classifications

• • 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
• • 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
  • C07C303/24—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfuric acids
• • 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
  • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
  • C07D307/32—Oxygen atoms
  • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form

Definitions

• the present invention relates to the production of methionine by combination of biotechnological and chemical steps.
• the present invention relates to the fermentative production of L-homoserine and subsequent chemical conversion to L-methionine in one or more steps.
• the amino acid methionine is currently industrially produced in large quantities worldwide and is of considerable commercial importance.
• Methionine is used in many fields, such as pharmaceutical, health and fitness products. In particular, however, methionine is used as a feed additive in many feeds for various farm animals, with both the racemic and the enantiomerically pure form of the methionine can be used.
• methionine is produced chemically via the Bucherer-Bergs reaction, which is a variant of the Strecker synthesis.
• the starting substances Methylmercaptopropionaldehyd (made of acrolein and methylmercaptan), hydrocyanic acid, ammonia and carbon dioxide to 5- (2-methyl-mercaptoethyl) - hydantoin (Methioninhydantoin) implemented, this then hydrolyzed alkaline to Alkalimethioninat and then by neutralization with acid such as sulfuric acid or Carbonic acid releases the methionine.
• methionine is industrially produced on a large scale, it is desirable to have an economic but also environmentally friendly process available.
• hydrocyanic acid is produced from methane and ammonia at high temperatures.
• Acrolein is produced by partial oxidation of propene, which in turn is derived from petroleum.
• the methionine process is described in more detail in EP 1256571, for example.
• the process for producing acrolein is described in more detail in EP 417723, for example. Both processes are associated with high technical complexity and high energy consumption.
• Methionine occurs in chemical synthesis as a racemic mixture of D and L enantiomers. This racemate can be used directly as a feed additive because under in vivo conditions
• Conversion mechanism exists that converts the unnatural D enantiomer into the natural L enantiomer. However, this conversion involves a loss of methionine, and hence a loss of bioefficiency compared to the same amount of pure L enantiomer. So it takes more racemic D, L-methionine compared to L-methionine to achieve the same effect.
• WO05 / 059155 describes a process for the improved isolation of L-methionine from fermentation broths.
• the improvement is achieved by a comparatively complicated sequence of steps, heating and dissolving the L-methionine in the fermentation broth, filtering off the biomass at a defined temperature and aftertreating the filtered methionine-containing biomass, evaporating the mother liquor, cooling, crystallizing, filtering off, washing and drying L-methionine from the mother liquor and return of mother liquors include, and that two different product streams a low and a high concentration of L-methionine product.
• the forced onset of two different methionine qualities however, in turn means additional effort and is also undesirable from a marketing perspective.
• Another task was a manufacturing process for
• a third object was to provide a technically feasible process which makes available L-methionine in suitable amounts and purities.
• deuterated homoserine derivatives HO-CHD-CH 2 -CH (HNCOOtBu) COOtBu or H 3 CC 6 H 4 SO 2 O-CHD-CH 2 -
• D, L-methionine which also do not emanate from homoserine but e.g. starting from 2-acetyl-4-butyrolactone via the 2-amino-4-butyrolactone or correspondingly protected 2-amino-4-butyrolactone, according to Snyder, Andreen, John, Cannon and Peters ("Convenient synthesis of dl-methionine", Journal of the American Chemical Society (1942), 64, 2082-4).
• L-homoserine can be produced by fermentation of microorganisms, in particular bacteria of the family Enterobacteriaceae or coryneform bacteria, wherein carbon sources such. As sucrose, glucose, fructose and glycerol or mixtures thereof and conventional
• Nitrogen sources such as B. ammonia can be used.
• Examples of the microbial production of L-homoserine using Enterobacteriaceae, especially Escherichia coli, can be found in US 6,303,348, US 6,887,691 or US 6,960,455 or EP 1217076 A1.
• L-homoserine obtained by fermentation makes it possible to arrive directly at the L-methionine, specifically when using chemical process steps according to the invention which do not impair the L configuration.
• using L-homoserine alone will produce a pure L-methionine that can be used directly in pharmaceutical and food applications, and also has higher bio-efficacy in animal nutrition compared to traditional D, L-methionine. This aspect of the method of the invention is generally of greatest use.
• an L-homoserine-containing solid product prepared from a L-homoserine-containing fermentation broth by removal of water is used. This has the advantage that by-products of fermentation only in the last
• Cleaning step can be separated at the stage of L-methionine and thus cleaning costs can be saved.
• by-products and / or by-products of the fermentation may also remain in the final product if they do not interfere with the subsequent reaction or are even desired in the final product. This is especially the case if they themselves have nutritive properties and L-methionine is used for feed production.
• Such nutritive compounds may be e.g. to act on other amino acids or proteins.
• a mixed product of L-methionine and by-products and / or by-products of the fermentative production of L-homoserine is also an object of the invention.
• the fermentation broth containing L-homoserine is expediently prepared by culturing a L-homoserine-withdrawing microorganism in a suitable nutrient medium.
• bacteria especially bacteria of the genus Corynebacterium or Escherichia.
• the concentration of L-homoserine in the fermentation broth is at least 1 g / l.
• an acidic catalyst selected from the group consisting of Bronsted acids having a pka of ⁇ 3.
• Such acids are, for example, HCl, HBr, HI, H 2 SO 4 , AlkaliHSCu, H 3 PO 4 , AlkaliH 2 PO 4 , where Alkali stands for lithium, sodium, potassium, rubidium or cesium,
• Polyphosphoric acid C 1 -C 12 -alkylsulfonic acid, C 10 -C 10 -arylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid acid or a copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-4-methyl-7-octene-sulfonic acid (Nafion).
• Nafion as a solid catalyst has the particular advantage that it can easily be separated from the reaction mixture and recycled after the reaction.
• Lewis acid catalysts with at least one low molecular weight Lewis acid selected from the group AlCl 3 , ZnCl 2 , BF 3 * OEt 2 , SnCl 2 , FeCl 3 may be mentioned here.
• heterogeneous acid catalysts from the group zeolite, montmorillonite and (WO 3 and Cs 2 O) -containing alumina can be used according to the invention.
• the aluminum oxides mentioned preference is given to those having 5-15% WO 3 and 5-15% Cs 2 O content.
• the reaction is carried out in solution and / or in suspension in the presence of water and / or an organic solvent. If the reaction is carried out in the presence of water, it may be expedient to start directly from an optionally freed from solid aqueous fermentation solution containing L-homoserine, since so advantageously further processing steps can be saved. But also a hydrous crude L-homoserine, can be used appropriately advantageous.
• water and / or at least one low molecular weight organic solvent selected from the group consisting of C 3 - to C 6 ⁇ ketones, preferably Methyl isobutyl ketone (MIBK) or acetone, straight-chain or branched C 1 -C 4 -alcohols, C 4 -C 10 -carboxylic acid esters, preferably ethyl acetate or butyl ester, C 3 -C 6 -carboxylic acid amides, preferably DMF or dimethylacetamide, C 6 -bis Cio-aromatics, preferably toluene and C3 to C 7 -cyclic carbonates, preferably ethylene carbonate, propylene carbonate, butylene carbonate are used. But methylmercaptan, used in corresponding excesses, can also act as a solvent or at least as a cosolvent.
• C 3 - to C 6 ⁇ ketones preferably Methyl isobutyl ketone (
• a process for the chemical conversion of L- and / or D-homoserine to methionine can also be carried out so that in a first step by introducing a leaving group Y at the C4 atom of homoserine, a compound of formula II
• This substitution is advantageously carried out by reacting the compound of the formula II with MeSH in the presence of a basic or acidic catalyst.
• Suitable basic catalysts are, in particular, NaOH, KOH, pyridine, trimethylamine, triethylamine or an acetate, carbonate or bicarbonate of the alkali metals or alkaline earth metals, where alkali is lithium, sodium,
• Potassium, rubidium or cesium and alkaline earth for magnesium, calcium or barium stands.
• Suitable acid catalysts are in particular HCl, HBr, HI, H 2 SO 4 , alkaliHSO 4 , H 3 PO 4 , AlkaliH 2 PO 4 , where alkali is lithium, sodium, potassium, rubidium or cesium, polyphosphoric acid, Ci-Ci 2 Alkylsulfonic acid, C ⁇ -CIO-arylsulfonic acid, trifluoromethanesulfonic acid,
• Trifluoroacetic acid or a copolymer of tetrafluoroethylene and perfluoro-3, 6-dioxo-4-methyl-7-octene-sulfonic acid (Nafion) is used.
• the reaction is preferably carried out in the presence of an organic solvent and / or water.
• the organic solvent used is preferably a low molecular weight organic solvent selected from the group consisting of C 3 -C 6 -ketones, preferably methyl isobutyl ketone (MIBK) or acetone, straight-chain or branched C 1 -C 4 -alcohols, C 4 -C 10 -carboxylic acid.
• ester preferably ethyl or butyl acetate, C3-C6-carboxylic acid, DMF or dimethylacetamide, preferably up ⁇ C ⁇ -Cio aromatics, preferably toluene, and C 3 to C 7 -Cyclic carbonates, preferably ethylene carbonate, propylene carbonate or butylene carbonate used.
• a process for the chemical conversion of L- and / or D-homoserine to methionine can also be carried out so that in a first step by acid-catalyzed cyclization the corresponding 2-amino-4-butyrolactone of the formula III or its salt (formula IV)
• Suitable acidic catalysts are acids selected from the group consisting of Bronsted acids having a pKa of ⁇ 3.
• alkali metal HSO 4 HCl, HBr, HI, H 2 SO 4 , alkali metal HSO 4 , H 3 PO 4 , alkali metal H 2 PO 4 , where alkali is lithium, sodium, potassium, rubidium or cesium, polyphosphoric acid, C 1 -C 12, are preferably used as the acidic catalyst Alkylsulfonic acid, C ⁇ -CIO-arylsulfonic acid, trifluoromethanesulfonic acid,
• Trifluoroacetic acid or a copolymer of tetrafluoroethylene and perfluoro-3, 6-dioxo-4-methyl-7-octene-sulfonic acid Nafion
• Strongly acidic ion exchange resins are also suitable as the acidic catalyst and, in particular, optionally substituted polystyrenesulfonic acid resins which are preferably crosslinked with divinylbenzene.
• heterogeneous acid catalysts from the group (WO 3 - and Cs 2 O) -containing alumina, zeolite and montmorillonite can be used according to the invention.
• the aluminum oxides mentioned preference is given to those having 5-15% WO 3 content and 5 -15% Cs 2 O content.
• Lewis acid catalysts can be used and in particular low molecular weight Lewis acids selected from the group AlCl 3 , ZnCl 2 , BF 3 * OEt 2 , SnCl 2 , FeCl 3 , which are available and inexpensive.
• a method of chemically transforming the homoserine to methionine can also be designed by performing the following steps:
• step b) hydrolysis of the obtained in step b) N-acyl-L- and / or D-methionine to the corresponding methionine.
• step a) either the primary O-acyl homoserine is formed primarily, which subsequently rearranges to the N-acyl homoserine V, or it is formed directly in a step V.
• NaOH, KOH, pyridine, trimethylamine, triethylamine or an acetate, carbonate or bicarbonate of the alkali metals or alkaline earth metals can be used as the basic catalyst in step b), where alkali is lithium, sodium, potassium, rubidium or cesium and alkaline earth metal for magnesium, Calcium or barium is available.
• Suitable acidic catalysts for step b) are, in particular, HCl, HBr, HI, H 2 SO 4 , alkali metal HSO 4 , H 3 PO 4 , alkali metal H 2 PO 4 , where alkali is lithium, sodium, potassium, rubidium or cesium, polyphosphoric acid, C 1 -C 12 -alkylsulfonic acid, C 6 -C 10 -arylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or a copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-4-methyl-7-octene-sulfonic acid (Nafion).
• a method of chemically transforming the homoserine into methionine can also be designed by performing the following steps:
• step b) transfers of the compound V obtained in step a) by introducing a leaving group Y at the C4 atom into a compound of the formula VI
• step b) reaction of the compound VI obtained in step b) with MeSH in the presence of a basic or acidic catalyst for N-acyl-L-methionine, N-acyl-D-methionine or a corresponding mixture of N-acyl-L- and / or D-methionine of the formula VII
• the formation of the compound V occurs depending on the exact choice of the implementation conditions either by Rearrangement of primarily formed O-acyl homoserine to N-acyl homoserine or by a combination of in situ lactonization and acylation with subsequent ring opening.
• acylation in step a) is preferably a
• the introduction of the leaving group Y occurs in the first step correspondingly and advantageously by reaction with p-toluenesulfonic acid chloride (p-TsCl), C 6 H 5 SO 2 Cl, H 3 CSO 2 Cl, H 5 C 2 SO 2 Cl or CF 3 SO 2 Cl.
• p-TsCl p-toluenesulfonic acid chloride
• Y phosphate (OPO 3 H)
• polyphosphoric acid is typically used to introduce the leaving group Y in the first step.
• Suitable basic catalysts in step c) are, in particular, NaOH, KOH, pyridine, trimethylamine, triethylamine or an acetate, carbonate or bicarbonate of the alkali metals or alkaline earth metals, where alkali is lithium, sodium, potassium, rubidium or cesium and alkaline earth metal for magnesium, Calcium or barium is available.
• Suitable acidic catalysts in step c) are in particular HCl, HBr, HI, H 2 SO 4 , alkaliHSO 4 , H 3 PO 4 , alkali metal H 2 PO 4 , where alkali is lithium, sodium, potassium, rubidium or cesium, polyphosphoric acid, C1-C12-
• a process for chemically transforming the L- and / or D-homoserine into methionine can also be designed by carrying out the following steps:
• step b) hydrolysis of the obtained in step b) N-acyl-L- and / or D-methionine to the corresponding methionine at temperatures of> 95 0 C.
• acylation in step a) is preferably a
• the N-acetylation in step a) takes place either by rearrangement of primarily formed O-acyl homoserine to N-acyl homoserine followed by ring closure or by a combination of in situ lactonization and direct N-acylation.
• Solvent preferably used a carboxylic acid RCOOH or R 1 COOH, wherein R and R 1 have the meaning given above, optionally in the presence of a further cosolvent from the Group consisting of C3 to C6 ketones, preferably acetone or MIBK, C 4 - to Cio-Carbonklar, preferably ethyl or butyl acetate, C3-C ⁇ ⁇ carboxylic acid amides such as DMF or dimethylacetamide, C ⁇ ⁇ preferably up to Cio aromatics, preferably toluene and C 3 to C 7 - cyclic carbonates, preferably ethylene carbonate propylene carbonate or butylene.
• a further cosolvent from the Group consisting of C3 to C6 ketones, preferably acetone or MIBK, C 4 - to Cio-Carbonklaer, preferably ethyl or butyl acetate, C3-C ⁇ ⁇ carboxylic acid amides such as DMF or dimethylacet
• the basic catalysts used in step a) are preferably pyridine derivatives, preferably dimethylaminopyridine (DMAP), or carbonyldiimidazole.
• DMAP dimethylaminopyridine
• Step a) is preferred at temperatures of 20 to
• 100 0 C in particular carried out at 50 to 90 0 C.
• the basic catalyst used in step b) is preferably a catalyst which is selected from the group consisting of tetraalkylammonium hydroxides with max. 48 C atoms, alkali metal or alkaline earth metal hydroxides, - carbonates, bicarbonates, acetates, where alkali is lithium, sodium, potassium, rubidium or cesium and alkaline earth metal for magnesium, calcium or barium, tertiary amines with max.
• Step b) are trialkylamines of the general formula NR 3 R 4 R 5 , where R 3 , R 4 and R 5 may be identical or different and are a linear or branched C 1 - to C 12 -alkyl radical, preferably methyl, ethyl, n-propyl, i-propyl, n-butyl or sec-butyl.
• Very particularly preferred basic catalysts are N (methyl) 3 , N (methyl) 2 (ethyl), N (methyl) (ethyl) 2 , N (ethyl) 3 , N (n-propyl) 3 , N (ethyl) (iPropyl ) 2 or N (n-butyl) 3 , but also diazabicyclooctane (DABCO), DBU, TBD, hexamethylenetetramine, tetramethylethylenediamine or tetramethylguanidine.
• DABCO diazabicyclooctane
• DBU diazabicyclooctane
• TBD hexamethylenetetramine
• tetramethylethylenediamine or tetramethylguanidine.
• Rb Cs-hydroxide, Mg, Ca, Ba hydroxide
• R 3 , R 4 , R 5 and R 6 may be identical or different and a linear or branched Ci to Ci2-alkyl radical, preferably methyl, ethyl, n-propyl, i-propyl, n-butyl or sec-butyl.
• Particularly preferred basic catalysts also R 7 R 8 NR 9 -substituted, crosslinked polystyrene resins are used, wherein R 7 , R 8 and R 9 may be the same or different and a linear or branched C 1 to C 4 alkyl, preferably Methyl, ethyl, n-propyl, n-butyl.
• step b) In order to achieve a rapid and as complete as possible sequence of the reaction in step b), 1 to 20 molar equivalents of base, calculated as hydroxide or N equivalent, preferably 1 to 10 molar equivalents of base used.
• an acidic catalyst is used in step b), it is advantageous to use an acidic catalyst selected from the group consisting of Bronsted acids having a pka of ⁇ 3 or Lewis acids.
• HCl, HBr, HI, H 2 SO 4 , alkali metal HSO 4 , H 3 PO 4 , and alkali metal haloH 2 PO 4 are preferably used as acidic catalysts, alkali metal being lithium, sodium, potassium, rubidium or cesium, polyphosphoric acid, C 1 -C 12 Alkylsulfonsaure, C ⁇ -CIO-Arylsulfonsaure, trifluoromethanesulfonic acid, trifluoroacetic acid or a copolymer of tetrafluoroethylene and perfluoro-3, 6-dioxo-4-methyl-7-octene-sulfonic acid (Nafion).
• acidic catalysts it is also possible to use strongly acidic ion exchange resins, which can easily be separated off after the reaction has taken place.
• heterogeneous acid catalysts from the group consisting of (WO3 and CS2O) -containing alumina, zeolite and montmorillonite can be used.
• WO3 and CS2O -containing alumina
• zeolite zeolite
• montmorillonite alumina
• Lewis acid catalysts are used here in an advantageous manner.
• the Lewis acid used here is preferably a low molecular weight Lewis acid selected from the group AlCl 3 , ZnCl 2 , BF 3 * OEt 2 , SnCl 2 , FeCl 3 .
• reaction in step b) is carried out in solution and / or in suspension in an organic solvent.
• water and / or at least one low molecular weight organic solvent selected from the group consisting of C 3 - to C6 ⁇ ketones, preferably MIBK or acetone, straight-chain or branched C x - to C 4 - alcohols, C 4 - to Cio-carboxylic acid ester , preferably ethyl acetate or butyl acetate, C 3 - to Ce -
• Carboxylic acid amides preferably DMF or dimethylacetamide, C ⁇ ⁇ to Cio-aromatics, preferably toluene and C 3 - to C 7 - cyclic carbonates, preferably ethylene carbonate, propylene carbonate or butylene carbonate are used.
• the hydrolysis in step c) can be carried out in aqueous solution and / or suspension.
• a low molecular weight organic solvent is selected from the group consisting of C 3 to C 6 ketones, preferably acetone or MIBK, straight or branched Ci- to C 4 alcohols, C 4 to Cio-carboxylic acid ester, preferably ethyl acetate or butyl ester, C3 to C6-carboxylic acid amides, preferably DMF or dimethylacetamide, C ⁇ ⁇ to C10-aromatics, preferably toluene and C3- to C7-cyclic carbonates, preferably ethylene carbonate, propylene carbonate or Butylene carbonate.
• the reaction in step c) is carried out generally at a temperature of 90 to 180 0 C, preferably at 100 to 160 0 C, in particular at 120 to 150 0 C, most preferably at 130 to 140 0 C.
• step c To accelerate the hydrolysis reaction in step c), it is additionally possible to work in the presence of an acidic, basic or Lewis acid catalyst or a combination of acidic and Lewis acid catalysts.
• a methionine process involving a combination of biotechnological and chemical steps according to the present invention has several advantages over a conventional process, especially in view of the aforementioned need for a more economical, safer process which should also provide L-methionine.
• the sugar used constitutes a renewable raw material, so that it makes a valuable contribution to the Resource conservation is done.
• sugars are much less hazardous than the industrial intermediates acrolein and blue-acid, so that the substitution of these raw materials with sugar as a feedstock significantly reduces the risk potential of a manufacturing process and thus increases safety.
• i-Propylthiol 20 ml was added with AlCl 3 (30 mmol) and stirred. Subsequently, the chloride salt of the aminolactone (10 mmol) was added and the mixture was stirred for 24 hours at room temperature. After quenching the reaction mixture with water, the yield of 2-amino-4-isopropylthiobutyric acid was determined by HPLC to be 77%.
• N-acetyl-2-aminobutyroactone (1 eq) was reacted with various bases in MeSH to give N-acetylmethionine.
• a mixture of N-acetylaminolactone, base and MeSH 14 Eq was heated in a closed autoclave. After cooling, venting and removing MeSH, the remaining oil was analyzed by HPLC. Further details as well as the obtained yield of N-acetyl-L-methionine are listed in the table below:

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• 2006
  • 2006-01-28 DE DE102006004063A patent/DE102006004063A1/de not_active Withdrawn
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