EP2054382A1 - Verfahren zur herstellung von d,l-2-hydroxy-4-alkylthiobuttersäuren - Google Patents

Verfahren zur herstellung von d,l-2-hydroxy-4-alkylthiobuttersäuren

Info

Publication number
EP2054382A1
EP2054382A1 EP07802607A EP07802607A EP2054382A1 EP 2054382 A1 EP2054382 A1 EP 2054382A1 EP 07802607 A EP07802607 A EP 07802607A EP 07802607 A EP07802607 A EP 07802607A EP 2054382 A1 EP2054382 A1 EP 2054382A1
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
butyrolactone
reaction
hydroxy
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Withdrawn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
EP07802607A
Other languages
German (de)
English (en)
French (fr)
Inventor
Patrick Deck
Kai Michael Exner
Boris Buschhaus
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.)
Evonik Operations GmbH
Original Assignee
Evonik Degussa 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 Evonik Degussa GmbH filed Critical Evonik Degussa GmbH
Priority to EP07802607A priority Critical patent/EP2054382A1/de
Publication of EP2054382A1 publication Critical patent/EP2054382A1/de
Withdrawn legal-status Critical Current

Links

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
    • 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 a process for the preparation of compounds of the formula (I)
  • R is C to C 6 alkyl
  • the present invention relates to a process for the preparation of compounds of the formula (II)
  • Methionine and methionine hydroxy analogue are among the economically most important amino acids in addition to L-glutamic acid and L-lysine.
  • Methionine is an essential sulfur-containing amino acid whose metabolically active form is S-adenosyl-methionine (SAM).
  • SAM S-adenosyl-methionine
  • methionine D, L-2-amino-4-methylthiobutyric acid
  • the body is able to convert the D-shape completely into the active L-shape.
  • the configuration of the ⁇ -amino group is irrelevant.
  • MHA methionine hydroxyanalogone
  • D L-2-hydroxy-4-methylthiobutyric acid
  • MHA methionine hydroxyanalogone
  • the amino group of methionine is substituted by a hydroxyl group.
  • the conversion takes place in the active L-form of methionine.
  • racemic MHA represents a complete replacement for methionine.
  • the methods for the preparation of methionine and MHA in feed quality are based essentially on the educts acrolein, methylmercaptan and hydrocyanic acid.
  • a process described in DE 1 906 405 starts with acrolein and mercaptan in a first step, which are converted to 3-methylmercaptopropionaldehyde (MMP). This is in a next step with hydrocyanic acid and ammonium hydro- gencarbonat converted to a hydantoin, which is then reacted alkaline to D, L-potassium methionate. Acidification yields D, L-methionine.
  • MMP 3-methylmercaptopropionaldehyde
  • DE 840 996 discloses a process for preparing thioethercarboxylic acids.
  • unsubstituted lactones or lactones with aromatic radicals such as phthalides or coumarins with alkali metal or alkaline earth metal compounds mercapto compounds are heated, which contain no unesterified carboxyl groups.
  • the reaction takes place without addition of solvent, if appropriate with an excess of lactone as solvent or in the presence of inert solvents such as benzene, toluene or decalin.
  • the object was to find, starting from less toxic starting materials, a cost-effective production process of D, L-2-hydroxy-4-alkylthiobutyric acid of the formula (I)
  • the object was to find, starting from less toxic starting materials, a cost-effective production process of MHA of the formula (Ia)
  • the object has been achieved by providing a process for preparing compounds of the formula (I),
  • RSM that is the reaction of compounds of the formula with thiolates RSM includes.
  • R means according to the invention d- to C ⁇ -alkyl.
  • These are, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methyl-butyl, 2-methylbutyl, 3-methylbutyl , 2,2-dimethylpropyl, 1-ethylpropyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1 , 2-dimethylbutyl, 1, 3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,
  • the residues may also contain one or more stereocenters.
  • R is C 1 to C 4 alkyl. These are, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl and mixtures thereof.
  • the radicals may contain at least one stereogenic center.
  • M is alkali metal, alkaline earth metal, Fe, Zn or a mixture thereof.
  • Alkali metal is Li, Na, K, Rb, Cs or a mixture thereof.
  • Alkaline earth metal is Be, Mg, Ca, Sr, Ba, or a mixture thereof.
  • n is equal to 1.
  • n is 2. In the case where M is Fe, n is 2 and / or 3.
  • M is Li, Na, K or a mixture thereof, preferably n is equal to 1.
  • M which may be alkaline earth metal, Zn or Fe, the radicals R of the corresponding thiolate (RS) n M may be the same or different.
  • Thiolates of the formula (RS) n M with identical or different radicals R and / or identical or different metals M may be used simultaneously.
  • the meandering line represents an S or R configuration at the associated carbon atom.
  • a formula containing a meandering line preferably represents any mixture, more preferably a racemic mixture, of the enantiomeric forms of the compound. Alternatively, such formula may stand for a particular unspecified enantiomeric form.
  • a carbon atom with four different substituents is a stereocenter. If a molecule has exactly one stereocenter, two different configurations of the corresponding molecule are possible. The two unrelated mirror-image forms of such a molecule are referred to as enantiomers. According to the rules of Cahn, Ingold and Prelog, a distinction is made between R and S enantiomers.
  • racemate A mixture with equal proportions of both enantiomers is called racemate or racemic mixture.
  • the molar ratio and the weight ratio of the two enantiomers in the racemate are the same because of the identical molecular mass of the enantiomers.
  • the thiolates (RS) n M can be used as solutions.
  • the concentration of thiolates (RS) n M is typically 10% by weight or more, preferably 20% by weight or more. It is also possible to use solutions having a concentration of 50% by weight or more, preferably 90% by weight or more.
  • the thiolates (RS) n M can be used in particular as a solution in the corresponding thiol (RS) n H.
  • An advantage according to the invention is that the stereoisomerism of the cyclic ester group ⁇ -containing hydroxy group of the compounds of the formula (II) is retained in the preparation of the compounds of the formula (I).
  • compounds of formula (II) racemic mixtures, so that the correspondingly obtained compounds of formula (I) are racemic mixtures.
  • Another preferred embodiment of the present invention is that one of the stereoisomeric forms is substantially predominant.
  • the enantiomeric excess of the isomer mixture used is preferably at least 90% ee.
  • the enantiomeric excess is defined as
  • the compound of the formula (II) is employed in enantiomerically pure form.
  • the process of the invention is preferably carried out in polar aprotic solvents.
  • a polar solvent generally has a permittivity value of 10 or more, preferably 20 or more, more preferably 40 or more, at a temperature of 293.2K.
  • a solvent is said to be aprotic if it is not or only with difficulty capable of cleaving off protons, since it either contains no hydrogen atoms or the hydrogen bonds have a high covalent character.
  • a measure of the cleavability of protons from compounds is the acidity K 5 . This is determined in water unless otherwise specified. Usually the negative decadic logarithm of the acidity, the pK s value, is given.
  • An aprotic solvent generally has a pK s value at a temperature of 293.2 K or, in the case of several possible cleavable protons, a lowest pK s value of 20 or more, preferably 22 or more, more preferably from 24 or more.
  • Solvents can be used neat or as a mixture.
  • Polar aprotic solvents may be mixed with other solvents, e.g. polar protic solvents or apolar solvents.
  • the proportion of the other solvent (s) on the solvent mixture usually does not exceed 10% by weight.
  • Preferred solvents to be used according to the invention are, for example, dimethylsulfoxide, N-methylpyrrolidone or mixtures thereof.
  • the inventive method is carried out at temperatures that ensure a sufficiently rapid flow of the reaction.
  • the reaction is conveniently carried out at temperatures of 50 0 C to 200 0 C.
  • these are preferably made of ⁇ -butyrolactone (form old.
  • ⁇ -Butyrolactone is available in large quantities as part of the value chain of the so-called Reppe chemistry. Starting from acetylene and formaldehyde, ⁇ -butyrolactone is obtained via the intermediates 1, 4-butynediol, 1, 4-butenediol and 1, 4-butanediol.
  • the process according to the invention for the preparation of compounds of the formula (I) comprises a preceding process step in which ⁇ -butyrolactone is converted into compounds of the formula (II).
  • a further object of the invention is a process in which ⁇ -butyrolactone of the formula (III) is first reacted to give compounds of the formula (IV) and the compounds of the formula (IV) are reacted in a subsequent step to give compounds of the formula (II)
  • the rest X denotes according to the invention a halogen atom.
  • a compound of the formula (IV) may always contain the same radical X or different radicals X.
  • Halogen means according to the invention fluorine, chlorine, bromine and / or iodine. Preference is given to chlorine or bromine. Particularly preferred is chlorine.
  • the compounds of the formula (II) are obtained by reacting ⁇ -butyrolactone with Formula (III) is first reacted to compounds of formula (IV) and the compounds of formula (IV) are reacted in a subsequent step to compounds of formula (II).
  • ⁇ -Bromo- ⁇ -butyrolactone can be obtained by reaction of bromine Br2 with ⁇ -butyrolactone at about 100 0 C in the presence of phosphorus tribromide PBr3.
  • the bromine compound obtained is optionally isolated, but preferably not isolated and immediately reacted with barium hydroxide to give ⁇ -hydroxy- ⁇ -butyrolactone.
  • barium hydroxide is used as Ba (OH) 2-8H2 ⁇ .
  • Phosphrtribromide is preferably used in amounts of from 1 to 20 mol%, more preferably from 5 to 15 mol%, based on ⁇ -butyrolactone.
  • phosphorus tribromide is used in an amount of 10 mol%, based on ⁇ -butyrolactone.
  • Phosphorus tribromide is usually added at temperatures of -10 to +10 0 C to ⁇ -butyrolactone.
  • a suitable solvent is present, preferably no solvent is present.
  • Bromine is also generally added at a temperature of -10 to + 10 0 C. Bromine is usually used in amounts of from 100 to 150 mol%, preferably from 110 to 140 mol%, based on ⁇ -butyrolactone.
  • bromine is used in an amount of 130 mol%, based on ⁇ -butyrolactone.
  • the reaction mixture is usually maintained for a period of time, e.g. heated for one to ten hours.
  • the temperatures are usually in the range of 80 to 150 ° C.
  • excess bromine is reduced after the reaction. This happens, for example, by adding NaHS ⁇ 3 solution.
  • ⁇ -chloro- ⁇ -butyrolactone from ⁇ -butyrolactone by chlorination without the addition of a catalyst at elevated temperatures, for example, 100-200 0 C, preferably 140-160 0 C amount can be obtained.
  • by-products may arise ⁇ , ⁇ -dichloro- ⁇ -butyrolactone and 2,4-dichlorobutyric acid.
  • the 2,4-dichlorobutyric acid is preferably not separated off for the further reaction, since in the alkaline hydrolysis the cyclic form of the ⁇ -hydroxy- ⁇ -butyrolactone is formed again.
  • the ⁇ , ⁇ -dichloro- ⁇ -butyrolactone can preferably be removed by distillation.
  • Chlorine is usually used in amounts of from 100 to 150 mol%, preferably from 110 to 140 mol%, based on ⁇ -butyrolactone. In a particularly preferred embodiment, chlorine is used in an amount of 130 mol%, based on ⁇ -butyrolactone.
  • the distillation preferably takes place at a reduced pressure, for example an absolute pressure of 1 mbar or less, preferably at 10 "1 mbar or less, more preferably 10" 2 mbar or less, instead.
  • the product is distilled several times.
  • reaction conditions for the treatment of ⁇ -chloro- ⁇ -butyrolactone with barium hydroxide are analogous to those for the treatment of ⁇ -bromo- ⁇ -butyrolactone with barium hydroxide.
  • All processes according to the invention can be carried out batchwise, semicontinuously or continuously at different scales.
  • the product in batch processes in quantities of 1 g to 1000 tons per batch, preferably 100 kg to 10 tons or in continuous processes with throughputs of 1 g to 1000 tons per hour, preferably 100 kg to 10 tons per hour.
  • Special designs are the laboratory scale, the pilot plant scale, the pilot plant scale and the production scale.
  • the starting materials are fed under the conditions mentioned to a suitable container and reacted there.
  • the resulting product remains in the reactor. If necessary, it can be further purified there. Alternatively, it may be transferred to other suitable containers such as distillation columns and further purified there.
  • the starting materials under the conditions mentioned are fed to a suitable container and reacted there. The resulting product is meanwhile removed from the reactor and optionally further purified.
  • Semicontinuous processes include continuous and discontinuous process steps.
  • Suitable containers for the methods may be, for example, containers made of glass, steel or stainless steel, which are optionally coated.
  • the containers are usually equipped with a matching stirring option such as magnetic stirrer or anchor stirrer.
  • the containers can be heated in a suitable manner, for example by means of oil baths or heating mantles operated electrically or with steam.
  • the containers are chosen to withstand the temperature and pressure conditions prevailing in the reaction. Purification can be carried out in a known manner, for example by distillation. If appropriate, unreacted starting material is recycled at a suitable point in the process.
  • the present invention provides easy access to D, L-2-hydroxy-4-alkylthiobutyric acids such as MHA, one of the most economically important amino acids. It can be used as inexpensive, readily available and non-toxic starting material ⁇ -butyrolactone, which is implemented in a few steps to the desired end product.
  • the yield was determined by weighing.
  • the purity of the product was analyzed by 1 H-NMR.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)
EP07802607A 2006-08-24 2007-08-15 Verfahren zur herstellung von d,l-2-hydroxy-4-alkylthiobuttersäuren Withdrawn EP2054382A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07802607A EP2054382A1 (de) 2006-08-24 2007-08-15 Verfahren zur herstellung von d,l-2-hydroxy-4-alkylthiobuttersäuren

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06119485 2006-08-24
PCT/EP2007/058426 WO2008022953A1 (de) 2006-08-24 2007-08-15 Verfahren zur herstellung von d,l-2-hydroxy-4-alkylthiobuttersäuren
EP07802607A EP2054382A1 (de) 2006-08-24 2007-08-15 Verfahren zur herstellung von d,l-2-hydroxy-4-alkylthiobuttersäuren

Publications (1)

Publication Number Publication Date
EP2054382A1 true EP2054382A1 (de) 2009-05-06

Family

ID=38717316

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07802607A Withdrawn EP2054382A1 (de) 2006-08-24 2007-08-15 Verfahren zur herstellung von d,l-2-hydroxy-4-alkylthiobuttersäuren

Country Status (10)

Country Link
US (1) US20090318715A1 (enrdf_load_stackoverflow)
EP (1) EP2054382A1 (enrdf_load_stackoverflow)
JP (1) JP2010501516A (enrdf_load_stackoverflow)
CN (1) CN101506153A (enrdf_load_stackoverflow)
AR (1) AR062504A1 (enrdf_load_stackoverflow)
BR (1) BRPI0717005A2 (enrdf_load_stackoverflow)
MX (1) MX2009001816A (enrdf_load_stackoverflow)
RU (1) RU2009110264A (enrdf_load_stackoverflow)
TW (1) TW200819419A (enrdf_load_stackoverflow)
WO (1) WO2008022953A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4431609A1 (en) 2023-03-14 2024-09-18 Adisseo France S.A.S. Method for improving 2, 4 dihydroxybutyric acid production and yield

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BR112012022506A2 (pt) * 2010-03-09 2017-09-19 Novus Int Inc preparação de metionina ou selenometionina a partir de homosserina através de um intermediário de lactona.
FR2966150B1 (fr) 2010-10-15 2012-10-12 Adisseo France Sas Procede de preparation de la 2-hydroxybutyrolactone
JP6342385B2 (ja) 2012-04-26 2018-06-13 アディッソ・フランス・エス．エー．エス．Ａｄｉｓｓｅｏ Ｆｒａｎｃｅ Ｓ．Ａ．Ｓ． ２，４−ジヒドロキシ酪酸を生成する方法
CN104471069B (zh) 2012-07-11 2018-06-01 安迪苏法国联合股份有限公司 制备2,4-二羟基丁酸盐的方法
CN103467424B (zh) * 2013-08-22 2016-04-27 南京华安药业有限公司 一种2,5-二羟基戊酸delta内酯的合成方法
EP3280694B1 (en) 2015-04-07 2021-11-24 Metabolic Explorer Modified microorganism for the optimized production of 2,4-dihydroxyburyrate
CN107771214B (zh) 2015-04-07 2022-01-18 代谢探索者公司 用于具有增加的2,4-二羟基丁酸外排物的优化的2,4-二羟基丁酸产生的修饰的微生物
ES2751048T3 (es) * 2015-04-30 2020-03-30 Haldor Topsoe As Proceso para la preparación de análogos alfa-hidroxi de metionina a partir de azúcares y derivados de los mismos
JP6806716B2 (ja) 2015-06-25 2021-01-06 ダイナミック フード イングリディエンツ コーポレーションＤｙｎａｍｉｃ Ｆｏｏｄ Ｉｎｇｒｅｄｉｅｎｔｓ Ｃｏｒｐ． ２，４−ジヒドロキシ酪酸の製造方法
FR3041658B1 (fr) 2015-09-30 2017-10-20 Arkema France Procede de production de l-methionine
FR3041659B1 (fr) 2015-09-30 2017-10-20 Arkema France Procede de production de l-methionine
AU2017280075A1 (en) 2016-06-24 2018-12-13 Novus International Inc. Hydroxy methionine analog formulations suitable for specialty chemical applications
KR101799987B1 (ko) 2016-11-15 2017-11-21 주식회사 씨원켐 2-하이드록시-감마-부티로락톤의 제조방법
CN112876394A (zh) * 2021-02-09 2021-06-01 中国科学院福建物质结构研究所 一种dl-羟基硒代蛋氨酸的制备方法
CN116924950A (zh) * 2022-04-12 2023-10-24 元素驱动(杭州)生物科技有限公司 一种2-羟基-4-取代硫基丁酸及其衍生物的制备方法
EP4299560A1 (en) 2022-07-01 2024-01-03 AMINO GmbH Method for the production of alpha hydroxy-alkylthio carboxylic acids and derivatives thereof

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4431609A1 (en) 2023-03-14 2024-09-18 Adisseo France S.A.S. Method for improving 2, 4 dihydroxybutyric acid production and yield
WO2024189069A1 (en) 2023-03-14 2024-09-19 Adisseo France S.A.S. Method for improving 2, 4 dihydroxybutyric acid production and yield

Also Published As

Publication number Publication date
RU2009110264A (ru) 2010-09-27
TW200819419A (en) 2008-05-01
BRPI0717005A2 (pt) 2013-10-08
AR062504A1 (es) 2008-11-12
WO2008022953A1 (de) 2008-02-28
MX2009001816A (es) 2009-05-28
JP2010501516A (ja) 2010-01-21
CN101506153A (zh) 2009-08-12
US20090318715A1 (en) 2009-12-24

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