EP2054382A1

EP2054382A1 - Method for the production of d,l-2-hydroxy-4-alkylthio butyric acid

Info

Publication number: EP2054382A1
Application number: EP07802607A
Authority: EP
Inventors: Patrick Deck; Kai Michael Exner; Boris Buschhaus
Original assignee: Evonik Degussa GmbH
Current assignee: Evonik Operations GmbH
Priority date: 2006-08-24
Filing date: 2007-08-15
Publication date: 2009-05-06
Also published as: WO2008022953A1; JP2010501516A; BRPI0717005A2; US20090318715A1; CN101506153A; AR062504A1; TW200819419A; MX2009001816A; RU2009110264A

Abstract

The invention relates to a method for producing compounds of formula (I) by reacting compounds of formula (II) with thiolates (RS)nM. The invention further relates to a method for producing compounds of formula (II) from y-butyrolactone.

Description

Process for the preparation of D, L-2-hydroxy-4-alkylthiobutyric acids

description

The present invention relates to a process for the preparation of compounds of the formula (I)

wherein R is C to C ₆ alkyl.

Furthermore, 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. The economic importance of methionine in the feed-saving rearing of livestock. Methionine is an essential sulfur-containing amino acid whose metabolically active form is S-adenosyl-methionine (SAM). In contrast to all other amino acids, methionine (D, L-2-amino-4-methylthiobutyric acid) can also be fully utilized as a racemate by the organism. The body is able to convert the D-shape completely into the active L-shape. Thus, in an industrial synthesis, the configuration of the α-amino group is irrelevant. Interestingly, the organism is also able to utilize methionine hydroxyanalogone (D, L-2-hydroxy-4-methylthiobutyric acid, MHA) as a complete replacement for methionine. In MHA, the amino group of methionine is substituted by a hydroxyl group. Again, in the body, the conversion takes place in the active L-form of methionine. Thus, also industrially produced, 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.

Also starting from MMP, according to the US 2,745,745 by reaction with hydrogen cyanide in the presence of sodium hydroxide at 35-40 ⁰ C., a cyanohydrin. Hydrolysis by strong mineral acids such as sulfuric acid gives as an intermediate the amide and finally MHA. The by-product is ammonium hydrogen sulfate.

DE 840 996 discloses a process for preparing thioethercarboxylic acids. In this case, 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)

In particular, the object was to find, starting from less toxic starting materials, a cost-effective production process of MHA of the formula (Ia)

According to the invention, the object has been achieved by providing a process for preparing compounds of the formula (I),

that is the reaction of compounds of the formula with thiolates RSM includes.

R means according to the invention d- to Cβ-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, 1, 2

Trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-3-methylpropyl, and mixtures thereof. The residues may also contain one or more stereocenters.

Preferably, 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.

Particularly preferred is R = methyl. In this case, the compound of the formula (I) MHA of the formula (Ia)

In the thiolates (RS) _n M, 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.

For the case that M is alkali metal, n is equal to 1.

In the case that M is alkaline earth metal, Zn or a mixture thereof, n is 2. In the case where M is Fe, n is 2 and / or 3.

Preferably, M is Li, Na, K or a mixture thereof, preferably n is equal to 1. For a given 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.

Preferably, only one thiolate of the formula (RS) _n M is used.

In all the preceding and following formulas, 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.

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.

In the context of this application, only the configuration is used on the acid or ester group α-carbon atom to determine whether a mixture of isomers, a racemate, or an enantiomer is present as a special case. If other stereocenters are present at the remainder R, these are not relevant for these statements on stereochemistry.

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 α-containing hydroxy group of the compounds of the formula (II) is retained in the preparation of the compounds of the formula (I). Usually used as compounds of formula (II) racemic mixtures, so that the correspondingly obtained compounds of formula (I) are racemic mixtures.

However, if a stereoisomeric form of the compound of the formula (II) predominantly exists, the compound of the formula (I) obtained therefrom likewise predominantly exists in this stereoisomeric form.

If no racemic mixture is used, another preferred embodiment of the present invention is that one of the stereoisomeric forms is substantially predominant.

If an isomer mixture is present, the enantiomeric excess of the isomer mixture used is preferably at least 90% ee. The enantiomeric excess is defined as

[R]: concentration of the R isomer; [S]: concentration of the S isomer.

In a further preferred embodiment, the compound of the formula (II) is employed in enantiomerically pure form.

In the case of the use of isomer mixtures of compounds of the formula (II) in which one of the enantiomeric forms is predominantly present, the process according to the invention gives compounds of the formula (I) in which one of the enantiomeric forms is also predominantly present.

If one of the enantiomeric forms of the compound of formula (II) is present exclusively, i. If the corresponding compound is enantiomerically pure, the process according to the invention gives a compound of the formula (I) which is also enantiomerically pure.

The process of the invention is preferably carried out in polar aprotic solvents.

The polarity of a solvent is quantified by its molecular dipole moment, which is related to macroscopic permittivity. Thus, with knowledge of the permittivity value of a solvent, statements about its polarity can be made. Permittivity, for example, the Handbook of Chemistry and Physics, 76 ^th edition, 1995, CRC Press, Inc., Boca Raton taken advertising to. 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. In this case, 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.

The compounds of the formula (II) used in the process according to the invention are known to the person skilled in the art. See Beilstein's Handbook of Organic Chemistry, Springer Verlag, Supplementary Works I, Volume XVIII, p. 296; Supplementary Movement II, Volume 18, p. 3; Supplementary Movement III, Volume 18, p. 3; Supplementary Works III / IV, Volume 18, p. 3; Supplement V, Volume 18, p. 3 and the references cited therein.

For the process according to the invention, these are preferably made of γ-butyrolactone (form old.

(III) γ-Butyrolactone is available in large quantities as part of the value chain of the so-called Reppe chemistry. Starting from acetylene and formaldehyde, γ-butyrolactone is obtained via the intermediates 1, 4-butynediol, 1, 4-butenediol and 1, 4-butanediol.

In a further embodiment, the process according to the invention for the preparation of compounds of the formula (I) comprises a preceding process step in which γ-butyrolactone is converted into compounds of the formula (II).

Preference is given to this γ-butyrolactone in a first step to compounds of the formula (I

Thus, a further object of the invention is a process in which γ-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. According to the invention, 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.

In a preferred embodiment of the process according to the invention for preparing compounds of the formula (I) by reacting compounds of the formula (II) with thiolates (RS) _n M, the compounds of the formula (II) are obtained by reacting γ-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).

α-Bromo-γ-butyrolactone can be obtained by reaction of bromine Br2 with γ-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 α-hydroxy-γ-butyrolactone. Usually, barium hydroxide is used as Ba (OH) 2-8H2θ.

Phosphrtribromide is preferably used in amounts of from 1 to 20 mol%, more preferably from 5 to 15 mol%, based on γ-butyrolactone. In a particularly preferred embodiment, phosphorus tribromide is used in an amount of 10 mol%, based on γ-butyrolactone. Phosphorus tribromide is usually added at temperatures of -10 to +10 ⁰ C to γ-butyrolactone. Optionally, 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 γ-butyrolactone. In a particularly preferred embodiment, bromine is used in an amount of 130 mol%, based on γ-butyrolactone.

After the addition of the bromine, 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.

Preferably, excess bromine is reduced after the reaction. This happens, for example, by adding NaHSθ3 solution.

can α-chloro-γ-butyrolactone from γ-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. As by-products may arise α, α-dichloro-γ-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 α-hydroxy-γ-butyrolactone is formed again. The α, α-dichloro-γ-butyrolactone can preferably be removed by distillation. With hot barium hydroxide solution, α-chloro-γ-butyrolactone or 2,4-dichlorobutyric acid can be converted into α-hydroxy-γ-butyrolactone. Chlorine is usually used in amounts of from 100 to 150 mol%, preferably from 110 to 140 mol%, based on γ-butyrolactone. In a particularly preferred embodiment, chlorine is used in an amount of 130 mol%, based on γ-butyrolactone.

Purification by nitrogen flushing and / or washing with water is possible. 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. Optionally, the product is distilled several times.

The reaction conditions for the treatment of α-chloro-γ-butyrolactone with barium hydroxide are analogous to those for the treatment of α-bromo-γ-butyrolactone with barium hydroxide. All processes according to the invention can be carried out batchwise, semicontinuously or continuously at different scales. For example, 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.

In discontinuous processes, 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. In continuous processes, 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. If desired, 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 γ-butyrolactone, which is implemented in a few steps to the desired end product.

In the following examples, the inventive method is illustrated in more detail. The examples further elaborate the claims and description without limiting them in any way. A) Synthesis of D, L-2-hydroxy-4-methylthiobutyric acid (MHA) α-hydroxy-γ-butyrolactone and sodium methylthiolate NaSCH3 were introduced into 20 ml of solvent (see Table 1) and incubated for several hours (reaction time) in the Table 1 heated reaction temperature. After cooling, the solvent was removed and the residue taken up in 1N HCl. The solution was extracted with methyl tert-butyl ether, the combined organic phases dried over MgSO ₄ and concentrated to dryness.

Amounts used, reaction times, solvents and yields are shown in Table 1.

The yield was determined by weighing. The purity of the product was analyzed by ¹ H-NMR.

Table 1

¹ ) Volume ratio DMSO: dimethylsulfoxide DMF: dimethylformamide

B) Synthesis of α-hydroxy-γ-butyrolactone Experiment 8 (according to the invention):

30g (0.348 mol) of γ-butyrolactone were added at 0 ⁰ C was slowly added with 9.5 g (0.035 mol) PBr. ₃ Thereafter, over a period of 3h slowly 71.9 g (0.450 mol) Br2 was added dropwise. After the solution had been heated for 6 h at 99 ° C, H2O was added and the residue of the bromine with little NaHSO ₃ -LSg. reduced. Then 220 g (0.7 mol) of Ba (OH) 2 ^* 8H2Ü added and the solution heated for 15 h at 100 ⁰ C. The barium was filled with conc. H2SO4 precipitated, filtered with suction and the solution concentrated to dryness. The solid was taken up in ethanol and the non-soluble te part separated. The EtOH was removed and the remaining solid at 110 ⁰ C (6-10 ^"3 mbar), with significant elimination of water entered The colorless oil obtained was distilled again to give 8.2 g (0.08 mol, yield: 23%). D, L-α-hydroxy-γ-butyrolactone.

Experiment 9 (according to the invention):

28 g (0.32 mol) of γ-butyrolactone were initially charged. Thereafter, a slow flow of chlorine gas at 125-140 ⁰ C was passed through the apparatus. After 23 g (0.32 mol) of chlorine had been added, the apparatus was purged with nitrogen to drive off the residual chlorine gas. After cooling, the crude product was washed with H 2 O and distilled.

The resulting α-chlorobutyrolactone was converted into the MHA by the method described in the example for the preparation of α-bromobutyrolactone. The resulting colorless oil was redistilled to obtain 7.1 g (0.07 mol) of D, L-α-hydroxy-γ-butyrolactone (yield: 22%).

Claims

claims

1. Process for the preparation of at least one compound of the formula (I)

where R is C ₁ -C ₆ -alkyl, characterized in that it comprises the reaction of compounds of the formula (II)

with at least one thiolate (RS) _n M, wherein R has the meaning as in formula (I) and M is alkali metal, alkaline earth metal, Fe and / or Zn and n = 1, when M is alkali metal, n = 2, if M is alkaline earth metal and / or Zn, n = 2 and / or 3 when M is Fe.

2. The method of claim 1, wherein R is d- to C ₄ -AlkVl.

3. The method of claim 2, wherein R is methyl.

4. The method according to one or more of the preceding claims, wherein M is Li, Na and / or K.

5. The method according to one or more of the preceding claims, wherein M is Na.

6. The method according to one or more of the preceding claims, wherein the compounds of formula (II) are used as enantiomeric mixtures or enantiomerically pure.

7. The method according to one or more of the preceding claims, wherein the compounds of formula (II) are used as racemic mixtures.

8. The method according to one or more of the preceding claims, wherein the reaction is carried out in polar aprotic solvents.

9. The method of claim 8, wherein as the solvent dimethyl sulfoxide, N-methylpyrrolidone or mixtures thereof are used.

10. The method according to one or more of the preceding claims including a preceding process step, in which γ-butyrolactone is converted to compounds of formula (II).

1 1. A process for the preparation of compounds of the formula (II), characterized in that γ-butyrolactone is first reacted to give compounds of the formula (IV),

wherein X is halogen, and the compounds of formula (IV) are reacted in a subsequent substep to compounds of formula (II).

12. The method according to claim 1 1, characterized in that γ-butyrolactone is reacted zunäch sleeve (IV),

14. The method of claim 12 or 13, wherein X is Cl.

15. The method according to claim 10, wherein the reaction of γ-butyrolactone to compounds of the formula (II) by a process according to one or more of claims 11 to 14 takes place.