DE10150063A1 - Production of alpha-lipoic acid, useful as a nutritional supplement and in pharmaceutical and cosmetic products, from 1,3-propanedithiol - Google Patents

Abstract

Production of alpha -lipoic acid from 1,3-propanedithiol comprises a multistep process culminating in the solvolysis of a 5-(1-oxo-1,3-dithian-6-yl)valeric acid derivative (VI). Production of alpha -lipoic acid comprises: (1) reacting 1,3-propanedithiol with an aldehyde or ketone of formula (Ia) or a (thio)acetal or (thio)ketal of formula (Ib) in the presence of a Lewis acid catalyst; (2) reacting the resulting 1,3-dithiane compound with an oxidizing agent to form a 1,3-dithiane 1-oxide of formula (II); (3) reacting (II) with acrolein in the presence of a base to form an allylic alcohol of formula (III); (4) reacting (III) with a trialkyl orthoacetate in the presence of an acid catalyst to form an allyl acetal of formula (IV); (5) heating (IV) at 60-145 deg C to form a 5-(1-oxo-1,3-dithian-6-yl)-4-pentenoic acid derivative of formula (V); (6) reducing (V) to form 5-(1-oxo-1,3-dithian-6-yl)valeric acid derivative of formula (VI); and (7) solvating (VI). R<1>, R<2> = H, A, Ar, pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl; R<1>+R<2> = (CH2)n; A = 1-3C alkyl; Ar = phenyl optionally substituted with A, OA, NH2, NHA or NAA; n = 1-5; R = A, 1-3C acyl, trifluoroacetyl, benzyl or benzoyl; R' = H, A or benzyl; X = O or S; R<3> = A. Independent claim are also included for compounds (III)-(VI) and compounds of formula (IIIa). R'' = H, 1-3C alkyl, 1-3C acyl, aryl-substituted 1-3C alkyl or aryl-substituted 1-3C acyl.

Description

The present invention relates to a method for multi-stage Production of α-lipoic acid using 1,3, dithians, new, any compounds produced by this process and their compounds Use.

α-Lipoic acid (thioctic acid, 1,2-dithiolan-3-pentanoic acid) has been around for about 50 Years known as a growth factor in microorganisms, but it is coming in low concentrations also in higher plants and animals. Originally, α-lipoic acid was used as Protogen A or acetate replacement factor referred to today as the common name thioctic acid. By the discovery of new properties in recent years is this Natural product strengthens in the interest of biology, biochemistry, medicine, Advanced nutrition science and technology.

α-Lipoic acid acts physiologically in hydrophilic and lipophilic media as Coenzyme of the oxidative decarboxylation of α-ketocarboxylic acids (e.g. Pyruvate, α-ketoglutarate). In addition, α-lipoic acid is also degrading certain amino acids involved as a cofactor. In addition, it contributes to Regeneration of vitamin C, vitamin E, glutathione and coenzyme Q10. Also have α-lipoic acid and its associated redox partner Dihydrolipoic acid (γ-lipoic acid, 6,8-dimercaptooctanoic acid) strong antioxidative and sometimes also pro-oxidative properties. On biological antioxidant should meet the following criteria, among others: (i) Specificity in trapping free radicals, (ii) Ability to chelate of metal ions, (iii) interaction with other antioxidants, (iv) Absorption and bioavailability as well as (v) on membranes active site bound or free in the cell. Because that Redox couple lipoic acid / dihydrolipoic acid above criteria for Antioxidants well fulfilled and because α-lipoic acid is physiologically easy in an equilibrium reaction can be converted into dihydrolipoic acid α-lipoic acid is often used as a "universal antioxidant" designated.

Racemic α-lipoic acid is used to treat liver damage (from poisons such as allyl alcohol or the poison of the white Tuber agaric) and neuropathies (e.g. diabetic polyneuropathy) authorized; their use as an effective inhibitor of replication of HIV-1 Viruses were discussed (see Klin. Wochenschr. 1991, 69 (15), 722-724). The Racemate of α-lipoic acid also exhibits cytoprotective, anti-inflammatory and antinociceptive (analgesic) properties, whereby it turns out has that with the pure optical isomers of α-lipoic acid (R-α- Lipoic acid or S-α-lipoic acid) in contrast to the racemate the R- Enantiomer is a predominantly anti-inflammatory and the S-enantiomer shows predominantly antinociceptive activity profile (cf. EP 812 590 A2). Furthermore, α-lipoic acid also represents one in lipophilic media readily soluble radical scavenger. After α-lipoic acid demonstrably the Stimulates glucose transport in muscle and fat cells (see "Lipoic Acid in Health and Disease ", Marcel Dekker Inc., New York 1997, pp. 87ff.) Is hers Use to treat diseases related to diabetes Type II possible. DE 198 18 563 A1 describes racemic or Enantiomerically pure α-lipoic acid also as an appetite suppressant (anorectic) and as an active ingredient to reduce body weight.

In competitive sports one tries to keep the oxidative stress low and therefore to keep cell performance high, so that lipoic acid not only as a medicine, but also as a food additive (Dietary Supplement) e.g. B. is in conversation in "energy drinks" (Challem, Muscle & Fitness 1997, 83).

Another application is in the cosmetic industry: The use of the 2-ethylhexyl or the hexadecyl ester of α-Lipoic acid in creams for skin lightening is in JP 81,120,611 described. As has now been shown, certain Mixtures and salts of racemic, enantiomerically pure or Enantiomerically enriched α-lipoic acid the tendency to polymerize of the labile cyclic disulfide can be effectively suppressed (cf. R. C. Thomas, L. J. Reed, J. Am. Chem. Soc. 1956, 78, 6148). The biological Activity of racemic, enantiomerically pure or Enantiomerically enriched α-lipoic acid or dihydrolipoic acid is used in such Mixtures or salts increased significantly, making an improvement mitochondrial function and an effective treatment of Complications related to type II diabetes, insulin resistance, Hyperglycaemia, arteriosclerosis, endothelial dysfunction, oxidative Stress, a disturbed fat metabolism or signs of aging Cell structures is connected. Also an improved treatment for Scarred tissue as well as tissue that is, for example, in the Radiotherapy or X-ray examinations of an ionizing Has been exposed to radiation.

Finally, such mixtures or salts are also used to treat Depression of a somatogenic, endogenous or psychogenic nature and of pharmacogenic depression and to promote cognitive Skills related to perception, cognition, remembering and Thinking and suitable for the treatment of thinking and memory disorders. In addition, the improved properties of this lipoic acid or Mixtures or salts containing dihydrolipoic acid also include them in the Treatment of symptoms related to Alzheimer's Disease, Parkinson's disease and Hutchinson's Illness (Veitstanz) seem particularly suitable.

Comes as an active pharmaceutical ingredient or food additive Racemic α-lipoic acid both as a pure solid in a mixture with other components, in solid, galenical formulations but also in Infusion solutions for use.

The large number of existing and potential applications is important the availability of large amounts of α-lipoic acid, this Demand will continue to skyrocket over the next few years. But because the availability of α-lipoic acid from natural sources is low and moreover, the isolation of the unstable, light and temperature sensitive Connection is extremely difficult, which must be for pharmaceutical or Dietary supplement applications required α-lipoic acid i. d. R. on can be obtained synthetically.

Synthesis possibilities for crude racemic α-lipoic acid as well as for enantiomerically pure R- or S-α-lipoic acid are, for example, in Crévisy et al., Eur. J. Org. Chem. 1998, 1949, Fadnavis et al., Tetrahedron Asym. 1998, 9, 4109, Dhar et al., J. Org. Chem. 1992, 57, 1699, Adger et al., J. Chem. Soc. Chem. Commun. 1995, 1563, Dasaradhi et al., J. Chem. Soc. Chem. Commun. 1990, 729, Gopalan et al., J. Chem. Soc. Perkin Trans. I 1990, 1897, Yadav et al., J. Sci. Ind. Res. 1990, 49, 400, Tolstikov et. al. Bioorg. Khim. 1990, 16, 1670, Gopalan et al., Tetrahedron Lett. 1989, 5705, described or summarized.

The usual cleaning method for crude α-lipoic acid thus obtained is on recrystallization from solvents such as. B. n-pentane, cyclohexane, Methylcyclohexane and ethyl acetate, or from mixtures of solvents, such as As ethyl acetate and hexane, as used for example in Brookes et al., J. Chem. Soc. Perkin Trans. 1 1988, 9, Segre et al., J. Am. Chem. Soc. 1957, 3503, Walton et al., J. Am. Chem. Soc. 1955, 77, 5144, Acker et al., J. Am. Chem. Soc. 1954, 76, 6483. As alternative additional cleaning method for lipoic acid that previously made was recrystallized from a mixture of cyclohexane and ethyl acetate, DE 197 26 519 A1 describes a treatment of the crude with lipoic acid enriched material with liquid or supercritical carbon dioxide proposed. In PCT / EP00 / 07802 by dissolving raw α-Lipoic acid in dilute aqueous alkaline solution, filter off existing solid contaminants and re-acidifying a crystalline α-lipoic acid obtained by the lack of impurities, such as B. polymeric disulfides or 1,2,3-trithiane-4-valeric acid (Epiliponic acid), as well as the complete freedom from organic solvents distinguished.

In many of the α-lipoic acid syntheses mentioned, the Dimercaptooctanoic acid is the immediate chemical precursor for Desired product. The literature known syntheses for Dimercaptooctanoic acid usually go from a common one Starting material, the adipic acid monomethyl ester, and operate a variety of process stages, but only very low chemical yields result.

But also the chemical conversion of dimercaptooctanoic acid to α- Lipoic acid and the subsequent cleaning of the end product significant problems: for example, the synthesis of racemic involves α-lipoic acid according to U. Schmidt, P. Grafen, Chem. Ber. 1959, 1711 the purification by distillation of those initially obtained synthetically Precursor dimercaptooctanoic acid, its oxidation to α-lipoic acid and subsequent purification of the reaction product by distillation. The mixture is then recrystallized from ethyl acetate at -70 ° C Process temperatures only with disproportionate effort are reached. Furthermore, the chemical lability of α-lipoic acid, the one under the distillation conditions of the purification step considerable proportion in a tough, highly viscous, rubber-like material polymerized, this process is impracticable from an economic point of view.

An alternative method for producing racemic α-lipoic acid is in J. Am. Chem. Soc. 1955, 77, 416, described here: the after the Oxidation of synthetic dimercaptooctanoic acid in solution α-Lipoic acid first freed from the organic solvent. The received Viscous oil is then extracted several times with Skellysolve B, whereby It should not go unmentioned that considerable proportions of a "polymeric material" are created in different quantities have to be separated at great expense. The combined extracts become crystallized out and finally, again only after additional Recrystallization from Skellysolve B - a rather unusual and not commonly available solvents - get an analytical grade product.

In Chem. Abs. 1965, 63, 16355e, is one of 2-ethoxyethyl bromide outgoing process for α-lipoic acid disclosed. The total yield however, is only 10%, which is considering the expensive Starting material is the more disadvantageous. Also in J. Am. Chem. Soc. 1957, 79, 3503 and in US 2,993,056 and on cyclohexanone based process comes to a total yield of only 19%.

The method known from DE 35 12 911 A1 is based on Monomethyl chloride of adipic acid and converts this into one Variety of process and cleaning stages, some of them high Chemical and energy requirements in α-lipoic acid. The total yield is less than 30%, which is considering the already relatively expensive Initial connection makes this process variant even more unattractive.

DE 35 12 911 A1 describes a process for dimercaptooctanoic acid, in which the starting compound is 2- (3-alkylthiopropionyl) cyclopentanone only elaborately represented by a multi-stage chemical synthesis must be, with the reaction with sodium in liquid ammonia -60 to -10 ° C high costs due to the necessary cooling and Safety devices caused.

According to US 5,489,694 for the synthesis of dimercaptooctanoic acid and α-Lipoic acid cyclohexanone in the presence of a radical initiator with a Implemented vinyl alkyl ether, the resulting 2-alkoxyethylcyclohexanone then with a peracid in a Baeyer-Villiger reaction to one Lactone implemented, which subsequently with thiourea in the presence of Hydrobromic acid or hydroiodic acid to dimercaptooctanoic acid is implemented. The crude dihydroliponic acid thus obtained is either isolated or in the presence of an iron (III) catalyst to α-lipoic acid oxidized. The crude α-lipoic acid is finally in one Thin film evaporator by continuous distillation at 0.2-0.02 mbar and distilled 60-200 ° C, and the distillate crystallized. The Disadvantages of this synthetic route are the low selectivity of the radical addition of cyclohexanone to the vinyl derivative of only about 70%, in the occurrence of product mixtures according to the Baeyer-Villiger Oxidation and the need for purification by distillation to see thermally labile α-lipoic acid.

Menon et al. have Lett in Tetrahedron. 1987, 28 (44), 5313-5314 the Synthesis of 1,3-dithians with acetone, (+) - menthone and (-) - menthone described. The conversions of the 1,3-dithiane obtained to the Corresponding 1,3-dithiane-1-oxides are accordingly carried out with Sodium periodate, a very expensive reagent, which is also due to the large molecular mass, the amount required for this sulfoxidation is high. The implementation of the 1,3-dithian-1-oxide with 5-bromovaleric acid in Presence of lithium diisopropylamide (LDA) and the subsequent Conversion of 1,3-dithian-1-oxide to 1,2-dithiolanes under acidic conditions Catalysis provides racemic or enantiomerically pure R - (+) - α-lipoic acid or S - (-) - α-lipoic acid. The authors report high yields from 70% for the entire sequence to R-α-lipoic acid starting from (-) - Menthon, however, the implementation was very vulnerable of sulfoxide with LDA compared to typical upscale effects, so that a industrial application seems impossible. Moreover, that is Reaction partner 5-bromovaleric acid for its part only via one lengthy and costly synthesis accessible.

From the known disadvantages of the prior art has for The present invention therefore has the task of being a powerful and Flexible process for the production of α-lipoic acid using of 1,3-dithians, which ideally should be at least z. T. already tested standard reactions for scaffolding and Functionalization operated, using the reagents easily available and with low procurement or manufacturing costs should be connected.

• a) in einer ersten Verfahrensstufe 1,3-Propandithiol mit einer Aldehyd- oder Ketonverbindung (1) der allgemeinen Formeln
  
  
  worin jeweils R¹ und R² unabhängig voneinander Wasserstoff, ein C_1-3-Alkyl, Phenyl oder ein halogen-, C_1-3-alkyl-, C_1-3-alkyoxy-, amino-, mono- oder bis (C_1-3-alkyl)aminosubstituiertes Phenyl, 2-, 3- oder 4- Pyridyl, 2-Hydroxy-6-hydroxymethyl-3-methyl-4-Pyridyl oder Benzyl bedeuten oder worin R¹ und R² gemeinsam einen -(CH₂)_n-Ring mit n = 1-5 bilden, R für C_1-3-Alkyl, C_1-3-Acyl, Trifluoracetyl, Benzyl oder Bertzoyl steht, R' = H, C_1-3-Alkyl oder Benzyl ist und X = O oder S bedeutet, in Gegenwart eines Lewis-Säuren-Katalysators (2) umsetzt,

dann

• a) gegebenenfalls nach erfolgter Reinigung, die aus Verfahrensstufe a) erhaltene 1,3-Dithianverbindung (3) mit einem Oxidationsmittel (4) zu einem 1,3-Dithian-1-oxid (5) der allgemeinen Formel II)
  
  
  worin R¹ und R² die genannte Bedeutung besitzen, oxidiert,

anschließend

• a) das aus b) erhaltene 1,3-Dithian-1-oxid (5) der allgemeinen Formel II in Gegenwart einer Lewis- oder Brönstedt-Base (6) an Acrolein zum entsprechenden Allylalkohol (7) der allgemeinen Formel III)
  
  
  worin R¹ und R² die genannte Bedeutung besitzen, addiert,

nachfolgend

• a) den Allylalkohol (7) der allgemeinen Formel III aus Stufe c) unter Lewis- oder Brönstedt-Säure (8)-Katalyse mit einem Orthoester (9)
  
  CH₃C(OR³)₃
  
  zum Allylacetal (10) der allgemeinen Formel IV)
  
  
  worin R¹ und R² die genannte Bedeutung besitzen und R³ jeweils C_1-3-Alkyl bedeutet, umsetzt,

dann

• a) den Allylorthoester (10) der allgemeinen Formel IV bei Temperaturen zwischen 60 und 145°C zur Octensäure-Verbindung (11) der allgemeinen Formel V)
  
  
  worin R¹, R² und R³ die genannte Bedeutung besitzen, weiterreagieren lässt,
• b) die aus e) erhaltene Octensäure-Verbindung (11) der allgemeinen Formel V zu einem 1,3-Dithian-1-oxid-6-valeriansäureester (12) der allgemeinen Formel VI)
  
  
  worin R¹ und R² und R³ die genannte Bedeutung besitzen, reduziert,

darauf

• a) den Valeriansäureester (12) der allgemeinen Formel VI zur α-Liponsäure
  
  
  solvolysiert,

und abschließend

• a) das Produkt α-Liponsäure isoliert und gegebenenfalls aufreinigt.

This task was solved with the help of a corresponding procedure, in which one

• a) in a first process step 1,3-propanedithiol with an aldehyde or ketone compound (1) of the general formulas
  
  
  wherein each R ¹ and R ² independently of one another are hydrogen, a C _1-3 alkyl, phenyl or a halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono- or bis (C _1-3 -alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or where R ¹ and R ² together form a - (CH ₂ ) form _n ring with n = 1-5, R is C _1-3 alkyl, C _1-3 acyl, trifluoroacetyl, benzyl or Bertzoyl, R '= H, C _1-3 alkyl or benzyl and X = O or S, in the presence of a Lewis acid catalyst (2),

then

• a) optionally after cleaning, the 1,3-dithiane compound (3) obtained from process step a) with an oxidizing agent (4) to give a 1,3-dithiane-1-oxide (5) of the general formula II)
  
  
  wherein R ¹ and R ^{2 have} the meaning given, oxidized,

subsequently

• a) the 1,3-dithiane-1-oxide (5) of the general formula II obtained from b) in the presence of a Lewis or Brönstedt base (6) on acrolein to give the corresponding allyl alcohol (7) of the general formula III)
  
  
  where R ¹ and R ^{2 have} the meaning given, added,

following

• a) the allyl alcohol (7) of the general formula III from stage c) with Lewis or Brönstedt acid (8) catalysis with an orthoester (9)
  
  CH ₃ C (OR ³ ) ₃
  
  to the allyl acetal (10) of the general formula IV)
  
  
  in which R ¹ and R ^{2 have} the meaning given and R ³ each denotes C _1-3 alkyl,

then

• a) the allyl orthoester (10) of the general formula IV at temperatures between 60 and 145 ° C to the octenoic acid compound (11) of the general formula V)
  
  
  wherein R ¹ , R ² and R ^{3 have} the meaning given, can react further,
• b) the octenic acid compound (11) of the general formula V obtained from e) to give a 1,3-dithiane-1-oxide-6-valeric acid ester (12) of the general formula VI)
  
  
  in which R ¹ and R ² and R ^{3 have} the meaning given, reduced,

thereon

• a) the valeric acid ester (12) of the general formula VI for α-lipoic acid
  
  
  solvolysis,

and finally

• a) the product α-lipoic acid isolated and optionally purified.

It has been completely surprising when implementing this overall process demonstrated that with the help of the new concept for the scaffolding structure eight C-atoms containing lipoic acid structure via Johnson-Claisen- Orthoester rearrangement Lipoic acid yields of regularly> 90% be achieved.

The early introduction of sulfur turned out to be an unexpected key step in the process described in the present invention: in almost all synthetic strategies known from the literature, sulfur is only introduced at the end of the reaction chain - and usually by nucleophilic substitution at positions C ₆ and C ₈ - this late introduction poses not insignificant problems with regard to cleaning and polymerization (disadvantageous for the product quality). In the proposed alternative construction of the C ₈ structure of α-lipoic acid, the sulfur is inserted into a key intermediate at a very early point in the synthesis according to the scheme "C ₃ + C ₃ + C ₂ → C ₈ ", which means that the otherwise problematic polymerization events and the necessary cleaning steps are completely eliminated, which was not to be expected in this form.

1,3-Propanedithiol (1) and acrolein (3) are suitable, commercially easily accessible C ₃ components for a suitable C ₈ framework in this novel, short, effective and highly flexible synthesis concept for α-lipoic acid. Similarly, triethyl orthoacetate (5) is a suitable substrate for the corresponding C ₂ component.

The first step of the synthesis according to the invention is the reaction of 1,3-propanedithiol with a suitable aldehyde or ketone of the formulas (1a) and (1b) in the presence of a Lewis acid catalyst (2). Since the carbonyl component during the synthesis is split off again and can in principle be recycled, can be used as aldehyde or ketone compound (1) ubiquitous, commercially extremely easily available and inexpensive aldehydes or ketones or their derivatives of aldehydes or ketones such as. B. acetone, cyclopentanone, cyclohexanone, 2,2-dimethoxypropane (DMP) or 1,3-dithiane, aldehydes or ketones of the so-called "chiral pool", preferably in enantiomerically pure form, such as. B. camphor, menthone, fenchone, but also physiologically acceptable aldehydes or ketones such as. B. anisaldehyde, vanillin, o-vanillin or vitamin B ₆ (pyridoxal) or tailored to the specific electronic and / or steric needs of the subsequent process steps b) to e) aldehydes or ketones such as. B. benzaldehyde or hexafluoroacetone are preferably used, which can particularly preferably also be used in chiral non-racemic form.

The protective class is the compound class of 1,3-dithians (thioacetals or -ketale) a commonly used and important tool in the organic synthesis, its main advantage being its easy removability is to be found under mild conditions and which makes other functional Groups in the molecule are spared. Unlike O / O acetals, the acidic S / S acetals can also be used for splitting conditions Easily remove using metal ions. Furthermore, they are very stable towards acids or alkali compounds (Houben-Weyl; "Methods of Organic Chemistry"; G. Thieme Verlag 1992; Vol.E14a / 3, 403-482; Greene, Th. W .; Wuts, P.G.M., "Protective Groups in Organic Synthesis "; John Wiley & Sons New York; 3rd edition 1999; 490-491).

To produce the 1,3-dithiane compound (3), the Process step a) uses a standard specification (Hoppmann, A .; Weyerstahl, P .; Zummack, W., Liebigs Ann. Chem. 1977, 1547-1556). As preferred Lewis acid catalyst (2) is boron trifluoride etherate used. The implementation of carbonyl compounds would also come along Zinc chloride and / or hydrogen chloride (e.g. according to Posner, T., Chem. Ber. 1903, 36, 296-304) in question; however, this alternative has the disadvantage that essential compared to the preferred boron trifluoride etherate more aggressive reagents are needed. In another variant considers the invention as Lewis acids (2), which either in Catalytic or stoichiometric amounts used are strong acidic ion exchangers such as B. Amberlyst®.

In practice it has been shown that for step a) a Water-free reagents of formulas (1a) and (1b) used and 1,3-propanedithiol is helpful because in this reaction anyway Water is formed and in the additional presence of which Reaction balance unfavorable on the side of the starting materials would be relocated. In addition, in the presence of water hydrolyze preferably used Lewis acid boron trifluoride etherate. Overall, it has proven to be advantageous if the process step a) in alcoholic solution and preferably in methanolic solution is carried out. An initial cooling to <20 ° C was found also as beneficial, with process stage a) in total preferred temperature ranges between -5 and + 5 ° C. should be.

After the reaction has ended, it may not be possible to implement what has been implemented Remove 1,3-propanedithiol by extraction with aqueous alkali. Excess compound (1) can be removed by distillation. For one Cleaning is a particularly pronounced and desired product purity practicable by vacuum distillation. As a rule, however Purity of the crude product thus obtained for further implementation perfectly adequate. The very unpleasant smell of 1,3-propanedithiol can be obtained by working in closed vessels, through the use of alkaline washers as well as through the Compliance with the safety regulations common in laboratories and technology to encounter. By treating the raw and from process step a) obtained 1,3-dithians with the oxidizing agent (4) in the next Process stage b) this unpleasant smell is advantageous but eliminated anyway.

The chemical literature knows numerous regulations for the oxidation of a sulfide to sulfoxide just mentioned (e.g. Houben-Weyl; "Methods of Organic Chemistry"; G. Thieme Verlag 1985; Vol. E11, 671-866). A possible side reaction associated with this, namely further oxidation to the sulfone, was, however, completely uncritical in the process according to the invention. In the present case, the choice of the temperature and the amount of the oxidizing agent (4) means that the sulfoxide (5) can be obtained practically exclusively. The oxidation of the second sulfur atom in the 1,3-dithane compound (3) takes place, if at all, only to an undetectable extent. The oxidizing agents (4) used in a preferred embodiment of process step b) comprise performic acid, peracetic acid or an aqueous hydrogen peroxide solution. These are readily available and cheap standard chemicals (Janssen, JWAM; Kwart, H., J. Org. Chem. 1977, 42, 1530-1533; Ogura, K .; Tuchihashi, G., Bull Chem. Soc. Jap. 1972 , 45, 2203-2204). This reaction step can also proceed via the intermediate formation of peracetic acid, which is supported by the solvent dependence of the reactivity: acetic acid>water> D ₂ O>methanol>isopropanol> tert-butanol, as well as the finding that sulfanes with a carboxyl group in the molecule are quickly oxidized, the solvent plays a minor role (Dankleff, MAP; Curci, R .; Edwards, JO; Pyun, HJ, J. Am. Chem. Soc. 1968, 90, 3209-3218). The reaction itself is very quick.

The invention provides that process step b) at temperatures is carried out between 0 and 25 ° C, it may be advantageous if after stirring for 10 minutes at 0 ° C for 20 minutes at room temperature is continued. After conventional processing is a Cleaning step required, otherwise the yield of the next one Process stage c) is reduced. This can be explained by the im Raw product traces of acid still present with the base used react. This possibly necessary cleaning can usually either by distillation or by chromatography.

Overall, it should be noted that with achiral reaction management and use of a non-chiral aldehyde or ketone compound (1) due to the chirality of the oxidized sulfur, racemic sulfoxides arise. However, this is the barrier to the conversion of optical isomers sufficiently high at room temperature so that In principle, enantiomers can be separated. In the present case was actually able to use high performance chromatography (HPLC) over a chiral column, for example a baseline separation of R-2,2-dimethyl-1,3- dithian-1-oxide and the corresponding S-configured compound can be achieved. After the next two process steps c) and d) can in principle be separated by the resulting diastereomers Chromatography, crystallization or using chemical methods be carried out so that with the present method too enantiomerically pure lipoic acid (or its derivatives) can be produced can.

When using enantiomerically pure aldehydes or ketones Formulas (1a) and (1b) result in diastereomers, with asymmetric ones Carrying out the reaction, for example, using chiral catalysts or In contrast, microorganisms would predominantly be an enantiomer of Sulfoxide formed (see Samuel, O .; Ronan, B .; Kagan, H. B., J. Organometall. Chem. 1989, 370, 43-50; Bortoloni, O .; Furia, F. D .; Licini, G .; Modena, G .; Rossi, M., Tetrahedr. Lett. 1986, 51, 6257-6260).

The monooxidation of process stage b) serves primarily to: To increase the acidity of the two protons in the α position to the sulfoxide and that resulting from deprotonation in process step c) Stabilize carbonion. It has now been shown that for deprotonation as Lewis base (6) stronger bases such as lithium diisopropylamide (LDA) and n-Butyllithium (n-BuLi) are particularly suitable, the substrate used 1,3-Dithian-1-oxide (5) sufficient to deprotonate. sodium hydride, Sodium amide and potassium tert-butoxide, for example, are less suitable.

The present invention provides for process step c) the carbon ion of the associated 1,3- Add Dithian-1-oxides (5) acrolein (propenal). This can be Addition to the double bond (conjugate addition, Michael addition) while maintaining the aldehyde group or alternatively by 1,2-addition the carbonyl group take place, the corresponding ally alcohol (7) emerges (cf.Goldmann, S .; Hoffmann, R. W .; Maak, N .; Geueke, K.-J., Chem. Ber. 1980, 831-844). By the appropriate choice of Product distribution can be very good reaction conditions influence: Favorable factors for a 1,2-addition are e.g. B. use strong bases of e.g. lithium as counter ion, low temperatures as well short reaction times, all in all on a kinetic reaction control suggesting.

As it can be helpful for this step c) the reagents and to clean solvents or to use them in absolute form Invention as preferred, freshly cleaned and in particular use absolute and polymer-free acrolein, since acrolein is used for Polymerization tends. As already mentioned, the sulfoxide (5) should not Contained traces of acid to increase the efficiency of deprotonation to ensure strong base.

The reaction of process step c) is a preferred one Embodiment at temperatures between -85 and + 15 ° C and is in usually completed after about 1 hour. First, the sulfoxide (1,3-dithian-1-oxide (5)) and the Lewis or Brönstedt base (6) approx. 30 React with each other for minutes so that the carbon ion can form. Then acrolein is added and the reaction mixture is left for about 30 more Stir for minutes at this temperature. The termination of the reaction then usually takes place by adding an aqueous Ammonium chloride solution, whereby the product, the allyl alcohol (7), is made the corresponding anion is released by protonation.

The 1,2-addition of acrolein to the sulfoxide (5) thus generates two additional stereo centers: one stereo center in the α position to the sulfoxide group and another on the neighboring carbon atom, which carries a hydroxyl group. The product obtained from process step c) thus contains three stereogenic centers, without taking into account a possible chiral nature of the introduced radicals R ¹ and R ² , and can thus form a total of three mutually enantiomeric diastereomer pairs.

In this context, the present invention sees as already mentions the option following process stage b) and / or c) perform a diastereomer separation, which is preferably done by Chromatography or crystallization should be done.

With the aldol addition of acrolein to the 1,3-dithiane-1-oxide (5), a C ₆ framework was initially built up in the course of process step c). The chain extension necessary for the lipoic acid synthesis by two further carbon units is subsequently carried out by means of a framework rearrangement as part of a variant of the Claisen rearrangement, the Johnson orthoester rearrangement.

In order to obtain the allyl orthoester (10) from the allyl alcohol (7), first an alkylation of the allyl alcohol function in the allyl alcohol (7) the orthoester (9) used. This step is done according to Process stage d) under acid catalysis. For this purpose the Reaction mixture as Lewis or Brönstedt acid (8) a weak one Acid, preferably propionic or hexanoic acid added (see Jones, G.B .; Huber, R. S .; Chau, S., Tetrahedron 1983, 49, 369-380). The resulting one the actual allyl orthoester eliminates one under acid catalysis Alcohol unit, so that before the actual rearrangement to the octenoic acid Compound (11) is a mixed ketene acetal according to formula (10). A mixture of diastereomeric ketene acetals is present completely uncritical in terms of effectiveness, because all isomers end up the reaction sequence lead to racemic α-lipoic acid.

Concerning. In process stage d), the invention provides in particular for the use of a C _1-6 orthoester (9), which was preferably obtained on the basis of acetic acid and should particularly preferably be in the form of triethyl orthoacetate; however, the use of a benzyl ortho ester based on acetic acid is also provided.

In general, it can be favorable for the claimed process, the Process steps c) and / or d) with toluene, xylene, isomeric xylenes and / or to carry out isomeric mesitylene as suitable solvents.

The process steps mentioned can be used for themselves or for both can also be carried out together in the presence of n-propanoic acid, which should then preferably be used in catalytic amounts, which the present invention also provides.

• 1. Beim Einsatz von Orthoestern von Carbonsäuren, die länger als zwei Kohlenstoffeinheiten sind, kann das resultierende Ketenacetal in zwei verschiedenen Konfigurationen bezüglich der Doppelbindung vorliegen. Es wurde gezeigt, dass bei diesem Schritt bei der Johnson- Orthoester-Umlagerung keine Stereoselektivität gegeben ist (Bolton, I. J.; Harrison, R. G.; Lythgoe, B., J. Chem. Soc. 1971, 2950).
• 2. Die Stereochemie bei der eigentlichen Umlagerung wird als hoch selektiv beschrieben Qohnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R., J. Am. Chem. Soc. 1970, 92, 741-743; Carey, F. A.; Sundberg, R. J., "Advanced Organic Chemistry"; VCH Weinheim 1995, 1056-1069) und verläuft über einen sesselartigen Übergangszustand, wenn die Substituenten in der Nähe des beteiligten π-Systems nicht zu groß sind. Bei der beschriebenen Reaktion wird praktisch ausschließlich das transkonfigurierte Produkt erhalten.

After the elimination, the actual rearrangement takes place, whereby there are generally two points to be considered from a stereochemical perspective:

• 1. When using orthoesters of carboxylic acids that are longer than two carbon units, the resulting ketene acetal can exist in two different configurations with regard to the double bond. It has been shown that there is no stereoselectivity in this step in the Johnson orthoester rearrangement (Bolton, IJ; Harrison, RG; Lythgoe, B., J. Chem. Soc. 1971, 2950).
• 2. The stereochemistry in the actual rearrangement is described as highly selective Qohnson, WS; Werthemann, L .; Bartlett, WR; Brocksom, TJ; Li, T.-T .; Faulkner, DJ; Petersen, MR, J. Am. Chem. Soc. 1970, 92, 741-743; Carey, FA; Sundberg, RJ, Advanced Organic Chemistry; VCH Weinheim 1995, 1056-1069) and runs through a chair-like transition state if the substituents in the vicinity of the π system involved are not too large. In the reaction described, the transconfigured product is obtained practically exclusively.

In process stage e), the implementation is relatively drastic Conditions necessary (see Gonzalez, F. B .; Bartlett, P. A., Org. Synthesis 1986, 64, 175-181). These include in a particularly preferred one Embodiment of the present invention temperatures between 70 and 120 ° C and particularly preferably between 100-110 ° C, in which Usually a reaction time of 24 hours is sufficient. Can be used as a solvent Toluene can be used; it can also be beneficial during the reaction add one or two catalyst to add the reaction accelerate. After the reaction is complete, the solvent together with unreacted orthoester (9) on one Rotary evaporators are removed in vacuo. Multiple Coevaporation with toluene removes most of what is still present Orthoester (9). After that, the octenic acid Compound (11) takes place, for example, by means of flash chromatography, where isolate two diastereomers. When using e.g. Enantiomerically pure 2,2-dimethyl-1,3-dithiane-1-oxide can thus be used principally produce enantiomerically pure lipoic acid, because with the following steps, the stereo center in position 6 no longer is attacked.

The order of reduction of the double bond and the generation of the dithiolane ring are in principle interchangeable. So in the context of present invention, the reduction can be carried out first, and followed by acid-catalyzed ring contraction.

Sulfur is more diverse in catalytic hydrogenation applications Metal catalysts known as "catalyst poison". A catalytic one Hydrogenation with molecular hydrogen is therefore rather disadvantageous, although now special catalysts that tolerate sulfur, are known (see Mashkina, A., Russ. Chem. Rev. 1997, 66, 417-441).

A reduction with diimine, which can be prepared in situ from suitable sources in particular, has therefore proven to be a useful alternative for process step f). Diimine is suitable for the selective reduction of double bonds with a relatively symmetrical electron distribution. Carbonyl, nitro, cyano groups or the like are not attacked (cf. Van Tamelen, EE; Davis, M .; Deen, MF, J. Am. Chem. Soc. 1965, 87, 71-72). Table 1 shows a compilation of selected reagents that are suitable for the production of diimine. Table 1 Selected reagents for the in-situ production of diimine

From the series of suitable precursor compounds of diimine in particular hydrazine, chloramine, aminosulfonate, potassium azodicarboxylate, p-toluenesulfone hydrazide and 2,4,6-triisopropylbenzenesulfonic acid hydrazine shown from which the diimine is released. Potassium azodicarboxylate can by reacting commercially available azodicarbonamide with Potassium hydroxide solution can be obtained (Heck, R. F .; Dieck, H. A., J. Org. Chem. 1975, 40, 1083-1090).

Hydrazine can also be used as a further diimine source Oxygen or other oxidizing agents can be oxidized to diimine to deliver (Abul-Hajj, Y., J. Org. Chem. 1971, 36, 2730-2731).

Very good results can also be achieved with 2,4,6-Triisopropylbenzenesulfonsäurehydrazid can be achieved. The solid is commercially available at Can be stored at room temperature and disintegrates when heated to Reducing agent diimine. For this purpose, the substrate, which unsaturated octenic acid esters (11), dissolved in tetrahydrofuran and mixed with the 2,4,6-Triisopropylbenzenesulfonsäurehydrazid added. After six hours The reaction is generally heating under reflux conditions completed and the valeric acid ester (12) can be worked up and chromatographic purification can be isolated.

It is recommended for achieving particularly good reduction results itself, process stage f) at temperatures between 50 and 140 ° C. perform and in particular between 80 and 110 ° C, which the present invention also considered.

Now that the structure of α-lipoic acid has been built up in principle, it is missing only two transformations: the structure of the 1,2-dithiolane ring and the solvolysis of the ester group of compound (12). The latter reaction leaves easily perform according to standard conditions because none base-sensitive functional groups are present and therefore special measures can be dispensed with. It is different in the so-called collapse, i.e. the ring contraction of a 1,3-dithian-1- oxides (5) to the corresponding 1,2-dithiolane, a reaction that has is known from sugar chemistry for about 40 years (Kuhn, R .; Baschang-Bister, W .; Dafeldecker, W., Liebigs Ann. Chem. 1960, 641, 160-176). In a preferred embodiment of the present invention has proven to be proven to be particularly favorable when process stage g) in acidic, preferably alcoholic solution is carried out, one methanolic hydrochloric acid solution with pH values between 2.5 and 6.5 is particularly preferable. The required methanolic Hydrogen chloride solution is usually not by introducing Hydrogen chloride gas made in methanol, but simpler, namely according to the invention, preferably in situ, by slowly adding drops of Acetyl chloride to anhydrous methanol and possibly with ice cooling. Such a thing prepared solution is not durable and over a longer period of time should therefore be freshly prepared immediately before implementation.

For the final solvolysis of the resulting valeric acid ester (12) proved in a hydrolysis cesium and potassium carbonate in the aqueous methanol as particularly suitable (cf. Paterson, L; Yeung, K.-S .; Ward, R. A; Smith, J. D .; Cumming, J.G .; Lanboley, S., Tetrahedron 1995, 51, 9467-9486; Ricca, J.-M .; Crout D.H.G., J. Chem. Soc. Perkin Trans. I 1993, 1225-1233; Kaestle, K. L .; Anwer, M. K .; Tapan, K.A .; Goldstein, G., Tetrahedr. Lett. 1991, 32, 327-330; Ishizuka, T .; Kunieda, T., Tetrahedr. Lett. 1987, 28, 4185-4188). The invention provides in particular in Process step g) of the solvolysis a hydrolysis step before or nachzuschalten.

For the hydrolysis of the valeric acid ester (12), the starting material is dissolved in methanol and continues to add water until it becomes cloudy. After that the Base added and stirred at room temperature. The further one Working up is extractive and provides practically quantitative yields.

In a further preferred embodiment of the present Invention is the resulting crude α-lipoic acid in aqueous solution, preferably with a pH between 7.5 and 16.0, or their salt in Dissolved water and then adjusted an alkaline pH; thereupon any solid impurities present are separated off, the aqueous solution obtained is then with the aid of a suitable Acid adjusted to a pH of -1.0 to 5.0 and the precipitated Lipoic acid isolated and dried by known methods.

The α-lipoic acid obtained in this way is characterized in that it is free of typical impurities such as polymeric disulfides or 1,2,3-Trithian-4-valerian (epiliponic acid) is and no more contains organic solvents, d. H. a solvent-free α-lipoic acid represents.

In addition to the process described, the present invention also claims the following compounds: Compound of the general formula A.

in racemic or diastereomerically pure form, in which R ¹ and R ^{2 are} each independently hydrogen, a C _1-3 alkyl, phenyl or a halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, is mono- or bis (C _1-3 -alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or in which R ¹ and R ² together form a - (CH ₂ ) _n ring with n = 1-5, and any mixtures of their diastereomers. Compound of the general formula B

in racemic or diastereomerically pure form, in which R ¹ and R ^{2 are} hydrogen, a C _1-3 alkyl, phenyl or a halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono- or bis (C _1-3 -alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or in which R ¹ and R ² together represent a - Form (CH ₂ ) _n ring with n = 1-5 and R = H, a C _1-3 alkyl, C _1-3 acyl or corresponding aryl substituted C _1-3 alkyl or C _1-3 acyl, in particular acetyl, trifluoroacetyl, benzyl or benzoyl, and any mixtures of their diastereomers, which is obtained in particular by the reaction of a compound of the general formula


wherein R ¹ and R ^{2 have} the meaning given, with an alkylating or acylating agent such as. As methyl bromide, trifluoroacetic acid chloride or benzoyl chloride. Compound of the general formula C

in racemic or diastereomeric form, in which R ¹ and R ^{2 are} each independently hydrogen, a C _1-3 alkyl, phenyl or a halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono- or bis (C _1-3 alkyl) amino-substituted phenyl, a 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl, or in which R ¹ and R ² together form a - (CH ₂ ) _n ring with n = 1-5 and in which R ^{3 represents} hydrogen, a C _1-6 alkyl or benzyl, and any mixtures of their diastereomers. Compound of the general formula D

in racemic or diastereomerically pure form, in which R ¹ and R ^{2 are} each, independently of one another, hydrogen, a C _1-3 alkyl, a phenyl or halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, are mono- or bis (C _1-3 alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or in which R ¹ and R ² together form a - (CH ₂ ) _n ring with n = 5 and R ^{3 represents} hydrogen, a C _1-6 alkyl or benzyl, as well as any mixtures of their diastereomers and / or their cis- to the C = C double bond or transient isomers. Compound of the general formula E.

in racemic or diastereomeric form in which R ¹ and R ^{2 are} each independently hydrogen, a C _1-3 alkyl, phenyl or halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono - or bis (C _1-3 alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or in which R ¹ and R ² together form a - (CH ₂ ) _n ring with n = 1-5 and R ^{3 represents} hydrogen, C _1-6 alkyl or benzyl, and any mixtures of their diastereomers.

The present invention particularly claims compounds of formulas A to E mentioned, with the inventive method or one of its variants were manufactured.

Finally, the present invention also includes the use of the compounds with the formulas A to E and their variants for Synthesis of racemic (±) -α-lipoic acid or enantiomerically pure R - (+) - or S - (-) - α-lipoic acid or any mixtures thereof that Use of a producible according to the inventive method α-Lipoic acid as a food supplement, in medicines and / or in Cosmetics, and especially for oral, dermal, parenteral, rectal, vaginal or topical application purposes. It is particularly preferred in this context the use of the invention producible α-lipoic acid in gels, semi-solid dosage forms or solid solutions.

However, the use of Compounds of formulas C, D and E for in vivo release of physiologically active 3-substituted 1,2-dithiolanes and one includes neutral or physiologically active aldehyde or ketone, again preferred as a dietary supplement, in Medicines and / or in cosmetics, and particularly preferred for peroral, dermal, parenteral, rectal, vaginal or topical Application purposes, especially in gels, semi-solid Dosage forms or solid solutions can be used.

Overall, the present invention thus proposes a method with whose help α-lipoic acid from readily available and inexpensive Starting compounds and implementation partners with great purity and is obtained in high yields, but also with the new compounds accessible, which can be used particularly in the health sector are.

The following examples illustrate the advantages of the Method according to the invention for the multistage production of α-lipoic acid using 1,3-dithians.

Examples

The solvents used were distilled before use. Anhydrous (absolute) solvents were added to 4 Å molecular sieve kept.

Finished plates with silica gel 60 F ₂₅₄ coating were used for thin layer chromatography (TLC) and silica gel 60, each from Merck, for flash chromatography. The detection was carried out by observing the quenching of fluorescence under a UV lamp at a wavelength of 254 nm, using 2% Ce (SO ₄ ) ₂ .4H ₂ O in 2 NH ₂ SO ₄ and 5% (NH ₄ ) ₆ Mo ₇ as immersion reagents O ₂₄ in 10% H ₂ SO _{4 was} used; after immersion in these solutions, the plates were heated with a hot air gun.

IR spectra were obtained using a Perkin Elmer 1600 FT-IR spectrometer from Films created on a silicon wafer.

NMR spectra were recorded with a DPX-250 or DPX-400 NMR spectrometer from Bruker. The spectra were calibrated using residual signals from the solvents (CDCl ₃ : ¹ H-NMR: 7.24 ppm; ¹³ C-NMR: 77.0 ppm).

Basic chemicals were purchased from Fluka and Aldrich.

Abbreviations used: dihydrolipoic acid (DHLS), Thin layer chromatography (TLC), room temperature (RT) and High performance liquid chromatography (HPLC).

example 1 Preparation of 2,2-dimethyl-1,3-dithiane (3) (process step a))

12 ml of 1,3-propanedithiol (0.12 mol) was placed in 250 ml of anhydrous methanol dissolved and cooled to 0 ° C. Then 10 ml of anhydrous acetone (1) (0.14 mol) and 15 ml of boron trifluoride etherate in ether were added. The The reaction mixture remained overnight, with the cold bath thawing. After 19 hours the precipitated white precipitate was filtered off and the solvent removed in vacuo. The residue was dissolved in 40 ml of 7% KOH Solution taken up and extracted 2 times with 100 ml of ether. The combined organic phases were 2 times with 30 ml of water washed and dried over potassium carbonate. The solvent was in Vacuum distilled off.

The product can be purified by means of Kugelrohr distillation (literature boiling point: 80 ° C, 2 Torr), but was used raw.
Yield: 12.55 g (76% of theory) of 2,2-dimethyl-1,3-dithiane (3).

Example 2 Oxidation of 2,2-dimethyl-1,3-dithiane (3) to the corresponding one Sulfoxide (5) (process stage b))

12.55 g (0.09 mol) of 2,2-dimethyl-1,3-dithiane (3) from Example 1 were dissolved in 20 ml of glacial acetic acid and cooled to 0 ° C. Then 10.3 ml of hydrogen peroxide solution (30%) (4) was added. After stirring for 10 minutes at this temperature, the cooling was removed and stirring was continued for 20 minutes at room temperature. 120 ml of dichloromethane were added to the reaction mixture and neutralized with potassium carbonate (approx. 25 g) until gas evolution ceased. The resulting precipitate was filtered off, the organic phase was dried over sodium sulfate and the solvent was removed in vacuo.
Yield: 12.59 g (84% of theory) of 2,2-dimethyl-1,3-dithiane-1-oxide (5).

The product can be purified by distillation in a high vacuum (literature boiling point: 109 ° C, 0.9 Torr) or by flash chromatography: stationary phase: silica gel 60 (approx. 50-80 g / g substance), mobile phase: chloroform / Methanol 25: 1. If the compound is used raw, the yield in the further reaction is only slightly reduced.
Physical properties: colorless oil, solidifies at temperatures <8 ° C.
DC:
(Hexane / ethyl acetate 1: 7)
R _f = 0.15
HPLC conditions for enantiomer separation:
Stationary phase: Chiracel OD-H
Mobile phase: 20% isopropanol in hexane
Conditions: temperature: 5 ° C, flow: 0.5 ml / min
Detectors: UV (λ = 254 nm) and
Refractive index differential detector (RI)
Retention times of the enantiomers: 15.7 and 18.9 min
(Baseline separation)
¹ H NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 7.24)
δ = 1.41 (s, 3H), 1.47 (s, 3H), 1.96-2.15 (m, 1H), 2.20-2.31 (m, 2H), 2.46-2.62 (m, 2H), 2.83-2.90 (m, 1H )
¹³ C NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 77.0)
δ = 16.6, 25.8, 25.8, 28.5, 46.7, 57.7
MS:
(EI, 70 eV, 600 µA)
HR: (ber./gef.): 164.0329 / 164.0332
m / z = 164 (M ⁺ ), 147, 123, 106, 90, 74, 59
IR:
(Film, cm ^-1 )
3456, 2965, 2924, 1654, 1458, 1444, 1424, 1378, 1362, 1293, 1228, 1167, 1120, 1049, 1035, 908, 868, 827, 701, 668, 577, 435

Example 3 Aldol addition of 2,2-dimethyl-1,3-dithiane-1-oxide (5) to the allyl alcohol (7) (Process stage c)) 3.1 Variant with n-Buyllithium as Lewis Base Catalyst (6)

492 mg (3 mmol) of the sulfoxide (5) obtained with Example 2 were dissolved in 5 ml of anhydrous tetrahydrofuran (THF) in a nitrogen atmosphere and cooled to -78 ° C. Then 2.24 ml of a 1.6 M solution of butyllithium (6) in hexane (3.6 mmol) were added and the mixture was left to stand for 15 minutes. Then 0.2 ml of acrolein (freshly distilled) was slowly added. After 45 minutes, the reaction was terminated with 0.5 ml of a 10% NH ₄ Cl solution. The reaction mixture was brought to room temperature, 15 ml of water were added and the mixture was extracted 3 times with 15 ml of dichloromethane each time. The combined organic phases were washed twice with 10 ml of water each time and dried over sodium sulfate. The solvent was removed in vacuo. The purification was carried out by means of flash chromatography (44 g of silica gel, mobile phase: CHCl ₃ / MeOH 35: 1).
Yield: 551 mg (83% of theory) of allyl alcohol (7)

3.2 Variant with lithium diisoproplamide (LDA) as Lewis base Catalyst (6)

577 mg of diisopropylamine (5.7 mmol, freshly distilled) were placed in 15 ml of anhydrous THF in a nitrogen atmosphere and cooled to -78 ° C. Then 3.5 ml of a 1.6 M solution of butyllithium (6) in hexane were added within 5 minutes. After stirring for 10 minutes, the cooling was replaced by an ice bath and stirred for a further 20 minutes. The mixture was then cooled back to -78 ° C. After 15 minutes, 812 mg of the sulfoxide (5) (5.0 mmol) obtained according to Example 2, dissolved in 4.5 ml of THF, were added; After stirring for a further 15 minutes, 0.8 ml of acrolein (freshly distilled) was added dropwise. The reaction was stopped by adding 2.5 ml of a saturated ammonium chloride solution. The solvent was removed in vacuo, water and dichloromethane were added to the residue, undissolved precipitate was filtered off and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was removed by vacuum distillation. The crude product was again purified by means of flash chromatography: 80 g of silica gel, hexane / ethyl acetate 1: 3, then 1: 5 and finally 1:10.
Yield: 486 mg (45% of theory) of allyl alcohol (7).
Physical properties: colorless oil
DC:
(Hexane / ethyl acetate 1: 7)
R _f = 0.23
(Chloroform / methanol 35: 1)
R _f = 0.22
¹ H NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 7.24)
δ = 1.44 (s, 3H), 1.50 (s, 3H), 1.61-1.69 (m, 1H), 2.02-2.19 (m, 1H), 2.44-2.54 (m, 2H), 2.76-2.87 (m, 1H ), 4.14-4.25 (br m, 2H), 5.22-5.40 (m, 2H), 5.75-5.90 (m, 1H)
¹³ C NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 77.0)
δ = 17.6, 22.5, 25.2, 26.0, 56.8, 58.6, 7 2.5, 118.2, 137.5
MS:
(EI, 70 eV, 600 µA)
HR: (ber./gef.): 220.0592 / 220.0601
m / z = 220 (M ⁺ ), 205, 179, 148, 107, 89, 74, 57
IR:
(Film, cm ^-1 )
3356, 2960, 2920, 2361, 2344, 1719, 1639, 1438, 1423, 1382, 1364, 1294, 1258, 1158, 1116, 1032, 993, 925, 847, 688, 585, 545

Example 4 Preparation of the octenic acid ester (11) (process stage d))

220 mg of allyl alcohol (7) (1 mmol) from Example 3.1 were dissolved in 2 ml of anhydrous toluene, 2.5 ml of triethyl orthoacetate (9) and 3 drops of propionic acid were added and the mixture was heated to 75-80 ° C. The reaction was carried out in a reflux apparatus in an argon atmosphere. After 18 hours, 3 drops of propionic acid were added dropwise and the mixture was stirred for a further 2 hours. The solvent was then removed by vacuum distillation. The crude product was purified by means of flash chromatography: 30 g of silica gel, hexane / ethyl acetate 3: 1, then 1: 3.
Yield: 197 mg (68% of theory) of octenic acid ester (11).
Physical properties: colorless oil
DC:
(Hexane / ethyl acetate 1: 3)
R _f = 0.34
¹ H NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 7.24)
δ = 1.22 (t, 3H, J = 7.2 Hz), 1.45 (s, 3H), 1.54 (s, 3H), 1.61-1.71 (m, 1H), 2.18-2.45 (m, 5H), 2.48-2.57 ( m, 1H), 2.77-2.88 (m, 1H), 3.05-3.14 (m, 1H), 4.10 (q, 2H, J = 7.2 Hz), 5.40-5.62 (m, 1H), 5.69-5.80 (m, 1H)
¹³ C NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 77.0)
δ = 14.2, 20.5, 22.9, 25.2, 25.7, 27.8, 33.6, 54.9, 60.4, 127.0, 134.4 (2 signals missing)
MS:
(EI, 70 eV, 600 µA)
HR: (ber./gef.): 290.1010 / 290.1021
m / z = 290 (M ⁺ ), 27 6, 248, 220, 200, 185, 155, 139, 113, 79, 57
IR:
(Film, cm ^-1 )
3339, 3061, 2922, 2361, 1732, 1584, 1424, 1341, 1160, 1088, 1036, 953, 927, 870

Example 5 Reduction of the octenic acid ester (11) to the saturated valeric acid ester (12) (process stage f)

90 mg (0.31 mmol) of the unsaturated ester (11) obtained according to Example 4 were dissolved in 10 ml of tetrahydrofuran (THF) and 400 mg (4.3 equivalents) of triisopropylbenzenesulfonic acid hydrazide (TPSH) were added. The THF was heated to boiling under reflux conditions. The reaction was terminated after 6 hours. The reaction mixture was diluted with 30 ml of diethyl ether and shaken with 10 ml of saturated sodium carbonate solution. The aqueous phase was extracted twice with 20 ml ether. The combined organic phases were washed with 10 ml of saturated sodium chloride solution and dried over sodium sulfate: the solvent was distilled off in vacuo and the crude product was purified by flash chromatography: stationary phase: 20 g of silica gel 60, mobile phase: hexane / ethyl acetate 1: 5.
Yield: 16 mg of the reduced ester (12) (18% of theory, based on compound (9)), in addition 22 mg (24%) of the starting compound (11) and 11 mg (approx. 12%) of a mixture of two connections.
Physical properties: colorless oil
DC:
(Hexane / ethyl acetate 1: 3)
R _f = 0.34
¹ H NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 7.24)
δ = 1.22 (t, 3H, J = 7.1 Hz), 1.45 (s, 3H), 1.52 (s, 3H), 1.40-1.73 (m, 6H), 1.76-1.88 (m, 1H), 1.99-2.16 ( m, 1H), 2.29 (t, 2H, J = 7.0 Hz), 2.37-2.51 (m, 2H), 2.78-2.90 (m, 1H), 4.09 (q, 2H, J = 7.1 Hz)
¹³ C NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 77.0)
δ = 14.2, 20.7, 22.7, 24.5, 25.5, 25.6, 26.1, 31.6, 33.9, 51.8, 58.5, 60.3, 173.3
MS:
(EI, 70 eV, 600 µA)
HR: (ber./gef.): 292.1167 / 292.1152
m / z = 292 (M ⁺ ), 247, 201, 165, 149, 123, 81, 55
IR:
(Film, cm ^-1 )
3401, 3104, 2930, 2360, 1734, 1556, 1459, 1404, 1376, 1338, 1183, 1105, 1045, 869, 442, 418

Example 6 Preparation of methyl lipoate (process stage g)) Preparation of the methanolic HCl solution

0.42 ml of acetyl chloride was added to 3 ml of anhydrous methanol Dropped ice cooling. The solution was stirred slowly and was closed with a piercing cap. After adding the Acetyl chloride was stirred for a few more minutes at room temperature and immediately use the manufactured solution.

16 mg (0.055 mmol) of the ester (12) from Example 5 were dissolved in 3 ml of 2 molar methanolic HCl solution and slowly stirred at room temperature for 2.5 hours. The reaction vessel was sealed with a piercing cap to prevent the escape of HCl gas. 5 ml of water were added to the reaction mixture, and 20 ml of ether were added. It was neutralized with 8 ml of saturated sodium carbonate solution and extracted with 10 and 5 ml of ether. The combined organic phases were washed with 7 ml of saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed in vacuo.
Yield: 12 mg (approx. 100% of theory) of methyl lipoate.
Physical properties: yellow oil
DC:
(Hexane / ethyl acetate 6: 1)
R _f = 0.53
¹ H NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 7.24)
δ = 1.38-1.73 (m, 6H), 1.82-1.95 (m, 1H), 2.30 (t, 2H, J = 7.3 Hz), 2.38-2.50 (m, 1H), 3.04-3.21 (m, 2H), 3.49-3.60 (m, 1H), 3.65 (s, 3H, OCH ₃ )
¹³ C NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ 77.0)
δ = 24.7, 28.7, 33.8, 34.6, 38.5, 40.2, 51.5, 56.3, 173.8
MS:
(EI, 70 eV, 600 µA)
HR: (ber./gef.): 220.0592 / 220.0599
m / z = 220 (M ⁺ ), 189 (M ⁺ - OCH ₃ ), 155, 123, 81, 55
IR:
(Film, cm ^-1 )
2930, 1735, 1654, 1559, 1437, 1201, 448, 419, 402

Example 7 Production of the end product lipoic acid by hydrolysis (Process stage g))

118 mg (0.54 mmol) of methyl lipoate, which were obtained in accordance with Example 6, were dissolved in 15 ml of methanol and enough water was added until a slight turbidity occurred (about 15 ml); then 155 mg (1.1 mmol) of potassium carbonate were added and the mixture was stirred for 5 hours. Then 35 ml of water and 35 ml of dichloromethane were added and acidified with half-concentrated hydrochloric acid (pH approx. 2-3). The phases were separated and the aqueous phase was extracted twice with 35 ml dichloromethane each time. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator.
Yield: 107 mg (97% of theory) of lipoic acid.
Physical properties: yellow crystalline solid
Melting point: 60-62 ° C
DC:
(Hexane / ethyl acetate 3: 1)
R _f = 0.32
¹ H NMR:
(CDCl ₃ , 300 MHz, CDCl ₃ : δ = 7.24)
δ = 1.38-1.55 (m, 2H), 1.56-1.7 4 (m, 4H), 1.89 (m, 1H), 2.36 (t, 2H, J = 7.3 Hz), 2.44 (m, 1H), 3.04-3.22 (m, 2H), 3.55 (br m, 1H), 11.2-11.8 (br s, 1H, COOH)
¹³ C NMR:
(CDCl ₃ , 250 MHz, CDCl ₃ : δ = 77.0)
δ = 24.2, 28.4, 33.6, 34.4, 38.3, 40.0, 56.1, 179.8
MS:
(EI, 70 eV, 600 µA)
m / z = 206 (M ⁺ ), 173 (M ⁺ - HS), 155, 141, 123, 81
IR:
(Film, cm ^-1 )
2928, 2865, 1693, 1466, 1429, 1323, 1285, 1079, 947, 734, 422

Claims (38)

1. A process for the multi-stage production of α-lipoic acid using 1,3-dithians, characterized in that a) in a first process step 1,3-propanedithiol with an aldehyde or ketone compound (1) of the general formulas


wherein each R ¹ and R ² independently of one another are hydrogen, a C _1-3 alkyl, phenyl or a halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono- or bis (C _1-3 -alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or where R ¹ and R ² together form a - (CH ₂ ) form _n - ring with n = 1-5, R is C _1-3 alkyl, C _1-3 acyl, trifluoroacetyl, benzyl or berizoyl, R '= H, C _1-3 alkyl or benzyl and X = O or S, in the presence of a Lewis acid catalyst (2), then a) optionally after cleaning, the 1,3-dithiane compound (3) obtained from process step a) with an oxidizing agent (4) to give a 1,3-dithiane-1-oxide (5) of the general formula II)


wherein R ¹ and R ^{2 have} the meaning given, oxidized, subsequently a) the 1,3-dithiane-1-oxide (5) of the general formula II obtained from b) in the presence of a Lewis or Brönstedt base (6) on acrolein to give the corresponding allyl alcohol (7) of the general formula III)


where R ¹ and R ^{2 have} the meaning given, added, following a) the allyl alcohol (7) of the general formula III from stage c) with Lewis or Brönstedt acid (8) catalysis with an orthoester (9)
CH ₃ C (OR ³ ) ₃
to the allyl acetal (10) of the general formula IV)


in which R ¹ and R ^{2 have} the meaning given and R ³ each denotes C _1-3 alkyl, then a) the allyl orthoester (10) of the general formula IV at temperatures between 60 and 145 ° C to the octenoic acid compound (11) of the general formula V)


wherein R ¹ , R ² and R ^{3 have} the meaning given, can react further, b) the octenic acid compound (11) of the general formula V obtained from e) to give a 1,3-dithiane-1-oxide-6-valeric acid ester (12) of the general formula VI)


in which R ¹ and R ² and R ^{3 have} the meaning given, reduced, thereon a) the valeric acid ester (12) of the general formula VI for α-lipoic acid


solvolysis, and finally a) the product α-lipoic acid isolated and optionally purified. 2. The method according to claim 1, characterized in that as the aldehyde or ketone compound (1) acetone, cyclopentanone, cyclohexanone, 2,2-dimethoxypropane, 1,3-dithiane, benzaldehyde or hexafluoroacetone or camphor, menthone and fenchone, preferably in enantiomerically pure Form, or physiologically acceptable compounds, such as. B. anisaldehyde, (o) vanillin, pyridoxal (vitamin B ₆ ), are used, particularly preferably in chiral, non-racemic form. 3. The method according to any one of claims 1 or 2, characterized characterized in that as a Lewis acid catalyst (2) boron trifluoride Etherate or an acidic ion exchange resin such as e.g. B. Amberlyst®, is used. 4. The method according to any one of claims 1 to 3, characterized in that process step a) in alcoholic solution, preferably in methanolic solution. 5. The method according to any one of claims 1 to 4, characterized in that process stage a) at temperatures <20 ° C, preferably in Temperature range between -5 and + 5 ° C, is executed. 6. The method according to any one of claims 1 to 5, characterized in that that in process step b) as oxidizing agent (4) performic acid, Peracetic acid or an aqueous hydrogen peroxide solution is used become. 7. The method according to any one of claims 1 to 6, characterized in that that process step b) at temperatures between 0 and 25 ° C. is carried out. 8. The method according to any one of claims 1 to 7, characterized in that as Lewis or Brönstedt base (6) lithium diisopropylamide or n- Butyllithium can be used. 9. The method according to any one of claims 1 to 8, characterized in that process stage c) at temperatures between -85 ° C and + 15 ° C is carried out. 10. The method according to any one of claims 1 to 9, characterized in that freshly cleaned, especially absolute and polymer-free acrolein is used. 11. The method according to any one of claims 1 to 10, characterized characterized in that following process stage b) and / or Process step c) a diastereomer separation, preferably by Chromatography or crystallization is carried out. 12. The method according to any one of claims 1 to 11, characterized characterized in that in process stage d) as Lewis or Brönstedt Acid (8) propionic or hexanoic acid is added. 13. The method according to any one of claims 1 to 12, characterized in that in process step d) a C _1-6 ortho ester (9), preferably based on acetic acid, particularly preferably triethyl orthoacetate, or a benzyl ortho ester based on acetic acid is used. 14. The method according to any one of claims 1 to 13, characterized characterized in that process steps c) and / or d) with toluene, Xylene, isomeric xylenes and / or isomeric mesitylene as a solvent be performed. 15. The method according to any one of claims 1 to 14, characterized characterized in that process steps c) and / or d) in Presence of n-propanoic acid, preferably in catalytic amounts, be performed. 16. The method according to any one of claims 1 to 15, characterized characterized in that the reaction temperature in process step e) between 70 and 120 ° C and particularly preferably between 100 and 110 ° C. 17. The method according to any one of claims 1 to 16, characterized characterized in that in process step f) as a reducing agent Diimine, which is particularly preferably generated in situ, is used. 18. The method according to claim 17, characterized in that the diimine from hydrazine, chloramine, aminosulfonate, potassium azodicarboxylate, p-toluenesulfone hydrazide or 2,4,6-Triisopropylbenzenesulfonsäurehydrazid is released. 19. The method according to any one of claims 1 to 18, characterized characterized in that process step f) at temperatures between 50 and 140 ° C, preferably between 80 and 110 ° C, is carried out. 20. The method according to any one of claims 1 to 19, characterized characterized in that process stage g) in acid, preferably alcoholic solution, particularly preferably in a methanolic solution Hydrochloric acid solution with pH values between 2.5 and 6.5 becomes. 21. The method according to claim 20, characterized in that the Acid solution is generated in situ, especially from acetyl chloride and Methanol. 22. The method according to any one of claims 1 to 21, characterized characterized in that in process stage g) of solvolysis Hydrolysis step upstream or downstream, which is particularly in Presence of cesium or potassium carbonate in aqueous methanol he follows. 23. The method according to any one of claims 1 to 22 that one for Purification in process step h) the crude α-lipoic acid or a salt thereof in aqueous solution, preferably with a pH between 7.5 and 16.0, then dissolves any solid impurities separates, the aqueous solution obtained to a pH between -1.0 and 5.0 and the precipitated α-lipoic acid isolated and dries. 24. Compound of the general formula A


in racemic or diastereomerically pure form, in which R ¹ and R ^{2 are} each independently hydrogen, a C _1-3 alkyl, phenyl or a halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, is mono- or bis (C _1-3 -alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or in which R ¹ and R ² together form a - (CH ₂ ) _n ring with n = 1-5, and any mixtures of their diastereomers. 25. Compound of the general formula B


in racemic or diastereomerically pure form, in which R ¹ and R ^{2 are} hydrogen, a C _1-3 alkyl, phenyl or a halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono- or bis (C _1-3 -alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or in which R ¹ and R ² together form a - Form (CH ₂ ) _n ring with n = 1-5 and R = H, a C _1-3 alkyl, C _1-3 acyl or corresponding aryl substituted C _1-3 alkyl or C _1-3 acyl, mean in particular acetyl, trifluoroacetyl, benzyl or berizoyl, and any mixtures of their diastereomers. 26. A compound according to claim 25, characterized in that it was obtained by reacting a compound of the general formula


wherein R ¹ , R ² and R have the meaning given, with an alkylating or acylating agent such as. As methyl bromide, trifluoroacetic acid chloride or benzoyl chloride. 27. Compound of the general formula C


in racemic or diastereomeric form, in which R ¹ and R ^{2 are} each independently hydrogen, a C _1-3 alkyl, phenyl or a halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono- or bis (C _1-3 -alkyl) amino-substituted phenyl, a 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl, or in which R ¹ and R ² together form a - (CH ₂ ) _n ring with n = 1-5 and in which R ^{3 represents} hydrogen, a C _1-6 alkyl or benzyl, and any mixtures of their diastereomers. 28. Compound of the general formula D


in racemic or diastereomeric form, in which R ¹ and R ² each independently of one another are hydrogen, a C _1-3 alkyl, a phenyl or halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono- or bis (C _1-3 -alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or in which R ¹ and R ² together form a - (CH ₂ ) _n ring with n = 5 and R ^{3 represents} hydrogen, a C _1-6 alkyl or benzyl, and any mixtures of their diastereomers and / or their cis to the C = C double bond or transient isomers. 29. Compound of the general formula E.


in racemic or diastereomeric form in which R ¹ and R ^{2 are} each independently hydrogen, a C _1-3 alkyl, phenyl or halogen, C _1-3 alkyl, C _1-3 alkoxy, amino, mono - or bis (C _1-3 -alkyl) amino-substituted phenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-6-hydroxymethyl-3-methyl-4-pyridyl or benzyl or in which R ¹ and R ² together form a - (CH ₂ ) _n ring with n = 1-5 and R ^{3 represents} hydrogen, C _1-6 alkyl or benzyl, and any mixtures of their diastereomers. 30. Compounds of claims 24 to 29, characterized in that they have been produced by a method of claims 1 to 23. 31. Use of a compound according to claims 24 to 30 for Synthesis of racemic (±) -α-lipoic acid or enantiomerically pure R - (+) - or S - (-) - α-lipoic acid or any mixtures thereof. 32. Use of the producible according to one of claims 1 to 23 α-Lipoic acid as a food supplement, in medicines and / or in cosmetics. 33. Use according to claim 32 for oral, dermal, parenteral, rectal, vaginal or topical application purposes. 34. Use according to one of claims 32 or 33 in gels, semi-solid dosage forms or solid solutions. 35. Use of a compound according to claims 27 to 29 for in- vivo release of physiologically active 3-substituted 1,2-dithiolanes and a neutral or physiologically active Aldehyde or ketone. 36. Use according to claim 35 as a dietary supplement, in Medicines and / or in cosmetics. 37. Use according to one of claims 35 or 36 for oral, dermal, parenteral, rectal, vaginal or topical Application purposes. 38. Use according to one of claims 35 to 37 in gels, semi-solid Dosage forms or fixed solutions.