DE102005007750A1 - Preparation of optically active alkyl succinic acid monoalkyl esters comprising enantioselective hydrogenation of ester compound in presence of catalyst, which carries phospholane ligand - Google Patents

Abstract

Preparation of optically active alkyl succinic acid monoalkyl esters (I) comprises enantioselective hydrogenation of ester compounds (II) in the presence of a catalyst, which carries a phospholane ligand (L). Preparation of optically active alkyl succinic acid monoalkyl esters of formula (I) comprises enantioselective hydrogenation of ester compound of formula (II) in the presence of a catalyst, which carries a phospholane ligand of formula (L). D, E : H or 1-10C alkyl; R : 1-10C alkyl, aryl or alkylaryl; R 2>1-6C alkyl, aryl or alkylaryl; R 1>H or R 2>; A : R 1>or heterocyclic compound of formula (b); and B1 : bridge member with 1-5C between two P-atom or Cp-Fe-Cp. [Image] [Image].

Description

The The invention relates to a novel process for the production of optical active alkyl succinic acid monoalkyl esters.

über eine asymmetrische Hydrierung ausgehend von ihren direkten ungesättigten Vorläufern ist bislang nicht befriedigend gelöst.Direct selective access to Type III systems or their optical antipodes

asymmetric hydrogenation based on its direct unsaturated precursors has not yet been satisfactorily solved.

This shows, for example, in the preparation of (2R) -methylsuccinic acid 4-methyl ester 4 out of cheap easily accessible itaconate Third

• K. Achiwa, Y. Ohga, Y. Itaka, Tetrahedron Lett. 1978, 19, 4683 gives compound 4 with 60% enantiomeric excess (= ee = [content enantiomer 1 - content Enantiomer 2} / [content enantiomer 1 + enantiomer 2]) in methanol.
• W.C. Christopheel, B.D. Vineyard, J. Am. Chem. Soc. 1979, 101, 4406 obtain compound 4 with 55% ee in methanol.
• S. Saito, Y. Nakamura, Y. Morita, Chem. Pharm. Bull. 1985, 33, 5284 gives compound 4 with 90% ee in benzene / MeOH 1/4.
• H. Kawano, Y. Ishii, T. Ikariya, M. Saburi, S. Yoshikawa, Tetrahedron Lett. 1987, 28, 1905 obtained compound 4 with 60% ee in toluene / THF.
• D. Carmichael, H. Doucet, J.M. Brown, Chem. Commun. 1999, 261 H. Kawano, T. Ikariya, Y. Ishii M. Saburi, S. Yoshikawa et al. J. Chem. Soc. Perkin Trans. 1 1989, 1571 obtained compound 4 with 94% ee in methanol.
• U. Berens, M. Burk, A. Gerlach (WO 00/27855; EP 1 127 061 B1 ) obtained Compound 4 with 95% ee in methanol.

The at the listed Process achieved optical purity is sufficient without additional Enrichment steps do not meet the requirements in the field of active substances, which in most cases an enantiomeric excess of ≥ 98% ee demand.

Other processes leading to higher optical purity use either high amounts of catalyst, ie, low substrate / catalyst ratio (s / c), which is uneconomical for industrial production, or reaction conditions (especially solvents) selected from an environmental point of view or are problematic for reasons of safety at work.
M. Easter Meier, B. Brunner, C. Korff, G. Helmchen, Eur. J. Org. Chem. 2003, 3453 obtain Compound 4 at a S / C ratio of 200/1 with 97.3% ee in dichloromethane in the _C6 H ₅ CF ₃ , also at s / c 200/1, achieved an ee of 98.3%. In dichloroethane, a purity of 99.3% ee is achieved at a s / c ratio of 1000/1.

Out the o.g. establish are all these procedures for a one-step direct synthesis of optically active succinic acid alkyl esters from their cheap, easily accessible olefinic precursors on an industrial scale not suitable.

task

It It was therefore the object of a new process for the preparation of optically active Alkylbernsteinsäuremonoalkylestern which can be prepared at low amounts of catalyst (s / c ≥ 20 000/1) and at the same time environmentally friendly Reaction conditions a complete reaction conversion as well high optical yield (≥ 98% ee), making it an efficient, environmentally sound, cost-effective technical synthesis allowed.

description the invention

wobei D und E unabhängig voneinander H, C₁-C₁₀ Alkyl,
R C₁-C₁₀-Alkyl, Aryl oder Alkylaryl bedeuten,
indem man eine Verbindung der Formel (II)

wobei D, E und R die o.g. Bedeutungen besitzen,
in Gegenwart eines Katalysators, der einen Phospholanliganden der Formel (L) trägt,

wobei:
R¹ und R² unabhängig voneinander C₁-C₆-Alkyl, Aryl, Alkylaryl,
R¹ außerdem Wasserstoff,
A entweder R¹ oder

mit B = ein Brückenglied mit 1 – 5 C-Atomen zwischen den beiden P-Atomen oder Cp-Fe-Cp bedeuten. enantioselektiv hydriert.A process has been found for the preparation of optically active alkyl succinic acid monoalkyl esters of the formula (I)

where D and E independently of one another are H, C ₁ -C ₁₀ -alkyl,
R is C ₁ -C ₁₀ -alkyl, aryl or alkylaryl,
by dissolving a compound of the formula (II)

where D, E and R have the abovementioned meanings,
in the presence of a catalyst bearing a phospholane ligand of formula (L),

in which:
R ¹ and R ² independently of one another are C ₁ -C ₆ -alkyl, aryl, alkylaryl,
R ¹ also hydrogen,
A either R ¹ or

where B = a bridge member with 1-5 C atoms between the two P atoms or Cp-Fe-Cp. enantioselectively hydrogenated.

The Compounds of the formula (I) are optically active compounds which are each intended to represent one enantiomer (R or S).

Under enantioselective hydrogenation will be understood below that not both enantiomers to the same extent by the hydrogenation but that one enantiomer (R or S) in high optical Purity, in particular with an ee value of 98, 99, 99.5% formed becomes.

The Starting compounds of the formula (II) are known from the literature and can be easily according to common Methods (for D = E = H; R = Me see, e.g. A.R. Devi, S. Rajaram, Ind. J. Chem. 2000, 398, 294-296 or R.C. Anand, V.A. Milhotra, J. Chem. Res. (S) 1999, 378-379 or R.N. Ram, I. Charles, Tetrahedron 1997, 53, 7335-7340) become. Preferred starting compounds (II) are those in which D and E independent each other is H, methyl, ethyl, propyl, butyl, pentyl, Hexyl, heptyl, octyl, nonyl, decyl, wherein the alkyl name includes both the unbranched and the branched isomers. Especially preferred are those starting compounds in which D and E H and methyl, especially those in which D and E are H and D, respectively and E is methyl. Further preferred starting compounds (II) are those in which D is H and E is butyl.

The radical R may denote C ₁ -C ₁₀ -alkyl, wherein individual H atoms of the alkyl radical may in turn be replaced by further radicals such as OH, NH ₂ , NO ₂ , CN, F, Cl, Br, J. Furthermore, R can also be aryl radicals such as phenyl, naphthyl, and also alkylaryl radicals such as benzyl, where the aryl radicals can also be substituted again. Preferred radicals R are methyl, ethyl, propyl, i-propyl and tert-butyl. Particularly preferred is R = methyl.

The Catalysts consist of a metal atom of the group Pd, Pt, Ru, Rh, Ni, Ir. Particularly preferred are catalysts with Rh, Ru or Ir as a metal atom, in particular Rh are catalysts for the inventive method suitable.

As metal sources for catalyst preparation, precursors such as Pd ₂ (DBA) ₃ , Pd (Oac) ₂ , [Rh (COD) Cl] ₂ , [Rh (COD) ₂ )] X, Rh (acac) (CO) ₂ , RuCl ₂ (COD), Ru (COD) (methallyl) ₂ , Ru (Ar) Cl ₂ , Ar = aryl, both unsubstituted and substituted, (Ir (COD) Cl] ₂ , [Ir (COD) ₂ ] X, Ni (allyl) X can preferably be used Instead of COD (= 1,5-cyclooctadiene), NBD (= norbornadiene) can also be used.

X can be any generally known anion in asymmetric synthesis known to those skilled in the art. Examples of X are halogens, such as Cl ^-, Br ^-, I ^-, BF ₄ -, ClO ₄ -, SbF ₆ -, PF ₆ -, CF ₃ SO ₃ -, BAr ₄ -. Preferred for X are BF ₄ ^- , CF ₃ SO ₃ -, SbF ₆ -, ClO ₄ -, especially BF ₄ - and CF ₃ SO ₃ -.

Furthermore, the catalysts of the process according to the invention contain one or more phospholane ligands of the general formula (L). Preferred substituents R ¹ and R ² are H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl. The substituent combination of R ¹ = H and R ² = methyl is particularly preferred.

Furthermore, those radicals R ^{1 are} preferred in which the two R ^{1 are} bridged, such as isopropylidene or benzylidene.

in the In the case of diphospholanes, those are preferred

Especially preferred are such bridge members B where n = 1 or 2 or m = 0.

Preferred ligands L are those in which A represents a further phospholane residue together with a bridging member B, where B can represent a bridge of 1 to 5 C atoms between the two phosphorus atoms. The expression 1-5 C atoms between the two phosphorus atoms does not mean that B consists of a maximum of 5 C atoms, but that the direct connection between the two P atoms no longer exists as 5 C atoms. For example, B may be a phenyl ring if the two P atoms are ortho attached to it.

The bridge member B can also be a ferrocene-type compound consisting from substituted or unsubstituted cyclopentadienyl radicals (Cp), which sandwich a Fe atom (Cp-Fe-Cp), where the P atoms are bound to the Cp residues.

Particularly preferred ligands L are:

Included in the invention Not only are they here formulaic pictured enantiomers but also their optical antipodes.

For the preparation of Rophos catalysts is on the EP 0 889 048 referenced, the entire contents of which are hereby incorporated by reference.

Ligand-metal complexes can be prepared by reacting in a known manner (for example Uson, Inorg. Chim. Acta 73, 275 1983, EP-A 0158875, EP-A 437690) by reaction with rhodium, iridium, ruthenium, Palladium, platinum; Nickel complexes containing labile ligands (eg, [RuCl ₂ (COD)] _n , [Rh (COD) ₂ ] BF ₄ , [Rh (COD) ₂ ] CF ₃ SO ₃ Rh (COD) ₂ ClO ₄ , [Ir (COD ) Cl] ₂ , p-cymene-ruthenium chloride dimer) catalytically active complexes synthesized. Instead of COD, NBD can also be used successfully for the preparation of the complexes.

As the expert knows the complex (= pre-catalyst) before use generated, isolated and then used "ready" or before the actual hydrogenation in the reaction vessel in situ be generated (s.u).

When solvent are all the specialist for asymmetric hydrogenation known solvents suitable. preferred solvent are lower alkyl alcohols such as methanol, ethanol, isopropanol, as well as toluene, THF, ethyl acetate. Particular preference is given in the inventive method Methanol as solvent used.

The invention Hydrogenation is usually carried out at a temperature of -20 to 150 ° C, preferred at 0 to 100 ° C and more preferably carried out at 10-80 ° C.

The invention Hydrogenation uses substrate / catalyst ratios s / c ≥ 20 000/1 and delivers ≥ 98% ee. Even with s / c 110 000/1 an ee of 98% is achieved.

By a suitable immobilization of the catalyst can be reduce the catalyst consumption even further.

Of the Hydrogen pressure can be in a wide range between 0.1 bar and 300 bar for the hydrogenation process according to the invention be varied. Very good results are obtained in a pressure range from 1-200 bar, preferably 1-100 bar.

The Workup of the reaction mixture is known to those skilled in the art Working methods. The product may e.g. converted into a carboxylate, precipitated and separated from the catalyst and then released again, Alternatively, the catalyst may also be adsorbed on a bed be what an easily feasible allowed chromatographic purification. Also a distillative separation the product of the catalyst is possible.

at the temporary transfer of the Product into the carboxylate and simple precipitation of the same from the reaction mixture is an ee increase to> 99.5% possible.

Come for this all bases known to those skilled in the art, with amines and guanidines as neutral bases and alkoxylates, carbonates, hydroxides, oxides as Metal bases are preferred. Particularly preferred are the metal bases the corresponding lithium compounds.

Further preferred embodiments are in the subclaims and the experimental part.

Experimental part

example 1

Preparation of the optically active methylsuccinic acid methyl ester (s / c 20000/1)

133 g (0.182 mmol) of (RophosARhCOD) CF ₃ SO ₃ (= precatalyst) in 21 ml of methanol were introduced under protective gas into a 4 l (enamel) autoclave from Pfaudler, and 526 g (3.65 mol) of 2-methylsuccinic acid were added. 4-monomethyl ester (= substrate) dissolved in 704 ml of methanol was added. The mixture was then hydrogenated at 40 ° C and 5 bar hydrogen. After 4 h, the substrate was fully reacted ( ¹ H NMR, 500 MHz). The enantiomeric excess of the product (2R) -methylsuccinic acid 4-monomethyl ester was determined by gas chromatography to> 98% (company: BGB analysis, column type: BGB-174, length: 30 m, inner diameter: 0.25 ml, film thickness: 0.25 μm, carrier gas: helium, admission pressure: 2.35 bar, temperature: 135 ° C., heating rate: 1.2 ° C./min, retention time R enantiomer: 23.3 min, retention time S enantiomer: 22.6 min). The s / c ratio was 20000: 1.

Example 2.

Production of the optical active Methylbernsteinsäuremethylesters (s / c 40000/1)

The The reaction described in Example 1 was carried out with a catalyst / substrate ratio s / c carried out by 40000/1. After 4 hours, the substrate was complete implemented. The enantiomeric excess of the product was> 98%.

Example 3

Production of the optical active Methylbernsteinsäuremethylesters (s / c 110000/1)

5.73 g (39.8 mmol) of 2-methylsuccinic acid 4-monomethyl ester in 12 ml of methanol were initially introduced under protective gas in a 50 ml glass autoclave and 0.12 ml of a solution of 6.6 mg (RophosARhCOD) CF ₃ SO ₃ (= Precatalyst) in 3 ml of methanol (0.00036 mmol precatalyst). The mixture was then hydrogenated at 60 ° C and 5 bar hydrogen. After 16 h, the starting material was completely reacted. The enantiomeric excess of the product was 98%.

Example 4

Production of the optical active Methylbernsteinsäuremethylesters on an industrial scale, followed by Li salt formation

75 kg of 4-methylenesuccinate (520, 4 mol) in 185 l of methanol were initially taken under protective gas in a 1 m ³ steel kettle. After addition of 19.0 g (RophosARhCOD) CF ₃ SO ₃ (= 26 mmol precatalyst, s / c 20 000/1) in 2 l of methanol was hydrogenated at 50 ° C and 4 bar hydrogen. After 4 hours, the substrate was completely reacted. The ee of the hydrogenation product was determined by chiral HPLC to be 99.4% (manufacturer column: Chiracel; column type: OD-H; mobile phase: 95% by volume heptane / 5% by volume 2-propanol - to 1 l of this mixture 0.1 ml Trifluoroacetic acid; retention times:
t _R ((R) -2-methylsuccinic acid 4-methyl ester) = 7.4 min
t _R ((S) -2-methylsuccinic acid 4-methyl ester) = 16.7 min).

The reaction solution was added in portions with a total of 22.2 kg of lithium hydroxide monohydrate and then 375 kg of methyl tert-butyl ether and cooled to 0 ° C. From the suspension obtained The Li-Carboxlyat was filtered off (yield: 65.8 kg). Whose ee (determined after release) was> 99.8%.

Example 5.

Preparation of the pre-catalyst in situ (general working instructions)

1.1 eq. Rophos A bistriflate salt (Rophos · 2 CF ₃ SO ₃ H) is treated with 1.1 eq. Amount of base (preferably amines such as triethylamine, Hünig base or similar) dissolved in methanol and slowly added at -10 ° C to a solution of 1 eq. the metal source, preferably (Rh [COD] ₂ ) X with X = BF ₄ , CF ₃ SO ₃ , SbF ₆ , PF ₆ , ClO ₄ , BAr ₄ ) was added dropwise. Subsequently, the mixture is allowed to come to room temperature. When using the free ligand, the base addition is eliminated.

Claims (9)

Process for the preparation of optically active alkyl succinic acid monoalkyl esters of the formula (I)

where D and E independently of one another are H, C ₁ -C ₁₀ -alkyl, R is C ₁ -C ₁₀ -alkyl, aryl or alkylaryl, by reacting a compound of the formula (II)

where D, E and R have the abovementioned meanings, in the presence of a catalyst which carries a phospholane ligand of the formula (L),

wherein: R ¹ and R ^{2 are} independently C ₁ -C ₆ alkyl, aryl, alkylaryl, R ¹ also hydrogen, A is either R ¹ or

where B = a bridge member with 1-5 C atoms between the two P atoms or Cp-Fe-Cp. enantioselectively hydrogenated. Method according to claim 1, characterized in that that D and E are hydrogen and R = Me. Method according to claim 1, characterized in that as ligand (L) a ligand from the group Rophos A, Rophos B, Me-KetalPhos, Me-f-KetalPhos is used. Method according to claim 1, characterized in that that the hydrogenation at a hydrogen pressure between 1 and 100 bar executed becomes. Method according to claim 1, characterized in that the hydrogenation is carried out in methanol. Method according to claim 1, characterized in that the hydrogenation is carried out at a temperature between 10 ° C and 80 ° C. Method according to claim 1, characterized in that that the catalyst used is immobilized. Method according to claim 1, characterized in that that the reaction product (I) obtained in the hydrogenation in a Carboxylate is transferred and is removed from the reaction mixture in this form. Method according to claim 8, characterized in that that the reaction product (I) in the form of a Li-carboxylate from the Reaction precipitated becomes.