EP1765763A2

EP1765763A2 - Method for the production of optically active alkyl succinic acid monoalkyl esters

Info

Publication number: EP1765763A2
Application number: EP05772382A
Authority: EP
Inventors: Frank Hettche; Christoph JÄKEL; Marko Friedrich; Rocco Paciello
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2004-07-07
Filing date: 2005-07-06
Publication date: 2007-03-28
Also published as: WO2006002999A2; JP2008505152A; US7557240B2; WO2006002999A3; US20080058547A1

Abstract

The invention relates to a method for producing optically active alkyl succinic acid monoalkyl esters of formula (I), wherein D and E independently represent H, C1-C10 alkyl, RC1-C10 alkyl, aryl, or alkylaryl.

Description

Process for the preparation of optically active alkyl succinic acid monoalkyl esters.

description

The invention relates to a novel process for the preparation of optically active alkyl-succinic acid monoalkyl esters.

State of the art

Direct selective access to Type III systems or their optical antipodes

R, R 1 = alkyl, aryl, arylalkyl via an asymmetric hydrogenation starting from their directly unsaturated precursors has not yet been satisfactorily resolved.

This is evident, for example, in the preparation of (2R) -methylsuccinic acid 4-methyl ester 4 from inexpensive, readily available monomethyl itaconate 3.

H ₂ , chiral cat ^* solvent

3 4

K. Achiwa, Y. Ohga, Y. Itaka, Tetrahedron Lett. 1978, 19, 4683 give compound 4 with 60% enantiomeric excess (= ee = [content of enantiomer 1 content enantiomer 2} / [content of enantiomer 1 + enantiomer 2]) in methanol.

W.C. Christopheel, B.D. Vineyard, J. Am. Chem. Soc. 1979, 101, 4406 give compound 4 with 55% ee in methanol.

S. Saito, Y. Nakamura, Y. Morita, Chem. Pharm. Bull. 1985, 33, 5284, obtain 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, JM 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 gives compound 4 with 94% ee in methanol.

U. Berens, M. Burk, A. Gerlach (WO 00/27855, EP 1 127 061 B1) obtain compound 4 with 95% ee in methanol.

The optical purity achieved in the processes cited does not therefore meet the requirements in the active substance range without additional enrichment steps, which in most cases require an enantiomeric excess of ≥98% ee.

Other processes that result in higher optical purity use either high amounts of catalyst, i. a low substrate / catalyst ratio (s / c), which is uneconomical for industrial production, or it reaction conditions (especially solvents) are selected, which are problematic from an environmental point of view or for reasons of safety at work.

M. Ostermeier, B. Brunner, C. Korff, G. Heimchen, Eur. J. Org. Chem. 2003, 3453, obtained compound 4 at a s / c ratio of 200/1 with 97.3% ee in dichloromethane, in C ₆ 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.

From the o.g. All these methods are not suitable for a one-step direct synthesis of optically active succinic acid alkyl esters from their cheap, readily available olefinic precursors on an industrial scale.

task

It is an object of the present invention to provide a novel process for preparing optically active alkylsuccinic acid monoalkyl esters which, at low catalyst amounts (s / c ≥20,000 / 1) and at the same time environmentally acceptable reaction conditions, achieve complete reaction conversion and high optical yield (≥ 98% ee), so that it allows an efficient, environmentally sound, cost-effective technical Syn¬ thesis.

Description of the invention

A process has been found for the preparation of optically active alkylsuccinic acid monoalkyl esters of the formula (I)

where D and E, independently of one another, denote H, C ₁ -C ₁₀ -alkyl, RC ₁ -C ₁₀ -alkyl, aryl or alkylaryl,

by dissolving a compound of the formula (II)

where D ₁ E and R have the abovementioned meanings,

in the presence of a catalyst bearing a phospholane ligand of formula (L),

R ²

(L) where:

R ¹ and R ² independently of one another are C ₁ -C ₆ -alkyl, aryl, alkylaryl, R ¹ furthermore 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 an enantiomer (R or S).

Enantioselective hydrogenation is to be understood below to mean that not both enantiomers are formed 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 % is formed.

The starting compounds of the formula (II) are known from the literature and can easily be prepared by customary methods (for D = E =H; R = Me see, for example, AR Devi, S. Rajaram, Ind. J. Chem. 2000, 39B, 294-296 or RC Anand, VA Milhotra, J. Chem. Res. (S) 1999, 378-379 or RN Ram, I. Charles, Tetrahedron 1997, 53, 7335-7340). Preferred starting compounds (II) are those in which D and E, independently of one another, have the meaning H, methyl, ethyl, propyl, butyl, pentyl, hexyl, tert-butyl, octyl, nonyl, decyl, the alkyl designation being both unbranched and the branched isomers. Particular preference is given to those starting compounds in which D and E are H and methyl, in particular those in which D and E are H or D and E are methyl. Further preferred starting compounds (II) are those in which D is H and E is butyl.

The radical R can be C _r Ci ₀ - alkyl, in which individual H atoms of the alkyl radical in turn by further radicals such as OH, NH _2, NO _2, CN, F, Cl, Br, J, may be replaced. 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 the metal atom, in particular Rh catalysts are suitable for the inventive method.

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 are preferably used. Instead of COD (= 1,5-cyclooctadiene), NBD (= norbornadiene) can also be used.

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

Furthermore, the catalysts of the process according to the invention contain one or more phosphoan 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 case of diphospholanes, those are preferred in which

Particular preference is given to those bridge members B in which 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 is a bridge of 1 to 5 C atoms.

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 does not comprise more than 5 C atoms. For example, B may be a phenyl ring if the two P atoms are ortho attached to it.

However, bridging compound B may also be a ferrocene-type compound consisting of substituted or unsubstituted cyclopentadienyl radicals (Cp) sandwiching an Fe atom (Cp-Fe-Cp), the P atoms being attached to the Cp radicals , Particularly preferred ligands L are:

Rophos B Rophos A

Me-KetalPhos Me-f-KetalPhos

Not only the enantiomers depicted here in the formula but also their optical antipodes are included in the invention.

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

Ligand MetaU Complexes can be prepared by using in a known manner {eg 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, [RuCI ₂ (COD) J _n , [Rh (COD) ₂ ] BF ₄ , [Rh (COD) ₂ ] CF ₃ SO ₃ Rh (COD) ₂ CIO ₄ , [Ir (COD) CI] 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 known to the person skilled in the art, the complex (= precatalyst) can be generated before use, isolated and then used "ready" or generated in situ in the reaction vessel before the actual hydrogenation (see below).

Suitable solvents are all solvents known to those skilled in the art for asymmetric hydrogenation. Preferred solvents are lower alkyl alcohols such as methanol, ethanol, isopropanol, and toluene, THF ₁ ethyl acetate. Particular preference is given to using methanol as solvent in the process according to the invention.

The inventive hydrogenation is generally carried out at a temperature of -20 to 15O ⁰ C, preferably at 0 to 100 ⁰ C and particularly preferably at 10 - leads 8O ⁰ C durchge.

The hydrogenation according to the invention uses substrate / catalyst ratios s / c ≥ 20 000/1 and thereby gives ≥ 98% ee. Even with s / c 110 000/1 an ee of 98% is achieved.

By suitable immobilization of the catalyst, the catalyst consumption can be lowered even further.

The hydrogen pressure can be varied within a wide range between 0.1 bar and 300 bar for the hydrogenation process according to the invention. Very good results are obtained in a pressure range of 1 to 200 bar, preferably 1 to 100 bar.

The work-up of the reaction mixture is carried out by methods known to those skilled in the art. The product may e.g. converted into a carboxylate, precipitated and so separated from the catalyst and then released again, alternatively, the catalyst can also be adsorbed on a bed, which allows easy to carry out chromatographic purification. A distillative removal of the product from the catalyst is also possible.

In the intermediate transfer of the product into the carboxylate and simple precipitation of the same from the reaction mixture, an ee increase to> 99.5% is possible.

All bases known to those skilled in the art are suitable for this purpose, with amines and guanidines being preferred as neutral bases and alkoxylates, carbonates, hydroxides, oxides as metal bases. With the metal bases, the corresponding lithium compounds are particularly preferred.

Further preferred embodiments are described 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 initially introduced under protective gas into a 4 l (enamel) autoclave from Pfaudler, and 526 g (3.65 mol) of 2-methylene-succinic acid were added. 4-monomethyl ester (= substrate) dissolved in 704 ml of methanol was added. The mixture was then hydrogenated at 40 ⁰ C and 5 bar hydrogen. After 4 h, the substrate was fully reacted ( ¹ H NMR, 500 MHz). The enantiomeric excess of the product (2f?) - methyl succinic 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 microns, carrier gas: helium, pressure: 2.35 bar, temperature: 135 ⁰ 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 20,000: 1.

Example 2.

Preparation of the optically active methylsuccinic acid methyl ester (s / c 40000/1)

The reaction described in Example 1 was carried out with a catalyst / substrate ratio s / c of 40000/1. After 4 hours, the substrate was completely reacted. The enantiomeric excess of the product was> 98%. Example 3

Preparation of the optically active methylsuccinic acid methyl ester (s / c 110000/1)

In a 50 ml glass autoclave under protective gas 5.73 g (39.8 mmol) 2

Methylenbernsteinsäure 4-monomethyl ester in 12 ml of methanol and 0.12 ml of a solution of 6.6 mg (RophosARhCOD) CF ₃ S0 ₃ (= pre-catalyst) in 3 ml of Me¬ ethanol added (0.00036 mmol precatalyst). The mixture was then hydrogenated at 6O ⁰ 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 optically active Methylbemsteinsäuremethylesters on an industrial scale, followed by Li salt formation

75 kg of 4-methylenesuccinate (520, 4 mol) in 185 l of methanol were initially introduced under protective gas in a ¹ m ³ steel kettle. After addition of 19.0 g (RophosARhCOD) CF ₃ S0 ₃ (= 26 mmol precatalyst, s / c 20 000/1) in 2 l of methanol was hydrogenated at 50 ⁰ 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 Retention times: t _R ((R) -2-methylsuccinic acid 4-methyl ester) = 7.4 min. F _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 added 375 kg of methyl-Fe / t-butyl ether and cooled to ^{0 0} C ge. From the obtained suspension, the Li-carboxylate was filtered off (yield: 65.8 kg). Its ee (determined after release) was> 99.8%.

Example 5.

Preparation of the precatalyst in situ (general procedure)

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, Hünigbase or similar) dissolved in methanol and at -10 ⁰ C slowly 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 , CIO ₄ , BAr ₄ ) is added dropwise. Subsequently, the mixture is allowed to come to room temperature. When the free ligand is used, the base addition is omitted.

Claims

claims:

1. Process for the preparation of optically active alkylsuccinic acid monoalkyl esters of the formula (I)

where D and E independently of one another are H, C ₁ -C ₁₀ -alkyl,

RC ₁ -C ₁₀ alkyl, aryl or alkylaryl,

by dissolving a compound of the formula (II)

where D ₁ E and R have the abovementioned meanings,

in the presence of a catalyst bearing a phospholane ligand of formula (L),

R ²

IL) ^' where:

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

2. The method according to claim 1, characterized in that D and E hydrogen and R = Me mean.

3. The method according to claim 1, characterized in that a ligand from the group Rophos A, Rophos B, Me-Ketal Phos, Me-f-Ketal Phos is used as ligand (L).

4. The method according to claim 1, characterized in that the hydrogenation is carried out at a hydrogen pressure between 1 and 100 bar.

5. The method according to claim 1, characterized in that the hydrogenation is carried out in methanol.

6. The method according to claim 1, characterized in that the hydrogenation is carried out at a temperature between 10 ⁰ C and 89 ⁰ C.

7. Method) according to claim 1, characterized in that the catalyst used is immobilized. ! ;

8. The method according to claim 1, characterized in that the reaction product obtained in the Hy¬ (I) is converted into a carboxylate and is removed in this form from the reaction mixture.

9. The method according to claim 8, characterized in that the reaction product (I) aus¬ falls in the form of a Li-carboxylate from the reaction mixture.