CN1980883B - Process for preparing optically active alkyl succinic acid monoalkyl esters - Google Patents

Abstract

The invention relates to a method for producing optically active alkyl succinic acid monoalkyl esters of formula , wherein D and E are H, C independently of one another₁-C₁₀Alkyl, R is C₁-C₁₀Alkyl, aryl or alkylaryl.

Description

Method for preparing optically active monoalkyl succinate

The present invention relates to a new method for preparing monoalkyl optically active alkyl succinates.

current technology

To date, a route to the direct and selective formation of type III systems and their optical antipodes from their directly unsaturated precursors by asymmetric hydrogenation has not been satisfactorily obtained.

This can be demonstrated, for example, by the preparation of (2R)-methylsuccinic acid 4-methyl ester 4 from itaconate monomethyl ester 3, which is readily available at low cost.

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

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

S. Saito, Y. Nakamura, Y. Morita, Chem. Pharm. Bull. 1985, 33, 5284 obtained 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.

Therefore, without an additional enrichment step, the optical purity achieved by the above method cannot meet the requirements in terms of active ingredients, which in most cases require an enantiomeric excess ≥ 98% ee.

Other methods that can achieve higher optical purity use a large amount of catalyst, that is, a low substrate/catalyst ratio (s/c), which is not economical for industrial production; or the selected reaction conditions (especially the solvent) from It is problematic from an environmental perspective or for reasons of occupational safety.

M. Ostermeier, B. Brunner, C. Korff, G. Helmchen, Eur. J. Org. Chem. 2003, 3453 Obtained compound 4 with 97.3% ee at s/c ratio of 200/1 in dichloromethane, In C ₆ H ₅ CF ₃ , 98.3% ee was also achieved with a s/c ratio of 200/1. In dichloroethane, a purity of 99.3% ee was achieved at a s/c ratio of 1000/1.

For the reasons mentioned above, all these methods are not suitable for direct one-step synthesis of optically active alkyl succinates on an industrial scale from olefinic precursors that are readily available at low cost.

purpose of invention

The object of the present invention is to provide a new method for preparing optically active alkyl succinic acid monoalkyl esters, which uses a small amount of catalyst (s/c≥20,000/1), and has reaction conditions coordinated with the environment, complete reaction conversion and high optical yield (≥98%ee), thus enabling efficient, environmentally acceptable, cost-effective industrial synthesis.

Contents of the invention

We have found a method for the preparation of optically active monoalkyl alkyl succinates of formula (I),

wherein D and E are independently of each other H, C ₁ -C ₁₀ alkyl,

R is C ₁ -C ₁₀ alkyl, aryl or alkylaryl,

The method is in the presence of a catalyst comprising a formula (L) phospholane ligand (phospholane ligand),

(L)

in:

R ¹ and R ² are independently of each other C ₁ -C ₆ alkyl, aryl, alkylaryl,

^R is additionally hydrogen,

A for R ¹ or

with the proviso that B=linker (Iinker) or Cp-Fe-Cp with 1-5 carbon atoms between two P atoms,

Enantioselective hydrogenation of compounds of formula (II):

wherein D, E and R have the meanings indicated above.

The compounds of formula (I) are optically active compounds which represent in each case one enantiomer (R or S).

Enantioselective hydrogenation is used hereinafter to refer to a hydrogenation which does not yield the two enantiomers to the same extent, one of the enantiomers (R or S) in high purity, especially in the enantiomer Excesses of 98%, 99%, 99.5% purity were formed.

Starting compounds of formula (II) are known from the literature and can be easily prepared by conventional methods (for D=E=H; R=Me, see e.g. A.R. Devi, S. Rajaram, Ind. J. Chem. 2000, 39B , 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). Preferred starting compounds (II) are those in which D and E independently of one another have the following meanings: H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl radical, decyl, wherein said alkyl includes unbranched and branched isomers. Particularly preferred starting compounds are those in which D and E are H and methyl, especially 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 group R can be a C ₁ -C ₁₀ alkyl group, wherein each H atom in the alkyl group can in turn be substituted by other groups such as OH, NH ₂ , NO ₂ , CN, F, Cl, Br, I. In addition, R can also be an aryl group such as phenyl, naphthyl; and an alkylaryl group such as benzyl, wherein the aryl group can be further substituted. Preferred R are methyl, ethyl, propyl, isopropyl and tert-butyl. R is particularly preferably methyl.

The catalyst comprises metal atoms selected from Pd, Pt, Ru, Rh, Ni, Ir. Particularly preferred catalysts have Rh, Ru or Ir as the metal atom, and Rh catalysts are particularly suitable for the process according to the invention.

Metal sources which may preferably be used in the preparation of the catalyst are precursors such as _Pd2 (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 = unsubstituted and substituted aryl, [Ir(COD)Cl] ₂ , [Ir(COD) ₂ ]X, Ni(allyl)X. Preference is also given to substituting NBD (=norbornadiene) for COD (=1,5-cyclooctadiene).

X in these cases can be any anion known to the person skilled in the art and available for asymmetric synthesis. Examples of X are halogens such as Cl ⁻ , Br ⁻ , I ⁻ , BF ₄ ⁻ , ClO ₄ ⁻ , SbF ₆ ⁻ , PF ₆ ⁻ , CF ₃ SO ₃ ⁻ , BAr ₄ ⁻ . X is preferably BF ₄ ⁻ , CF ₃ SO ₃ ⁻ , SbF ₆ ⁻ , ClO ₄ ⁻ , especially BF ₄ ⁻ and CF ₃ SO ₃ ⁻ .

The catalyst of the process according to the invention additionally comprises one or more phospholane ligands of the formula (L). Preferred substituents ^R1 and ^R2 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.

Also preferred are R ¹ groups in which two R ¹ form a bridge, such as isopropylidene or benzylidene.

In the case of diphospholanes, preferred are those represented by the following formulae.

Particularly preferred linkers B are those in which n=1 or 2 or m=0.

Particularly preferred ligands L are those in which A represents a further phospholane residue and a linker B, in which B may represent a bridge of 1 to 5 carbon atoms between two phosphorus atoms. Said 1-5 carbon atoms between two phosphorus atoms does not mean that B contains at most 5 carbon atoms, but that the direct link between two phosphorus atoms contains no more than 5 carbon atoms. B can be, for example, a benzene ring, provided that two phosphorus atoms are attached to the benzene ring in the para position.

However, the linker B can also be a ferrocene-type compound consisting of a substituted or unsubstituted cyclopentadienyl group (Cp) containing Fe atoms in a sandwich form (Cp-Fe-Cp), where the P atoms bond Junction to Cp base.

Particularly preferred ligands L are:

The present invention includes not only the enantiomers represented by these structural formulas but also their optical antipodes.

For the preparation of Rophos catalysts, reference is made to EP 0889048, which is hereby incorporated by reference.

Ligand-metal complexes can be synthesized by including labile ligands such as [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-methylcymene ruthenium chloride dimer) rhodium, iridium, ruthenium, palladium, platinum, nickel complex reaction Synthesis of catalytically active complexes in a known manner material preparation. NBD can also be used to prepare complexes instead of COD, with good results.

As is known to those skilled in the art, complexes (=precatalysts) can be generated and isolated prior to use and then used in time, or generated in situ in the reaction vessel prior to the actual hydrogenation (see below).

Suitable solvents are all solvents known to the person skilled in the art for asymmetric hydrogenations. Preferred solvents are lower alkyl alcohols such as methanol, ethanol, isopropanol and toluene, THF, ethyl acetate. Methanol is particularly preferably used as solvent in the process of the invention.

The hydrogenation according to the invention is usually carried out at a temperature of -20°C to 150°C, preferably 0-100°C, particularly preferably 10-80°C.

The process of the invention employs in each case a substrate/catalyst ratio (s/c) of >20,000/1, resulting in >98% ee. Even with a s/c ratio of 110,000/1, 98% ee was achieved.

The use of the catalyst can be further simplified by suitably immobilizing the catalyst.

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

The reaction mixture is worked up using procedures well known to those skilled in the art. The product can, for example, be converted to the carboxylate, precipitated and thus removed from the catalyst, and then released again; an alternative possibility is to immobilize the catalyst on a bed by adsorption, which enables easy chromatographic purification. The catalyst can also be removed from the product by distillation.

The enantiomeric excess can be increased to >99.5% by intermediate conversion of the product to the carboxylate and simple precipitation from the reaction mixture. Suitable bases for this are all bases known to the person skilled in the art, among which amines and guanidines are preferred as neutral bases and carboxylates, carbonates, hydroxides, oxides as metallic bases. Particularly preferred metal bases are the corresponding lithium compounds.

Other preferred embodiments are described in the appended claims and the experimental section.

Experimental part

Example 1

Preparation of optically active methyl methyl succinate (s/c 20,000/1)

133 mg (0.182 mmol) (RophosARhCOD) CF ₃ SO ₃ (=prefabricated catalyst) were introduced under protective gas into 21 ml methanol in a 4 liter (enamel) Pfaudler autoclave and 526 g (3.65 mol ) 4-monomethyl 2-methylenesuccinate (=substrate). Hydrogenation is then carried out at 40° C. and 5 bar hydrogen. Substrate conversion was complete after 4 hours ( ¹ H-NMR, 500 MHz). The enantioexcess of the product (2R)-methylsuccinate 4-monomethyl ester determined by gas chromatography>98% (source: BGB-Analytik, column type: BGB-174, length 30m, internal diameter: 0.25ml, film thickness: 0.25 μm, carrier gas: helium, inlet pressure: 2.35 bar, temperature: 135 °C, heating rate: 1.2 °C/min, retention time of R enantiomer: 23.3 min, retention time of S enantiomer: 22.6 min). The s/c ratio was 20,000:1.

Example 2

Preparation of optically active methyl methyl succinate (s/c 40,000/1)

The reaction described in Example 1 was carried out at a catalyst/substrate ratio s/c of 40,000:1. Substrate conversion was complete after 4 hours. The enantiomeric excess of the product was >98%.

Example 3

Preparation of optically active methyl methyl succinate (s/c 110,000/1)

5.73 g (39.8 mmol) of 4-monomethyl 2-methylenesuccinate were introduced into 12 ml of methanol in a 50 ml glass autoclave under protective gas and 0.12 ml of 6.6 mg (RophosARhCOD) CF ₃ SO was added Solution of ₃ (=pre-catalyst) in 3 ml methanol (0.00036 mmol pre-catalyst). Hydrogenation is then carried out at 60° C. under 5 bar hydrogen. The conversion of the precursor was complete after 16 hours. The enantiomeric excess of the product is 98%.

Example 4

Preparation of optically active methyl methyl succinate on an industrial scale followed by lithium salt formation

75 kg of 4-monomethyl methylenesuccinate (520.4 mol) were introduced into 185 liters of methanol in a 1 m ³ steel vessel under protective gas. 19.0 g of (RophosARhCOD)CF ₃ SO ₃ (=26 mmol of prefabricated catalyst, s/c 20,000/1 ) dissolved in 2 liters of methanol were added, followed by hydrogenation at 50° C. under 4 bar of hydrogen. Substrate conversion was complete after 4 hours. The enantiomeric excess of the hydrogenated product was determined to be 99.4% by chiral HPLC (manufacturer of column: Chiracel; column type: OD-H; mobile phase: 95vol% n-heptane/5vol% 2-propanol-0.1ml Tris Fluoroacetic acid/1L of the mixture; retention time:

t _R ((R)-4-methyl 2-methylsuccinate) = 7.4 minutes

t _R ((S)-4-methyl 2-methylsuccinate) = 16.7 minutes).

To the reaction solution, a total of 22.2 kg of lithium hydroxide monohydrate was added in portions, followed by 375 kg of methyl tert-butyl ether, and cooled to 0°C. Lithium carboxylate was removed from the obtained suspension by filtration (yield: 65.8 kg). Its enantiomeric excess (determined after release) is >99.8%.

Example 5

On-site preparation of prefabricated catalysts (general procedure)

Dissolve 1.1 equivalent of RophosA-Bistriflate salt (Rophos*2CF ₃ SO ₃ H) and 1.1 equivalent of base (preferably amine such as triethylamine, Hünig's base, etc.) in methanol, and slowly drop into 1 equivalent of metal at -10°C source, preferably a solution of (Rh[COD] ₂ )X, where X=BF ₄ , CF ₃ SO ₃ , SbF ₆ , PF ₆ , ClO ₄ , BAr ₄ . The mixture was then allowed to reach room temperature. If free ligand is used, no base is added.

Claims (17)

1. the method for a preparation formula (I) optically active alkyl succinic acid monoalkyl esters,

Wherein D and E are H, C independently of one another ₁-C ₁₀Alkyl,

R is C ₁-C ₁₀Alkyl, phenyl or benzyl,

This method in the presence of the catalyzer that comprises formula (L) phospholane part,

Wherein:

R ¹Be hydrogen, C ₁-C ₆Alkyl or benzyl,

R ²Be C ₁-C ₆Alkyl or benzyl,

A is R ¹Or

Condition be B=between two P atoms, have 1-5 carbon atom the connection base or

Cp-Fe-Cp，

Enantioselectivity ground hydrogenation of formula (II) compound

Wherein D, E and R have above-mentioned meaning.

2. the method for claim 1, wherein D and E are that hydrogen and R are Me.

3. the method for claim 1 wherein is selected from part among Rophos A, the Rophos B as part (L):

4. the method for claim 1, wherein said hydrogenation is carried out under the hydrogen pressure of 1-100 crust.

5. the method for claim 1, wherein said hydrogenation is carried out in methyl alcohol.

6. the method for claim 1, wherein said hydrogenation is carried out under 10 ℃-80 ℃.

7. the method for claim 1, use therein catalyzer is fixed.

8. the method for claim 1, wherein the reaction product that is obtained by hydrogenation (I) is converted into carboxylate salt and removes from this reaction mixture with this form.

9. method as claimed in claim 8, wherein said reaction product (I) precipitates from this reaction mixture with the form of carboxylic acid lithium.

10. the method for a preparation formula (I) optically active alkyl succinic acid monoalkyl esters,

Wherein D and E are H, C independently of one another ₁-C ₁₀Alkyl,

R is C ₁-C ₁₀Alkyl, phenyl or benzyl,

This method in the presence of comprising the catalyzer that is selected from the part among Me-KetalPhos and the Me-f-KetalPhos,

Enantioselectivity ground hydrogenation of formula (II) compound

Wherein D, E and R have above-mentioned meaning.

11. method as claimed in claim 10, wherein D and E are that hydrogen and R are Me.

12. method as claimed in claim 10, wherein said hydrogenation is carried out under the hydrogen pressure of 1-100 crust.

13. method as claimed in claim 10, wherein said hydrogenation is carried out in methyl alcohol.

14. method as claimed in claim 10, wherein said hydrogenation is carried out under 10 ℃-80 ℃.

15. method as claimed in claim 10, use therein catalyzer is fixed.

16. method as claimed in claim 10, wherein the reaction product that is obtained by hydrogenation (I) is converted into carboxylate salt and removes from this reaction mixture with this form.

17. method as claimed in claim 16, wherein said reaction product (I) precipitates from this reaction mixture with the form of carboxylic acid lithium.