DD253995A1 - PROCESS FOR THE PREPARATION OF (R) - AND (S) -PHENYL-ALLANINE AND THEIR DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of (R) - and (S) -phenylalanine and its derivatives by catalytic asymmetric hydrogenation of prochiral unsaturation in the presence of chiral metal complex catalysts. The hydrogenation products are easy to convert to (R) - and (S) -phenylalanine. The prochiral starting materials used are N-acylamino-cinnamic acids or their esters, which are produced according to the invention by neutral or cationic Rh (I) chelates of aminophosphine phosphinite ethers, which represent inexpensive and readily accessible chiral ligands, with optical yields of 80 to 95% and high reaction rates be hydrogenated. It is also possible to prepare Cu complexes from the ligands, which act as depot ligands and contribute to a reduction in the use of rhodium. The process leads to price equality in the production of (S) - and (R) -phenylalanine.

Description

Field of application of the invention

The invention relates to a process for the preparation of (R) - and (S) -phenylalanine and its derivatives, in particular the N-acylamino acids and their esters, by catalytic asymmetric hydrogenation of cinnamic acid derivatives in the presence of cationic or neutral Rh (I) - Complex catalysts with chiral ligands. The resulting N-acyl-phenylalanines are valuable intermediates in both antipodes for (L) - and (D) -phenylalanine, which is important as an essential amino acid or in the D-form as a pharmaceutical. In addition, (L) -phenylalanine forms a component for the synthetic sweetener aspartame.

Characteristic of the known state of the art

It is known that phenylalanine and its derivatives can be prepared from prochiral precursors by homogeneous catalytic asymmetric hydrogenation with complex catalysts containing chiral ligands. The chiral ligands, generally phosphines, diphosphines, phosphinites, aminophosphine phosphinites, can carry the chiral elements in the trivalent phosphorus or the substituents on the phosphorus. For example, mono- and bisphosphines (DE-AS 21 61 200, DE-OS 21 23063, DE-AS 2210938, DE-OS 2456937, DE-OS 2908358, DE-OS 3000445, DE-AS 2759683, DD-PS 132487 and DD-PS 140036). A summary of the variety of ligands used for the hydrogenation of

Amino acid precursors are used in L. Marko and J. Bakos, "Aspects of Homogeneous Catalysis Vol.4,145-202, / 1981 /; D.Reidel Publishing Comp., Dordrecht, Netherlands.

As unsaturated, prochiral substrates were cinnamic acid derivatives of the general formula for the hydrogenation

H COOR

in the Ar NHCOR ¹

R is hydrogen or an alkyl radical,

R ^{1 is} hydrogen, an alkyl or aryl radical and

Ar is an aryl radical,

applied. - '·

The chiral complex catalysts used in the patents and publications for the hydrogenation of cinnamic acid derivatives / (Z) -2-N-acylamino-3-aryl-acrylic acids and esters / adhere to various disadvantages. In many cases, the ligands contained in them can only be prepared over several stages; in many cases only one antipode is accessible, especially when starting from the chiral pool, and frequently a high stereoselectivity with a low catalyst activity is found, or vice versa, so that these catalysts for a technical implementation of asymmetric synthesis hardly come into question.

Object of the invention

It is the object of the invention to obviate the drawbacks mentioned above and to develop a process which, using a low-cost technical starting material readily available in both antipodes, gives a ligand which allows to prepare both antipodes of the phenylalanine with high speed and stereoselectivity.

Explanation of the essence of the invention

The object of the invention is achieved by a process for the preparation of (R) - and (S) -phenylalanine and its derivatives of general formula I,

Ar-CH - C - COOR ',

¹ 1

NHCOR

in the

R is hydrogen or an alkyl radical,

R ^{1 is} hydrogen, an alkyl or aryl radical and

Ar is an aryl radical,

by catalytic asymmetric hydrogenation of cinnamic acid derivatives of the general formula II,

H COOR

C = C H

Ar NHCOR ¹

in which R, R ¹ and Ar have the above meaning, in the presence of rhodium (I) complex catalysts with chiral ligands, according to the invention as the chiral ligand Aminophosphinphosphinitether of formula III

0 - CH ₀ --CH - CH ₂

CO

0 N-CH (CH ₃ ) ₂ ",

»F

PPh ₂ PPh ₂

is used. The hydrogenation takes place in an alcoholic solution or suspension.

The particular advantage of the invention results from the use of the technically readily available, available in both antipodes propranolos, a known / 3-Receptorenblockers the structure

0 - CH - CH - CH ₂

OH N-CH (CH, ) _o H ^A ~.

as a basis for an aminophosphine phosphinite ether ligand, which with Rh (I) compounds becomes a highly active and stereoselective hydrogenation catalyst. The pronounced solvolysis resistance, such as the easy handling of the

Complex allow the execution of the hydrogenation in alcoholic solution, preferably in methanolic solution, at temperatures between -20 to 50 ⁰ C, preferably at room temperature.

The hydrogenations are carried out in the pressure range from 0.05 to 2 MPa, preferably at atmospheric pressure, over hydrogen. For catalyst preparation, the chiral ligands can be reacted in situ together with a rhodium complex containing easily displaceable ligands, and the substrate or prepared with a rhodium complex to a stock solution or first to form a crystalline chiral rhodium complex, which can then be added to the substrate solution. Both neutral and cationic complexes can be used. A particular advantage of the method is that with the chiral ligand, a Cu complex can first be formed, from which the catalytically active species is formed in situ with the above-mentioned rhodium complexes. In this way, an excess can be introduced as Depotligand in the hydrogenation, which acts not reactively blocking but on the contrary in any deactivation processes. Thus, it can also be achieved to reduce the rhodium content, which brings advantages according to the invention.

The substrate / catalyst ratio should be 1000: 1 to 5000: 1.

Because of the easy accessibility of the propranolol as enantiomers and the only one-step synthesis to the desired ligand not only economically advantageous parameters are given, but it is also possible to optionally win (S) - or (R) -phenylalanine.

embodiments example 1

6.28 mg (0.01 mmol) of S - (+) - PPP and 4.06 mg (0.01 mmol) of rhodium-bis (1,5-cyclooctadiene) tetraflouroborate / Rh (COD) ₂ / B ₄ are dissolved in 15 ml dissolved oxygen-free methanol and 205 mg (1 mmol) of Ζ-α-acetaminocinnamic added. After argon exchange of the thus prepared complex with hydrogen results in a half-life of about 4min (room temperature 0.1 MPa H ₂ ) in nearly quantitative yield (R) -N-acetylphenylalanine in an optical yield of 87.2 ± 0.2%.

Example 2

Analogously to Example 1, with 219.2 mg (1 mmol) of methyl Z-a-acetaminocinnamate in almost quantitative yield with a half-life of 2 min, (R) -N-acetylphenylalanine methyl ester is obtained in an optical yield of 86.1 + 0.4%.

Example 3

To a solution of 1 mmol of α-acetaminocinnamic acid in 15 ml of methanol are added 2.47 mg of bis- (1,5-cyclooctadiene) -chloro-rhodium (I) / (Rh (COD) Cl / ₂ ) and 6.27 mg ( 0.01 mmol) of (S) - (+) - PPP was added and the complex was dissolved with stirring (10 min). After replacement with hydrogen, hydrogenation is carried out at room temperature and 0.1 MPa of H ₂ , whereby (R) -N-acetylphenylalanine is formed in an optical yield of 87.9 ± 0.1% with a half-life of 7 min in almost quantitative yield.

Example 4

According to Example 1, with the Cu complex prepared from R (-) - PPP and CuCI and / Rh (COD) Cl / ₂ using Za-acetaminocinnamic acid with a half-life of 2 min (S) -acetylphenylalanine with an ee of 87 ,8th%.

Example 5

0.01 mmol of the Cu complex prepared from (R) - (-) - PPP and CuCl and 0.0025 mmol / Rh (COD) Cl / ₂ are dissolved in 15 ml of methanol, admixed with 1 mmol of α-acetaminocinnamic acid and analogously Example 1 hydrogenated. At a half-life of 4 min, (S) -N-acetylphenylalanine is formed with an ee of 84.6 ± 0.3%.

Example 6.

0.01 mmol of the S - (+) - PPP ligand and 0.01 mmol / Rh (COD) ₂ / BF ₄ are stirred for 1 hour under argon in 50% aqueous methanol. Then 1 mmol of ZaN-Acetaminozimtsäuremethylester, dissolved in 5 ml of methanol, was added and hydrogenated analogously to Example 1. At a half-life of 35 min, the phenyialanine ester is formed with an ee of 82.2% (R).

Example 7

To a solution of 2.05 g (10 mmol) Ζ-α-acetaminocinnamic acid in 15 ml of methanol are added 4.06 mg (0.01 mmol) / Rh (COD) ₂ / BF ₄ and 6.28 mg S - (+) - PPP given. After replacing the argon with hydrogen, hydrogenation is carried out at room temperature and 0.1 MPa of H ₂ , with (R) -N-acetylphenylalanine having a half-life of about 13 min in nearly quantitative chemical yield with an ee of 89.4 ± 0.7 % is formed.

Example 8

To a solution of 1 mmol of methyl Z-acetaminocinnamate in 15 ml of methanol are added 0.01 mmol / Rh (COD) ₂ / BF ₄ and 0.01 mmol of R - (-) - PPP. After a stirring time of 10 min, it is exchanged for hydrogen and hydrogenated at room temperature and 0.1 MPa H ₂ , with a half-life of about 3 min in virtually quantitative yield with an ee of 84.0 ± 0.1% (S). Acetylphenylalanine methyl ester is formed.

Example 9 '

As in Example 1, 2.05 g (10 mmol) of α-acetaminocinnamic acid are hydrogenated with 9.26 mg of the crystalline catalyst prepared from S- (+) - PPP and / Rh (COD) ₂ / BF ₄ in 15 ml of methanol. At a half-life of 10 minutes, at 100% conversion, (R) -N-acetylphenylalanine is produced in an optical yield of 84%.

Example 10 '

With 1 ml of the catalyst stock solution prepared from 0.1 mmol of (S) - (+) - PPP and 0.05 mmol / Rh (COD) CIZ ₂ , 1 mmol of Ζ-α-acetaminocinnamic acid in an optical yield of 86.8 % to (R) -N-acetylphenylalanine hydrogenated.

Example 11

4.10 g (20 mmol) of Z-α: acetaminocinnamic acid are hydrogenated with 0.01 mmol each of S - (+) - PPP-Cu and S - (+) - PPP-Rh analogously to Example 1 using 30 ml of methanol in suspension. With a half-life of 70min at 100% conversion, (R) -N-acetylphenylalanine is produced in an optical yield of 71%.

Example 12

10 mmol (2.81 g) of methyl N-benzoylcinnamate in 30 ml of methanol are hydrogenated in accordance with Example 1 with a half-life of 45 min. The turnover is 100%. The optical yield is 81%. After recrystallization, the optical purity is 94.4%.

Claims (3)

1. A process for the preparation of (R) - and (S) -phenylalanine and its derivatives of general formula I, H · Ar - CH 2 --C - COOR I NHCOR in the R is hydrogen or an alkyl radical, R ^{1 is} hydrogen, an alkyl or aryl radical and Arein aryl radical mean, by catalytic asymmetric hydrogenation of cinnamic acid derivatives of the general formula II, H COOR ^X C = C 'II Ar NHCOR in which R, R ¹ and Ar have the above meaning, in the presence of rhodium (I) complex catalysts with chiral ligands, characterized in that as the chiral ligand Aminophosphinphosphinitether of formula III 0 - CH ₀ - CH - CH ₀
\ ² ) ! ² ω θ N - CH (CH ₃ ) ₂ "I PPh ₂ PPh ₂ or its copper complex are used and the hydrogenation is carried out in an alcoholic solution or suspension. 2. The method according to claim 1, characterized in that a Küpferkomplex is first prepared with the chiral ligand, which then forms the catalytically active species in situ with the rhodium complex. 3. The method according to claim 1 and 2, characterized in that the alcohols are used as the solvent ethanol or methanol.