DD253996A1 - PROCESS FOR THE PREPARATION OF (L) -DOPA AND THEIR DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of (L) -DOPA (& S! -DOPA) and its derivatives by catalytic asymmetric hydrogenation of prochiral unsaturated precursors in the presence of chiral metal complex catalysts. The hydrogenation products are easy to convert to (L) -DOPA. The prochiral starting materials used are O-functionalized cinnamic acid derivatives, especially their esters, which are hydrogenated according to the invention by neutral or cationic Rh (I) chelates of O, N-diphenylphosphino-propranolol as ligands with optical yields of 80% and high reaction rates. From the ligands also Cu-I-chelates can be produced, which act as depot ligands and contribute to a reduction of rhodium use. The process, because of the industrial accessibility of propranolol and the only required single-step synthesis to the ligand, combined with the high activity and stereoselectivity in the catalytic reaction, represents an economic advance.

Description

in which R, R ¹ , R ² and R ^{3 have} the above meanings, in the presence of rhodium (I) complex catalysts with chiral ligands, characterized in that as the chiral ligand Aminophosphinphosphinitether of formula III

0 - CH - CH - CH ^ \ \ ^d

0N - CH (CH ₇ ) IM

1 f ^ö 2

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 first a copper complex is 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 or 2, characterized in that as substrates (Z) -2-N-acetyl or benzoylamino-3- (3,4-hydroxy-methoxy- or 3,4-dimethoxy- or 3, 4-acetoxy-methoxyphenyl) -acrylic acids are used.

4. The method according to claim 1 to 3, characterized in that are used as substrates, the methyl or ethyl esters of acrylic acids.

5. The method according to claim 1 to 4, characterized in that the alcohols used are ethanol or methanol as the solvent.

Field of application of the invention

The invention relates to a process for the preparation of (L) -DOPA ((S) -DOPA) and its derivatives, in particular of the N-acylated DOPA and its esters, by catalytic asymmetric hydrogenation of those in the aromatic radical in 3,4-position 0 -functionalized (S) -acyl-phenylalanines and their esters. They can be converted to (L) -DOPA by known routes. (L) -DOPA alone, as in combination with known decarboxylase inhibitors, is used to treat Parkinson's syndrome.

Characteristic of the known state of the art

It is known that derivatives of phenylalanines, especially those according to DOPA, can be prepared by homogeneous catalytic asymmetric hydrogenation with complex catalysts which contain, as chiral ligands, derivatives of trivalent phosphorus and as central atom Rh (I). As chiral ligands bisphosphines, bisphosphinites, bisaminophosphines, Aminophosphinphosphinite and monophosphines can be used (DE-AS 2161200, DE-OS 21 23063, DE-AS 2210938

DE-OS 2456937, DE-OS 2908358, DE-OS 3000445, DE-AS 27 59683, DD-PS 132487, DD-PS 140036, DD-PS 210057). An overview of the ligands that can be used can be found in L. Marko and J. Bakos, Aspects of Homogeneous Catalysis, Vol. 4,145-202, / 1981 /; D.Reidel Publishing Comp., Dordrecht, Netherlands.

For example, P-chiral diphosphines form the basis of the Monsanto process for L-DOPA production (US Pat. No. 4,008,281). As substrates for the asymmetric hydrogenation, the prochiral unsaturated cinnamic acid derivatives of the general formula _f

H COOH

3,4-RR Ar NHGOR,

in which R ¹ , R ^{2 is} O-functionalized substituents and R ^{3 is} an alkyl or aryl radical used.

The known complex catalysts adhere to various disadvantages. In many cases, the chiral ligands contained in them are costly and accessible only over many steps. Aminophosphine phosphinites and biphosphinites have a high solvolysis sensitivity, and often the complex catalysts prepared from the chiral compounds of the trivalent phosphorus as ligands are only slightly catalytically active, although their enantioselectivity is good and vice versa. In addition, there is often a defect that certain process advantages can not be exploited because only certain substrates are hydrogenated with high enantioselectivity, for example the N-acyl cinnamic acids rather than the more advantageous esters. Another shortcoming is that when resorting to the chiral pool, only one antipode of the chiral ligand can be obtained, which need not always lead to the desired target product in the catalytic reaction, as in the known DIOP, for example, based on natural tartaric acid and leads to (R) -amino acids, which is the case.

Object of the invention

It is the object of the invention to avoid the abovementioned disadvantages and to develop a process which converts the cited substrates into the (L) -DOPA precursors with high activity and stereoselectivity using a technically readily available, inexpensive optically active ligand from which in a known manner (L) -DOPA is obtained.

Explanation of the essence of the invention

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

NHCOR ³

in the

R is hydrogen or alkyl,

R ₁ , R ₂ O-functionalized substituents, where as substituents hydrogen, alkyl, acyl, alkoxyacyl, aryl or alkylene and act

R _{3 is} hydrogen, an alkyl or aryl radical,

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

H ^ COOR

3 "

NHCOR

in which R, R ¹ , R ² and R ^{3 have} the above meanings, 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 ₂ - CH -

0N - CH (CH ₃ ) ₂

III

PPh ₂ PPh ₂

or its copper complex are used and the hydrogenation is carried out in an alcoholic solution or suspension.

A particularly advantageous solution is achieved by using the readily available ligand III which can be prepared in a one-step reaction, which leads to a highly active and enantioselectively active catalyst. The existing Solvolysebeständigkeit and oxygen insensitivity of the Rh complex make easy handling and reaction in alcoholic solution, preferably in methanol, at temperatures between -20 to 50 ⁰ C, preferably at room temperature and normal pressure hydrogen possible.

According to the invention, not only the cinnamic acid derivatives but preferably also their esters can be hydrogenated at high speed and stereoselectivity, which may have procedural advantages.

To prepare the catalyst, the active precatalysts can be formed in situ from the ligand and a rhodium complex in the presence of the substrate, or a stock solution can be prepared from which catalyst solution can be metered or the crystalline rhodium complex can be prepared. The Rh (I) complexes required for catalyst preparation contain olefins, diolefins, CO or alcohols as readily displaceable ligands.

Both neutral and cationic complexes can be used according to the invention. A particular advantage of the method is that from the chiral ligand and Cu (I) -SaIz to next a copper complex can be formed from the in situ with said Rh (l) complexes with easily displaceable ligands, the catalytically active species is formed.

In this way, an excess can be introduced as Depotligand in the hydrogenation, which acts not reactively blocking but on the contrary at any deactivating the catalyst. Thus, it can also be achieved, while maintaining the high reaction rate, to apply higher substrate-catalyst ratios.

Because of the ready accessibility of the propranolol, the well-controlled resolution, and the single-step reaction to the desired ligand, not only are advantageous economic parameters given for ligand synthesis, but process advantages for the (S) -DOPA are also realized.

embodiment example 1

6.28 mg (0.01 mmol) of (R) -H-PPP (Propraphos) and 4.06 mg (0.01 mmol) of rhodium-bis-cyclo-octadiene-1-tetrafluoroborate (/ Rh (COD) ₂ / BF ₄ j are dissolved in 15 ml of oxygen-free 1 mmol of (Z) -2-N-acetylamino-3- (3-hydroxy-4-methoxyphenyl) -acrylic acid is added after argon exchange with hydrogen at a half-life of about 5 minutes at full conversion under normal hydrogen pressure and room temperature DOPA derivative in an enantiomeric excess of 83.3% (S).

Example 2

Analogously to Example 1, when using (Z) -2-N-benzoylamino-3- (3,4-dimethoxyphenyl) -acrylic acid in a half-life of about 3 minutes at 100% conversion of the DOPA derivative in an enantiomeric excess of 91, 2% (S).

Example 3

Analogously to Example 1, when using (Z) -2-N-acetylamino-3- (3,3-dioxymethylenephenyl) -acrylic acid in a half-life of 7 min at 100% conversion, the DOPA derivative is formed in an enantiomeric excess of 67.2 % (S).

Example 4

To a solution of 1 mmol of (Z) -2-N-benzoylamino-3- (3,4-dimethoxyphenyl) -acrylic acid in 15 ml of methanol are added 6.28 mg (0.01 mmol) of RH-PPP and 2.47 mg (0, 01 mmol) bis- / (1,5-cyclooctadiene) -chloro-rhodium (I) / (/ Rh (COD) Cl / ₂ ) and the complex was formed under argon by stirring (10 min). After replacing the argon with hydrogen, hydrogenation is carried out at room temperature and 0.1 MPa H ₂ , the (S) -DOPA derivative being obtained in a half-life of 15 min at 100% conversion in an enantiomeric excess of 81.9%.

Example 5

To 0.01 mmol (RH-PPP-Cu, prepared from RH-PPP and CuCl dissolved in 15 ml of methanol, 0.01 mmol (2.47 mg) / Rh (COD) CU _{2 are} added and the mixture is allowed to stand for 10 min Argon stirred.

After addition of 1 mmol of (Z) -2-N-benzoylamino-3- (3,4-dimethoxyphenyl) -gryl acid, hydrogenation is carried out analogously to Example 1. With a half-life of about 4 minutes, a turnover of 100% is achieved. The enantiomeric excess is 87.1% (S) -DOPA derivative.

Example 6

To 0.01 mmol of RH-PPP and 0.01 mol / Rh (COD) ₂ / BF ₄ in 30 ml of methanol are added 10 mmol (Z) -2-N-benzoylamino-3- (3,4-dimethoxyphenylj-acrylic acid methyl ester and after Argon-hydrogen exchange hydrogenated analogously to Example 1. The initial suspension is dissolved at almost twice the half-life of 50 min and the DOPA derivative crystallizes spontaneously or when rubbed on completion of the hydrogenation (100% conversion). The second fraction has an optical purity of 80%, and in two further examples the optical purity of the directly crystallized hydrogenation product was 98.4 and 97.6% (S).

Example 7

To 0.01 mmol (RT) -H-PPP and 0.005 mmol / Rh (COD) Cl / ₂ in 15 ml methanol are added 0.04 mmol of (R) -H-PPP-Cu and 5 mmol (Z) -2-N- Benzoylamino-3- (3,4-dimethoxyphenyl) acrylic acid and hydrogenated according to Example 1. With a half-life of 27 min and 100% conversion, an enantiomeric excess of 87.3% (S) is obtained.

Claims (1)

1. Process for the preparation of (L) -DOPA and its derivatives of general formula I, H MHCOR ³ in the R is hydrogen or alkyl, R ¹ , R ² O-functionalized substituents, where as substituents hydrogen, alkyl, acyl, alkoxyacyl, aryl or alkylene and act
, R ^{3 is} hydrogen, an alkyl or aryl radical,
by catalytic asymmetric hydrogenation of cinnamic acid derivatives of the general formula II, COOR
/ ^ NHCOR ³ -. "