DD253947A1 - METHOD FOR PRODUCING CHIRAL TRANSITION METAL COMPLEX CATALYSTS - Google Patents

Abstract

The invention relates to a process for the preparation of chiral transition metal complex catalysts. From ethers of optically active amino alcohols via their Aminophosphinphosphinitderivate invention optically active ligands are prepared. From these reaction products to win the highly active catalyst precursors by reaction with a metal compound of the metals of the VIII. Subgroup of the PSE. The complex compounds act as catalysts for the enantioselective preparation of optically active compounds which are used as pharmaceuticals, sweeteners u. a. Find use. The catalysts can be used for C-C-knotting reactions, hydroformylations, hydrosilylation, carbonylation and hydrogenation processes, preferably also for the hydrogenation of substituted enamides. Optionally, (R) - like (S) - compounds can be prepared.

Description

Field of application of the invention

The invention relates to a process for preparing chiral transition metal complex catalysts which catalyze C-C linking, hydroformylation, hydrosilation, carbonylation and hydrogenation reactions.

These enantioselectively active metal complex catalysts can thus be employed for the preparation of optically active compounds which are used, for example, as pharmaceuticals, chiral intermediates or sweeteners.

Characteristic of the known state of the art

It is known that numerous optically active phosphines and diphosphines are suitable ligands for chiral catalysts, which in the majority of cases are used for asymmetric hydrogenations, in particular of amino acid precursors (L Marko and J. Bakos, Aspects of Homogeneous Catalysis Vol.4,145 bis 202 [1981], D. Reidel Publishing Comp., Dordrecht, The Netherlands). For example, P-chiral diphosphines are the parent algae for the Monsanto process for making L-DOPA (US Pat. No. 4,008,281).

Chiral diphosphines, whose chirality is located in the carbon skeleton between the phosphorus atoms, are also known for their catalytic activity (Brown and Chaloner, Homogeneous Catalysis with Metal Phosphine Complexes, L.H. Lignolet in Modem Inorganic Chemistry, Plenum Press, New York and London 1983). "

It is also known to use mono- and bisphosphinites (phosphine ester esters) of optically active alcohols as ligands for asymmetric hydrogenations and other reactions (DD-WP 140036, J. Organometal Chem. 253 [1983], 249 and J. Org. Chem [1981], 5427). It is also known to use optically active diamines (bisphosphinous acid amides) or amino alcohols (aminophosphine phosphinites) instead of the optically active alcohols as starting materials for the preparation of chiral, chelating ligands (J. Mol. Catalysis 1 [1976], 451 and 5 [1979], 303 Tetrahedron Letters 1977, 3497-3500; Izv. Akad. NaukSSS 'Ser. Khim. 1984, 729; J. Organometal Chem. 251 [1983], 79). Various diamines and 1,2-amino alcohols were used, which were mostly reacted with diaryl halophosphines to form the phosphinous acid derivatives. Recently, also Aminophosphinphosphinite have been described as ligands for optically active complex catalysts (DD-WP 210057).

All these known catalysts adhere to the disadvantages that they have to be prepared over several stages of chiral starting compounds, which are sometimes costly and not readily available in optically active form (ephedria, pseudoephedrines, glucose phosphinites, aminophosphine phosphinites of cyclic amino alcohols), and in many cases give poor stereoselectivity, are highly susceptible to solvation or are not suitable for practical applications because of too low activity despite good selectivity.

In addition, there is a defect that the chiral starting material, often accessible only as an antipode, sets the configuration of the target product, which in some cases is consistent with the desired configuration of the target product.

Object of the invention

It is the object of the invention, starting from cheap and technically easily accessible in significant quantities optically active compounds by single-step synthesis to obtain chiral ligands which can be used in the form of their complex compounds as enantioselective catalysts, the above-mentioned deficiencies do not occur.

Explanation of the essence of the invention

The object of the invention is achieved by a process for preparing chiral transition metal complex catalysts of general formula I,

O - R ^ ⁹ - CR ¹⁰

H . Y

1 *

/ Ν;

in the R, R ¹

-CO- PR ⁷ R ⁸

R ² _C - N - PR ^b R ^S

Hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, fused aryl, substituted fused aryl,

R ² , R ³ , R ⁹ , R ^{10 are} hydrogen, alkyl, aryl,

Hydrogen, alkyl, branched alkyl, substituted alkyl, aryl, substituted aryl, aminocarbonyl, aryloxycarbonyl, cycloalkyl, substituted cycloalkyl, together - (CH ₂ )) -, wherein Z is an integer between 3 and 12.

R ⁵ , R ⁶ , R ⁷ , R ⁸ aryl, cycloalkyl, substituted aryl,

M is a metal of Group VIIIb of the PSE,

Y halogen, pseudohalogen, carboxylate,

L CO, alcohol, amine, olefin, diolefin,

X is an anion of a strong, non-complexing acid such as BFJ, CIOJ,

k 1,

I is a number between O and 3,

a number between 0 and 4 as well

a number between 0 and 3

-, PFi ₁ CF ₃ COO-

mean,

by reacting ether optically active amino alcohols in a one-step reaction in the presence of acid-binding agents at temperatures between -20 and 120 ° C with Diorganylhalogenphosphinen and the thus obtained optically active Aminophosphinphosphinit-ether either directly with metal compounds of the metals of VIII. Subgroup of the Periodic Table of the Elements in the optically active catalyst complexes transferred or first complexed with a metal of the I. or II. Subgroup of the Periodic Table of the Elements and then by adding a metal compound of the metals of VIII. Subgroup of the Periodic Table of the Elements, the optically active catalyst complexes are formed in situ.

For the preparation of the ligands mentioned, it is possible to start from ethers of synthetic amino alcohols, such as aminohydroxypropanol, in particular, in particular, from the industrially occurring precursors, intermediates or end products in the case of pharmaco-syntheses to β-receptor blockers or further, pharmacologically active substances. Particular mention should be made of propranonol [3-isopropylamino-2-hydroxy-1- (1-naphthoxy (-propane].

As an acid-binding agent, the addition of triethylamine has been excellent.

The reaction of the aminoalcohol ether with the Diorganylhalogenphosphin, for example Diarylchlorphosphin, in the presence of triethylamine can be carried out in the temperature range between -20 and 120 ⁰ C, preferably a temperature between 40 and 80 ° C is set. The optically active aminophosphine phosphinite ether is usually obtained as an oil.

The particular advantage of the method is that compounds are obtained which are distinguished by a remarkable stability against oxidative and solvolytischen influences. While, for example, when using phosphinites of ephedrine due to rapid alcoholysis a reaction in alcohols (in methanol or ethanol, for example, in an asymmetric hydrogenation) is excluded, according to the invention the Aminophosphinphosphinite the ether, preferably the branched ether (R ⁴ = branched alkyl), stable , so that weak acids lead in large excess> 10 ³ to no change in the pre-catalyst or the active catalyst species.

As metal compounds of the metals of the VIII. Subgroup of PSE neutral catalysts can be used for catalyst preparation, which in turn preferably contain olefins, diolfines, CO or alcohols as easily displaced, bare ligands and as anions preferably halogens, pseudohalogens or carboxylates. If cationic complexes are used, the easily displaceable ligands such as olefins, diolefins, etc., and preferably the noncomplexing anions of strong acids ₍ such as BFJ, PFi, CIOJ, SOJ "or CF ₃ COO".

The optically active aminophosphine phosphinite ethers are converted into the optically active catalyst complexes in molar or excess molar ratio, preferably in a ratio of 1: 1, and in particular with metal-olefin complexes, preferably of rhodium (I).

Example 7

277 mg of the prepared according to Example 1 (+ (PPP are dissolved in 1 ml of tetrahydrofuran and treated with a solution of 179 mg of [Rh (COD) ₂ ] BF ₄ Jn 3ml dichloromethane, the red color of the rhodium complex turns to orange red After standing, it is concentrated in vacuo to 1 ml and the cationic complex is precipitated by slow dropwise addition of ether, The ether-washed complex is dried in vacuo over P ₂ O ₅ .

Calc. Rh 11.12 P 6.69 N 1.62 Found. Rh 10.70 P 6.70 N 1.67

Example 8

0.01 mmol of the prepared according to Example 1 ligand (+) PPP and 0.01 mmol of [Rh (COD) ₂ BF ₄ are stirred for 1 hour under argon in 50% aqueous methanol. The catalyst solution thus prepared can be used for hydrogenation and results in no loss of optical activity.

Example 9

2.25 g (3.58 mmol) of the (-) PPP prepared according to Example 2, dissolved in 25 ml of benzene, are treated with O, 335 g of CuCl (3.58 mmol) dissolved in 50 ml of EtOH, and the mixture is refluxed with stirring for 30 minutes heated. After standing overnight at -3 ° C, the colorless precipitate is filtered off, washed with EtOH and dried over P ₂ Os. Yield 2.4 g (92.3% of theory). Dimer complex Mol: 726.67

C 66.11 H 5.41 N 1.93 P 8.53 Cl 4.88 Cu 8.74 F. C 64.46 H 5.50 N 1.97 P 8.50 Cl 5.50 Cu 9.05 [a] _D -136.7 ° (c = 0.28 CHCl ₃ ).

Example 10

Analogously to Example 9, the Cu complex is prepared using the ligand (+) PPP according to Example 1. The yield is 91% d. Th. Dimer complex Mol: 726.67

C 66.11 H 5.41 N 1.93 P 8.53 Cl 4.88 Cu 8.74 F. C 65.59 H 5.39 N 2.00 P 7.80 Cl 5.20 Cu 8.48 Hd + 140.1 ° (c = 0.71 CHCl ₃ ).

Example 11

0.01 mmol of the Cu complex prepared according to Example 9 from Ia] ₀ -136.7 ° and 0.0025 mmol [Rh (COD) Cl] ₂ are transferred into 15 ml of methanol in the catalyst solution. The solution hydrogenates without loss of activity and selectivity ζ. Β. (Ζ) -α-Acetaminocinnamic acid (1 mmol) with a half-life of 4 min to (S) -acetylphenylalanine with an ee of 84.6 ± 0.3%.

Example 12

The prepared according to Example 7 cationic rhodium complex of the ligand of Example 1 is stored for 3 days in air. The complex is air stable and does not lose any activity and selectivity.

-4- 253 94:

According to the invention, a particular advantage of the process is that the crude aminophosphine phosphinines, which often form as oils, although they have a sufficient purity for the subsequent catalytic reactions, can be converted into metal chelates of group Ib and Hb of the PSE. The reactions are carried out in alcohol, preferably ethanol and methanol or benzene-alcohol mixtures, and lead to crystalline, in each case solid, powdery products which, as a further advantage, in addition to a cleaning effect which is achieved in this way, the stabilization to have an advantageous storage, a better dosage and generally easier handling.

According to the invention, the use of these transition metal chelates of group I b and II b, preferably of the Cu (I) chelates, leads to a substantial reduction in the amounts required for the subsequent catalytic reactions of expensive noble metals, predominantly Rh, Ru, Ir, Pd and Pt. While free, excess ligand in the catalytic system can inhibit and reduce the selectivity due to the occupation of additional coordinate sites, a depot ligand is introduced by the abovementioned chelates, so that worked with greatly reduced precious metal complex, or a destructive degradation by addition of Cu complexes are prevented can.

For catalytic reactions, the complex compounds in substance or by formation in the reaction vessel, d. H. applied in situ. Another possibility is a separate in situ preparation and a subsequent addition in dissolved form to the substrate. In any case, a prehydrogenation of the catalyst is unnecessary, so that a particularly simple procedure is given. As solvents for the catalytic reactions, it is possible to use alcohols, preferably alcohols, particularly preferably methanol, but also aromatic and aliphatic hydrocarbons or mixtures with alcohols.

According to the invention, the transition metal complex catalysts are used for the hydrogenation of amino acid precursors

 Owing to the presence of both antipodes of the starting product, optionally (R) and (S) -amino acids can be prepared at extremely high reaction rates and in high optical purity.

embodiments

All reactions are carried out under argon.

example 1

Propraphos (PPP)

3 g (10 mmol) of (S) -lsopropylamino-2-hydroxy-1- (1-naphthoxy) -propane hydrochloride (propranolol hydrochloride), [ α ] _D -22.3 ° (c = 1.335, EtOH), slurried in 30 ml Benzene, are added dropwise with 8.4 ml (60 mmol) of triethylamine and heated to 5O ⁰ C. 3.9 ml (21.7 mmol) of chlorodiphenylphosphine dissolved in 10 ml of benzene are added dropwise with stirring, and after the addition has ended, the mixture in which triethylammonium chloride precipitates is heated to 50 ° C. for a further 2 hours. After standing: filtered overnight (residue 4.2 g of triethylamine hydrochloride = 94%). The solvent is removed in vacuo and the yellowish, oily residue is dissolved in 100 ml of ether. Upon standing, further hydrochloride separates from the filter. After distilling off the solvent, the oily residue is treated twice more with hexane and then dried in vacuo. The yield is 5.6 g (92%). [a] _D - + 75.5 ° (c = 1,082CHCI ₃ ) m / e 627 · M ⁺ .

C 76.54 H 6.26 N 2.23 P 9.87 f. C, 75.14, H, 6.56, N, 2.12, P, 9.72

Example 2

10 mmol (R) - (+) - propranolol hydrochloride [a] _D = + 21.9 ° (c = 0.920 EtOH) are reacted analogously to Example 1

The yield of (-) PPP is 93%. Ia] ₀ -75.9 ° (c = .555 CHCl ₃ ).

Example 3

6.28 mg (0.01 mmol) of the (+) PPP prepared according to Example 1 and 4.06 mg (0.01 mmol) of rhodium-bis-O-cyclooctadiene) tetrafluoroborate ([Rh (COD) ₂ ] BF ₄ ) dissolved in 15 ml of oxygen-free methanol and the solution stirred for 10 min under argon It is then used as a catalyst solution for asymmetric hydrogenation.

Example 4

6.28 mg (0.01 mmol) of the (-) PPP prepared according to Example 2 are mixed with 2.47 mg (0.01 mmol) of bis (1,5-cyclooctadiene) -chloro-rhodium (I) ([Rh (COD CI] ₂ ) was dissolved in 15 ml of methanol with stirring, and the complex formation was completed by stirring under argon for 10 minutes. This solution was used as a catalyst.

Example 5 <

To a solution of 0.1 mmol of the ligand prepared according to Example 1 in 10 ml of methanol are added 0.1 mmol of [Rh (COD) Cl] ₂ , which dissolves quickly. From this stock solution of the catalyst aliquots are removed and used for hydrogenation.

Example 6

0.99 g of the (+) PPP prepared according to Example 1 are dissolved in 3 ml of dichloromethane and admixed with 3 ml of a solution of 0.569 g of [Rh (COD) Cl] ₂ in dichloromethane. After standing for 12 hours, concentrate in vacuo and precipitate the neutral complex slowly with ether. After drying over P ₂ O ₅ , the catalyst can be used.

Claims (11)

claims: 1. A process for preparing chiral transition metal complex catalysts of general formula I, in the R ₁ R ^{1 is} hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, fused aryl, substituted condensed aryl,
R ² , R ³ , R ⁹ , R ^{10 are} hydrogen, alkyl, aryl,
R ^{4 is} hydrogen, alkyl, branched alkyl, substituted alkyl, aryl, substituted aryl, Aminocarbonyl, aryloxycarbonyl, cycloalkyl, substituted cycloalkyl, R ³ -R ⁴ together- (CH ₂ )) -, wherein Z is an integer between 3 and 12, R ⁵ , R ⁶ , R ⁷ , R ⁸ aryl, cycloalkyl, substituted aryl,
M is a metal of Group VIIIb of the PSE, Y halogen, pseudohalogen, carboxylate, L CO, alcohol, amine, olefin, diolefin, X is an anion of a strong, non-complexing acid _t such as BF ₄ ", CIO4, SO ₄ "", PFä, CF ₃ COO-,
k 1, I is a number between O and 3, m is a number between 0 and 4, and η is a number between 0 and 3 mean, characterized in that the ether of optically active amino alcohols are reacted in a single-step reaction in the presence of acid-binding agents at temperatures between -20 and 120 ⁰ C with Diorganylhalogenphosphinen and optically active Aminophosphinphosphinitether thus obtained either directly with metal compounds of the metals of VIII. Subgroup of the Periodic Table the elements are converted into the optically active catalyst complexes or first complexed with a metal of the I. or II. Subgroup of the Periodic Table of the Elements and then by adding a.Metallverbindung the metals of VIII. Subgroup of the Periodic Table of the Elements, the optically active catalyst complexes are formed in situ , 2. The method according to claim 1, characterized in that are used as the starting material ethers of synthetic amino alcohols or optically active amino alcohol ethers, which are often as ß-, Receptorenblocker pre-, intermediate or end products. 3. The method according to claim 1 and 2, characterized in that triethylamine is used as the acid-binding agent. 4. The method according to claim 1 to 3, characterized in that the reaction of the amino alcohol with the Diorganylhalogenphosphin takes place at 40 to 8O ⁰ C. 5. The method according to claim 1, characterized in that the resulting Aminophosphinphosphinit ether in the molar or excess molar ratio, preferably in the ratio 1: 1 and in particular with metal-olefin complexes, preferably of rhodium (I), converted into the optically active catalyst complexes becomes. 6. The method according to claim 1, characterized in that first the Aminophosphinphosphinitether is transferred with a copper compound in the metal chelate and then by addition of a metal compound of the metals of the VIII. Subgroup of the PSE, the optically active catalyst complexes are formed in situ. 7. The method according to claim 1 and 6, characterized in that is used as the metal of the VIII. Subgroup of the PSE rhodium (I). 8. The method according to claim 1,6 and 7, characterized in that the optically active catalyst complexes are isolated before use as cationic or neutral complexes in crystalline form. 9. The method according to claim 1,6 and 7, characterized in that the optically active catalyst complexes are formed by combining the components in the reaction vessel in solution. 10. The method according to claim 1 and 6, characterized in that the optically active catalyst complex is formed with a metal of the VIII. Subgroup of the PSE in deficit. 11. The method according to claim 1,6 and 7, characterized in that the optically active catalyst complexes are formed separately in solution and the catalyst solution is added to the reaction vessel.