DD210057A1 - METHOD FOR PRODUCING OPTICALLY ACTIVE COMPLEX CATALYSTS - Google Patents

Abstract

The invention relates to a process for the preparation of optically active metal complexes of optically active amino alcohols via their Phosphinigsaeurederivate. The enantioselectively catalytically active, optically active chelate complexes are obtained according to the invention by reacting an optically active beta (primary or sec. Amino) alcohol in the presence of proton acceptors at -70 to +100 degrees Celsius with a diorganyl halophosphine and the crude or purified reaction product against easily displaceable ligands of soluble complexes of the 0- to 4-valent metals of subgroup VIII of the PSE. The complexes obtained are of importance as catalysts for the enantioselective synthesis of optically active substances (e.g., pharmaceuticals) from optically inactive precursors in hydrogenation, hydrosilylation, isomerization, carbonylation, oligomerization, and other C-C knotting reactions. The catalysts may preferably be used for the enantioselective hydrogenation of Z-α-acetylaminocinnamic acid or its esters for the preparation of (R) (-) - N-acetyl-beta-phenylalanine or its esters.

Description

Title of the invention

Process for the preparation of optically active complex catalysts

Field of application of the invention

The invention relates to a process for the preparation of optically active metal complexes from optically active amino alcohols via their phosphinous acid derivatives. Such complexes have as catalysts for the enantioselective synthesis of optically active substances (z, B, Pharraaka) from optically inactive precursors in hydrogenation, hydrosilylation, isomerization , Carbonylation, Oligomerization, and Other CC-Knotting Reactions Meaning «

Characteristic of the known technical solutions

It is known that many optically active phosphines and diphosphines can be combined with transition metal ions, preferably VIII, subgroup of the Periodic Table of the Elements, to form complex catalysts with enantioselective (asymmetric) activities. For example, according to Knowles u. Mitarb, the P-chiral ligands o-anisylmethylcyclohexylp-phosphine (Chem, Technol, 1972 , p. 590) and (R, R) -1,2-ethanediylbis (o-anisylphenylphosphine) (U.S. Patent 4,008,281 , J. Amer. , 1987, 59, 5946) with rhodium-1,3 (I) complexes with partly highly enantioselective, catalytic hydrogenation activity, Kagan and Mitarb described another Rhodiuakomplex with similar effects, in which the (R, R) -2,3-0-isopropylidene-2,3-dihydroxy-l, 4-bis ^ - (diphenylphosphino) -

-7, JlllLi982 * üli58O

Butan (DIOP) with aer chirality at the C atoms 2 and 3 serves as asymmetry-inducing ligand (0th Atner <, former Soc. 94 (1972), 6429).

It is also known that, instead of the phosphines, mono- and bis (phosphinous acid esters) of optically active alcohols can also be used as ligands for enantioselective metal complex catalysts, as described by H. Pracejus, M., Bursian (DD-WP 92 031) for cellulose derivatives and by R. Selke u. H. Pracejus (DD-WP 140 036) for monosaccharide derivatives has been described.

Furthermore, diphenylphosphinous acid derivatives of optically active mono- and diaraines have also been successfully used for the same purpose (Fiorini et al., Mol. 3, Catalysis 1 (1975), 451, ibid, J5 (1979), 303, G. Praceus u. Co-workers, Tetrahedron Letters 1977, 3497-3500).

Summaries of the known technical solutions can be found z, B * in L. Marko * u. D * Bakos, "Aspects of Homogeneous Catalysis 4" (1981), 145-202, by V. Caplar, G. Comisso et al. V. Sunjic, Synthesis 1981 , 85-116, to D. Valentine et al. O. W, Scott, Synthesis 1978 ', 329-356, HB Kagan, Topics in Stereochemistry 1 ^ 3' (1979), 179 et seq., And H, Pracejus, Wiss, Z. d. Ernst Moritz Arndt University Grsifswald, in press.

All these catalysts have the disadvantage that they must be synthesized either over several stages of natural or commercially available precursors with considerable effort or provide unsatisfactory enantioselectivities or reaction rates and are very limited in their .Anwendungsbereich »

Object of the invention

It is the object of the invention to show simplified routes for the synthesis of optically active cos complex catalysts with enantioselective effects and at the same time the possibilities of a targeted structural transformation of this

used complex ligands to expand by a new principle *

Explanation of the essence of the invention

This object is achieved by a process for the preparation of optically active complex catalysts in the form of enantioselectively catalytically active, optically active chelate complexes of the general formula I,

> 2, 3

f It - C - 0 - P I

-C-N-P

n +

in the

R: H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, alkoxycarbonyl, aryloxycarbonyl or arainocarbonyl

R ² , R ³ : H, alkyl, aryl

R ¹ - « ⁴ , R ^1- R ⁵ or R ⁴ -R ⁵ : - (CH ₂ ) _n - or substituted

R ⁶ R ⁷ R ₂ , R ₂

X or 2X

with η β 1 to 12

Aryl or substituted aryl, alkyl or substituted alkyl

8iaren-2 * 2 * -diyl, - (CH ₂ ) - with η = 2 to S

Metal of the VIII subgroup of the PSE

Cl, Br, J, 1 "3-citrate _s carboxylate, carbonate

Mono- or diolefin, arene, CO, H ₃ O ₁ alcohol, Am in

PF, "

Anion of a strong acid, ζ · Β, BF. ,. , ^,, .., F ₃ C-COO ", ^u - a--« _A - -

4 '"6 ClO ~, HSO."", F ^ ₅ C-COO", or anion of a two:

basic strong acid, e.g.

k: 1 or 2 1: 0 to 3 m: 0 to 4 η: 0 to 3

mean, by synthesis of Q, N-bis- (phosphinous) ~ derivatives of optically active ß ~ amino alcohols and subsequent complex formation with transition metal compounds, according to the invention an optically active ß- (prim _e - or sec · - amino) alcohol in the presence reacted proton acceptors at -70 ⁰ C to + 100 ⁰ C with a Diorganylhalogenphosphin and the crude or purified reaction product is exchanged for easily displaceable ligands of soluble complexes of O- to 4-valent metals of VIII. Subgroup of the PSE *

The resulting metal chelates are characterized by the fact that the struc- ture-related chirality is superimposed on an electronic asymmetry stemming from the different electron densities of the O or N atoms, which has an effect on the san- goselectivity of catalytic effects.

As chirals starting materials for ligand synthesis serve either naturally occurring optically active amino alcohols such as ephedrine, derivatives of o ^ -Acjino-.beta.-hydroxy acids or amino sugars or by Racesnattrennung of synthetic ß-Äjninoalkohole derived compounds, the z.T. as by-products of industrial processes are readily available or can be produced. They can also be constituents of macromolecules,

As metal compounds for the catalyst synthesis either cationic metal complexes with neutral ligands such as olefin, diolefin, arene, CO, Arnin, alcohol, etc. and non-complexing anions such as B ^ ₄ "> ^{p {=} g ~» ^c l ° 4 ~ >

SO or else electrically neutral halogeno, β-diketonato, carboxylato and carbonato koraplexes rait the same neutral ligands are used, wherein the anionic ligand is retained in the complex or by nach-

^ _ feuf ^ _- ? --Y "V · *? =" W

trägliche action electrophilic ions such as Ag or Η can be removed ^τ "In some cases, preferably the metals of the nickel triad also labile complexes with the central atom of zero-valent are suitable as starting materials"

The resulting optically active chelate complexes can either be used as catalysts directly after their formation in solution or else be isolated beforehand in crystalline form. Suitable solvents for the use of the catalysts are z, β. aromatic and aliphatic hydrocarbons, cyclic and acyclic ethers and esters, alcohols and optionally also the substrates to be reacted themselves, provided that they are liquid ·

The catalysts obtained according to the invention are preferably suitable for the enantioselective hydrogenation of Z- "C-acetylaminocinnamic acid or its methyl ester for the preparation of (R) (-) - N-acetyl-.beta.-phenylalanine or the methyl ester thereof,

embodiments

Example 1

In a solution of 3.1 g (18.8 mmol) of (IR, 2S) - £ phedrin and 7 ml (50 üimol) of triethylamine in 110 ml toluene under inert conditions and with stirring bsi 50 ⁰ C 8.38 g (38 iamol ) Diphenylchlorphosphine, dissolved in 40 ml toluene, added dropwise. The mixture is heated for a total of 40 minutes and stirred for a further 30 minutes, then the precipitated triethylammonium chloride (90 % d, Th ") is filtered off with suction and from the virtually quantitatively obtained crude product the ON-bis (diphenylphosphino) - (IR; 2S) -ephedrine is isolated by repeated dissolution isolated from η-hexane as a colorless oil, which is characterized by 2 equal ³¹ p-nmr signals at - 111.55 and - 63.83 ppm (against H ₃ PO ₄ ) · pure yield about 27 % ö » Th. .

^ υ

Example 2

3.0 g (18.2 mmol) (IR; 2R) -pseudoephedrine were reacted with triethylamine (7 ml) and diphenylchlorophosphine (8.1 g) in toluene (225 ml) analogously to Example 1. »After filtering off the aninic hydrochloride and evaporation, the residue obtained was redissolved from hexane and diethyl ether, giving a total of 2.2 g (23 %) of pure, crystalline, 0.15 n-bis (diphenylphosphino) - (1R; 2R) -pseudoephedrine, m.p. to 112 ⁰ C and higher amounts of less pure parliamentary groups

31 were obtained. In the P-NMR spectrum, typical signals were found at - 110.43 ppm and -63.04 ppm (vs. H ₃ PO ₄ ). The rotation was / ° / / _Q ²⁰ - 29.0 ° (c = 0.8, toluene) ·

Example 3

To a solution of 600 rag (0.95 nmol) of the ephedrine derivative according to Example 1 was added 2l5 mg of solid sis - / (1,5-cyclocctadiene) · chloro-rhodium (I) / which rapidly dissolved. The solution was dissolved either directly as Catalyst used or converted according to Example 4 in the cationic complex ·

Example 4 ^:

The solution of the chloro complex prepared according to Example 3 was admixed with a solution of 0.98 mbar silver tetrafluoroborate in toluene and decanted from the rapidly precipitating silver chloride. After standing for a few days, pale yellow crystals of (O, N-8is (diphenyiphosphino ) - (IR; 2S) -ephedrine) - (!, S-cyclooctadisine) rhodium (I) tetrafluoroborates, which were washed with a small amount of benzene. Mp. 168 to 170 ⁰ C, .Ausbeute about 30%.

Example 5

The ligand prepared according to Example 2 is reacted analogously to Example 3 in the molar ratio ligand: Rh = 1: 1 with bis - / (l # 5-cyclooctadiene) -chloro-rhodiuni (I) / and the resulting solution either used directly as a catalyst or previously transferred to Example 7 in the cationic complex.

Example 6

The procedure is analogous to Example 3 and 5, but instead of the Cyclooctadienkomplexes the bis- / di- (ethylene) -chlororhodiura (I) / applied »

Example 7

The prepared according to Example 5 solution of the chloro-rhodium (I) complex is reacted analogously to Example 4 with ÄgBF. This gives yellow crystals of (ON-bis (diphenylphosphino) - (IR; 2R) -pseudoephedrine) - (lS-cyclooctadiene) rhodium (I) tetrafluoroborate of mp, 172 to 187 ⁰ C,

Example 8

The prepared according to Example 4 cationic rhodium complex was at 30 C / 0.1 MPa iU pressure in benzene solution for the enantioselective hydrogenation of Z-aC ~, 4c8tylarainozinitsäuremethylester (1 mol% catalyst) used, in a rapid reaction at almost quantitative conversion (R. ) ( 'JN-.Acetyl-ßphenylalaninmethylester originated in an optical yield of 81% · the free Z-C6- ^ cetylan3inoziratsäure an optical .Ausbeute was dissolved in dioxane as a medium under similar conditions of 80% (R) (-) - N-acetylphenol alanine achieved »Similar results were observed with the crude catalyst solution obtained in situ,

Example 9

The optically active Rhodiusskomplex prepared according to Example 7 was used analogously to Example 8 for the hydrogenation of Z - ^ - Acetylaminozimtsäuremethylester. In benzene as the solvent, N-acetyl- (R) -phenylalanine ethyl ester was obtained in an optical yield of 14 %, in methanol, however, its (S) -enantiomer in an optical yield of 3 % .

1 4 U 4 ö D

Example 10

2.6 g (17.2 mmol) of R (-) - 2-methyiamino-1-phenyl ethanol of the theoretical value C CJ'q - -41 ° (c = 1

EtGH) and 5 g (about 50 aaol) of Et ₃ N with 8.2 g (37.3 mmol) of diphenylchlorophosphine in ether and worked up accordingly.

Pure yield 52 %; oil, / aC / _n ~ + ¹ ^ > ⁷ ° (c = 1, toluene),

P-NMR; 110.5 ppm and 67.2 ppm,

Example 11

According to Example 1, 3 g (19.84 mmol) of R (-) - 2-phenyl-2-methylaminoethanol of the rotation value / <* C / _D ⁼ -75.9 (c = 1, EtOH) in the presence of Et ₃ N (50 mmol) reacted with 9.2 g (41.8 mmol) of diphenylchlorophosphine in ether / benzene solution.

Conversion 91 %, pure yield (after working up analogous to Example 1) 72 %; Oil, / oL / _Q - 0 ° (c = 2, toluene); ³¹ P - NMR: 114.7 ppm and 59.5 ppm »

Example 12

From the ligand obtained according to Example 10 (0.58 mmol) and 143 mg (0.53 msa of Rh) of solid bis- / (l, 5-cyclooctadiene) -chloro-rhodium (I) /, a toluene solution of the chlorocospeplex was prepared analogously to Example 3 manufactured*

Example 13

A portion of the solution obtained according to Example 12 (with 0.473 ramoi Rh content) became the solution of 0.473 mmol AgBF. given in toluene * A brown oil separated. From the supernatant solution, as in example 4, the corresponding tetrafluoborate complex crystallized after 1 day. The same compound was obtained from the brown oil when dissolved in acetone, separated from AgCl and the exhaust steam residue treated with ether dsr Äcetonlösung wufde _e

- 7 F1C7

240486 5

Example 14

Analogously to Example 3 (690 mg = 1.33 raraol) was dissolved in 10 ml of toluene and 328 mg of bis from the obtained according Seispiel 11 ligand - / (l, 5-cyclooctadiene) -chloro-rhodium (I) / a neutral complex produced, the was converted into the cationic complex and isolated analogously to Example 13.

+66.5 °; / <s (/ "o = + 62.9 ° (c = 0.2, MeOH)

546 Example 15

73.6 mg (0.267 mmol) of bis (cyclooctadiene) -Ni (O) / were added to dissolve 286 mg of the 1-bisphedrine derivative prepared according to example 2 in 6 ml of benzene. The Ni complex dissolved under color deepening. Upon addition of hexane, crystals separated by days.

For ^C g3 ^H 5Q ° 2 ^N 2 ^P 4 ^{Nii over # Ni 5 '21} λ N 2.49 % P 11.0 %

ge f. 4.73 % 2.48 % 11.13%

Example 16

To 104 mg (0.27 mmol) of bis (benzonitrile) palladium (III) chloride was added the solution of 144 mg (0.27 mmol) of the y-ephedrine ligand prepared according to Example 2 in 8 ml of benzene. The coarse crystals of the benzonitrile complex dissolved, while very fine, almost colorless crystals precipitated.

calc. P 8.7% gef. 8.6 %

Claims (6)

X Αϋ invention claim 1 * Process for the preparation of optically active conjugated catalysts in the form of snantioselectively catalytically active, optically active chelate complexes of the general formula I, R ^v in the , R: H ₁ alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, aikoxycarbonyl, aryloxycarbonyl or arainocarbonyl ; H, alkyl, aryl R ¹ - !? ⁵ or R ⁴ -R ^5: - ⁽⁰¹ ^ rT ^{oc he substituted} - (CH _{2) n} - with η = 1 ^to! : Aryl or substituted aryl, alkyl or substituted alkyl ; Biaren-2 * 2 * -diyl, - (CH-) - with η = 2 to : Metal of the VIII * subgroup of the PSE : Cl, Br, 3, 1.3-oionate, carboxylate, carbonate : Mono- or diolefin, arene, CO, H ₂ O, alcohol, amine X or 2X: anion of a strong acid, ζ, Β. BF ClO. HSO F ₀ C-COO k 1 in η or anion of one 2 strong 2-basic acid, z * B, SO 1 or 2 O to 3 O to 4 O to 3 mean, £ <4 U * 4 (JU * J by synthesis of ON-bis (phosphinous acid) derivatives of optically active β-amino alcohols and subsequent complex formation with transition metal compounds, characterized in that an optically active ß- {prim.- or sec, amino) alcohol in the presence of proton acceptors at -70 ⁰ C to + 100 ⁰ C reacted with a Diorganylhalogenphosphin and the crude or purified reaction product is replaced by easily displaceable ligands of soluble complexes of O to 4 valent metals of VIII. Subgroup of the PSE. 2. Method according to item 1, characterized in that naturally occurring, optically active amino alcohols and their derivatives are used as starting materials « 3. The method according to item 1, characterized in that synthetic β-amino alcohols with «(. 'Or ß-aryl groups are used as starting materials, which are readily available as by-products of industrial processes or easily produced from these. 4. The method according to item 1 to 3, characterized in that the amino alcohols with diarylchlorophosphines and tert. Aradnen- be reacted at temperatures of 0 to 50 C. 5 «method according to item I ₁ characterized in that the ON-bis (phosphinigsäurederivate) of the optically active ß-amino alcohols in a molar ratio of 1: 1 to 2: 1 with cationic metal complexes, preferably rhodium (I) -olefin complexes, under Formation of optically active chelate complexes are reacted. 6. The method according to item 1, characterized in that the same optically active ligands with electrically neutral metal complexes, preferably chloro-rhodium Koraplexen implemented. Verfahrenφ A method according to item i and S, characterized in that the resulting Neutralks complexity of the ON-3- {phos> ~ phinigsäurederivate) of ß-uAasinoalkoholen by subsequent action of Ag * ions, preferably in the form of AgBF., In cationic complexes according to Point 5 to be converted « 8 »process according to item 1 and 5 to 7, characterized in that the optically active Chelatkompisxa obtained are isolated before use as catalysts in crystalline form. 9 * Process according to item 1 and 5 to 7, characterized in that the catalysts are synthesized only by merging the components in solution and used without isolation. 10. The method according to item 1, S and 9, characterized in that & the catalysts are used in Kohlenwasserstoffef ethers, esters or alcohols as a solvent » 11 »method according to item 1 and 5 to 10, characterized in that 'the optically active' chelate complexes are used for enantioselective syntheses.