SE430219B - SUMMARY OF USE AS A CATALYST FOR ASYMMETRIC HYDRATION OF BETA-SUBSTITUTED ALFA ACYLAMINOACRYL ACIDS AND / OR SALTS THEREOF - Google Patents

Description

excellent yields of the desired enantiomer are obtained from such olefin compounds if a compound consisting of an optically active metal coordination complex falling under the structural formula M1XnL5 or M2X2L2 is used as catalyst. where M1 is rhodium, ruthenium, iridium or osmium, M2 is palladium or platinum and X 1 is hydrogen, chlorine; fluorine, bromine or joe, n is an integer 1 or 5, each of the symbols L representing a phosphine or arsine ligand, at least one of which is optically active. Such a reaction is illustrated in the following reaction scheme, where the fsubstituent is phenyl: Q omg-coon io fl a-o fi-coon IH optically A _ FH active Acyl catalyst in Acyl Such processes for asymmetric hydrogenation are the subject of Swedish patent 7106040-4 (publ No. 55 552) and is treated in detail in its description. The gas substituent may be, for example, hydrogen, alkyl, Z-substituted alkyl, aryl, substituted aryl, aralkyl, amino, benzylamino, dibenzylamino, nitro, carboxyl and carboxyl ester, etc. The person skilled in the art In this field, the substituent can be selected from a large number of groups, and in this choice it is only necessary to ensure that the desired amino acid is obtained as the end product.

Examples of amino acids whose enantiomers with the catalyst according to the invention can be easily prepared are alanine, p-chlorophenylalanine, tryptophan, phenylalanine, 5- (5,4-dihydroxyphenyl) -alanine, 5-hydroxytryptophan, lysine, histidine, tyrosine, leucine, glutamic acid and valine.

The acyl group may be substituted or unsubstituted and examples include acetyl, benzoyl, formyl, propionyl, butyryl, toluyl, nitrobenzoyl and other acyl variants used as protecting groups in peptide synthesis, etc. It is preferred that such catalytic hydrogenation of decubstituted or substituted -acrylic acids are carried out in the presence of a base. few-substituted fi lacylamido-acrylic acids and / or salts thereof are precursors to the substituted or unsubstituted alanines. The compounds of the following structural formula give excellent results in hydrogenation with the catalyst according to the invention and therefore represent compounds which are particularly suitable for the purpose: 'm - c = f: - coon H §HZT represents hydrogen, carboxyl, unsubstituted or substituted: substituted alkyl, thienyl, β-indolyl, β-imidazolyl, furyl, piperenyl or BP Cq Dr and each of the symbols B, C and D, one independently representing hydrogen, alkyl, carboxyl, hydroxyl (and metal salts thereof), alkoxy, halogen, acyloxy, aryloxy, aralkyloxy, amino, alkylamino, nitro or cyano, Z represents substituted or unsubstituted acyl of the type indicated above and p, q and r are integers O-5 , where the sum p + q + r is at most 5.

An especially preferred embodiment, which is also illustrative of hydrogenation with the catalyst according to the invention, is the preparation of the substituted and unsubstituted phenylalanines by catalytic asymmetric hydrogenation. Unsaturated precursors for such Obamino acids can be prepared according to Erlenmeyer's azlactone synthesis, wherein a substituted or unsubstituted benzaldehyde is reacted with an acylglycine, for example acetylglycine, and acetic anhydride to azlactone, which is hydrolyzed to the unsaturated precursor pair. Such a reaction is illustrated by the following reaction scheme, in which benzaldehyde and acetylglycine are used as examples of reactants: I '4 OO * n _ n _' _ (1) Q-c fi o + cnšc-rë fl- cnacoon + o (c-cH5> 2 -> <\: /> c1¶ = c_: o (2j Q-Qfßç- (lho Ocmçicøo fi 1%? W * 9 va CH; f "CH3. In such reactions, the substituents on the phenyl group may be selected from a large number of groups and the choice may be limited only by the phenylalanine which is the desired end product. In addition, such substituent groups may themselves be precursors to substituents which are desired. If, for example, the substituted benzaldehyde is vanillin and it is desired to produce 5- (5,4-dihydroxyphenyl) -alanine, the unsaturated precursor may be x-acetamido-4. -hydroxy-5-methoxy-cinnamic acid, which would give N-acetyl-5- (4-hydroxy-5-methoxyphenyl) -alanine by hydrogenation, which can then be converted to 5- (5,4-dihydroxyphenyl) -alan The g-L-enantiomer of such phenylalanines is particularly desirable. Thus, for example, 5- (5,4-dihydroxyphenyl) -L-alanine (L-DOPA) is well known for its utility in treating the symptoms of Parkinson's disease. Likewise, L-phenylalanine has been found to be useful as an intermediate for the preparation of the alkyl esters of L-aspartyl-L-phenylalanine, which have recently been found to be excellent synthetic sweeteners. According to the present invention, there are now optically active hydrogenation catalysts as defined in the following claims, which catalysts are soluble rhodium coordination complexes with at least one catalytically active phosphine ligand. By "soluble" is meant that the catalysts are soluble in the reaction mass and the intended catalyst is consequently homogeneous catalysis.

IVO 45 20 25 BO * iv Rhx (AR * 5R5R7) 5 X 7900354-7 The phosphine ligand may, for example, have the formula AR5R5R7, where A is phosphorus and each of the symbols R5, R6 and R? one independently of the other represents a hydrogen atom; an alkyl or alkoxy group having 1-42 carbon atoms; a substituted alkyl group in which the substituents are selected from the following, namely amino, carbonyl, aryl, nitro and alkoxy, which alkoxy contains at most 4 carbon atoms; an aryl group; an aryloxy group; a phenyl group; a phenyl group substituted with less than 5 substituents, the substituents being selected from the following, namely alkoxy and alkyl, hydroxy, aryloxy, amino and nitro; cycloalkyl having at least 5 carbon atoms; substituted cycloalkyl; pyrryl; thienyl; furyl; pyridyl; piperidyl; and 5-cholesteryl. The optical activity of the metal coordination complexes of the invention lies in the phosphine ligand. This optical activity can be due either to the fact that there are three different groups on the phosphorus atom or to the fact that an optically active group is attached to the phosphorus atom. In the coordination metal complex, only one ligand needs to be optically active for the catalyst according to the invention to function.

If the optical activity of the ligand is that an optically active group is attached to the phosphorus atom, there need be only one such group and the other two groups may be the same or inactive. In this case, only one of the groups R5, R6 or R? be optically active and the remaining two groups may be identical or inactive.

Useful catalysts fall under the following formulas for coordination metal complexes but are not limited thereto. The formulas indicate an asterisk asymmetry and thus optical activity. The asterisk denotes the asymmetric atom or the disymmetric group.

I Rhx (A * R5R6R7) 5 vi: II i Rnx (A * R5R6R7) 2 (AR5R6R7) VIII III RhX (A * R5R6R7) (AR5R6R7) 2 IX RhX5 (A * n5R6R7) 5 Rnx5 (A * R5R6R7) 2 ( AR5R5R7) Rhx5 (A * R5R6R7) (AR5R6R7) 2 RhX¿ (AR * 5R5R7) 5 Rhx5 (AR * 5R5R7) 2 (AR5R5R7) Rnx3 (AR * 5R5R7) (AR5R “R7) 2 v RhX (AR * 5R5R7) (AR5R6R7) xx VI Rhx (AR * 5R5R7) (AR5R6R7) 2 7900354-7 45 In the list of catalysts given above as examples, the disymmetric group may be R5, R6 or R? and is not limited to any single group. In addition, there may be a combination of groups attached to the metal.

Of course, the above formulas represent not only the coordination metal complexes containing two or three ligands but also the coordination metal complexes in which the number of ligand-metal coordination bonds is smaller and in which bonds are provided by multi-toothed ligands. Thus, for example, it may happen that the complex includes only two ligands if one of the two ligands is bidentate, ie. gives two coordination bonds. Thus, it can only contain one ligand, if this is three-toothed, ie. makes three coordination bonds.

Among the substituents on the phosphorus atoms may be mentioned methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, acetoxyphenyl, methylphenyl, ethylphenyl, ethylphenyl, butylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, hydroxyphenyl, phenoxyphenyl, o-anisyl, 5-cholesteryl, benzyl, pyrryl, furyl, pyridyl, thienyl, piperidyl, mentyl, bornyl and pinyl.

Among the above-mentioned substituents fr.o.m. butyl t.o.m. dodecyl, of course, includes isomers thereof. However, the substituents are not limited to those listed above.

For the purpose of the invention the following optically active phosphines may be used, but the invention is of course not limited thereto; metyletylfosfin, metylisopropylfosfin, etylbutylfosfin, isopropylisobutylfosfin, methylphenylphosphine, etylfenylfosfin¿ propylfenylfosfin, butylfenylfosfin, fenylbensylfosfin, fenylpyrrolfosfin, etylisopropyliso ~ butylphosphine, methylphenyl 4-methylphenylphosphine, ethylphenyl-4- methylphenylphosphine, metylisopropylfenylfosfin, IO 15 20 25 50 55 7 7900354 '7 ethylphenyl- 2,4,5-trimethylphenylphosphine, phenylbenzyl-4-dimethylaminophenylphosphine, phenylpyridylmethylphosphine, phenylcyclopentylethylphosphine, cyclohexylmethylisopropylphosphine, o-methoxyphenylmethylphenylphosphine and o-methoxyphenylcycloxyphyl. D.

For the purpose of the invention, particularly preferred are the optically active phosphines which contain at least one phenyl group which bears a substituent in the ortho position, for example hydroxy; alkoxy having 1 to 12 carbon atoms; and aryloxy. Excellent results have been obtained with methylphenyl-o-anisylphosphine and methylcyclohexyl-o-anisylphosphine.

The latter compound and the optically active coordinating metal complex hydrogenation catalysts thus prepared are new and it has been found that the desired enantiomers of substituted and unsubstituted phenylalanines are readily prepared in excellent yields when using such optically active ligands. in the manner according to the invention.

Although only one optically active group or ligand is required in the coordination metal complex catalyst, it is preferred to facilitate the preparation that all three ligands be mutually equal. It is also preferred that the asymmetry reside with the phosphorus atom.

It has been found that excellent yields of the desired enantiomers can be obtained not only with the optically active hydrogenation catalysts described above, which are coordination metal complexes of rhodium, but good yields can also be obtained when the hydrogenation is carried out in the presence of a catalyst which consists of a solution of rhodium and at least one equivalent of one phosphine ligand per mole of rhodium, provided that the ligand is optically active. By way of example, the catalyst may be prepared by dissolving a soluble rhodium compound in a suitable solvent together with a ligand, the ligand: metal ratio being at least one equivalent of ligand per mole of rhodium, preferably two equivalents of ligand per mole of rhodium. Likewise, it has been found that the catalyst can be prepared in situ by adding a soluble metal compound to the reaction mass together with an addition of the appropriate amount of the optically active ligand to react. the mass either before or during the hydrogenation.

Useful soluble rhodium compounds include rhodium trichlorohydrate, rhodium tribromide hydrate, rhodium sulfate, organic rhodium complexes with ethylene, propylene, etc. and bisolefins such as 1,5-cyclooctadiene and 1,5-hexadiene, bicyclo-2,2,1-hepta- 2,5-diene and other dienes, which can form bidentate ligands, or an active form of metallic rhodium, which is easily solubilized; It has been found that the catalyst of the invention preferably contains the optically active phosphine ligand in a ratio of about 1.5 to about 2.5 (preferably 2.0) equivalents of ligand per mole of metal. For handling and storage, it is preferred in practice that its optically active catalyst be in solid form and it has been found that this can be achieved with solid, cationic coordination metal complexes. . .

Cationic coordination metal complexes containing two equivalents of phosphine per mole of metal and a chelating bis-olefin can be used as catalysts according to the invention. Thus, using the organic rhodium complexes described above, such cationic coordination rhodium complexes can be prepared by slurrying the organic rhodium complexes again into alcohol, for example ethanol; add two equivalents of the optically active phosphine to form an ionic solution, then add a suitable anion, for example tetrafluoroborate, tetraphenylborate or any other anion which precipitates or crystallizes a solid cationic coordination metal complex either directly from the solution or during treatment in a suitable solvent. Examples of cationic coordination metal complexes are cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroborate, cyclooctadien-1,5-bis (methyl-cyclohexyl-o-anisylphosphine) -rodium tetraphenyl 1-Hepta-2,5-diene-bis (methylcyclohexyl-o-anisyl-phosphine) -rodium tetrafluoroborate.

Without limiting the invention to any particular theory, it is believed that the catalyst is in the form of a first-dium which, upon contact with hydrogen, is converted to active form.

This conversion can of course be carried out during the actual hydrogenation of the olefin bond or the catalyst or its precursor can be hydrogenated before the addition to the olefin material to be hydrogenated.

The hydrogenation is usually carried out in a solvent such as benzene, ethanol, toluene, cyclohexane or a mixture of two or more of these. Almost any aromatic, saturated alkane or cycloalkane which is inactive against the hydrogenation conditions of the hydrogenation with the catalyst according to the invention can be used as solvent. Since the hydrogenation has been shown to be specific, solvents such as nitrobenzene can also be used. However, methanol is preferred as the solvent.

As stated above, the catalyst is added to the solvent either in the form of a compound as such or in the form of the components of the compound, which in that case form the catalyst in situ. When the catalyst is added in the form of its components, these may be added before or simultaneously with the β-substituted α-acylamidoacrylic acid. Components for the preparation of the catalyst in situ are the soluble metal compound and the optically active phosphine ligand.

The catalyst can be added in any effective catalytic amount, usually in an amount between about 0.0001 and about 5% by weight of metal contained in the catalyst based on the amount of B-substituted α-acylamidoacrylic acid and / or salt thereof. Measures should be taken within practical limits to avoid contact between the catalyst or the reaction mass and oxidizing material. In particular, precautions should be taken to avoid contact with oxygen. It is preferred to prepare the hydrogenation reaction and carry out the hydrogenation itself in gases (other than H2) which are inert to both reactants and the catalysts, for example nitrogen or carbon dioxide. As pointed out above, it has now been found that the asymmetric hydrogenation is increased by the presence of a base in the reaction mass. Although the asymmetric hydrogenation can be carried out in a reaction mass which is free from base and up to in an acidic reaction mass, the yield is improved if small amounts of a basic material are added to the reaction mass in the reaction mass, namely npp to at most one equivalent per mole of acrylic acid.

It is surprising that a small amount of base, which is added to a t.o.m. acidic reaction mass gives improved asymmetric hydrogenation and it has been found that the formation of a small amount of salt of acrylic acid is sufficient to obtain improved results. Useful bases include tertiary bases, such as triethylamine, further NaOH and almost any other 10 -basic material which forms a salt with carboxylic acids.

After adding the components to the solvent, hydrogen is added to the mixture, until between about 1 and about 5 times the molar amount of B-substituted α-acylamido-acrylic acid or an amount required for complete hydrogenation to the desired level is added. The pressure in the system necessarily varies, as it depends on the type of β-substituted α-acylamidoacrylic acid, the type of catalyst, the dimensions of the hydrator, the amount of components and the amount of solvent and / or base. Lower pressures, including atmospheric pressure and subatmospheric pressure can be applied as well as higher pressures. The reaction temperature can be between about -20 and about 140 ° C. Higher temperatures can be applied but are not normally required and can lead to accelerated side reactions. When the reaction is complete, which is determined in a conventional manner, the solvent is removed and the products and the catalyst are separated by ordinary means.

Many naturally occurring products and medicines _ occur in an optically active form. In this case, usually only the I or D form is effective. Synthetic preparation of these compounds has hitherto required further steps, namely separation of the products into their enantiomers.

This is time consuming and expensive. The catalyst according to the invention enables the production of optically active products, whereby said time-consuming and expensive separation is eliminated at the same time as the yields of the desired enantiomers are increased and the amount of undesired enantiomer is reduced. Desired enantiomers of α-amino acids can be prepared by hydrogenating the appropriately β-substituted α-acylamidoacrylic acid in the manner set forth herein followed by the removal of the acyl group on the α-amino group and the other protecting groups in a conventional manner, so as to obtain the desired enantiomer.

It has now been found that α-amino acids prepared from the β-substituted α-acylamidoacrylic acids and / or salts thereof can be readily prepared with a large predominance of the desired enantiomer, which makes the catalyst of the present invention particularly valuable.

The following examples show in more detail how the hydrogenation with the catalyst according to the invention is carried out, but of course the invention is not limited to these details. "Parts" means parts by weight, unless otherwise expressly stated. In the examples,% optical purity has been determined by the following equation (the optical activities are of course expressed as the specific rotations, which are determined in one and the same solvent1) = observed optical activity for the mixture X 400% optical = purity optical activity of the pure enantiomer Example 1: The optically active phosphines and arsines can be prepared in the manner described by Mislow and Krpium, J. Am. Chem. Soc., 89, 4784 (1967). ._ 121119012 + 2 cušon Ph P (oc1¶5) 2 In a suitable vessel equipped with a stirrer, temperature measuring device and loading device, 250 parts of phenyldichlorophosphine, 240 parts of pyridine and 495 parts of hexane were charged. The solution was cooled to about 5-40 ° C and a mixture of 96 parts of methanol and 27 parts of hexane was added with stirring over about 1.5 hours. The mixture thus obtained was stirred for a further 2.5 hours while heating to about 25 ° C. The reaction was carried out in an inert nitrogen atmosphere. The pyridine hydrochloride formed during the reaction was filtered off and the filtrate was concentrated. The yellow residue was distilled, collecting a colorless fraction with a distillation range of 95.5-97 ° C / 47 mm Hg (82% yield of dimethylphenylphosphonite). (Harwood and Grisley J. Am. Chem.

Soc., 82, 425 (1960)). O + cn I ----> Pniå-ocn Ph1 = (ocH5) 2 5 I 5 7900354-vi 40 15 20 25 50 12_ In a suitable vessel equipped with stirrer, temperature measuring device and coating device, 14 parts of dimethylphenylphosphonite, 2.5 parts were charged. parts methyl iodide and 9 parts ~ toluene. The solution thus obtained was slowly heated.

The reaction was extermic and the temperature rose to about 440 ° C. The reaction mixture was kept at a temperature of about 100-120 ° C and an additional 185 parts of dimethylphenylphosphonite was added slowly. Additional amounts of methylene oil in portions of about 1 part each were added time after time during the phosphonite addition. The reaction mixture was kept at about 410 ° C for an additional 1 hour after the components were added. The reaction mixture was then distilled and a portion was collected at distillation intervals tis-fxiurc / fv; mm Hg, - (96% yield of methylphenylmethylphosphinate). (Harwood and Grisley J. Am. Chem. Soo., 82, 425 p (49eo)), GH; 9 c fl š O \ + Pcl5 ---- e> P - cl p ///, P-OCH; Ph Ph_ In a suitable vessel equipped with a stirrer, condenser, temperature measuring device and coating device, 187 parts of methylphenylmethylphosphinate and 1600 parts of carbon tetrachloride were charged. To this mixture was added 229 parts of phosphorus pentachloride in three portions of 50 parts each and one portion of 79 parts. An increase in temperature was observed with the addition of the first three portions. The mixture was stirred at about 60 ° C for two hours and then the carbon tetrachloride and phosphorus oxychloride were distilled off. The residue was distilled and a fraction with a distillation range of 158-441 ° C / 47 mm Hg was collected. (95% yield of methylphenylphosphine chloride). (Methods Der-Organishen Chemie (Houben- weyl) vel. XII / I p. 243.) 'i ca C 5 CH? 9. 5 Q bas CH5 \\ 9 / \ I> -cl +? '_>: PÜ-o' Ph p I OH Ph CH // CHÉ \ cH “/ GH CH5 on; In a suitable vessel equipped with a stirrer, condenser, temperature measuring device and loading device, 78 parts of menthol (few /% 5 = -50 ° in ethanol) and 72 parts of diethyl ether were charged. To the solution thus obtained was added 449 parts of triethylamine and the mixture was cooled to about 0 ° C. To the mixture was added with stirring 87 parts of methylphenylphosphine chloride over the course of about 4.5 hours while maintaining the temperature at about 0 ° C. The mixture was allowed to stand. until the temperature rose to about 25 ° C, after which it was heated under reflux for about 10.5 hours.

The triethylamine hydrochloride was filtered off from the mixture and the filtrate was concentrated to give a solid which melted at 50-6S ° C and which was found to be a mixture of .1-menthylmethylphenylphosphinate diastereoisomers (60% S and 40% R).

The mixture of Al-menthyl-methylphenylphosphinate diastereoisomers prepared as above was partitioned between the components by crystallization several times in hexane and crystallization in diethyl ether to give a solid, melting at 78-82 ° C and showing be the S-form of'.Q-mentyl-methylphenylphosphinate.

CH 5 - o o Ph n 'Ph u Érxlo g + caöc fi zc fl amgs; \ P * Û -cazcazc fi š GH; at 0:13 / ° H \ ena en; In a suitable vessel equipped with a stirrer, a temperature measuring device, a coating device and a condenser, an inert nitrogen atmosphere was blown in and then 9.5 parts of magnesium, 7 parts of diethyl ether and a reaction-initiating amount of iodine were charged. A small amount of bromopropane was added to initiate the reaction, whereupon a mixture consisting of 4? parts of bromopropane and 125 parts of diethyl ether were slowly added at such a rate that mild refluxing of the reaction mixture was maintained. The reaction mixture was then cooled to about 25 ° C and stirred for an additional two hours. i vaoor fi sla-i? g 1.4 'IO '15 20 25 50 55 _ To this mixture was added a mixture consisting of 12 parts of S-form of -α-menthyl-methylphenylphosphinate (prepared as above) and 88 parts of benzene. The diethyl ether was then removed and the mixture thus obtained was heated at 78 ° C for 64 hours.

The magnesium complex reaction product was decomposed with a solution of ammonium chloride and then filtered. The precipitate was extracted with hot benzene and the extract was combined with the filtrate. The organic layer was dried over sodium sulfate and the solvents were removed to give a yellow oil. This was chromatographed on a silica gel column to give a mixture of hexanesbenzene diethyl ether (5: 1: 4) to give an optically active phenylmethylpropylphosphine oxide in 61% yield.

Ph-. u a 5 Ph _ D). \\) '//, P * -CH2-cH2-CH; + Hslclš + Ef5N '--- +>.-CH2cH2cH5 cnš. e g CH5 In a suitable vessel, which was charged with an inert nitrogen atmosphere and which was equipped with a stirrer, temperature measuring device and loading device, 16 parts of trichlorosilane and 88 parts of benzene were charged at a temperature of approximately OfC. To this mixture was added at a temperature of about 4-6 ° C a mixture consisting of 22 parts of triethylamine and 44 parts of benzene. The mixture thus obtained was then heated to about 25 DEG C. and a mixture of 8.2 parts of optically active phenylmethylpropylphosphine oxide (prepared as above) and 22 parts of benzene were added. The mixture was then heated to about 60 ° C over two hours and then cooled to about 2590 ° C.

The silicon complex obtained as a reaction product was decomposed with 75 parts of a 20% solution of sodium hydroxide and then with 55 parts of water. The mixture thus obtained was allowed to stand for about 45 hours, after which it was divided into layers. The organic layer was extracted with 5% hydrochloric acid, twice with water and then dried over sodium sulfate.

The solvent was distilled off to give methyl propylphenylphosphine in 95% yield with 69% optical purity. 10 45 20 25 50 15 7900 354 '7 A process for producing r <<1ium (III) chloride-tris- (methyl-propylenylphosphine) is described below.

A suitable vessel containing a nitrogen atmosphere is charged with 0.542 g (10,000 ml) of hydrochloric acid trihydrate and 10 ml of methanol, followed by 0.76 g (0.0046 mol) of the optically active methyl acetate prepared as above. The propylphenylphosphine in 5 ml of methanol was added dropwise over 15 minutes. The mixture was allowed to stand for one hour, during which time a yellow precipitate formed. This was filtered off to give 0.21 g of the rhodium complex with specific rotation [α] 25 = -69.2 ° (a mixture of benzene and ethanol in a volume ratio of 1: 1). Concentration of the filtrate gave an additional 0.15 g of the product with specific rotation [5] å5 = -56.4 ° (a mixture of benzene and ethanol in a volume ratio of 1: 1).

Example 2: The general procedure described in Example 1 was repeated and the mixture of the β-menthyl-methylphenylphosphinate diastereoisomers was cleaved by crystallization from hexane and / or hexane ethers to give an S-form, melting at 78-82 ° C and having specific rotation Åälås = -94 ° (benzene) and an R-shape, which melted at 86-87 ° C and had specific rotation [Q / äs = -17 ° (benzene). 0:15 ocnš I o ngar O Ph .I-pßr) _. od-É l ___: h \;> r) @ .cíïâø / CH \ os; o cH5 H5 'CHE / In a suitable vessel equipped with a stirrer, temperature measuring device, loading device and condenser an inert nitrogen atmosphere was blown in, whereupon 18.5 parts of magnesium turnings, 14 parts of diethyl ether and a reaction-initiating amount of iodine were charged. o-Anisyl bromide was added to initiate the reaction, and then a mixture of 158 parts of o-bromoanisole and 400 parts of diethyl ether was slowly added at such a rate that mild reflux boiling was maintained. After the addition was added, the mixture was refluxed for a further two hours. § 79 55 'IG To the mixture was added a mixture consisting of 74 parts of either the R- or S-form of 1L-menthyl-methylphenylphosphinate (choice of the S- or R-form depends on which enantiomer desired to be obtained by the asymmetric hydrogenation) and 450 parts of benzene. The diethyl ether was then removed and the mixture was stirred at 7 ° C for 64 hours.

The magnesium complex obtained as a reaction product was decomposed with a solution of ammonium chloride and the product was extracted from the aqueous phase with benzene. After the benzene was removed, the remaining oil was distilled, first removing a menthol fraction. Finally, distill the product over at 180 DEG-19 DEG C./0.5 nm Hg. The required methylphenyl-o-anisylphosphine oxide was formed in 60% yield. Using the R-form, a product with specific was obtained. rotation [Q] š5 = + 27 ° (methanol). Using the S-shape, a product with opposite rotation was obtained.

CH O p-d 9 ocnš 'Ph 7 # 5 rn - ex) + Hsici + Et N _ - _; \\\ rX) - / f 5 5 // - CH; _ cs; .

In a suitable vessel containing an inert nitrogen atmosphere and equipped with a stirrer, temperature measuring device and loading device, 46 parts of trichlorosilane and A 400 parts of benzene were charged at a temperature of about 5 ° C. To the mixture was added at 4-6 ° C a mixture of 42 parts of triethylamine and 50 parts of benzene. The mixture thus obtained was stirred at 70 DEG C. and a mixture of 7.5 parts of optically active methylphenyl-o-anisylphosphine oxide in 50 parts of benzene was added. The mixture was heated to 70 ° C for 1 hour and then cooled to 25 ° C. D -The silicon complex obtained as a reaction product was decomposed by adding under nitrogen 75 parts of a 20% sodium hydroxide solution at 25 ° C under cooling. The desired methylphenyl-o-anisylphosphine was obtained from the organic layer.

It had specific rotation [Q / š5 = + 4¶ ° (methanol§ when the phosphine oxide with specific rotation prepared above was /% 5 = + 27 ° (methanol) was used. Using the opposite enantiomer of the phosphine oxide, phosphine was obtained with reverse rotation. D 40 45 20 25 50 55 7900351 »'7 47 Example_5: Preparation of methylcyclohexyl-o-anisylphosphine AND AND .. 5 0) 5% ah / c") Wo --- »9:33 CH; A one liter autoclave was charged with 445 parts of the (+) - methylphenyl-o-anisylphosphine oxide prepared as above, 28 parts of 5% rhodium on carbon and 250 parts of methanol, the batch was heated to 75 ° C and stirred under a hydrogen atmosphere When the hydrogen uptake ceased, the NMB spectrum showed that the reaction described in the above equation proceeded to 75%. An additional 7.0 parts of catalyst was added, the batch was added again again under hydrogen pressure 56 kp / cma overpressure and the reaction was continued to a conversion of 96%. was filtered off and the methanol was evaporated in vacuo. The crude oil was taken up in 200 parts of dibutyl ether and cooled to 0 ° C. The precipitated crystals were filtered off and washed with hexane. 65 parts of methylcyclohexyl-o-anisylphosphine oxide were obtained in this way, which melted at 408-140 ° C and had a specific rotation [Q] O = + 65 ° (methanol).

The phosphine oxide prepared as above can be reduced to methylcyclohexyl-o-anisylphosphine in 95% yield using HSiCl and triethylamine in the manner set forth above for methylphenyl-o-anisylphosphine. The resulting methylcyclohexyl-o-anisylphosphine is a liquid with specific rotation Z @ 7šo = + 98.5 ° (methanol).

Asymmetric hydrogenation of α-benzamido-4-hydroxy-5-methoxy-cinnamic acid A hydrogenation apparatus equipped with a pressure gauge, temperature measuring device and heating device was charged with 25 parts of α-benzamido-4-hydroxy-5-methoxy-cinnamic acid, 186 parts of methanol and 64 parts 5% sodium hydroxide. The batch was carefully blown clean to remove each trace of air and the hydrogen pressure was finally set at 3.5 kp / cm? overpressure and the temperature of 25 ° C.

A catalyst solution was prepared by dissolving 0.0059 s of rhodium-4,5-Hexadianchloria (δ âh (1,5-hexaeian) o; 7¿) with melting point 415-447 ° C, Example 4: 47900354-vi 40 45 20 '25 50 55 48 elemental analysis fi% C% H g% Cl baby food 52.68 4.57 in 16.08 found ~ §2.41 4.44 45.82 u. "Am. Cham. Saa., 86.217 (1964)) i 2 Then, 0.0159 g of (+) - methylphenyl-o-anisylphosphine was added, _ [&] š5 = + 42 ° (methanol) in 1.5 ml of benzene.

Faafinaxia is carried out without an amide pact of 70-75 ° C, e (/ d] åP = + 25.9 ° (methanol)). Hydrogen was then passed through the mixture for five minutes. The catalyst solution thus obtained was then pressed into an autoclave with hydrogen pressure.

The hydrogenation started immediately and was completed after 5-4 halters at 25 ° C and 5.5 kp / cmg overpressure.

Analysis of the solution thus obtained showed an optical purity of 56.4% corresponding to an I / D # mixture of the sodium salt of N1benzoyl-5- (4-hydroxy-5-methoxyphenyl) -alanine in a ratio of 78:22. The benzoyl-substituted amino acid can be prepared in 95% yield by evaporation of the methanol and neutralization of the sodium salt with hydrochloric acid. The Ifenantiomer thus obtained can be converted to IFDOPA by simple hydrolysis to remove the blocking groups benzoyl and methyl on the substituent in the 5-position of the phenyl group.

Example Gel: A one liter autoclave was sent with 25.0 g of benzamido-4-hydroxy-5-methoxy-cinnamic acid, 500 ml of methanol and 0.6 ml of 5% aqueous NaOH. The batch was stirred at 25 ° C below 2.8 kp / cm (overpressure) of pure hydrogen gas, until it could be established with certainty that no leakage occurred. Approximately 1 ml (0.01% Rh, 0.05% phosphine) of the following catalyst solution was added through a partition without depressurizing the pressure. The catalyst solution had been prepared by dissolving under Na of 0.0050 g [Fb (4,5-hexadiene) 017, melting point 145-417 ° C, elemental analysis% .C% H% Cl calculated 52.681 4, §7 46.08 found 32.44 4.41 g 45.82 in 0.35 ml of a solution of methylphenyl-o-anisylphosphine l / d / â = = 42 ° (methanol) with specific rotation / Ä /% 5 = + 42 ° e (methanol) in benzene containing 0.041 g / ml and diluting to 49 ml with methanol. The phosphine oxide precursor had a melting point of 70-75 ° C, ([Q]% 0 = + 25.9 ° (methanol).

Stirring at 4400 rpm was maintained in the reaction mass and hydrogen began to be absorbed after 2-5 minutes of induction time. The hydrogenation was completed in 2 hours.

The methanol was evaporated and the acid was dissolved in one mole of an aqueous solution of NaOH. The neutral catalyst was extracted with benzene and set aside for recovery. The free amino acid was then precipitated by the addition of concentrated H01 with copious inoculation. 24 g of N-benzoyl-(- (Lx-hydroxy-α-methoxirenynalanine were obtained containing 75% of the I-enantiomer and 2?% Of the D-enantiomer. The I-enantiomer can be converted to IFDOPA by hydrolysis as indicated in Example 4.

Examples 6-21: Other optically active α-amino acids were prepared in a manner similar to those set forth in Examples 4 and 5 using a catalyst containing rhodium-4,5-hexadiene chloride and phosphine ligand of the structural formula / 0115 R-PX Q The examples are compiled in the table below: 20 7 9G035lr '7 mmu hmu.

H.ñ¶H.QN.IO O fl n_v OH fl- u. _. _ Û. mz. : z _ _ _. _ _ _ wm mßloß .êñ o. . mooošoummu møoufunwmu EU 1 ¶ \ / _ onu ono _ _ o Qwwuww am .hmummummum .. mooolwuïmmu moon fi oumzu, ¶ x _ 2%: “Tu _ .NEUAX. ,,. a .u ._... š = wH. x fi uho uonsm 989% Size: G30. ._ .Emswxm ¶. mmsnioomx: Hoëwmh fl mpmm _ ¶. "mvmø .må ¶ ¶ _ 79003-5-4-'7 21 Hßw fi nmno ä“ WR âw ¶, ¶ m .moö 3 Qæwxww mm Rmummummu w Qwwlww å -Nmummummu & .vm flfl mn o ° mSw «a novmmh fl mvøm xw š? æumw .mmm ouu W _, ímz \ / OH _ EZ _ _ w mooumu- mul®. »Vn _ ._ mmu _ nu _ mz _ m: oonïmu: u. Ä x vxø fl onm OHU _. _.

IOOUÅVHEU mmu _ 0 "_ _ mz» _ N _ moouÖu xu G fi uÖ fl O. I. I... Mooowöhwäoë moou | oumul® H o fi x _ Hwmëwxm '19oo¶zs4-A7 22 m.VH, m \ mw | ww AM M. ¶ _. _ _ W ¶ zøoufzu- .ÜIÛ _. Fi x _ nmam fl .mh @. -Mzomzu mo Hhm fifl mno 9 ¶ mv? Eä Û. Mmuö.

R .vo flfl wn Oo fi sm uovmmäamvmx x fi pmo wmsašïmx: mmu _. now. ._ EZ .m. moouáo .. mu | ® AX _ PMSOOHA, _ 3 ~. . : oou-onæu.l® 3 MID _ _.

HU. _ f _ _, EZ _ _. moouónmuü _ Ha _HwNEwXü_ CwWm fi O 7900351+ 'A7 25 A fl onmnm fi v fl h fl mn. ømóv., 13%? u% \ fi N wmpmnwm _ _ .o èü fl o fi wwow .. _ Nm. . . ^ Ho fi mßwEv 0% O + HÛN Q wm m \ mw | wæ mä | mUNEUmIU R, ®wn fl oH ommäw uovmmäwmemz xm fl šo mmeaäïmx "mvmu .mßh II ..

O "_ EZ _ moou | mu | AX _ EOOUIIU ^ X -mmulmom O fl-. MDUO Hn fl Nnolwóm _ _ m O EU mao OH ._ _ EZ *, fi ww fi m .O moouóumu .vw, ommu mao. _ EOOUIUHIU OI MH fl wmñwäm 79GO3Eh'7 om 24 m \ Q @ mg # ß «-m>« Qaw wwßmnwm _L @ fl x ° q fi Hmo «_OømEm_u wmasšv .ha” øvæø .mmm whm @ Hmom fi Hhuwvmw fl wäum Hovmuham _m. OO _ M: ooošukmuuøl o: AK mao mao vå5UOHß. Ouo. _. D _ I m2. _ _ ¶.. Moonïuuzu än 9 ,. 3 í. ¶ ommu>. Fi wm fl o. Wmmawfxul 790Û35-lw7 \ '25 io .woášmv .E __ o _ _% Honm% øEv _ .fl hømw _m_ TLLQ ___ fl _ JF _7æ2 @ _. _ U _ m w fi omämw .èxovws ._ _ onu __ _ _ ouu _ mßnww aäm _ _ _ wwßmnmw EZ _ luw fl ošu umm: :: oooónmu om 3 _- / m Rx m _ _ m EU _ O EU O 30. _ o "_ ._ _. . . . _ n fl ød fl ovv _ ._ _ _ _ _ _ _ _ _ _ orw + nG% \ M \ mä _ _ mä. _ w .b.3218 å -Nmvë moQY fl QwmQIÛIoÉH moo fl vónmblom _ .SH. _. vn _. . . ._ _ _ __ _ omxu ._ _ ommu _ .vmn fl mn Oou fl m _ Hovmmwamvmx väß fl oum: wwmHO Hmmšwxw Mmïmo wmëåoäx "mpmw .whm _ _ _96 J _ _ _ Å __ _ __ \ mmu Nm ü møoofm _ __ _ MO m% Hhw fi nmno. Ouw, Wb _ _ \ o. _ _ Ma. _ _ Om SHR ma »_ moou | mwlw fi mou®zo | wmmo _ en o ._ måne _ _ _. _ Oßní _ å .mßfoß man _ _ _ _ moonïmu-Nmolßøm. _ _ _ _ _ nn _. m .W _ mmo: _ _. _ o mo .flfi &. @ ox fl m fi Uomëw flfl mww fl. __ ußæwowm .á ä fl pmo wmaašïå »nouåšmhvmw _ .nU_" mvmu .mhm 0 _ _ _ 9 fl ..

NZ _ .wooolwu fl o Olwnmv ß _. en »._ _ _ _ ma _ nu .. _. \\ moonïwumnïmnf. _ __ mun mao _ _ OIÜ \ fl O o c fl w _ _ _. å _ _ moou | o fl mol®o_m __ ammo. ø fi ï fl o .rm Homemxm 10 15 20 25 50 55 7900354 ~? 27 Eekekie beekiekedeee with 25.0 g (0.55 ml) of deaoetamido-4-hydroxy-5-methoxy-cinnamic acid acetate, 500 ml of methanol and 0.56 ml of 50% Neon. Adtekieven eettee under a pressure of 2.46 kp / cm? overpressure with a mixture of N2 and H2 (50:50). A catalyst solution was prepared by dissolving 0.050 g (0.025 meq.) ¿§H (4,5-hexediene) c; 7ë 1 0.5 ml of the benene, then adding 0.051 meq under a nitrogen atmosphere. (+) - methyloyclohexyl-o-anisylphosphine (optical purity about 90%) in 2.4 ml of benzene. Hydrogen was bubbled through this solution for 10 minutes, Rhodium »1,5-hexadiene chloride, see Examples 4 and 5 here Example 22: above. but obtained on this eat: (+) meey1eyk1enexy1-e-enieyl- feefin, hydrogen kefermig, kekpunke 110-114 ° o / 0.09 mena- / d7š ° = + 9s, 5 @ (e = «1 meon) at 90% .epe1ek purity ¿d / § ° = + s9 ° (e = 1 in MeOH).

The catalyst solution was then introduced into the autoclave and the hydrogenation was carried out at 60 ° C. It was completed in 4 hours. The product, namely N-acetyl-5- (4-hydroxy-5-methoxyphenyl) -alanine acetate, which was recovered by evaporation of the solvent, had specific rotation lä / â5 = +58.2 (Na salt in water). Pure N-acetyl-5- (4-hydroxy-5-methoxyphenyl) -alanine acetate, also in the form of sodium salt in water, had a specific rotation of + 54.0 °. Thus, the optical purity of the resulting hydrogenation product was 70.7% or better than 85% of the enantiomer and 15% of the D-enantiomer.

The procedure described above was repeated with (-) - methylcyclohexyl-O-anisylphosphine (optical purity about 80%). A hydrogenation product containing a major amount of the D-enantiomer was obtained (optical purity of the reaction product mixture was 65%). By appropriate choice of the (+) - or (-) - phosphine, one can thus produce the respective enantiomers in large yield.

Example 2 §: The procedure described in Example 22 was repeated using the (-) - methylcyclohexyl-O-anisylphosphine (epeiek purity ee so%) lä / š ° = -75.6 ° (e = «1 neon) sem the optically active ligand and α-benzamido-4-hydroxy-5-methoxycinnamic acid as the β-substituted α-acylamidoacrylic acid. The resulting hydrogenation product was N-benzoyl-5- (4-hydroxy-5-methoxyphenyl) -alanine containing a major amount of the phosphorus 4 + 7 10 45 20 25 50 ~ 35 28 D enantiomer (optical purity of the reaction product mixture about 65% ).

Example 24: In a pressure flask purged with nitrogen, α-benzamido-4-hydroxy-5-methoxy-cinnamic acid (1.67 g, 5.0 mol), cycloactadiene-1,5-bis (methylcyclohexyl) was charged. o-anisylphosphine) iridium tetrafluoroborate, clear red solid (24.7 mg, 0.025 mol), and 20 ml of anhydrous methanol. The mixture was stirred and purged with nitrogen for 15 minutes. The pressure in the pressure flask was raised to 7 kp / cm 2 overpressure by blowing hydrogen, and the mixture was stirred and heated at 100 ° C for 4 hours 20 minutes. An aliquot of this reaction mixture was subjected to NHR spectrometric analysis, which showed that 59% of the starting material had been converted to the product N # benzoyl-5- (4-hydroxy-5-methoxyphenyl) -alanine. Polarimetric analysis of the reaction mixture after neutralization according to standard procedures showed that the product was poptically active with fd / â “= 9.5 °.

Example 253 To a solution of 2.005 g of N% acetyl-indolyl-α-acetamidoacrylic acid in 60 ml of methanol was added 0.004 g of cyclooctadiene-1,5-bis (methylcyclohexy-1-o-anisylphosphine) rhodium tetrafluoroborate, orange crystals with a melting point of 170-175 ° C. The mass thus obtained was carefully purified, first with nitrogen and then with hydrogen, and then stirred under a hydrogen overpressure of 2.7 kp / cm? at 25 ° C, The hydrogenation to N, N'-diacetyl-tryptophan was completed in 2.5 hours. The solution was diluted to 400 ml and analyzed for optical torque. The solution had Z &] êP = 20, fl °.

The theoretical value for the pure optical enantiomorph is 25.9 °. An optical purity of 77.5% had thus been obtained. The product can be isolated by evaporating the solvent and crystallizing the residue.

Example 26: Optically active methylpropylphenylarsine is prepared as described by Mislow and co-workers in JACS go, 955 (1975) - 0 -. A catalyst solution was prepared by mixing 2 ml of methanol, 0.2 g (+) - methylpropylphenylarsine ([d] šP = + 10.7 °, 80%, 0.16 mmol) and 0.025 g rhodium (cyclooctadiene-4 »5) -acetonylacetonate (0.08 mmol), m.p. 425-428 ° C (dec.). After stirring for 10 minutes under a nitrogen atmosphere 40 45 25 50 55 29 'raooss fl- rv the whole amount of solids had gone into solution. A solution of 4.0469 g of α-acetamide-4- hydroxy-5-methoxy-cinnamic acid acetate in 25 ml of methanol was carefully purged with nitrogen and then placed under a hydrogen overpressure of 5.9 kp / cm at 50 ° C. To the reaction mixture was added through a septum 4.0 ml of the above catalyst solution. The hydrogenation began and was completed in 2.5 hours, as evidenced by a pressure drop of 0.8 kp / omg. The resulting mass was diluted to 50 ml and tested for specific optical torsional power, which was found to be / α] β = -2.55 °. A test solution using pure N-acetyl-3- (4-hydroxy-5-methoxy-phenyl) -phalanine acetate and the same amount of catalyst gave a correction of this torsional ability of the catalyst of 0.7 °. The hydrogenation thus gave a net rotation of -1.8 °.

The pure optical enantiomorph had [/ /% P = 4040.8 °. The optical purity was thus 4.4%.

Evidence that the arsine was not optically pure was obtained by its conversion to the sulfide (Mislow et al. In JACS 92, 955 (4973)) and measurement of the optical purity with a chemical shift reagent (NMR Chiral Shift Reagent, Whitesides and co-workers JACS gg, 1058 ( 1974)). This experiment showed that the methylpropylphenylarcin used had an optical purity of only 45%. Thus, if the hydrogenation had been carried out with the optically pure arsine, an optical purity of 9.5% would have been achieved. By evaporation of the methanol and recrystallization from the concentrated solution, the product was obtained. Example 22: Preparation of cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroborate. In a 4 liter flask was charged under nitrogen 500 ml of methanol and 15.4 g (0.054 mol of Zsbdium- (cyclooctadiene-1.5) chloride] and 50.5 g (98%, 0.42 mol) of methicyclohexyl-o -anisylphosphine was added to the solution and the whole was stirred for 1/2 hour to give a red / orange solution.The solution of sodium tetrafluorene: 015 .mu.g, 0.42 ml) in 1 ml of water was added over a period of hour. Orange crystals separated and were collected. They were washed with water (2 x 30 ml). The product was dried under vacuum at 25 ° O and weighed. 45 g of product with a melting point of 470-175 ° C were obtained in this way. This material was approximately 96% optically pure.

Claims (4)

A compound for use as a catalyst for asymmetric hydrogenation of α-substituted o (-acylamino-acrylic acids and / or salts thereof, "characterized in that it consists of a rhodium coordination complex with at least one optically active phosphine ligand, which complex is obtained from a solution containing a soluble rhodium compound and K is at least one equivalent of an optically active phosphine ligand containing at least one ortho-substituted phenyl group, which ortho-substituent is selected from a group consisting of hydroxy, al- coxy with 1 to 12 carbon atoms and aryloxy. Catalyst according to Claim 1, characterized in that the optically active phosphine ligand contains a K-methyl group. Catalyst according to claim 1, characterized in that the optically active phosphine ligand is methyl-phenyl- or anisylphosphine. Catalyst according to Claim 1, characterized in that the optically active phosphine ligand is methyl-cyclo-ahexyl-o-anisylphosphine.