SE430220B - 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 ralxnrš or 1421 is used as the catalyst. : 21? where M1 is roaium, ruthenium, iridium or osmium, M2 is palladium or platinum and X is hydrogen, chlorine; fluorine, bromine or iodine, 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, in which the fi x substituent is phenyl: active Acyl catalyst Acyl - p orm -coo fl i * _12 a GHz-CH-ooo fi i »1H optlskt_. . ¿% H Such procedures for asymmetric hydrogenation are the subject of Swedish patent 7106040-4 (Publ. No. 400 552) and are discussed in detail in its description. The substituent may be, for example, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, amino, benzylamino, dibenzylamino, nitro, carboxyl and carboxylic ester, etc. Those skilled in the art may select the β-substituent from a large number of groups and need in this selection only make sure 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 unsubstituted 4Reaacylamidoacrylic acids be carried out in the presence of a base. Β-substituted β-acylamido-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: T - Q = P - COOH H h fi ZT represents hydrogen, carboxyl, unsubstituted or sub substituted alkyl, thienyl, β-indolyl, fbimidazolyl, furyl, piperenyl or Bp c- Cq Dr and each of the symbols B, C and D, one independently of the other, represents 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 kind indicated above and p, q and r are the integer O-5, 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: vanessa-n i - ioio ll - Il. '' '(1) Q-CHO + CH5C-1 \ 1H- CH2COOH- + O (C-CH3) 2 -) <\: /> - CH = (, JT_ (|) = O _ 'à V: cH 5 (2) Quinn-om .____.___ + h3'dI In such reactions, the substituents on the phenyl group can be selected from a large number of groups and the choice is limited only by the phenyl group. phenylalanine, which is the desired end product. In addition, such substituent groups themselves may be precursors to substituents desired in the final product and can be readily converted to such desired substituents. For example, the substituted benzaldehyde is vanillin. and it is desired to produce 5- (5,4-dihydroxyphenyl) -alanine, the unsaturated precursor may be α-acetamido-4-hydroxy-5-methoxy-cinnamic acid, which would give N-acetyl-5- ( 4-Hydroxy-5-methoxyphenyl) -alanine by hydrogenation. Converted to 5- (5,4-dihydroxyphenyl) -alanine by simple hydrolysis in the L-enantiomer of such phenylalanines are 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, 20-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 shown to be excellent synthetic sweeteners. The optically active hydrogenation catalysts useful in the process of the invention are soluble coordination complexes containing a metal of the group rhodium, iridium, ruthenium, osmium, palladium and platinum in combination with at least one catalytically active phosphine or arsine ligand. These catalysts are soluble in the reaction mass and are therefore referred to as homogeneous catalysts.

The phosphine or arsine ligands may, for example, have the formula ARSRÖIÜ, RS, RÖ and R7, one independently representing a hydrogen atom or an alkyl or alkoxy group having 1-12 carbon atoms; a substituent A is phosphorus or arsenic and each of the symbols is an 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 3 substituents, the substituents being selected from the following, namely alkoxy and alkyl, hydroxy, aryloxy, amino and nitro; cycloalkyl having at least 3 carbon atoms; substituted cycloalkyl; pyrryl; thienyl; furyl; pyridyl; piperidyl; and 3-cholesteryl.

Optical activity of the metal coordination complexes of the invention lies in the phosphine or arsine ligand. This optical activity may be due either to the presence of three different groups on the phosphorus or arsenic atom or to the fact that an optically active group is attached to the phosphorus or arsenic atom.

As illustrative examples of coordination metal complexes may be mentioned those of the formula M ¥ XnL3 or M2X2L2, where M1 is one of the metals rhodium, iridium, ruthenium or iososium and M2 is palladium or platinum; X is hydrogen, fluorine, bromine, chlorine or iodine; L, as indicated above, is phosphinyl or the arsine ligand; and n is an integer 1 or 3.

In the above formulas for coordination metal complexes, only one ligand (L) needs to be optically active for the method of the invention to work.

If the optical activity of the ligand is that an optically active group is attached to the phosphorus or arsenic 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 Ra, RÖ or R7 need 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. Asterisk denotes the asymmetric atom or the dissymmetric group. By way of example, A *) indicates that the phosphorus or arsenic atom is asymmetric. No asterisk means "no optical activity".

M1X (A *> R5R6R7) 5 M1x (A *) R5R6R7) 2 (AR5R6R7) M1X (A *) R5R6R7) (AR5R6R7) 2 M1X (AR *) 5R6R7) 5 Mix (AR *) 5R6R7) (AR5R6R7) 2 M1 (A *) R5R6R7) 5 Mlxš (A *) R5R6R7) 2 (AR5R6R7) WM1X3 (A *) R5R6R7) (AR5R6R7) 2 M1x (AR *) 5R6R7) 2 (AR5R6R7) M1X3 (AR *) 5R6x7 AR *) 5R6R7) 2 (AR5n6R7) M2x¿ (A * ÜR5R6R7) (AR5R6R7) s ~ M1X5 (AR *) 5R5R7) (AR5R6R7) 2 _M2X2 (AR *) 5R6R7) 2 M2X2 (A *) R5R2R2) AR *) 5R6R7) (AR5R6R7) RnX (A¿R5R6R7) 5 RhX5 (A * k5R6R7) 3 Rhx5 (A * R5R6R7) 2 (AR5R5R7) -Rhx5 (A * R5R6R7) (AR5R6R7) 2 RnXR (AR * RhX3 (AR * 5R6R7) 2 (AR5R5R7) Rhx (A * R5R6R7) 2 (AB5R6R7) RnX (A ° 'R5R6R7) (A125126R7) 2 Rhx (AR * 5R5R7) 5 _ RhX (AR * 5R6R7) 2 (AR5RXR7 (AR * 5R5R7) (AR5R5R7) 2 RhX5 (AR * 5R6R7) (AR5R6R7) 2 where M1, M2, X, A, R5, R6 and R6? has the meanings given above. In the above list of catalysts exemplified, the dissymmetric group may be R5, R6 or R6? 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, as in formulas LÉXZLZ and MIXHL3, respectively, but also the coordination metal complexes in which the number of ligand-metal coordination bonds is described by the number L in the formula and in which these bonds are provided by multi-toothed ligands.

Thus, for example, although there may be only two ligands in a certain coordination metal complex, the formula MIXHL3 still represents the complexes, if one of the two ligands is bidentate, ie. provides two coordination bonds. Likewise, the formula MlXnL3 also represents the complexes in which there is only one ligand, namely if it is three-toothed, i.e. provides three coordination bonds. The substituents on the phosphorus and arsenic atoms may be methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, acetoxyphenyl, methyl ethylphenyl, propylphenyl, butylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, hydroxyphenyl, phenoxyphenyl, o-anisyl, 3-cholesteryl, benzyl, pyrryl, furyl, pyridyl, thienyl, piperidyl, mentyl, bornyl and pinyl. Among the above-mentioned substituents fr.o.m. butyl t.o.m. Of course, isomers thereof are included. However, the substituents are not limited to those listed above.

For the purpose of the invention, the following optically active phosphines and arsines may be used, but the invention is of course not limited thereto: methylethylphosphine, methylisopropylphosphine, ethylbutylphosphine, isopropylisobutylphosphine, methylphenylphosphine, ethylphenylphosphine, propylphenylphenylphenylphenylphenylphenylphenylphosphyl, - 4-methylphenylphosphine, ethylphenyl-4-methylphenylphosphine, metylisopropyl- fenylfosfin.etylfenyl-2,4,5-trimetylfenylfosfin, phenylbenzyl-4- gdimetylaminofenylfosfin, fenylpyridylmetylfosfin, fenylcyklopentyl- etylfosfin, cyklohexylmetylisopropylfosfin, o-methoxyphenylmethyl phenylphosphine, _o-metoxifenylcyklohexylmetylfosfin and corresponding to the arsenic analogues. For the purpose of the invention, particularly preferred are the optically active phosphines and arsines which contain at least one phenyl group which carries a substituent in the ortho position, for example hydroxy; alkoxy having 1-2 carbon atoms; and aryloxy. Excellent results have been obtained with methylphenyl-o-anisylphosphine and methyl-oclohexyl-o-anisylphosphine. The latter compound and the optically active coordination metal complex hydrogenation catalysts thus prepared are novel and it has been found that the desired Substituted and unsubstituted phenylalanines are readily prepared in excellent yields when using such optically active ligands in the method of the invention.

Although only one optically active group or ligand is required in the coordination metal complex catalyst, it is preferred for ease of preparation that all three ligands in the formula M1XnL3 described above be equal. It is also preferred that the asymmetry be located at the phosphorus or arsenic 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 one of the metals rhodium, iridium, ruthenium, osmium, palladium and platinum, but without can also obtain good yields when the hydrogenation is carried out in the presence of a catalyst consisting of a solution of the metals rhodium, iridium, ruthenium, osmium, palladium and platinum and at least one equivalent of one phosphine and / or arsine ligand per mole metal, provided that the ligand is optically active.

By way of example, the catalyst may be prepared by dissolving a soluble metal compound in a suitable solvent together with a ligand, the ligand: metal ratio being at least one equivalent of ligand per mole of metal, preferably two equivalents of ligand per mole of metal. 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 the reaction mass either before or during the hydrogenation.

Rhodium is preferred as the metal. 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 may form bidentate ligands, or an active form of metallic rhodium, which is readily solubilized.

It has been found that the method of the invention is preferably carried out in the presence of an optically active phosphine or arsenic ligand, the ligand being present in a ratio of about 1.5 to about 2.5 (preferably 2.0) equivalents of ligand per mol metal. In practice, for handling and storage, it is preferred to use the optically active catalyst in solid form. It has been found that these results can be achieved with solid, cationic coordination metal complexes. Cationic coordination metal complexes containing two equivalents of phosphine or arsine per mole of metal and a chelating bis-olefin can be used as catalysts for the purpose of the invention. Thus, using the organic rhodium complexes described above, such cationic coordination rhodium complexes can be prepared by suspending the organic rhodium complex in an alcohol, for example ethanol, adding two equivalents of the optically active phosphine or arsine to form an ionic solution, whereupon a Suitable anion is added, for example tetrafluoroborate, tetraphenylborate or any other anion which precipitates or crystallizes a solid co-ordinating coordination metal complex either directly from the solution or by treatment in a suitable solvent. Examples of cationic coordination metal complexes which may be mentioned are cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine-2-rhodium tetrafluoroborate, cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) -rodium tetraphenylborate and 2,icyclic -2,5- 10 15 20 25 30 35 40 a79oozss-A 40 dienebis (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroboratate Without binding the invention to any particular theory, it is believed that the catalyst is in the form of a precursor which upon contact with 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 inert to the hydrogenation conditions in the process of the invention can be used as a solvent. Since the by-preparation according to the invention has been found to be specific, such solvents as nitrobenzene can also be used. However, nanolanol is preferred as the solvent.

As indicated 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 loosely substituted O6 acylaminoacrylic acid. Components for the preparation of the catalyst in situ V are the soluble metal compound and the optically active phosphine or arsine ligand.

The catalyst may be added in any effective catalytic amount, usually in an amount between about 0.000l and about 5% by weight of metal contained in the catalyst based on the amount of β-substituted ε-acylaminoacrylic acid and / or salt thereof. 7 Measures should be taken within practical limits to avoid contact between the catalyst or the reaction mass and the oxidizing material. In particular, precautions should be taken "to avoid contact with oxygen; it is preferred to prepare the hydrogenation reaction and to carry out the actual hydrogenation in gases (other than H 2) which are inert to both reactants and catalysts, for example nitrogen or carbon dioxide. It has 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, namely up to a maximum of one equivalent per liter 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 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 substituted adacacamine amacrylic acid or an amount required for complete hydrogenation to the desired level is added. The pressure in the system necessarily varies, since it depends on the type fl-substituted α-acylamino-acrylic 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 110 ° 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 L- or D-shape is effective. Synthetic preparation of these compounds has so far required further steps, namely separation of the products into their enantiomers. This is time consuming and expensive. The method 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 β-amino acids can be prepared by hydrogenating the suitably β-acylaminoacrylic acid in the manner of the present invention 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 receives the desired enantiomer. 'It has now been shown, atta <-amino acids produced by the U! The α 4 -acylamidoacrylic acids and / or salts thereof can be readily prepared with a large predominance of the desired enantiomer, which makes the present invention particularly valuable.

The following examples show in more detail how the method according to the invention is carried out. Of course, however, 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 solvent):% optically observed optical activity for the mixture X 10 (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 Korpiun, J. Am.

Chem. soc ”89, 4784 (1967). ----- + 1- PhPC12 + 2 CH3OH a P (0cH3) 2 A suitable vessel equipped with a stirrer, temperature measuring device and coating device was coated with 250 parts of phenyldichlorophosphine, 240 parts of pyridine and 495 parts of hexane. The solution was cooled to about 5-10 ° C and a mixture consisting 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 / 17 mm Hg (s2% yield of dimethylphenylphosphonif).

(Harwooa and Gxisley J. Am. Chem. Soc., Az, 423 (1960)) _ g v. _ _ O PhP (ocH3) 2 + cH3I_ -----> Ph? -Ocns CH3 _ A suitable vessel equipped with stirrer, temperature measuring device and protection device was charged with 11 parts of dimethylphenylphosphonite, 2; 5 parts of methyl iodide and 9 parts of toluene.

* The solution thus obtained was slowly heated. The reaction was exothermic and the temperature rose to about 110 ° C. Reaction mixtures were maintained at a temperature of about 100 DEG-120 DEG C. and a further 185 parts of dimethylphenylphosphonite were added slowly. Additional amounts of methyl iodide in portions of about 1 part each were added time after time during the phosphonite addition. The reaction mixture was kept at about 110 DEG C. for a further 1 hour after the components were added. The reaction mixture was then distilled and a portion was collected with a distillation range of 148 DEG-149 DEG C./17 mm Hg (96% yield of methylphenylmethylphosphinate).

Grisley J. Am. Chem. Soc., 82, 423 (1960)).

Harwbod and CH3 O fl CH3 O * \\ u P-OCH3 + PCIS O /// i Ph - _ Ph A suitable vessel equipped with a stirrer, condenser, temperature measuring device and loading device was charged with 187 parts of methylphenylmethylphosphinate and 1600 parts of carbon tetrachloride.

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 distillation range 1ss-141 ° c / 17 mm Hg was collected. (952: replacement of mephylphenylphosphine chloride). (Methods of Organic Chemistry (Houben-Weyl) Vol.

XII / I p. 243). ca: H3 O _ CH3 _ cH3 \\ o 3 * ^ // É-cl +. s_ Q __lfE1 fi, /, É “) - o: Ph fl a. Ph CH - § '' / CH \ _ i / \ CH CH CH3 CH; 3 3. -! A suitable vessel equipped with a stirrer, condenser, temperature measuring device and loading device was charged with 78 parts of 1-menthol QExJâ5 = -500 in ethanol) and 72 parts of diethyl ether. To the solution thus obtained was added 119 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 1.5 hours while maintaining the temperature at about 0 ° C. 10 15 20 25 V '30 35 40 'i i eveooss-s-a -14 The landing was allowed to stand until the temperature rose to about 25 ° C, after which it was heated under reflux for about 10 hours. The triethylamine hydrochloride was filtered off from the mixture and the filtrate was concentrated. This gave a solid which melted at 50-65 ° C and which was found to be a mixture of X-menthyl methylphenylphosphinate diastereoisomers (60% S and 40% R).

The mixture of 1-menthyl-methylphenylphosphinate diastereoisomers prepared as above was partitioned 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 ÅLmentyl methylphenylphosphinate. cnš Ph 0 Ph \\ 0) \ nx) "x v g P -o + - cæäcnzcnzxugsr ___; / P _ CHZCHZCHB C fl s CH _ CH: _ / \ g C33 cH3.

A suitable vessel equipped with a stirrer, a temperature measuring device, a coating device and a condenser was charged with an inert nitrogen atmosphere and then with 9.5 parts of magnesium, 7 parts of diethyl ether and a reaction initiating amount of iodine. A small amount of bromopropane was added to initiate the reaction, whereupon a mixture consisting of 47 parts of bromopropane and 233 parts of diethyl ether was 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.

To this mixture was added a mixture consisting of 12 parts of S-form of-Ethmentyl-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 reactive 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 but a mixture of hexane: benzene: diethyl ether (3: 1: 1) to give an optically active phenylmethylpropylphosphine oxide in 61% yield.

Ph 0 Ph O \\ “X) CH cn CH + Hsicl + st N ----> \\ Éx) cn CH c P” 2 '2' 3 3 3, / * 2 2 H3 CH3 ons A suitable vessel, which was charged with an inert nitrogen atmosphere and which was equipped with a stirrer, temperature measuring device and charging device, was charged with 16 parts of trichlorosilane and 88 parts of benzene at a temperature of about 0 ° C.

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 ° 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 2 ° C. The silica complexes obtained as a reaction product were decomposed with 75 parts of a 20% solution of sodium hydroxide and then with 35 parts of water. The mixture thus obtained was allowed to stand for about 15 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, and methylpropylphenylphosphine was obtained in 95% yield with 69% optical purity.

A process for preparing rhodium (III) chloride tris- (methylpropylphenylphosphine) is described below: A suitable vessel containing a nitrogen atmosphere was charged with 0.342 g (0.00l3 mol) of rhodium (III) chloride trihydrate and 10 ml of methanol, whereupon 0 .76 g (1.0646 mol) of the optically active methylpropylphenylphosphine prepared in the above manner in 3 ml of methanol were 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 and 0.21 g of rhodium complex fi with specific rotation MÉS = -69.2 ° (a mixture of benzene and ethanol in a volume ratio of 1: 1) was obtained.

Concentration of the filtrate gave an additional 0.13 g of the product with specific rotation (= -56.4 ° a mixture of P (D-benzene and ethanol in a volume ratio of 1: 1). 10 15 20 25 35. Example 2: The general procedure described in Example 1 was repeated and the mixture of the Elementyl methylphenylphosphinate diastereoisomers was cleaved by crystallization from hexane and / or hexane ethers to give an S-form, melting at 78 ° C. -82 ° C and had specific rotation -94 ° (benzene) and an R-shape, which melted at 86-8 ° C and had specific rotationÅ% äš5 = -17 ° (benzene). r oH3 ccH3_ ~ - p _ lo _ Mgßr Ph o Ph - Fx) _ o S _ + --- +> \\ §x) 'i-CH i 1 / i / \ CH 3 O CH3 CH3 _ C fl š / 7 A suitable vessel equipped with a stirrer, temperature measuring device, loading device and condenser was charged with an inert nitrogen atmosphere and with 18.3 parts of magnesium turnings, 14 parts of diethyl ether and a reaction-initiating amount of iodine. A small amount of o-anisyl bromide was added to initiate the reaction, and then a mixture of 138 parts of o-bromoanisole and 400 parts of diethyl ether was slowly added at such a rate that mild refluxing was maintained. After the addition was added, the mixture was refluxed for a further two hours.

To the mixture was added a mixture consisting of 74 parts of either the R or S form of Atmentyl methylphenylphosphinate (choice of the S or R form depends on which enantiomer is desired to be obtained by the asymmetric hydrogenation) and 450 parts of benzene. The diethyl ether was then removed and the mixture was heated at 78 ° 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, the product distilled over at 180-190 ° C / 0.5 mm Hg. The crude methylphenyl-o-anisylphosphine oxide was formed in 60% yield. Using the R-form, a product with specific rotation was obtained EkJâ5 = 427 ° (methanol). In use, the S-form gave a product with opposite rotation. 790035544 10 15 20 .I- CJ. 17 ocu o 3 Ph \ cHso Il Ph -l x) _. © + Hslcla + staN ___; A suitable vessel containing an inert nitrogen atmosphere and equipped with a stirrer, temperature measuring device and loading device was charged with 16 parts of trichlorosilane and 100 parts of benzene at a temperature of about 5 ° C. To the mixture was added at 4-6 ° C a mixture of 12 parts of triethylamine and 50 parts of benzene.

The mixture thus obtained was heated to 70 ° C and a mixture of 7.5 parts of optically active methylphenyl-o-anisylphosphine oxide in 30 parts of benzene was added. The mixture was heated to 70 ° C for one hour and then cooled to 25 ° C. q The silica complexes obtained as a reaction product were decomposed by the addition under nitrogen of 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 a specific rotation EK] 55 = + 41 ° (methanol) when the specific rotation of the phosphinoxia prepared in the manner indicated above (e.g. + 27 ° (methanol) was used. Using the opposite enantiomer of the phosphine oxide, phosphine was obtained with reverse rotation.

Example '3: Preparation of methylcyclohexyl-o-anisylphosphine (Ocn3 and ocn3 '-'-' \ pg, \ + H 5% Rn / c - 3); A one liter autoclave was charged with 143 parts of the (+) - methylphenyl-o-anisylphosphine oxide prepared as above, 28 parts of 5% rhodium on carbon and 250 parts methanol- The batch was heated to 75 ° C and stirred under a hydrogen atmosphere with a pressure of 56 kp / cm 2 overpressure. When the hydrogen uptake ceased, the NMR spectrum showed that the reaction described in the equation given above proceeded to 75%. An additional 7.0 parts of catalyst was added, the batch was refluxed under hydrogen pressure of 56 kp / cm 2 and the reaction was continued to a 96% vacuum reaction. The crude oil was taken up in 200 parts of dibutyl ether and cooled to 0 ° C. The crystals which precipitated were filtered off and washed with the catalyst, filtered off and the methanol was evaporated off under hexane-4'4 hexane. There were thus obtained 63 parts of methylcyclohexyl-o-anisylphosphine oxide, which melted at 108 DEG-110 DEG C. and had a specific rotation EXS6 = + 63 DEG (methanol). The phosphine oxide prepared as above can be reduced to methylcyclohexyl-o-anisylphosphine in 95% yield using HSiCl 3 and triethylamine in the manner set forth above for methylphenyl-o-anisylphosphine. a liquid with specific rotation EgJâo = + 98.5 ° (methanol).

Example 4: Asymmetric hydrogenation of - <- benzamido-4-hydroxy-3-methoxy-cinnamic acid _g A hydrogenation apparatus equipped with pressure gauge, temperature measuring device and heating device was loaded with. 25 parts of β-benzamido-LL-hydroxy-β-methoxy-cinnamic acid, 186 parts of methanol and 64 parts of 5% sodium hydroxide. The batch was carefully blown 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 g of sodium 1,5-hexadiene chloride (Low (10 -5-hexadiene) Cl 2) J] Am. Chem. Soc. 86,217 (1964) in 2 ml of benzene under a nitrogen atmosphere.

Then 0.039 g (+) - methylphenyl-o-anisylphosphine in 1.3 ml of benzene was added, then hydrogen was passed through the mixture for five minutes. The catalyst solution thus obtained was then pressed into an autoclave with hydrogen pressure. The hydration started immediately and ended after 3-4 hours at ZSOC and 3.5 kp / cm? overpressure.

Analysis of the solution thus obtained showed an optical purity of 56.4% corresponding to an L / D mixture of the sodium salt of "N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) -alanine in the amount ratio 78 : 22.

The N-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 L-enantiomer thus obtained can be converted to L-DORA by simple hydrolysis to remove the blocking groups benzoyl and methyl on the substituent in the 3-position of the phenyl group.

Example 5: A one liter autoclave was charged with 25.0 g of 1-benzamido-4-hydroxy-3-methoxy-cinnamic acid, 300 ml of methanol and 0.6 ml of 5% aqueous solution of NaOH. The batch was stirred at 25 ° C below 2.8 kp / cm 2 (gauge pressure) of pure hydrogen gas, until it could be established with certainty that no leakage occurred. Approximately 1 ml (0.01% Rh, 0.05% phosphorus) of the following catalyst solution was added through a partition without depressurizing the pressure. The catalyst solution had been prepared by dissolving under N 2 of 0.005O g [One (1,5-hexadiene) Gl72, molten Punk® 115-11700 elemental analysis:% C% H% Cl calculated 52.58 4.57 15.08 found 52, 41 4.41 15.82 in 0.55 ml of a solution of methylphenyl-o-anisylphosphine [ESYÉE = + 42 ° (methanol) with specific rotation _ / _ 5c 1235 = + 42 ° (methanol) in benzene containing 0.041 g / ml and dilute to 1 ml with methanol. The phosphine oxide precursor had a melting point of 70-75 ° C, (α / D = + 25.9 ° (methanol).

Stirring at 1400 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-5- (4-hydroxy-5-methoxyphenyl) -alanine containing 75% of the Ifenantiomer and 27% of the D-enantiomer were obtained. If the enantiomer can be converted to IFDOPA by hydrolysis in the manner set forth in Example 4.

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Hhwwnmuo om mß | oß man mmoè mä mß »oß gsm x .fi immp ooêæ _ Éæw fl xw fl mo wmsašomx Jääwh fi mpmm" mumw. Mhm .au o ÄH _ moou | mo | ~ mo | mo _ _ O "m \\ N0 / mmu 1 ma _ \. . mooofmmïm fi woël fi ïwmmo mm O ... u -o-o o \ Ouæ .MZ _ _ _ moø fl ïmohwolmom _ _ Q ommo »xøuon ..1: | 11 .: 0% _ _ _ m É \ mo møouuwumnïmo / ä _ mms ß _ 0% mmm _ _ o _ mz _ .moovfïmofuñïwmmo _ om _. . _ ø oi .. ä __ _ moon fl onmvüom E, _ ømmu_. . .mw% fl wummm f! r ||. | .l. .En .Iilv Än !! Example 22: An autoclave was charged with 25.0 g (0.085 mol) of α-acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate, 300 ml methanol and 0.56 ml 50% NaOH. The autoclave was placed under a pressure of 2.46 kp / rev overpressure with a mixture of Nä and H2 (50:50).

A catalyst solution was prepared by dissolving 0.85 g (0.25 meq.) Of β (1,5-hexadiene) c_1_72 in 0.5 ml of benzene, then adding 0.051 meq under a nitrogen atmosphere. (+) - methylcyclohexyl-o-anisylphosphine (optical purity about 90%) in 2.4 ml of benzene. Hydrogen was bubbled through this solution for 10 minutes, Rhodium f1,5-hexadiene chloride, see Examples 4 and 5 above. In this way, Ehn obtained (+) methylcyclohexyl-o-anisylphosphine, liquid, boiling point 110 DEG-14 DEG C. ° C / 0.19 mmHg. [α]% O = + 89 ° (c = 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 solution flour, had specific rotation zajšï + 5e, 2 (Na san; in water). Pure Nacetyl-5- (4-hydroxy-5-methoxyphenyl) -Ir alanine acetate, also in the form of sodium salt in water, had a specific rotation / λ] = + 54.0 °. Thus, the optical purity of the obtained hydrogenation product was 70.7% or better than 85% of the irenantiomer and 15% of the D-enantiomer.

The procedure described above was repeated with (-) - methylcyclohexylphoanisylphosphine (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%). Thus, by appropriate selection of the (+) or (~) phosphine, one can produce the respective enantiomers in large yield.

Example 25: The procedure described in Example 22 was repeated using the (-) - methylcyclohexyl-o-anisylphosphine (optical purity about 80%) was / šO = -? 5.6 ° (c = 1 in MeOH) as the optically active ligand and α-benzamido-4-hydroxy-5-methoxy-cinnamic acid as the B-substituted α-acylamidoacrylic acid. The hydrogenation product obtained consisted of N-benzoyl-3- (4-hydroxy-5-methoxyphenyl) -alanine containing a major amount of 10 .mu.g of 50 50, Example 25: p, 28 mass-z.

The D-enantiomer (optical purity of the reaction product mixture about 65%). 2 s Example 24: In a pressure flask purged with nitrogen, u-benzamido-4-hydroxyphs-methoxy-cinnamic acid (1.6 μg, 5.0 mol), cyclooctadiene-4,5-bis (methylcyclohexyl) was charged -o-anisylphosphine), iridium tetrafluoroborate, clear red solid (21.7 mg, p 0.025 mol), and 20 ml of anhydrous methanol. The mixture was stirred and purged with nitrogen for 45 minutes. The pressure in the pressure piston was raised to 7.kp/cm? 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 NNE spectrometric analysis, which showed that 59% of the starting material had been converted to the product Nëhensoyl-5- (4-hydroxy-5-methoxyphenyl) -alanine. Polymerometric analysis of the reaction mixture after neutralization according to standard procedures showed that the product was optically active with [d]% 4 = 9.5 °.

To a solution of 2.005 g of N-acetyl-indolyl-d-acetamidoacrylic acid in 60 ml of methanol was added 0.0074 g of cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) rhodium tetrafluoroborate, orange crystals with a melting point of 17041 - 5 ° C. The mass thus obtained was carefully blown clean, in the tube with nitrogen one then with hydrogen, one 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 torsion. The solution had [&] ïP = 20.1 °.

Theoretical value for the pure optical enantiomorph is 25.9 °.

Thus, an optical purity of 77.5% had been obtained. The product can be isolated by evaporating the solvent and crystallizing the residue.

Example 26: Optically active methylpropylphenylarsine was prepared as described by Nislow and co-workers in JACS 25, 955 (1975) - A catalyst solution was prepared by mixing 2 ml of methanol, 0.2 g (+) - methylpropylphenylarsine (/ ä]% P = å + 10,? °, 80%, 0.16 mmol) and 0.025 g of rhodium (oyklooctadiene-1,5) -acetonylaoetonate (0.08 mmol), m.p. 125-128 ° 0 (dec.). After stirring for 40 minutes under a nitrogen atmosphere 79oozss + A 10 45 25 50 55 29 the whole amount of solids had gone into solution. A solution of 4.0469 g of α-acetamido-4-hydroxy-5-methoxy-cinnamic acid acetate in 25 ml of methanol was thoroughly purged with nitrogen and then placed under a hydrogen overpressure of 3.9 kp / omg 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 / cmg. The resulting mass was diluted to 50 ml and tested for specific optical torque, which was found to be Za]% P = ~ 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 / d]% 0 = -40.8 °. The optical purity was thus 4.4%.

Evidence that the arsine was not optically pure was obtained by its conversion to the sulfide (Mislow and co-workers in JACS 22, 955a (1975)) and measurement of the optical purity with a chemical shift reagent (NMR_Chira1 Shift Reagent, Whitesides and co-workers JACS 2§, 4058). (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. Evaporation of the methanol and recrystallization from the concentrated solution recovered the product.

Example 22: Preparation of cyclooctadiene-4,5-bis (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroborate. In a 4-liter flask was charged under nitrogen 500 ml of methanol and 15.4 g (0.051 mol of Abdium- (cyclooctadiene-4.5) chloride] 50.5 g (98%, 0.12 mol) of methyloyclohexyl chloride. 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 tetrafluoroborate (45 μg, 0.12 mol) in 160 ml of water was added over a period of Orange crystals separated and were collected, washed with water (2 x 50 ml) The product was dried under vacuum at 25 ° C and weighed to give 45 g of product with a melting point of 170-175 ° C. material was approximately 96% optically pure.

Claims (1)

Compound for use as a catalyst for asymmetric hydrogenation of β-substituted OC-acylaminoacrylic 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 solid and cationic, contains two equivalents of one optically active phosphine ligand per mole of rhodium and a chelating diolefin. _2. Catalyst according to Claim 1, characterized in that the solid rhodium coordination complex is cyclooctadiene-1,5-bis- (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroborate. Catalyst according to claim 1, characterized in that the solid cationic coordination rhodium complex is cyclooctadiene-1,5-bis- (methylcyclohexyl-o-anisylphosphine) rhodium tetraphenylborate. Catalyst according to claim 1, characterized in that the solid, cationic coordination rhodium complex is bicyclo-2,2,2-phylhepta-2,5-diene-bis- (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroborate.