Catalytic asymmetric hydrogenation and catalyst therefor

The invention relates to a process for the catalytic hydrogenation of β-substituted-α-acylamidoacrylic acid and / or its salt asymmetrically.

If an olefin which is optically active in its saturated form is hydrogenated, the reaction product obtained is usually optically inactive mainly due to the formation of equal amounts of both enantiomorphic forms, i.e. the formation of a racemic mixture. To obtain the desired enantiomorphic form, the mixture must be separated into its various optically active components. Such a procedure is cumbersome and expensive and often results in the decomposition of the desired enantiomorph. Because of these drawbacks, increasing attention has been paid to the development of asymmetric syntheses that would yield another enanthionic morphological form as the major product.

It has now been found that the desired enantiomorphic form of α-amino acids can be obtained in excellent yields from olefinic β-substituted-acylamido-acrylic acids and / or their salts by the catalytic hydrogenation process according to the invention, characterized in that the 8-substituted-α-acylamino-acrylamido-acrylamido or a salt C 07 B 1/00 ​​is hydrogenated with a coordination metal complex which is soluble and contains a metal selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum, and that the ligand contains at least one optically active phosphine or arsine ligand.

The following reaction equation illustrates the reaction of the invention. By way of example, the β-substituent is phenyl and the notation * denotes an asymmetric carbon atom.

Λ-ch₂-ch-cooh

-CH = C-C00H

NH »

Acyl optically active catalyst

NH f

The acyl β-substituent may be, for example, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, amino, benzylamino, dibenzylamino, nitro, carboxyl and carboxylic ester or the like. It will be apparent to one skilled in the art that the β-substituent can be selected from a wide variety of very different groups and that its choice is limited only by the fact that the desired end product must be an α-amino acid.

examples of α-amino acids whose enantiomorphs can be prepared quickly and easily by the process of this invention include alanine, p-chlorophenylalanine, tryptophan, phenylalanine, 3- (3,4-dihydroxyphenyl) alanine, 5-hydroxytryptophan, lysine, histidine, tyrosine , leucine, glutamic acid and valine.

The acyl group may be substituted or unsubstituted, and examples of such groups include acetyl, benzoyl, formyl, propionyl, butyryl, toluyl, nitrobenzoyl, or other acyl derivatives used as protecting groups in peptide syntheses, or the like.

It is preferred that the catalytic hydrogenation of β-substituted acylamidoacrylic acids according to the invention is carried out asymmetrically in the presence of a base.

β-Substituted-α-acylamido-acrylic acids and / or their salts are intermediates in the preparation of substituted and unsubstituted alanines.

Particularly suitable for the process of this invention, which provides them with excellent results, are compounds having the following structural formula

T - C = C - COOH H NH t

Z wherein T is selected from the group consisting of hydrogen, carboxyl, unsubstituted and substituted alkyl, thienyl, β-indolyl, β-imidazolyl, furyl, piperonyl and a group

<img file="FI55992B_D0001.tif" />

wherein B, C and D are independently selected from the group consisting of hydrogen, alkyl, carboxyl, hydroxyl and their metal salts, alkoxy, halogen, acyloxy, aryloxy, aralkyloxy, amino, alkylamino, nitro and cyano, wherein Z is selected from the group consisting of include substituted or unsubstituted acyl as described above, and p, q and r are integers from 0 to 5, provided that the sum of p, q and r is not greater than 5.

A preferred embodiment of the invention, which also illustrates the process according to the invention, is the preparation of substituted and unsubstituted phenylalanines by catalytic, asymmetric hydrogenation. Unsaturated precursors of these α-amino acids can be prepared by Erlenmeyer azlactone synthesis, in which a substituted or unsubstituted benzaldehyde is reacted with an acylglycine, such as acetylglycine, and acetic anhydride to form a precactylated azlactone, which is then hydrolyzed. Such a reaction is observed using benzaldehyde and acetylglycine as reactants in the following reaction equations:

<img file="FI55992B_D0002.tif" />

In these reactions, the substituents on the phenyl group can be selected from a wide variety of groups and their choice is limited only by the fact that the desired end product should be phenylalanine. In addition, it may be that such groups of substituents are themselves precursors of the desired substituents in the final product, which can be directly converted to the desired substituents. For example, if the substituted benzaldehyde is vanillin and it is desired to prepare 3- (3,4-dihydroxyphenyl) -alanine, the desired precursor may be α-acetamido-4-hydroxy-3-methoxy-cinnamic acid, which upon hydrogenation affords N-acetyl-3- (4-hydroxy-3). -methoxyphenyl) -alanine, which can then be converted to 3- (3,4-dihydroxyphenyl) -alanine by simple hydrolysis.

Of the enantiomorphs of such phenylalanines, the L-forms are particularly desirable. For example, 3- (3,4-dihydroxyphenyl) -L-alanine (L-DOPA) is well known for its utility in the treatment of Parkinson's disease. Similarly, L-phenylalanine has been found to be useful as an intermediate in the preparation of alkyl esters of L-aspartyl-L-phenylalanine, which have recently been found to be excellent synthetic sweeteners.

The optically active hydrogenation catalysts used in the process of this invention are soluble coordination complexes containing a metal selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum in combination with at least one optically active phosphine or arsine ligand. These catalysts are soluble in their reaction mass and are therefore called homogeneous catalysts.

The phosphine or arsine ligand may be, for example, a ligand having

6 7 5 6 is the structural formula AR RR, where A is phosphorus or arsenic and R, R and

.....

R are each independently selected from the group consisting of hydrogen; alkyl or alkoxy having at least 1 carbon atom and up to 12 carbon atoms; substituted alkyl, wherein the substituent group is selected from the group consisting of amino, carbonyl, aryl, nitro, and alkoxy, wherein the alkoxy group has up to 4 carbon atoms; aryl; aryloxy; phenyl; substituted phenyl, wherein the substituent group is selected from the group consisting of alkoxy, alkyl, hydroxy, aryloxy, amino and nitro, wherein the phenyl has less than 3 substituents; cycloalkyl having at least 3 carbon atoms; substituted cycloalkyl; pyrryl; thienyl; furyl; pyridyl; piperidyl; and 3-cholesteryl.

The optical activity of the metal coordination complex of the invention is due to a phosphine or arsine ligand. This optical activity can be due either to the presence of 3 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.

Examples of such coordination metal complexes are as follows. . 1 .2 ·. complexes of structural formula M or M 3 °^lssa is a metal selected from the group consisting of rhodium,. . . . . . 2 iridium, ruthenium and osmium; M is selected from the group consisting of palladium and platinum; X is selected from the group consisting of hydrogen, fluorine, bromine, chlorine and iodine; L is a phosphine or arsine ligand as further defined above; and n is an integer 1 or 3.

In the structural formula of the coordination metal complex described above, only one ligand (L) must be optically active in order for the reaction to be performed.

If the optical activity of the ligand is based on having an optically active group attached to a phosphorus or arsenic atom, only one such group is required and the other two groups may be the same or inactive. Thus, only one of the groups R, R or R need be optically active and the remaining two groups may be identical or inactive.

The catalysts used may be coordination metal complexes having the following structural formulas. In these structural formulas, asterisking means asymmetry and thus optical activity. An asterisk means an asymmetric atom or an asymmetric group. For example, the notation R * means that the phosphorus or arsenic is asymmetric. The absence of an asterisk indicates that there is no optical activity.

<td>(i)</td><td>M¹X (A * R⁵R⁶R⁷)₃</td><td>(ix)</td><td>M^XX (A * R⁵R⁶R⁷) (WITH⁵R⁶R⁷)</td>

<td>(Ii)</td><td>m¹x (a * r⁵r⁶r⁷)₂(WITH⁵R⁶R⁷)</td><td>(x)</td><td>M¹X "(AR *⁵R⁶R⁷).</td>

<td>(iii)</td><td>M¹X (A * R⁵R⁶R⁷) (WITH⁵R⁶R⁷)₂</td><td>(xi)</td><td>M-Lx (AR *⁵R⁶R⁷) (WITH⁵R⁶R⁷)</td>

<td>(iv)</td><td>M¹X (AR^ä5R⁶R⁷)</td><td>(Xii)</td><td>M-hc (AR *⁵R⁶R⁷) (WITH⁵R⁶R⁷)₂</td>

<td>(V)</td><td>m¹x (with *⁵r⁶r⁷)₂ (WITH⁵R⁶R⁷)</td><td>(xiii)</td><td>m²x (A * R⁵R⁵R⁷)</td>

<td>(we)</td><td>M¹X (AR *⁵R⁶R⁷) (WITH⁵R⁶R⁷)₂</td><td>(xiv)</td><td>M²X₂(A * R⁵R⁶R⁷) (WITH⁵R⁶R⁷)</td>

<td>(are you coming)</td><td>M¹X- (A * R⁵R⁶R⁷)</td><td>(xv)</td><td>M²X₂(WITH *⁵R⁶R⁷)</td>

<td>(viii)</td><td>M¹X3 (A * R⁵R⁶R⁷ ) 2 (AR⁵R⁶R⁷ )</td><td>(xvi)</td><td>M²X₂(WITH *⁵R⁶R⁷) (WITH⁵R⁶R⁷)</td>

T 2 * 5 6 7

In these structural formulas, M, M, X, A, R, R and R have the same meaning as defined above.

It is to be understood that in the structural formulas of the catalysts mentioned above by way of example, the asymmetric group may be any of R, R and R and is not limited to any particular group. In addition, different combinations associated with the metal are possible.

It should also be noted that the structural formulas described above do not only represent coordination metal complexes containing two or three ligands, as in the case of the structural formulas M ^ 2 ^ 2 J, respectively.^a With respect to XL 1, this is the case, but also present coordination metal complexes in which the number of ligand-metal coordination bonds is determined by the number of ligands (L) contained in the structural formula and in which these bonds are provided with polyhydric ligands of the type. Although, for example, a given coordination metal complex has only two ligands, structural formula M ^ XL_q still represents such a complex if one or two of the ligands are bidentate, in other words it has two coordination bonds. Similarly, structural formula M ^ XL_O also means complexes with only one ligand, if this ligand is tridentate, in other words it is associated with three coordination bonds.

Ί

Substituents for phosphorus and arsenic atoms include, for example, methyl, ethyl, propyl, isopropyl, butyl and its isomers, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, desyl and its isomers, undecyl and its isomers, dodecyl and its isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, acetoxylphenyl, methyltenyl, ethylphenyl, propylphenyl, butylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, hydroxyphenyl, phenoxyphenyl, o-anisyl, 3-cholesteryl, benzyl, pyrryl, furyl, pyridyl, thienyl, piperidyl, menthyl, bornyl and pinyl.

Examples of optically active phosphines and arsines are e.g. the following: metyylietyylifosfiini, methyl isopropyylifosfiini, etyylibutyylifosfiini, isopropyl isobutyylifosfiini, metyylitenyylifosfiini, etyylifenyylifosfiini, propyylifenyylifosfiini, butyylifenyylifosfiini, fenyylibentsyylifosfiini, fenyylipyrrolifosfiini, ethyl-isopropyl-isobutyylifosfiini, metyylitenyyli-4-metyylifenyylifosfiini, ethylphenyl, 4-metyylifenyylifosfiini, isopropyylifenyylifosfiini methyl, 2-ethylphenyl, 4,5 -trimethylphenylphosphine, phenylbenzyl-4-dimethylaminophenylphosphine, phenylpyridylmethylphosphine, phenylcyclopentylethylphosphine, cyclohexylmethylisopropylphosphine, o-methylphenylmethylphenylphosphine, o-methoxyphenylethylphenylcyclohexylcyclohexylcyclohexyl

Optically active phosphines and arsines containing at least one phenyl group having a substituent in the ortho position, such as hydroxy; alkoxy having at least one carbon atom and up to 12 carbon atoms; and aryloxy are particularly preferred compounds for use in the process of this invention. Quite excellent results have been obtained with methylphenyl-o-anisylphosphine and methylcyclohexyl-o-anisylphosphine. The latter compound together with the optically active coordination metal complex used as a hydrogenation catalyst prepared using it are new substances. It has been found that the desired enantiomorphs of substituted and unsubstituted phenylalanines can be prepared directly in excellent yields using such optically active ligands in the process of the invention.

Although only one optically active group, i.e. a ligand, is required in the coordination metal complex catalyst, it is preferred to facilitate the preparation that all three ligands of the structural formula M 2 L. described above are the same. It is also preferred that the asymmetry be at either the phosphorus or arsenic atom.

It has been found that the desired enantiomorphs can be obtained in excellent yields not only by the optically active hydrogenation catalysts described above, which are coordination metal complexes in which the metal is selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum, but also by hydrogenation. in the presence of a catalyst consisting of a solution of a metal selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum, and at least one equivalent of phosphine and / or arsenic ligand per mole of metal, provided that the ligand is optically active. For example, the catalyst can be prepared by dissolving a soluble metal compound in a suitable solvent together with a ligand such that the molar ratio of ligand to metal is at least one equivalent of ligand per mole of metal, preferably two equivalents of ligand per mole of metal. It has also been found that the catalyst can be formed in situ by adding a soluble metal compound to the reaction mass while adding a suitable amount of optically active ligand to the reaction mass either before or during the hydrogenation.

It is best to use rhodium as the metal. Suitable soluble rhodium compounds include rhodium trichlorohydrate, rhodium tribromide dihydrate, rhodium sulfate, organic rhodium complexes with ethylene, propylene, and the like, and bis-olefins such as 1,5-cyclooctadiene and 1,5-hexadiene-2,5-hepta-bicyclo. with diene and other diets that can form bidentate ligands, or the active form of metallic rhodium, which has already been made soluble.

It has been found that the process of the invention is best carried out in the presence of an optically active phosphine or arsine ligand, with about 1.5 to 2.5, preferably 2.0 equivalents of ligand per mole of metal being used. In practice, it is best that the optically active catalyst be in solid form to facilitate handling and storage. It has been found that advantageous results can be achieved with solid, cationic coordination metal complexes.

According to the invention, 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 example, using the organic rhodium complexes described above, such a cationic coordination rhodium complex can be prepared by slurrying the organic rhodium complex in an alcohol such as ethanol and adding two equivalents of optically active phosphine or arsine to form an ionic solution followed by a suitable anion or tetrafluoroborate which provides a fixed, precipitation or crystallization of the cationic coordination metal complex either directly from solution or by treatment with a suitable solvent.

Examples of suitable cationic coordination metal complexes are cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) rhodium tetrafluoroborate, cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphenyl) teraphenephosphinethethosphetine) rhodium , 5-diene-bis (methylcyclohexyl-o-anisylphosphine) rhodium tetrafluoroborate.

According to the process of the invention, within its basic idea, the catalyst can be initially added to the reaction mixture in an inactive intermediate form and then converted by contact with hydrogen to the active form. This conversion can, of course, be performed during the hydrogenation of the olefinic bond itself, or it can be accomplished by subjecting this inactive catalyst to hydrogen prior to the addition of the olefinic material to be hydrogenated.

The hydrogenation reaction is usually carried out in a solvent such as benzene, ethanol, toluene, cyclohexane or mixtures of these solvents. In this case, almost any aromatic solvent or saturated alkane solvent or cycloalkane solvent which is inactive under the hydrogenation conditions can be used. Because the hydrogenation process of the invention has been found to be specific, solvents such as nitrobenzene can also be used. The best solvent is methanol.

As mentioned above, the catalyst can be added to the solvent either as such or as components which then form the catalyst in situ. If the catalyst is added as its components, it may be added before or during the addition of the β-substituted-α-acylamidoacrylic acid. In preparing the catalyst in situ, the components are a soluble metal compound and an optically active phosphine or arsin ligand. The catalyst may be added in any catalytically effective amount, and generally this amount is between about 0.0001 and 5% by weight of the metal contained in the catalyst, based on the content of β-substituted-α-acylamidoacrylic acid and / or its salts.

Whenever possible, the process according to the invention should use means which prevent the catalyst or reaction mass from coming into contact with oxidizing agents, in particular care must be taken to prevent the catalyst or reaction mass from coming into contact with oxygen. It is best to carry out the preparation of the catalyst and the reaction itself in gases other than hydrogen which are inert to both the reactants and the catalysts. Examples of such gases are nitrogen and carbon dioxide.

As mentioned above, it has been found that asymmetric hydrogenation is promoted by the presence of a base in the reaction mass. Although asymmetric hydrogenation can be performed in a reaction mass without any base, and even under acidic conditions, it can be greatly improved by the addition of a small amount, up to a maximum of one equivalent of basic material per mole of acrylic acid. Surprisingly, even a small amount of base added to the acidic reactant provides this improvement in asymmetric hydrogenation, and in fact it has been found that the formation of a small amount of salt in acrylic acid is sufficient to achieve these improved results.

Bases used in accordance with the invention include, for example, tertiary bases such as triethylamine and sodium hydroxide, as well as almost any other basic materials that form a salt with carboxylic acids. After the components are added to the solvent, hydrogen is added to the mixture in an amount of about 1 to 5 times the molar amount of B-substituted-α-acylamidoacrylic acid, or an amount sufficient to bring the hydrogenation to the desired point. The system pressure may vary as needed as it depends on the type of β-substituted-α-acylamidoacrylic acid, the type of catalyst, the size of the hydrogenation equipment, the number of components, and the amount of solvent and / or base. Both lower pressures, such as atmospheric pressure and reduced pressure, as well as higher pressures can be used. Reaction temperatures can range from about -20 ° C to about 110 ° C. Higher temperatures may also be used, although they are not normally necessary and may lead to an increase in side reactions.

When the reaction is complete, as prescribed by conventional means, the solvent and products are removed and the catalyst is separated in the usual manner.

Many naturally occurring products and drugs are in optically active forms. In these cases, usually only one of the L and D forms is effective. In the past, the preparation of such compounds has required the use of an additional step in separating the products into their enantiomorphic forms. Such a procedure is expensive and time consuming. The process according to the invention gives optically active products directly, whereby the time-consuming and expensive separation of enantiomorphs is eliminated, while the yield of the desired enantiomorph is improved and the yield of by-product enantiomorphs is reduced.

The desired α-amino acid enantiomorphs can be prepared by hydrogenating the appropriate β-substituted-α-acylamidoacrylic acid by the method of this invention, followed by removal of the acyl group in the α-amino group as well as other protecting groups in a conventional manner to give the desired enantiomorph.

It has been found that the α-amino acids prepared from β-substituted-acylamidoacrylic acids and / or their salts by the process according to the invention contain essentially almost entirely the desired enantiomorphs, which makes the present invention particularly valuable.

The following examples are intended to illustrate in more detail how the method according to the invention is carried out. It is to be understood that the details given in the examples are not intended to limit the scope of the invention. In the following examples, parts are by weight unless otherwise indicated. In the examples, the percentage of optical purity is determined according to the following equation, in which the optical activities are expressed as specific rotations and determined in the same solvent.

Optical Determined optical activity of the mixture x 100% purity Optical activity of the pure enantiomorph

Example 1

Optically active phosphines and arsines can be prepared by a method known from the literature (Mislow, Korpiun, J. Am. Chem. Soc. 89 (1967) 4784).

PhPCl₂ + 2 CH 2 OH -) Ph-P (OCH₃)₂

A suitable reaction vessel equipped with stirring means, temperature measuring means and material addition means was charged 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 of 96 parts of methanol and 27 parts of hexane was added over about 1-1/2 hours with stirring. The resulting mixture was stirred for an additional 2-1 / 2 hours, at which time it warmed to about 25 ° C.

This reaction was performed under an inert nitrogen atmosphere.

The pyridine hydrochloride formed during the reaction was removed by filtration, and the filtrate was concentrated. The resulting yellow residue was distilled and the product was collected as a colorless fraction boiling at 95.5-97 ° C / 17 mmHg. (yield of dimethylphenylphosphonite 82%). (Harwood, Grisley, J. Am. Chem. Soc. 82 (1960) 423).

PhP (0CH ~) "+ CH_I -PhP-OCH"

2 3 f \ 3 ^CH3

A suitable reaction vessel equipped with stirring means, temperature determining means and material addition means was charged with 11 parts of dimethylphenylphosphonite, 2.5 parts of methyl iodide and 9 parts of toluene. The resulting solution was heated slowly. The reaction is exothermic, causing the temperature to rise to about 110 ° C, after which the reaction mixture was maintained at about 100-120 ° C and a further 185 parts of dimethylphenylphosphonite were slowly added. During the addition of the phosphonite, about 1 more methyl iodide was added. The reaction mixture was then maintained at about 110 ° C for an additional hour after the addition of the components. The reaction mixture was then distilled and the product was collected as a fraction boiling at 148-149 ° C / 17 mmHg. (96% yield of phenylmethyl phosphinate). (Harwood, Grisley, J. Am. Chem. Soc. 82 (1960) 423).

CH5 «

-&gt;

P-AND ^{+ PC1}5 ^CH3 \ S

P - Cl

Ph

Ph

A suitable reaction vessel equipped with stirring means, condensing means, temperature measuring means and material addition means 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 50 parts portions and one 79 parts portion. In this case, an increase in temperature was observed with the addition of the first three batches. The mixture was stirred at about 60 ° C for two hours and then the carbon tetrachloride and phosphorus oxychloride were removed by distillation. The residue was distilled and a fraction boiling at 138-141 ° C / 17 mmHg was collected. (95% yield of methylphenylphosphine chloride). (Methoden Der Organishen Chemie (Houben-Weyl) Vol. XII / I p. 243).

<img file="FI55992B_D0003.tif" />

To a suitable reaction vessel equipped with stirring means, condensing means, temperature measuring means and li25 o storage means for the materials was added 78 parts of 1-menthol (/ a / ^ = -50^u in ethanol) and 72 parts of diethyl ether. 119 parts were added to the resulting solution

...... . . . The mixture obtained from triethylamine 3a was cooled to about 0 ° C. To this mixture, 87 parts of methylphenylphosphine chloride was added with stirring over about 1 to 1/2 hour while maintaining the temperature at about 0 ° C. The mixture was then allowed to warm to about 25 ° C and then heated at reflux for about 10-1/2 hours.

The mixture was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. Concentration of the filtrate gave a solid with a melting point of 50-65 ° C as a mixture of 1-menthyl methylphenylphosphinate diastereoisomers (60% S and 40% R).

The mixture of 1-menthylmethylphenylphosphinate diastereoisomers prepared above was decomposed into its components by crystallization several times from hexane and then crystallization from diethyl ether to give a solid having a melting point of 78-82 ° C and the S-form of 1-menthylmethylphenylate.

Ph

CH.

<img file="FI55992B_D0004.tif" />

CH₃CH₂CH₂MgBr

Ph. 0 -&gt; ^ P * CH

CH₂CH₂CH₃

In a suitable reaction vessel equipped with stirring means, temperature determining means, material addition means and condensing means, 9.5 parts of magnesium, 7 parts of diethyl ether and the amount of iodine required to initiate the reaction were added under an inert nitrogen atmosphere. A small amount of bromopropane was added to initiate the reaction, and then a mixture of 47 parts of bromopropane and 123 parts of diethyl ether was added at a rate at which the reaction mixture gently refluxed. The reaction mixture was then cooled to about 25 ° C and stirred for an additional 2 hours.

To this mixture was added a mixture of 12 parts of the S-form of 1-menthylmethylphenylphosphinate prepared above and 88 parts of benzene. The diethyl ether was then removed and the resulting mixture was heated at 78 ° C for 64 hours.

The magnesium complex reaction product was decomposed with ammonium chloride solution and 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 oil was column chromatographed on a silica gel column using a mixture of hexane, benzene and diethyl ether (3: 1: 1) as eluent to give optically active phenylmethylpropylphosphine oxide in 61% yield.

^{+ And}3^OF &gt; *-^CH2^CH2^CH3

Ph

Ph

CH 2 ZP-CH 8 -CH 8 -CH 8 + HSiCl 2

CH

A suitable reaction vessel, maintained under an inert nitrogen atmosphere and equipped with stirring means, temperature determining means and material addition means, was charged with 16 parts of trichlorosilane and 88 parts. benzene at a temperature of about 0 ° C. To this mixture was added a mixture of 22 parts of triethylamine and 44 parts of benzene at a temperature of about 4-6 ° C. The resulting mixture was then warmed to about 25 ° C and a mixture of 8.2 parts of the optically active phenylmethylpropylphosphine oxide prepared above and 22 parts of benzene was added. The mixture was then heated to about 60 ° C for two hours and then cooled to 25 ° C.

The silicon complex obtained as a reaction product was decomposed with 75 parts of a 20% solution of sodium hydroxide and then with 35 parts of water. The resulting mixture was allowed to stand for about 15 hours and the resulting layers were separated. The organic layer was then extracted with 5% hydrochloric acid, then twice with water and then dried over sodium sulfate. The solvent was removed by distillation to give methylpropylphenylphosphine with an optical purity of 69% in 95% yield.

The preparation of rhodium-III-chloride-tris- (methylpropylphenylphosphine) was performed as follows:

A suitable reaction vessel with a nitrogen atmosphere was charged with 0.342 g (0.0013 moles) of rhodium III chloride trihydrate and 10 ml of methanol. 0.76 g (0.0046 mol) of the optically active methylpropylphenylphosphine prepared above in 3 ml of methanol were then added dropwise over 15 minutes. The mixture was allowed to stand for 1 hour during which time a yellow precipitate separated from the solution. This precipitate was removed by filtration to give 0.21 g of a rhodium complex having a specific rotation / α / θ = -69.2 ° (mixture of benzene and ethanol, 1: 1 by volume).

Concentration of the filtrate gave an additional 0.13 g of product with a specific rotation / α / θ ^ = -56.4 ° (mixture of benzene and ethanol, 1: 1 by volume).

Example 2

Following the general procedure of Example 1, a mixture of diastereoisomers of 1-menthylmethylphenylphosphinate was separated into its enantiomorphs by crystallization from hexane and / or a mixture of hexane and ether to give the S form having a melting point of 78-82 ° C and a specific rotation (benzene) of , and the R-form, which had a melting point of 86 to 87 ° C and a specific rotation / α / θ = -17 ° (benzene).

<img file="FI55992B_D0005.tif" />

<img file="FI55992B_D0006.tif" />

To a suitable reaction vessel equipped with stirring means, temperature determining means, material addition means and condensing means were added 18.3 parts of magnesium turnings, 14 parts of diethyl ether and a sufficient amount of iodine to initiate the reaction under an inert nitrogen atmosphere. A further small amount of o-anisyl bromide was added to initiate the reaction and then slowly at a rate, the reaction mixture refluxed slightly, a mixture of 138 parts of o-bromoanisole and 400 parts of diethyl ether. At the end of the addition, the mixture was refluxed for another two hours.

To this mixture was then added a mixture of 74 parts of either the R-form or the S-form of 1-menthylmethylphenylphosphate (the choice of the S- or R-form used depends on the enantiomorph desired by asymmetric hydrogenation) and 450 parts of benzene. The diethyl ether was then removed and the resulting 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 layer with benzene. The benzene was evaporated off and the residual oil was distilled off, first removing the menthol fraction and recovering the product which boiled at 180-190 ° C and 0.5 mmHg.

Crude methylphenyl-o-anisylphosphine oxide was obtained in 60% yield. Using the R form, the product of was obtained

five o specific rotation fa / ^ = + 27 ° (methanol). Using the S-form, a product with a specific rotational capacity in the opposite direction was obtained.

<img file="FI55992B_D0007.tif" />

A suitable reaction vessel under an inert nitrogen atmosphere equipped with stirring means, temperature determining means and material addition means was charged at a temperature of about 5 ° C with 16 parts of trichlorosilane and 100 parts of benzene. To this mixture was added a mixture of 12 parts of triethylamine and 50 parts of benzene at 4 to 6 ° C. The resulting mixture 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 at 70 ° C for one hour and then cooled to 25 ° C.

The silicon complex obtained as a reaction product was decomposed by adding 75 parts of 20% sodium hydroxide under a nitrogen atmosphere at 25 ° C while cooling. The desired methyl-o-anisylphosphine was obtained from the organic layer and had a specific rotation JajN = + 41 ° (methanol) when using the above preparations.^u 2 5 o phosphine oxide having a specific rotation / α = D = + 27 ° C (methanol). Using an enantiomorph with the opposite rotational specificity of phosphine oxide, an enantiomorph with a corresponding opposite rotational capacity was obtained.

Example 3

Preparation of methylcyclohexyl-o-anisylphosphine

<img file="FI55992B_D0008.tif" />

To a one liter autoclave were added 143 parts of the (+) - methylphenyl-o-anisylphosphine oxide prepared above, 28 parts of 5% rhodium precipitated on carbon and 250 parts of methanol.

The reaction mixture was heated at 75 ° C and stirred with hydrogen 2 at 56 kp / cm. At the end of the hydrogen consumption, nmr analysis showed that the reaction shown in the above reaction equation was 75% gone. An additional 7.0 parts of catalyst was added, and the pressure of the autoclave was raised to a further pressure of 56 kp / cm, whereby the reaction was found to be 96% complete.

The catalyst was filtered off and the ethanol was removed in vacuo. The crude oil was dissolved in 200 parts of dibutyl ether and cooled to 0 ° C. The separated crystals were filtered and washed with hexane. This gave 63 parts of methylcyclohexyl-o-anisylphosphine oxide having a melting point of 108-110 ° C and a specific rotation capacity of α / λ θ = + 63 ° (methanol).

The phosphine oxide obtained above can be reduced to methylcyclohexylioanisylphosphine in 95% yield using HSiCl 2 and triethylamine in the same manner as described above for the preparation of methyltenyl-o-anisylphosphine.

The methylcyclohexyl-o-anisylphosphine obtained is a liquid with a specific rotation / α / ^ ^ = + 98.5 ° (methanol)

Example 4 Asymmetric hydrogenation of g-benzamido-4-hydroxy-3-methoxy-cinnamic acid

A hydrogenation apparatus equipped with a pressure gauge, temperature measuring means and heating means was charged with 2 to 5 parts of α-benzamido-4-hydroxy-3-methoxy-cinnamic acid, 186 parts of methanol and 64 parts of 5% sodium hydroxide. The batch was thoroughly purged to remove any remaining air and adjusted to a final hydrogen pressure of 3.5 kp / cm and a temperature of 25 ° C.

The catalyst solution was prepared by dissolving 0.0059 g of rhodium-1,5-hexadiene chloride ((Rh (1,5-hexadiene) Cl / 2)) in two ml of benzene under a nitrogen atmosphere, J. Am. Chem. Soc. 86 (1964) 217). Then 0.0139 g of (+) - methylphenyl-o-anisylphosphine in 1.3 ml of benzene was added. Hydrogen was then passed through the mixture for 5 minutes. The resulting catalyst solution was then passed to an autoclave under hydrogen pressure. The hydrogenation began immediately and was complete

After 3-4 hours at a temperature of 25 ° C and a pressure of 3.5 kp / cm².

Analysis of the obtained solution showed that the optical purity was 56.4%, which corresponded to a ratio of 78:22 of the mixture of L- and D-forms of the sodium salt of N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) -alanine.

The N-benzoyl-substituted amino acid can be obtained in 95% yield by evaporating off the methanol and neutralizing the sodium salt with hydrochloric acid. The resulting L-enantiomorph can be converted to L-DOPA by hydrolysis of the benzoyl and methyl protecting groups at the 3-position of the phenyl.

Example 5

A one-liter autoclave was charged with 25.0 g of α-benzamido-4-hydroxy-3-methoxy-cinnamic acid, 300 ml of methanol and 0.6 ml of

5% aqueous sodium hydroxide solution. The batch was stirred at 25 ° C and pure hydrogen at 2.8 kp / cm 2 until no more hydrogen was consumed. About 1 ml of the following catalyst solution (0.01% Rh, 0.05% phosphine) was then added through the septum without reducing the pressure. (The catalyst solution was prepared by dissolving 0.0050 g (Rh (1.5 hexadiene) Cl) under a nitrogen atmosphere).₉ To 0.33 ml of a solution containing o-anisylphosphine in benzene having a specific rotation (α / D = + 42 ° (methanol) and containing 0.041 g / ml and diluted with 1 ml of methanol).

The reaction mass was stirred at 1400 rpm, whereupon hydrogen began to be absorbed after an induction time of 2-5 minutes and the hydrogenation was complete in two hours.

The methanol was evaporated and the acid was dissolved in one mole of aqueous sodium hydroxide solution. The neutral catalyst was extracted with benzene and the extract was recovered for recovery. The free amino acid was then precipitated by the addition of concentrated hydrochloric acid with the addition of abundant base crystals. This gave 24 g of N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) -alanine containing 73% of the L-enantiomorph and 27% of the D-enantiomorph. The L-enantiomer was converted to L-DOPA by hydrolysis according to Example 4.

5599

Examples 6-20

Other optically active α-amino acids were prepared using procedures similar to Examples 4 and 5. The following table shows the hydrogenated olefinic compounds, the phosphine ligands used in the rhodium catalyst, and the optical purities obtained.

Example Olefin Product Catalyst (Ligand) Optical purity dP

CM co

<img file="FI55992B_D0009.tif" />

X

O o

O

IXO -X

II cm o

II

-O

<img file="FI55992B_D0010.tif" />

X o

oo

IX CJ -X tsp

C/O

X

O &lt;X5

CM

X a

+ iti + J

&amp;

C

V e

• B

P

O.

OI co

CM • HP • P&gt;. &gt; 0 r “I Iti P Iö

I

CM

X

O

CM

X o

c/o

X o

I am

X

O

CM

X

About what

X

About what

<img file="FI55992B_D0011.tif" />

<img file="FI55992B_D0012.tif" />

<img file="FI55992B_D0013.tif" />

Product Catalyst Optical purity

LO n

LO CO., LTD

H 04

<img file="FI55992B_D0014.tif" />

• B

G

O

O

O

I o

ro

O

X oooo ι xnxo -x -oo

II ro

II

X

O

O

O

I o

Example Olefin Product Catalyst Optical purity ph n CH_O

CM

C/O

<img file="FI55992B_D0015.tif" />

<img file="FI55992B_D0016.tif" />

Example Olefin Product Catalyst Optical purity

<img file="FI55992B_D0017.tif" />

O

O GO

CM

<img file="FI55992B_D0018.tif" />

<img file="FI55992B_D0019.tif" />

THE

<img file="FI55992B_D0020.tif" />

Example 22

The autoclave was charged with 25.0 g (0.085 mol) of α-acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate, 300 ml of methanol and 0.36 ml of

50% sodium hydroxide. The pressure of the autoclave was adjusted to a pressure of 2 with a 50:50 mixture of nitrogen and hydrogen

2.5 kp / cm.

The catalyst solution was prepared by dissolving 0.0050 g (0.023 milliequivalents) of Rh (1.5 hexadiene) Cl /₂ In 0.5 ml of benzene and adding 0.051 milliequivalents of (+) methylcyclohexyl-o-anisylphosphine (optical purity about 90%) in 2.4 ml of benzene under a nitrogen atmosphere. Hydrogen was passed through this solution for 10 minutes.

The catalyst solution was then added to the autoclave. The hydrogenation was performed at 60 ° C and was complete in four hours.

Evaporation of the solvent gave N-acetyl-3- (4-hydroxy-3-methoxyphenyl) -alanine acetate having a specific rotation of 2 5 / a /_D = + 38.2 (sodium salt in water). Pure N-acetyl-3- (4-hydroxy-3-methoxyphenyl) -L-alanine acetate also had a sodium 2 S o salt in water with a specific rotation [α] D = '54.0.

Thus, the obtained hydrogenation product had an optical purity of 70.7%, i.e., it contained 85% of the L-enantiomorph and 15% of the D-enantiomorph.

Using a similar procedure and (-) - methylcyclohexyl-o-anisylphosphine (optical purity about 80%), a hydrogenation product containing the D-enantiomorph as the main component was obtained (the optical purity of the reaction product mixture was 65%). Thus, by selecting the appropriate (+) - or (-) - phosphine in each case, both enantiomorphs can be prepared as main products.

Example 23

A procedure similar to Example 21 was performed using (-) methylcyclohexyl-ananicylphosphine as the optically active ligand and α28-benzamido-4-hydroxy-3-methoxy-cinnamic acid as the O-substituted-α-acylamido-acrylic acid.

The hydrogenation product obtained was N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) alanine, which contained the D-enantiomorph as the main product (the optical purity of the reaction product mixture was 65%).

Example 24

Abensamido-4-hydroxy-3-methoxycinnamic acid (1.67 g, 5.0 mol), cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) iridium tetrafluoroborate (21.7 g) were charged to a pressure vessel purged with nitrogen. mg, 0.025 mol) and 20 ml of anhydrous methanol. The mixture was stirred and nitrogen was bubbled through for 2 minutes. The pressure in the vessel was raised to 7 kp / cm gauge by blowing in hydrogen, and the mixture was stirred and heated to 100 ° C for 4 hours 20 minutes. A portion of this reaction mixture was analyzed by NMR spectrometry to reveal that 59% of the starting material had been converted to the product N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) -alanine. Polarometric analysis of the reaction mixture after neutralization by standard methods showed that the product was optically active (α) = 9.3.

Example 25

To a mixture of 2.005 g of N-acetylindolyl-α-acetoamidoacrylic acid and 60 ml of methanol was added 0.0074 g of cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) rhodium tetrafluoroborate. The mass thus obtained was thoroughly purged, first with nitrogen and then with hydrogen, and then mixed with a hydrogen overpressure of 2.7 kp / cm² at 25 ° C. Hydrogenation to N, N'-diacetyl-tryptophan was completed in 2.5 hours. The solution was diluted to 100 ml and analyzed for optical rotation, which οϋΓαΊ²⁰ = 20.1 °. Theoretical of pure optical enantiomorphine^LJThe value of D „is 25.9 °. Thus, 77.5% of an optically pure product was obtained. The product can be isolated by evaporating the solvent and crystallizing the residue.

Example 26

Optically active methylpropylphenylarsine was prepared

Mislow et al. according to JACS 95, 953 (1973)).

The catalyst solution was prepared by stirring 2 ml of methanol,

0.2 g of methylpropylphenylarcin (80%, 0.16 mmol) and 0.025 g of rhodium (cyclooctadiene-1,5) acetonylacetonate (0.08 mmol).

after stirring for 1 minute under nitrogen, all of the solids had dissolved. A solution of 1.0469 g of α-acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate and 25 ml of methanol was thoroughly purged with nitrogen and subjected to a hydrogen overpressure of 3.9 kp / cm at 50 ° C. Using a septum, 1.0 ml of the above-mentioned catalyst solution was added to the reaction mixture.

Hydrogenation was started and completed in 2.5 hours, manifested as a pressure drop of 0.8 kp / cm. The resulting mass was diluted to 50 ml and its specific optical rotation was determined to be

Ga Ί θ = -2.53 °. Test solution using pure N-acetyl * -^JD

3 (4-hydroxy-3-methoxy-phenyl) -L-alanine acetate and the same amount of catalyst, gave a value for the correction of the catalyst circulation

0.7 °. The hydrogenation thus gave a net rotation of -1.8 °. The value of the pure optical enantiomorph was Γα1²θ = -40.8 °. This was the optical purity^JD being 4.4%.

Evidence that arsine is not optically pure was obtained by converting it to sulfide (Mislow et al. JACS 95, 953 (1973)) and measuring optical purity with a chemical transition reagent (NMR Chiral Shift Reagent, Whitesides et al. JACS 96. 1038 (1974)). )). This experiment showed that the optical purity of the methylpropylphenylarcin used was only 45%. Thus, if the hydrogenation had been performed with optically active arsine, an optical purity of 9.5% would have been achieved. Removal of methanol and recrystallization from concentrated solution gave the product.

Example 27

Preparation of cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) rhodium tetrafluoroborate. 300 ml of methanol and 15.4 g (0.031 mol / rhodium (cyclooctadiene-1,5) chloride / g) were added to a 1 liter flask under a nitrogen atmosphere. 30.3 g (98%, 0.12 mol) of methylcyclohexylhexyl-o-anisylphosphine were added. The solution containing sodium tetrafluoroborate (13.7 g, 0.12 mol) and 160 ml of water was added over 1 hour. The orange crystals separated and were collected and washed with water (2 x 30 mL). The product was dried in vacuo at 25 ° C and weighed. In this way, 45 g of product with a melting point of 170-175 ° C were obtained. This material was approximately 96% optically pure.