Catalytic asymmetric hydrogenation and catalyst therefor

(54) Name: Compound for use as catalyst, for asymmetric hydrogenation of substituted ° C-acylamino-acrylic acids and / or salts of various acids

IN

The present invention relates to a compound for use as a catalyst for asymmetric hydrogenation of β-substituted OÉ-acylamino-acrylic acids and / or salts.

of such acids. j

When an olefin, which in its saturated form is optically ac-.

tiv, hydrated ,. usually an optically inactive product is obtained, mainly due to an equal amount of the two enantiomers being formed (racemic mixture). In order to obtain the desired enantiomer, the racemic mixture must be divided into sino-optical components. This process is laborious, costly and often results in destruction of the undesired enantiomer. Few because of these difficulties have unequivocally attempted to * enable asymmetric synthesis, which gives a major amount of;

the desired enantiomer. The present invention relates to!

a compound which is suitable as a catalyst in asymmetric hydrogenation of substituted α-acylamido acrylic acids and / or salts of such acids and it has now been found that

7409524-1 excellent yields of the desired enantiomer are obtained from such olefinic compounds if using as a catalyst a compound consisting of an optically active metal coordination complex which falls under the structure.

<img file="SE412394B_D0001.tif" />

iridium or osmium, h is palladium or platinum and

X is hydrogen, chlorine, fluorine, bromine or iodine, n is an integer 1 or 3, each of the symbols 1 representing a phosphine or arsenic ligand, at least one of which is optically active. Such a reaction is illustrated in the following reaction scheme, wherein the γS substituent is phenyl:

<img file="SE412394B_D0002.tif" />

&gt;

RH

IN

Acyl optically active catalyst

<img file="SE412394B_D0003.tif" />

RH

IN

acyl

Such procedures for asymmetric hydrogenation are the subject of the Swedish patent '⁷106040-4 (publ. No. 400 552) and is dealt with 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. The person skilled in the art can select the in this selection, it is only necessary to ensure that the desired ofr amino acid is obtained as the final product.

Examples of &lt;X-amino acids, whose enantiomers with the catalyst of the invention can be readily prepared, may be mentioned 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 as examples can be mentioned 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 substituted-it-acylamido-acrylic acids be carried out in the presence of a base.

- substituted W-acylamido acrylic acids and / or sal 3

7409524-1 thereof are precursors to the substituted or unsubstituted alanines.

The compounds with. The following structural formula gives excellent results in hydrogenation with the catalyst of the invention and therefore represents compounds which are particularly suitable for the purpose:

T - C = O - COOH 1 I

H NH i

Z

T represents hydrogen, carboxyl, unsubstituted or substituted alkyl, thienyl, β-indolyl, β-imidazolyl, furyl, pyrene, yl or

<img file="SE412394B_D0004.tif" />

and each of the symbols B, C and D, each independently 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 above type and p, q and r are integers 0-5, with the sum p + q + r not exceeding 5 ·

A particularly preferred embodiment, which is also illustrative of hydrogenation with the catalyst of the invention, is the preparation of the substituted and unsubstituted phenylalanines by catalytic asymmetric hydrogenation. Unsaturated precursors for such α-amino 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. Such a reaction is illustrated by the following reaction scheme, using benzaldehyde and acetylglycine as examples of reaction components:

7409524-1 (2) (1)

<img file="SE412394B_D0005.tif" />

ο

Tf ο

TT + CH₅C-NH-CH₂000H + O (O-CH₅)₂-4

<img file="SE412394B_D0006.tif" />

I ch,

CH = CC = 0 IIN 0

V

IN

CH, hydrolysis

Λ //

CH = &lt;p-C00H

KH.

IN

C = 0

CH, or

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 phenylalanine which is the desired final product. In addition, it may occur that such substituent groups themselves are precursors to substituents desired in the final product and can easily be converted to such desired substituents. For example, if the substituted benzaldehyde is vanillin and wished to produce 3- (3,4-dihydroxyphenyl) -alanine, the unsaturated precursor may be ctf-acetamido-4-hydroxy-3-methoxy-cinnamic acid which would give N-acetyl3- ( 4-hydroxy-3-methoxyphenyl) -alanine by hydrogenation. This can then be converted to 3- (3,4-dihydroxyphenyl) alanine by simple hydrolysis.

The L-enantiomer of such phenylalanines is particularly desirable. Thus, for example, 3- (3,4-dihydroxyphenyl) -Lalanine (L-DOPA) is well known for its utility in treating the symptoms of Parkinson's disease. Similarly, 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 contemplated optically active hydrogenation catalysts which are soluble rhodium coordination complexes containing at least one catalytically active phosphine ligand, which complex has the formula RhX_nL 2, where X represents H, Cl, P, Br or I, n is 1 or 3 and Lj represents three phosphine ligands, at least one of which is optically active and contains an o-anisyl group. By soluble is meant that the catalysts are soluble in the reaction mass and the intended catalysis is thus homogeneous catalysis.

b

7409524-1. 5 G 9

For example, the phosphine ligand may have the formula AR &lt;RR,

6 where A is phosphorus and each of the symbols R, E and R¹'one independently of the other represents a hydrogen atom; an alkyl or alkoxy group having 1 to 12 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 not more than 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 The coordinate coordination complexes lb of the invention reside with the phosphine ligand. This optical activity may be due either to the fact that there are three different groups on the phosphorus atom or that an optically active group is attached to the phosphorus atom.

In the above-mentioned formulas for coordination metal complexes, only one ligand (L) needs to be optically active for the catalyst of the invention to function.

If the optical activity of the ligand consists in that an optically active group is bound to the phosphorus atom, there is only one such group and the other two groups may be the same or inactive. In this case, only five of the groups need R^z, E or R^f be optically active and the remaining two groups may be indentative or inactive.

Useful catalysts fall under the following formulas for coordination metal complexes but are not limited to them. In the formulas, an asterisk asymmetry indicates optical activity. The asterisk denotes the asymmetric atom or the asymmetric group.

<td>IN</td><td>RHX (A * E⁵R⁶R⁷)₃</td><td>VII</td><td>RHX₅(ARE⁵R^r'R⁷)₅</td>

<td>II</td><td>EhX (A * R⁵R⁶R⁷ (g) AR⁵R^fR⁷ )</td><td>VIII</td><td>RHX₅ (A * R⁵R^GR⁷(2) AR⁵RV '</td>

<td>III</td><td>RHX (A * R⁵R⁶hrs⁷) (AR⁵E⁶R)₂</td><td>IX</td><td>RhXj (A * R⁵R^SR⁷) (AE⁵E^GR⁷).</td>

<td>IV</td><td>Uh; in (AR *⁵E⁶R⁷)₅</td><td>X</td><td>RHX₅(ARE*⁵R⁶R⁷)₅</td>

<td>V</td><td>Clit X (AR * WÖ ₂ (AR⁵R⁶R⁷ )</td><td>XI</td><td>RHX ^ (AR *⁵R⁵R⁷) 2 (AR⁵R³R</td>

<td>WE</td><td>RHX (AR *⁵E '^SE⁷) (AR⁵R⁶R⁷) _?</td><td>XII</td><td>RHX₅(ARE*⁵R⁷R⁷)(ARE⁵R'R⁷)</td>

7409524-1 where X, A, E⁵, R⁶ and R? has the above meanings.

In the above list of catalysts, the dissymmetric group may be R, R ° or Roch is not limited to any single group. In addition, there may be a combination of groups bonded to the metal.

Of course, the above formulas represent not only those coordination metal complexes containing two or three ligands, but also those coordination metal complexes in which the number of ligand-metal coordination bonds corresponds to the number of L in the formula and in which these bonds are provided by multi-ligand ligands. Thus, although it may occur, for example, that there are only two ligands in a particular coordination metal complex, the complex is still operable if one of the two ligands is bivalent. provides two coordination obstacles. Similarly, the formula represents RhX_nAlso, the complexes in which there is only one ligand, namely, if it is tripartite, i.e. provides three coordination bonds.

Among the substituents on the phosphorus atoms are methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, acetoxyphenyl, methylphenyl, ethylphenyl, ethylphenyl, hutylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, hydroxyphenyl, phenoxyphenyl, o-anisyl, 3-cholesteryl, hensyl, pyrryl, furyl, pyridyl, thienyl, piperidyl, mentyl, bornyl and pinyl. Among the abovementioned substituents from butyl tom dodecyl is of course included isomers thereof. However, the substituents are not limited to those listed above.

For the purpose of the invention, the following optically active phosphines used, but the invention is of course not limited to these: metyletylfosfin, metylisopropylfosfin, etylbutylfosfin, isopropylisobutylfosfin, methylphenylphosphine, etylfenylfosfin, propylfenylfosfin, butylfenylfosfin, fenylbensylfosfin, fenylpyrrolfosfin, etylisopropylisobutylfosfin, methylphenyl 4-methylphenylphosphine, ethylphenyl- 4-methylphenylphosphine, methylisopropylphenylphosphine,

7409524-1 Ethylphenyl-2,4,5-trimethylphenylphosphine, phenylbenzyl-4-dimethylaminophenylphosphine, phenylpyridylmethylphosphine, phenylcyclopentylethylphosphine, cyclohexylmethyl isopropylphosphine, o-methoxyphenylmethylphenylphosphine and o-methoxyphenylphenylphosphine

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

The latter compound and the optically active coordination metal complex hydrogenation catalysts thus produced are novel 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.

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 are alike. It is also preferred that the asymmetry be in the phosphorus atom.

It has been found that excellent yields of the desired enantiomers can be obtained, not only with the above-described optically active hydrogenation catalysts, 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 consisting of a solution of rhodium and at least one equivalent of one phosphine ligand per mole of metal, provided the ligand is optically active. By way of example, the catalyst can be prepared by dissolving a soluble metal compound in a suitable solvent together with a ligand, wherein the ligand: metal ratio is at least one equivalent of ligand per mole of metal, preferably two equivalents of ligand per mole of metal. Similarly, it has been found that the catalyst can be prepared in situ by the addition of a soluble metal compound to the reaction mass together with the addition of the appropriate amount of the optically active ligand to the reaction mass either before or during hydrogenation.

Useful soluble rhodium compounds include rhodium trichlorohydrate, rhodium tribromide hydrate, roclium sulphate, 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 two-toothed ligands, or an active compound of metallic rhodium, which is readily solubilized.

It has been found that the catalyst of the invention preferably contains the optically active phosphine ligand at a ratio of about 1.5 to about 2.5 (preferably 2.0) equivalents of ligand per mole of metal. In practice, for operation and storage, it is preferred that the optically active catalyst be in solid form and it has been found that this can be achieved with solid, cationic coordination; metal complexes.

Cationic coordinate ion metal complexes containing two equivalents of phosphine per mole of metal and a chelating bis-olefin can be used as catalysts of the invention. Thus, using the above-described organic rhodium co-complexes, such cationic coordination rhodium complexes can be prepared by slurrying the organic rhodium complexes in an alcohol, for example ethanol, adding two equivalents of the optically active phosphine to form an ionic solution, and adding 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 upon treatment in a suitable solvent.

Examples of cationic coordination metal complexes include cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroborate, cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) -rodium tetlophenylborate boron 2,5-diene-bis (o-methylcyclohexyl anisylfosfin) -rodiumtetrafluorborat.

Without binding 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 hydrogenation of the olefin bond itself or the catalyst or precursor thereof may be hydrogenated prior to 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 them. Almost any aromat, saturated alkane or cycloalkane which is inactive against the hydrogenation conditions of the hydrogenation with the catalyst of the invention can be used. as a solvent. Once the hydrogenation has been found to be specific, solvents such as nitrobenzene can also be used. However, as a solvent, methanol is preferred.

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 this case form the catalyst in situ. When the catalyst is added in the form of its components, these can be added before or simultaneously with the β20 substituted α-acylamidoacrylic acid. Components for producing the in situ catalyst 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 0.0004 and about 5% by weight of the metal contained in the catalyst based on the amount of S-substituted α-acylamidoacrylic acid and / or salt thereof.

Measures should be taken within practical limits to avoid contact of the catalyst or reaction mass with oxidizing materials. 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 H₉) which are inert to both the reaction components and the catalysts, for example nitrogen or carbon dioxide.

As noted 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 hash and even in an acid purification machine, the yield is improved if

The iodine composition sets small amounts of a basic material, namely up to a maximum of one equivalent per mole of acrylic acid.

Surprisingly, a small amount of resin added to an empty acidic reaction mass provides improved asymmetric hydration and it has been found that the formation of a small amount of acrylic acid salt is sufficient to obtain improved results.

Useful bases include tertiary bases such as triethylamine, further HaOH and almost any other

-10 basic material which forms a salt with carboxylic acids.

After addition of the components to the solvent, hydrogen is added to the mixture until about Ί to about 5 times the mole amount of β-substituted α-acylamido-acrylic acid or an amount required for complete hydrogenation to the desired level is added. The pressure in the system varies with necessity as it depends on the type of β-substituted α-acylamidoacrylic acid, the type of catalyst, the dimensions of the hydration apparatus, the amount of components and the amount of solvent and / or hash. lower pressures, including atmospheric pressure and subatmospheric pressure can be applied as well as higher pressures.

The reaction temperature may range from about -20 to about 1 ° 0. Higher temperatures can be applied but are not normally required and can lead to accelerated side reactions.

When the reaction is completed, which is determined in a conventional manner, the solvent is removed and the products and catalyst are separated by conventional means.

Many naturally occurring products and medicines occur in an optically active form. In this case, usually only the L or D form is effective. Synthetic preparation of these compounds has so far required additional steps, namely separation of the products into their enantiomers. This is time consuming and expensive. The catalyst of the invention enables the production of optically active products, thereby eliminating said time-consuming and expensive separation while increasing the yields of the desired enantiomers and reducing the amount of undesired enantiomers.

Desired enantiomers of α-amino acids can be prepared by hydrogenation of the appropriate β-substituted α-acylamido40 acrylic acid in the manner described herein

7409524-1 agent):

% optical purity

Example 1:

by removing the acyl group on the α-amino group and the other protecting groups in a conventional manner 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 high overweight by the desired enantiomer, making 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. By parts is meant 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 solution-observed optical activity for the X 100 optical activity mixture of the pure enantiomer

The optically active phosphines can be prepared in the manner described by Mislow and Korpiun, J. Am. Chem. Soc., 89, 4-784 (1967).

PhPCl₂ + 2 CH 2 OH -&gt; Eh-P (0CH₃)₂

In a suitable vessel equipped with stirrer, temperature measuring device and lifting device 250 parts of phenyldichlorophosphine, 240 parts of pyridine and 495 parts of hexane were charged. the solution was cooled to about 5 to 30 ° C and a mixture of 96 parts of methanol and 27 parts of hexane was added with stirring over the course of about 1.5 hours. The mixture thus obtained was stirred for an additional 2.5 hours while heated to about 25 ° C. The reaction was carried out in an inert nitrogen atmosphere.

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 interval of 95 »5 ° 97 ° C / 17 mm Hg (82% yield of dimethylphenylphosphonite). (Harwood and Grisley J. Am. Chem. Soc., 82, 423 (I960). Θ »PhP-OCH,

IN ³

CH_Z5

EHP (OCH)₂ + CH

7b0952b-1

In a suitable vessel equipped with a stirrer, temperature measuring device and lifting device 44 parts of dimethylphenylphosphonite, 2.5 parts of methyl iodide and 9 parts of toluene were charged. The solution thus obtained was heated slowly. The reaction was exothermic and the temperature rose to about 410 ° C. The reaction mixture was kept at a temperature of about 40 ° C-42 ° C and a further 485 parts of dimethylphenylphosphonite was added slowly. Additional amounts of methyl iodide in portions of about 4 parts each were added time after another during the phosphonite addition. The reaction mixture was kept at about 44 ° C for an additional 4 hours after the components were added. The reaction mixture was then distilled off and a portion of distillation interval 448-449 ° / 47 mm Hg was collected (96% yield of methylphenylmethylphosphinate). (Harwood and Grisley J. Am. Chem. Soc. 82, 423 (4960).

OH

V 0. P-OCH

OH,

RClr tt: p - ci

ph

ph

In a suitable vessel equipped with a stirrer, condenser, temperature measuring device and lifting device 487 parts of methylphenylmethylphosphinate and 4600 parts of carbon tetrachloride were charged. To this mixture, 229 parts of phosphorus pentachloride were added in three portions of 50 parts each and a portion of 79 parts. A temperature rise was observed upon 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 of distillation interval 438-444 ° 0/47 mm Hg was collected. (95% yield of methylphenylphosphine chloride). (Methods of Organic Chemistry (Houben30 Weyl) Vol. XII / I p. 243.)

CH_Z 0

ph

<img file="SE412394B_D0007.tif" />

CH

7409524-1

In a suitable vessel equipped with a stirrer, condenser, temperature measuring device and loading device, 78 parts of -Z-menthol (/ o = -50 ° in ethanol) and 72 parts of diethyl ether were charged. To the solution thus obtained was added

ΊΊ9 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. The mixture was allowed to stand. until the temperature rises to about 25 ° C, then heated under reflux for about 10.5 hours.

The triethylamine hydrochloride was filtered off from the mixture and the filtrate was concentrated. There was thus obtained a solid melting at 50-65 ° C and found to be a mixture of β-menthylmethylphenylphosphinate diastereoisomers (60% S and

40 % R).

The mixture of JL -methyl-methylphenylphosphinate diastereoisomers prepared in the manner described above was divided into its components by crystallization several times in hexane and crystallization in diethyl ether to give a solid subs20 melting at 78-82 ° C which was found to be S-form of β-mentyl-methylphenylphosphinate.

<img file="SE412394B_D0008.tif" />

CH₃CH₂CH₂KgBr

ph

OH

V lf \ .pX) /

-oh₂OH₂CH₅

In a suitable vessel equipped with a stirrer, a temperature measuring device, a loading 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 of 4-7 parts of bromopropane and 123 parts of diethyl ether was slowly added at such a rate that gentle reflux of the reaction mixture was maintained. The reaction mixture was then cooled to about 25 ° C and stirred for a further two hours. ·

7409524-1

To this mixture was added a mixture consisting of 12 parts of S-form of Z-mentylmethylphenylphosphinate (prepared in the above manner) 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 removed to give a yellow oil. This was chromatographed on a silica gel column but a mixture of hexane: hensene: diethyl ether (3^:4: 1) to give an optically active phenylmethylpropylphosphine oxide in 61% yield.

Ph Ph.

P^x-CH₂-CH₂-CH₅ + HSiCl ^ + Et ^ N -5 »^ P ^^ - C ^ CHpCH ^

CH, CH,

2

In a suitable vessel loaded with an inert nitrogen atmosphere and 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 about 0 ° C. To this mixture was added at a temperature of about 4-6 ° C a mixture 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 inactive Pony] methylpropyl] phosphine oxide (prepared as above) and 22 parts of benzene were added. The mixture was then heated to about 60 ° C over the course of two hours and then cooled to about 25 ° C ·

The silica 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, then 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 methylpropyl 35 phenylphosphine was obtained in 95% yield. optical purity.

7409524-1

Ί5

One method of preparing rhodium (II) chloride tris (methyl-propylphenylphosphine) is described below.

A suitable vessel containing nitrogen atmosphere was charged with 0.342 g (0.0013 mole) of rhodium (IIl) chloride trihydrate and 10 ml of methanol, whereupon 0.76 g (0.0046 mole) of the optically active methylpropylphenylphosphine prepared in the above manner ml of methanol was added dropwise over the course of 15 minutes. The mixture was allowed to stand for an hour, during which a yellow precipitate formed. This was filtered off to give 0.21 g of the rhodium complex with specific rotation / ά7β = -69.2 ° (a mixture of benzene and ethanol in a 1: 1 v / v ratio).

Concentration of the filtrate yielded an additional 0.13 g of the product with specific rotation = -36.4 ° (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-trenethyl-methylphenylphosphinate diastereoisomers was cleaved by crystallization in hexane and / or hexane ether to give an S-form melting at 78-82 ° C and having specific rotation = -94 ° (benzene) and an E-form, which melted at 86-87 ° C and had qc specific rotation / o / j) = -17 ° (benzene).

<img file="SE412394B_D0009.tif" />

In an appropriate vessel equipped with a stirrer, temperature measuring device, loading device and condenser, an inert nitrogen atmosphere was injected, whereupon 18.3 parts of magnesium turning chips, 14 parts of diethyl ether and a reaction initiating amount of iodine were charged. A small amount of o-anisyl bromide was added to initiate the reaction and then slowly a mixture of 138 parts of o-bromoanisole and 400 parts of diethyl ether was added at such a rate that gentle reflux was maintained. After the addition was added, the mixture was refluxed for another two hours.

7409524-1

To the mixture was added a mixture consisting of 74 parts of either the R or S form of Λ-mentethylmethylphenylphosphinate (choice of the S or R form depends on the enantiomer desired to be obtained by the asymmetric hydrogenation) and

450 benzene. The diethyl ether was then removed and the mixture 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 residual oil was distilled, removing a menthol fraction first. Finally, the product was distilled over at 10S-19 ° 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 / α / β was obtained³= + 27 ° (methanol). Using the S-shape, a product with the opposite twist was obtained.

AND-,

Ph - i?^z)- z

CH

HSiCl- + Et, K

3

<img file="SE412394B_D0010.tif" />

In a suitable vessel containing inert nitrogen atmosphere and equipped with stirrer, temperature measuring device and lifting device 16 parts of trichlorosilane and 100 parts of benzene were charged at a temperature of about 5^σθ · A mixture of 12 parts of triethylamine and 50 parts of benzene was added to the mixture at 4-6 ° C. 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 1 hour and then cooled to 25 ° θ ·

The silica complex obtained as a reaction product was decomposed by 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 specific rotation / island / p³= + 4-1 ° (methanol) when the phosphine oxide produced with specific rotation as specified above / ά / ρ³= + 27 ° (methanol) was used. Using &lt;the opposite enantiomer of the phosphine oxide, phosphine was obtained with the opposite twist.

7409524-1

Example 3 · Preparation of methylcyclohexyl-o-anisylphosphine

<img file="SE412394B_D0011.tif" />

OCIU ₊ „₂ % Bh / C&gt;

CH.

<img file="SE412394B_D0012.tif" />

A one-liter autoclave was charged with 143 parts of the (+) methylphenyl-o-anisylphosphine oxide prepared in the above manner, 28 parts of 5% rhodium on carbon, and 250 parts of methanol. The batch was heated to 75 ° and stirred under a hydrogen atmosphere at a pressure of 56 kp / cnT overpressure. When hydrogen uptake ceased, the NMR spectrum showed that the reaction described in the above equation proceeded to

75 % · An additional amount of 7.0 parts of catalyst was added, the batch was again put under hydrogen pressure 56 kp / cm 'overpressure and the reaction was continued to a turnover of 96%. The catalyst was filtered off and the methanol was evaporated under vacuum. The crude oil was taken up in 200 parts of dibutyl ether and cooled to 0 ° C. The crystals that precipitated were filtered off and washed with hexane. There were thus obtained 63 parts of methylcyclohexyl-o-anisylphosphine oxide, which melted at 108-110 ° 0 and had specific rotation / ot / p = + 63 ° (methanol).

The phosphine oxide prepared in the above manner can be reduced to methylcyclohexyl-o-anisylphosphine in 95% yield using HSiCl 2 and triethylamine in the manner given above for methylphenyl-o-anisylphosphine. The methylcyclohexyl-o-anisylphosphine obtained is a specific rotation liquid / ά / ρ ° = + 98.5 ° (methanol).

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

A hydration apparatus equipped with a pressure gauge, temperature measuring device and heating device was charged with 25 parts of benzamido-4-hydroxy-3-methoxy-cinnamic acid, 186 parts of methanol and 64 parts of 5% sodium hydroxide. The kit was thoroughly blown to remove any trace of air and the hydrogen pressure was finally adjusted to 3.5 kp / cm overpressure and the temperature of 25 ° C ·

A catalyst solution was prepared by dissolving 0.0059 E of rodiura-1,5-hexadiene chloride (Sh Sh (1,5-hexadiene) 01 ^), m.p.

7409524-1

<td>elemental analysis:</td><td> % 0</td><td>% HRS</td><td>% Cl</td>

<td>calculated</td><td> 32,68</td><td> 4,57</td><td> 16,08</td>

<td>found</td><td> 32,41</td><td> 4,4-1</td><td> 15,82</td>

(J. Am. Chem. Soc., 86,217 (1964)) in 2 ml of benzene under a nitrogen atmosphere. Then, 0.0139 g (+) - methylphenyloanisylphosphine, (o / µ) - + 42 ° (methanol) in 1.3 ml of benzene was added. The phosphine oxide precursor had a melting point of 70-75 °^c, pQ (A / q = + 25.9 ° (methanol)). Thereafter, hydrogen was passed through the mixture for five minutes. The catalyst solution thus obtained was then pressed into a hydrogen pressure autoclave. Hydration started immediately and ended after 3-4 p

hours at 25 ° θ and 3.5 kp / cm 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 N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) alanine in the ratio 78:22.

The U-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-DOPA by simple hydrolysis to remove the blocking groups of benzoyl and methyl on the substituent at the 3-position of the phenyl group.

Example 5^: Hn one-liter autoclave was charged with 25.0 g of 25 benzamido-4-hydroxy-3-methoxy-cinnamic acid, 3θθ of methanol and 0.6 ml of 5% aqueous NaOH. The batch was stirred at 25 ° 0 p

below 2.8 kp / cm (overpressure) of pure hydrogen gas, until it could be safely ascertained that no leakage occurred. About 1 ml (0.01% Rh, 0.05% phosphine) of the following catalyst solution was added through a partition without relieving the pressure. The catalyst solution had been prepared by dissolving under 0.0050 g / Rh (1,5-hexadiene) 3 + 2 'mp 115-117 ° C.

<td>elemental analysis:</td><td>% C</td><td>% HRS</td><td>% Cl</td>

<td>55 calculated</td><td> 32,68 .</td><td> 4,57</td><td> 16,08</td>

<td>found</td><td> 32,41</td><td> 4,41</td><td> 15,82</td>

in 0.33 ml of a solution of methylphenyl-o-anisylphosphine / α / β p + + (9 ° (methanol) with specific rotation / α / β + = + 42 ° (methanol) in benzene containing 0.041 g / ml) ml and dilution

7409524-1 to 1 ml with methanol. The phosphine oxide precursor had a melting point of 70-75 °^c+ 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 hydration was completed in 2 hours.

The methanol was evaporated and the acid dissolved in one mole of an aqueous solution of NaOH. The neutral catalyst was extracted with benzene and put away for recovery. The free amino acid was then precipitated by the addition of concentrated HG1 under copious inoculation. 24 g of Nbenzoyl-3- (4-hydroxy-3-methoxyphenyl) alanine were obtained containing 73% of the L-enantiomer and 27% of the D-enantiomer. The lenantiomer can be converted to L-DOPA by hydrolysis as described in Example 4.

Examples 6-21: Other optically active ≤ x-amino acids were prepared in a manner similar to that of Examples 4 and 5 using a catalyst containing rhodium 1,5-hexadiene chloride and phosphine ligand of the structural formula

<img file="SE412394B_D0013.tif" />

The examples are summarized in the table below:

7409524-1 ice cream. data:

Catalyst kp ° C / mmHg

Example Olefin Product, ligand mp ° G Optical purity,%

OH

M

<img file="SE412394B_D0014.tif" />

<img file="SE412394B_D0015.tif" />

go

X 0-2II

OH

X o

in-anisyl

O cn * -&gt; XX II XX 0—2 —0—0

I cn

X o

O

X II XO— 2-0 - 0 II and

7409524-1, ΜΡ m φ • Η 33 ρ β a φ Ο β &amp; 0 p (g Φ go Ögo • ο ö

Mo tn ft £, µ:

ο

Ρ π!

«

Ν

Γ “I &lt;ί

Ρ¹

<td></td><td>(Μ</td><td>C0</td>

<td>co</td><td>τΗ</td><td> 0)</td>

<td>ΝΛ</td><td colspan="2">κ \</td>

<td> \</td><td></td><td>its</td>

<td> 00</td><td>οο</td><td> [&gt;-</td>

<td> 00 1</td><td> 00 1</td><td>1 ο</td>

<td> &lt;0</td><td>vb</td><td>ts</td>

<td> 00</td><td>οο</td><td>ft</td>

<td>ft</td><td>ft</td><td> 0</td>

<td>JM</td><td>JM</td><td>co</td>

I χ^Ν υ

of »υ

m

X υ

A^N υ

χ^Ν

4η

X υ

<img file="SE412394B_D0016.tif" />

I ο

<img file="SE412394B_D0017.tif" />

7409524-1

Λί-Ρ ra φ rlÄ fi ft ω onm

Μ · in

A 'f iH

CÖ 60 -ptg tö SO Ό So \ S • OS rao ra ir \ i&gt; I o

OO 'ra k ​​\ \

oo co

I ω

oo a

Ai

H o

P &lt;0 ra

H (Ö

P $

CM

<td></td><td>H</td><td></td>

<td></td><td>b</td><td>ΰ</td>

<td></td><td>CQ</td><td>_W</td>

<td></td><td>•HRS 3</td><td>t-t υ</td>

<td></td><td>Cu IN</td><td>tn A</td>

<td></td><td>O</td><td>u</td>

<img file="SE412394B_D0018.tif" />

O

II, υtn • r

<td>υ</td><td></td><td></td><td>υ «</td>

<td>1 υ</td><td></td><td></td><td>1 υ</td>

<td>II</td><td>O</td><td>cn</td><td>II</td>

<td>are</td><td>C II</td><td>A</td><td>A</td>

<td>υ- i</td><td>s - υ -</td><td>υ</td><td>υ</td>

<img file="SE412394B_D0019.tif" />

O tn ii a • u-υ φ

s §

&amp;

0) ii

7409524-1 &lt;} r

Λ4-Ρ CO tt) ΗΛ -P 0 ft tt) ο μ

ol

ΟΙ ΙΌ

<img file="SE412394B_D0020.tif" />

fO \

CO co

IN

ID

CO a

rM

N wo

- $ + rH O bO II O 0 &lt;1) 0 o Sd-pcr «I c \ ifttä« H ra * &lt;· ρ ra poo &lt;ui Ö¹ tt) o! O v Θ 0 &lt;H 'K + t zs

hrs

Oh u

+&gt;

rt w

&gt;

rH tti +&gt;

rt +&gt;

X

Ö • K

Ή

<img file="SE412394B_D0021.tif" />

rH

Q)

D g

£

7409524-1 data · Optical

Example Olefin Product Catalyst^Ραγηη ° Γ 'Eg ^ has

<img file="SE412394B_D0022.tif" />

t .ö • H

K o

A

One τ1

KA OD ~ • ri -PV tH ra mp ft o: oS tuM ra

H&gt;,

M

0)

-P «

Φ ii

O

M m

<img file="SE412394B_D0023.tif" />

O

OH

<img file="SE412394B_D0024.tif" />

<img file="SE412394B_D0025.tif" />

<img file="SE412394B_D0026.tif" />

7409524-1

A! -P co Φ -p

A Φ O 14

CÖ bO

S ^ o • ο Θ ​​coo cn ^ ° v ΙΛ 03 cr +

I II oo_ _ CT'CVI AH &lt;o ft tö * PA! &gt; i v&gt; i

Ο τ) κ \ * ·· Η f'S ** / * - * »OM ts 00 K \ οωι + ooq © oo ii g KS.H +&gt; LOO TO VP co cy R -p M 4 ft K, Q ft 0: 0 S 10¹ 0

P 4 4 CO Sj

<img file="SE412394B_D0027.tif" />

7409524-1

Α1Ρ ω φ • η Λ Ρ Η ft φ Ο β

Ο CM

ΙΛ (Μ

<img file="SE412394B_D0028.tif" />

<img file="SE412394B_D0029.tif" />

7409524-1

Example 22: An autoclave was charged with 25.0 g (0.085 mole) of o-acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate, 300 ml of methanol and 0.36 ml of 50% NaOH. The autoclave was put together

<img file="SE412394B_D0030.tif" />

hrs₂ (50:50)·

A catalyst solution was prepared by dissolving 0.0050 g (0.023 meq) / Sh (1,5-bexadiene) Cl₂ in 0.5 ml benzene, whereupon 0.051 meq was added under 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-1,5-hexadiene chloride, see Examples 4 and 5 above.

There was thus obtained (+) methylcyclohexyl-o-anisylphosphine, liquid, boiling point 110-114 ° C / 0.09 mmHg / o²⁰= + 98.5 ° (c = 1 in MeOH) at 90% optical purity / ά / ρ ° = + 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-3- (4-hydroxy-3-methoxyphenyl) -alanine acetate, which was recovered by evaporation of the solvent.

<img file="SE412394B_D0031.tif" />

in water). Pure N-acetyl-3- (4-hydroxy-3-methoxyphenyl) -Lalanine acetate, also in the form of sodium salt in water, had

<img file="SE412394B_D0032.tif" />

the resulting hydrogenation product was thus 70.7% or better than 85% of the L 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%). Thus, by appropriate selection of the (+) - or (-) - phosphine, the respective enantiomers can be prepared in large yield.

Example 23 The procedure described in Example 22 was repeated using (-) - methylcyclohexyl-o-anisylphosphine * on (optical purity about 80%) / a / p = -75.6 ° (c = 1 in MeOH) as the optically active ligand and oc-benzamido-4-hydroxy-3-methoxycinnamic acid as the H-substituted α-acylamidoacrylic acid. The resulting hydrogenation product was N-benzoyl-3- (4hydroxy-3-methoxyphenyl) -alanine containing a major amount of '7409524-1 *.

The D-enantiomer (optical purity of the reaction product mixture approximately 65%) ·

Example 24: In a pressurized flask purified with nitrogen, α-benzamido-4-hydroxy-3-methoxy-cinnamic acid (1.6 g, 5, θ mol) was charged, cycloactadiene-1,5-bis (methylcyclohexyl-o -anisylphosphine) iridium tetrafluoroborate, clear red solid (21.7 mg,

0.025 mol), and 20 ml of anhydrous methanol. The mixture was stirred and bubbled with nitrogen for 15 minutes. The pressure in the pressure flask was bent to 7 kp / cm overpressure by blowing in hydrogen, and the mixture was stirred and heated at 400 ° C for 20 minutes. A portion of this reaction mixture was subjected to NMR spectrometric analysis, showing that 59% of the starting material was converted to the product N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) alanine. By polarization metric analysis of the reaction mixture after neutralization according to standard procedures showed that the product was optically active with F / q = 9.3 °

Example 25 = In a solution of 2.005 g of N-acetyl-indolyl-ocacetamidoacrylic acid in 60 ml of methanol, 0.0074 g of cyclo-octadiene -4,5-bis (methylcyclohexyl-o-anisylphosphine) rhodium tetrafluoroborate, orange crystals having a melting point of 47 475 ° C. The mass thus obtained was carefully bled, 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 torsion. the solution had = 20.4 °.

Theoretical value of 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 is prepared in the manner stated by Mislow and co-workers of JACS 95, 953 (4973).

catalyst solution was prepared by admixing 2 ml of methanol, 0.2 g (+) - methylpropylphenylarsine (λ = + 40.7 °, 80 ^c(a, 0.46 mmol) and 0.025 g of rhodium (cyclooctadiene 4.5) acetonylacetonate (0.08 mmol), mp 425-428 ° C (dec.). After stirring for 40 minutes under a nitrogen atmosphere i

7409524-1, the whole set of solids had dissolved. A solution of 1.0469 g of α-acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate in 25 ml of methanol was carefully purged with nitrogen for p.

and was then put under a hydrogen overpressure of 3.9 kp / cm at 50 ° C. To the reaction mixture was added through a septum

1.0 ml of the above catalyst solution. The hydration began and was completed in 2.5 hours, as indicated by p

a pressure drop of 0.8 kp / cm ”. The resulting mass was diluted to 50 ml and tested for specific optical torsion, which was found to be “/ p = -2.53 ° A test solution using pure N-acetyl-3 (4-hydroxy-3-methoxy-phenyl) ) -L-alanine acetate and the same amount of catalyst gave a correction of this rotational power of the catalyst of 0.7 °. The hydration thus gave a net twist of -1.8 °.

p Q

The pure optical enantiomorph had / o / p = -40.8 °. Thus, the optical purity was 4.4%.

Evidence that the arsine was not optically pure was obtained by its conversion to the sulfide (Mislow and co-workers of JACS 95, 953 (1973)) and measurement of optical purity with a chemical displacement reagent (RMR Ohiral Shift Reagent, Whitesides and co-workers JACS 96, 1038 (1974)). This experiment showed that the methylpropylphenylarsine used had an optical purity of only 45 ° / o. Thus, if the hydration had been carried out with the optically pure arsine, an optical purity of 9.5% would have been achieved. The product was recovered by evaporation of the methanol and recrystallization from the concentrated solution.

Example 27 Preparation of cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroborate. Into a 1 liter flask, 300 ml of methanol and 15.4 g (0.031 mol / rhodium (cyclooctadiene-1.5) chloride / l, 30.3 B (98%, 0.12 mol) methyl cyclohexyl) were charged under nitrogen. 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 (13.7 g, 0.12 mol) in 160 ml of water was added over the course of one hour. Unpainted crystals separated and collected. They were washed with water (2x30 ml). The product was dried under vacuum at 25 ° θ and weighed. This yielded 45 g of product with a melting point of 170-175 ° θ. This material was about 96% optically pure.

7409524-1