CH624088A5 - Process for the preparation of enantiomorphs of acyloxypropionic acid derivatives with high optical purity - Google Patents

Description

This invention relates to a process for the preparation of enantiomorphs with high optical purity of acyloxypropionic acid derivatives by asymmetric hydrogenation of the 55 geometric Z isomers of corresponding acyloxypropenoic acid derivatives.

Homogeneous catalysis, i.e. those catalyzed reactions in which both the reactants and the catalysts are soluble in the reaction mass are known to be particularly valuable in processes in which an asymmetrical result is obtained. For example, it was found that in the homogeneous catalytic hydrogenation of an olefin which is capable of forming a racemic mixture, one of the two possible optically active enantiomorphs in a larger amount and the other optically active in the presence of an optically active catalyst Enantiomorphs obtained in a smaller amount. The state of the art in terms of homogeneous catalytic

3rd

624 088

Hydrogenation of olefins in 1972 is summarized in "Modern Synthetic Relations" by Herbert O. House, 2nd edition, W.A. Benjamin, Inc., Menlo Park, CA, USA, 1972, pp. 28-34. The possibility of asymmetric hydrogenation is not mentioned.

On the second priority date of DE-OS No. 2 123 063 by the patentee (March 8, 1971), it was assumed that the inventiveness of the catalytic asymmetric hydrogenation described in DE-OS was that the optically active catalyst forms a complex with the olefin substrate , and that the success or failure in using the complex depends on whether there is a nitrogen atom in the olefin to which a hydrogen atom is attached that forms a hydrogen bond with the optically active catalyst, thus providing the rigidity that is required so that only one of the isomers is obtained.

Accordingly, at the time when the present invention was conceived, it was assumed that with the aid of the optically active catalysts described in the present patent specification, only a substrate containing a-acylamido groups could be asymmetrically hydrogenated with the aim of achieving a high degree of optical purity. Prior to the present invention, it was believed that asymmetric hydrogenation would be achieved by chelating the catalyst with the olefin and adhering to both the olefin double bond and the hydrogen atom attached to the nitrogen atom of the a-acylamido group of the olefin is bound, binds as described in DE-OS.

It was subsequently found that the older theory was wrong and that the asymmetric hydrogenation occurs because the noble metal phosphine ligand catalyst chelates with the olefin substrate on the double bond and on the oxygen atom of the acyl group, and that it has nothing to do with that in the acylamido group contained NH bond has to do. It has been found that olefin substrates which are not substituted by an a-acylamido group can also be successfully asymmetrically hydrogenated. This is the basis of the present invention, in which an olefin which does not contain an a-acylamido group but instead contains an a-acyloxy group is asymmetrically hydrogenated.

The present invention is thus closely related to the relationship between the catalyst and the olefin substrate, which must fit in a special way if one wants to obtain an enantiomorph with an optical purity of at least 86%. If this optical purity is not achieved, the asymmetric hydrogenation cannot usually be regarded as successful.

The method according to the invention is defined in claim 1. It delivers enantiomorphs with excellent values of optical purity.

The E / Z system of the nomenclature of geometric isomers (cis-trans nomenclature) is e.g. B. in "The Journal of Organic Chemistry", Vol. 35, No. 9, September 1970, pages 2849 to 2867. It was introduced by the Chemical Abstracts Service.

The symbols R, R1, R2 and R3 can, for example, alkyl groups, such as methyl, ethyl, propyl groups etc., and aryl groups, such as phenyl, 4-chlorophenyl, 3,4-dihydroxyphenyl, 4-methylphenyl groups etc., mean. Such substituent groups are sometimes precursors of substituents that one actually desires. If, for example, the desired substituent is a hydroxyl group, the olefin in the formula C or D may contain an acetoxy group as a substituent which, after the catalytic asymmetric hydrogenation, can be converted into a hydroxyl group by simple hydrolysis.

The optically active enantiomorphs which can be prepared according to the invention are particularly desirable since the optical activity is a characteristic property of compounds which are biologically active; this means that normally only one of the optically active enantiomorphs can be used in living organisms. For example, those optically active enantiomorphs obtainable according to the invention which contain a substituent which can be converted into an a-hydroxyl substituent of a carboxylic acid by simple hydrolysis are particularly valuable because a-hydroxycarbon acids can serve as a substitute for a-amino acids.

The starting compounds of the formula C give excellent results in the process according to the invention and are therefore particularly suitable for the invention.

Particularly preferred compounds of the formula C are the Z isomers of 2-acetoxy-3-phenyl-2-propenoic acid ethyl ester, 2-acetoxy-2-propenoic acid methyl ester and 2-acetoxy-2-propenoic acid ethyl ester. According to the invention, the L-enantiomorphs of the corresponding esters of phenyllactic acid or lactic acid, which can be used to prepare the free acids, can easily be prepared from these compounds.

The hydrogenation reactions according to the invention are usually carried out in a solvent such as benzene, ethanol, 2-propanol, toluene, cyclohexane or mixtures of these solvents. Almost any aromatic alkane or cycloalkane solvent which is inert under the conditions of the process according to the invention can be used. The preferred solvents are alcohols, especially methanol, ethanol and 2-propanol, for example those alcohols which correspond to the ester group in the olefinic substrate to be hydrogenated are particularly desirable.

The optically active catalysts used according to the invention preferably contain at least 0.5 mol of bisphosphine ligand per gram atom of metal. These catalysts are soluble in the reaction mass and are therefore referred to as “homogeneous” catalysts. Preferred bis-phosphine ligands of the formula I contain two different aryl groups on each phosphorus atom, those in which such an aryl group has an alkoxy substituent in the ortho position are particularly preferred.

More preferred bis-phosphine ligands correspond to the formula:

x-f-ch ^ -p-x (ii)

y y wherein X represents an optionally substituted phenyl group and Y is an optionally further substituted 2-alkoxyphenyl group, the alkoxy radical of which has 1 to 6 carbon atoms, the substituents not being allowed to cause any significant disturbance of the steric conditions around the phosphorus atom and X and Y are different.

Particularly preferred optically active bis-phosphine ligands correspond to the formula:

m-p-ch2ch2-p-m (iii) Q Q

where M is a group of the formula:

and Q means a group of the formula:

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

624 088

4th

means where R 'and R ", which are the same or different, each represent hydrogen, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms and R'" is an n-alkyl group having 1 to 6 carbon atoms means that M and Q are different.

A particularly preferred optically active bis-phosphine ligand is 1,2-bis (o-anisylphenylphosphino) ethane.

Further examples of suitable optically active bisphosphine ligands are:

1,2-bis- (o-anisyl-4-methylphenylphosphino) -ethane 1,2-bis- (o-anisyl-4-chlorophenylphosphino) -ethane 1,2-bis- (o-anisyl-3-chlorophenylphosphino) - ethane l, 2-bis- (o-anisyl-4-bromophenylphosphino) -ethane 1,2-bis- [(2-methoxy-5-chlorophenyl) phenylphosphino] -ethane l, 2-bis - [(2-methoxy -5-bromophenyl) phenylphosphino] ethanol 1,2-bis (2-ethoxyphenylphenylphosphino) ethanol 1,2-bis- [o-anisyl- (p-phenylphenyl) phosphino] ethanol 1,2-bis [(2-methoxy-4-methylphenyl) phenylphosphino] ethanol 1,2-bis (2-ethoxyphenyl-4-chlorophenylphosphino) ethanol 1,2, bis (o-anisyl-2-methylphenylphosphino) ethanol l , 2-bis- (o-anisyl-4-ethylphenylphosphino) -ethane l, 2-bis- (o-anisyl-3-ethylphenylphosphino) -ethane l, 2-bis- (o-anisyl-3-phenylphenylphosphino) -ethane .

These bis-phosphine ligands, as stated in claim 1, must be optically active and therefore must not be in the meso form.

The optical activity of the catalysts used according to the invention derives from the bis-phosphine ligand and results from the fact that the ethane bridge and two different groups (A and D) are bonded to the phosphorus atoms.

Examples of suitable coordination complexes can be represented by the formula MeTL, in which Me is at least one of the transition metals rhodium, iridium and ruthenium, T is hydrogen, fluorine, bromine, chlorine or iodine and L is the optically active bisphosphine ligand defined above is.

It was found that excellent optical purity levels of the desired optical enantiomorphs can be achieved, not only with the catalysts of the formula MeTL described above, but also when carrying out the hydrogenation in the presence of at least one of the transition metals rhodium, iridium in solution from a solution and ruthenium and at least 0.5 mole of the optically active bis-phosphine ligand per gram atom of metal formed catalyst. For example, such catalysts can be obtained by dissolving a soluble compound of the corresponding metal together with an optically active bis-phosphine ligand of the formula I in a suitable solvent, at least 0.5 mol of ligand per gram atom of metal, preferably 1 mol of ligand per gram atom of metal. It has been found that the catalyst can be formed in situ by adding a soluble metal compound to the reaction mass together with an appropriate amount of the optically active bis-phosphine ligand either before or during the hydrogenation.

The catalyst is preferably a coordination complex of rhodium. Soluble rhodium compounds that can be used to prepare such complexes include Rhodium trichloride hydrate, rhodium tribromide hydrate, rhodium sulfate and organic rhodium complexes with ethylene, propylene, etc. and dienes, such as 1,5-cyclooctadiene, 1,5-hexadiene, bicyclo-2,2, l-hepta-2,5-diene and other dienes that can form bidentate ligands or active forms of metallic rhodium that can be easily solubilized.

In a preferred embodiment of the invention, the ratio of optically active bis-phosphine ligand to metal is about 0.5 to about 2.0 moles, preferably 1.0 mole, per gram atom. In practice it is preferred that the optically active catalyst is in solid form with regard to its handling and storage. It was found that excellent results can be obtained with fixed, cationic coordination complexes.

Cationic coordination complexes containing one mole of the optically active bis-phosphine ligand per gram atom of metal and a chelating diene are preferred as catalysts. For example, using organic rhodium complexes of the type described above, such cationic coordination complexes of rhodium can be prepared by slurrying the organic rhodium complex in an alcohol such as ethanol, adding one mole of the optically active bis-phosphine ligand per gram atom of rhodium, so that one Solution is formed, and then a suitable anion, for example the tetrafluoroborate, tetraphenylborate or any other anion, is added so that a solid, cationic coordination complex either precipitates directly from the solvent or crystallizes out or precipitates after treatment in a suitable solvent or crystallized out.

Examples of suitable cationic coordination complexes are cyclooctadiene-l, 5- [l, 2-bis- (o-anisylphenylphosphino) -ethane] rhodium tetrafluoroborate, cyclooctadiene-l, 5- [l, 2-bis- (o-anisylphenylphosphino) -ethane] -rhodiumtetraphenylborate and bicyclo-2,2,1-hepta-2,5-diene- [1,2-bis- (o-anisylphenyl-phosphino) -ethane] rhodium tetrafluoroborate.

Without prejudging the present invention, it is believed that the catalyst is actually present as a catalyst precursor and that it is converted to an active form upon contact with hydrogen. This conversion can of course either take place during the actual hydrogenation or can be brought about by bringing the catalyst (or the precursor) into contact with hydrogen before the addition to the reaction mass to be hydrogenated.

As mentioned above, the catalyst can be added to the solvent either as such or in the form of its components which then form the catalyst in situ. If the catalyst is added in the form of its components, it can be added before or after the addition of the olefinic substrate. The components for the preparation of the catalyst in situ are the soluble metal compound and the optically active bis-phosphine ligand. The catalyst can be added in any catalytically effective amount; it is generally used in an amount in the range of 0.001 to 5% by weight of metal contained therein, based on the olefinic substrate to be hydrogenated.

As far as practically possible, it should be avoided that the catalyst or the reaction mass comes into contact with oxidizing materials. In particular, care should be taken to ensure that any contact with oxygen is avoided. The preparation of the reaction mass and the actual reaction should preferably be carried out in gases other than hydrogen which are inert with respect to the two reactants and the catalyst, such as nitrogen or argon.

The procedure is preferably as follows: after the addition of the reactants and the catalyst to the solvent, hydrogen is added to the mixture until about 0.5 to 5 moles of hydrogen are present per mole of the olefinic substrate. The pressure in the system depends on the type of reactants, the type of catalyst, the

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

624 088

Size of the hydrogenation device, the amount of reactants and the catalyst and the amount of solvent. Low pressures, including atmospheric and vacuum, as well as higher pressures can be used.

The reaction temperatures can range from about -20 ° C to about 110 ° C. Higher temperatures can be used, but are usually not required and can increase side reactions.

After the end of the reaction, which can be determined using conventional methods, the product can be obtained using conventional methods.

Many naturally occurring substances and medicines exist in optically active forms. In these cases, usually only the L or only the D form is effective. In the synthetic preparation of these compounds it was previously necessary to split the products into their enantiomorphs in an additional step. This split is expensive and time consuming. The method according to the invention enables the desired optical enantiomorphs to be imaged directly with excellent optical purity, as a result of which the very time-consuming and expensive separation of the optical enantiomorphs is largely unnecessary. Furthermore, the method according to the invention provides the desired optically active enantiomorph in higher yield, while at the same time the yield of the undesired optically active enantiomorph is reduced.

The process according to the invention is particularly advantageous because it not only provides an unusually high optical purity of the desired optically active enantiomorph, but also results in a high hydrogenation rate at low catalyst concentrations.

In the examples, the percent optical purity (% OR) is determined according to the following equation (the optical activities, expressed as specific rotation, of course, all being determined in the same solvent):

% OR - of the isomer mixture x OA of the pure isomer where OA means the observed optical activity.

example 1

I. Preparation of the Z-isomer of 2-acetoxy-3-phenyl

2-propenoic acid ethyl ester

A solution containing 22 g of ethyl phenylpyruvate, 65 g of acetic anhydride and 20 mg of p-toluenesulfonic acid monohydrate is heated to reflux for 2.5 hours. The excess acetic anhydride is driven off from the reaction mass and the crude Z isomer of 2-acetoxy-3-phenyl-2-propenoic acid ethyl ester thus obtained is distilled at about 1.6 torr (boiling range 120 to 135 ° C). The product obtained crystallizes on standing in the cold and is obtained by filtration and recrystallized from ethanol; Yield 12.1 g; Melting point 41 to 47 ° C; a second recrystallization gives 10.5 g of melting point 47 to 49 ° C; a third recrystallization gives 9.2 g of melting point 47 to 49 ° C.

II. Preparation of 2-acetoxy-3-phenylpropanoic acid ethyl

ester

(A) 1.9903 g of the Z isomer of ethyl 2-acetoxy-3-phenyl-2-propenate and 0.0175 g of cyclooctadiene-l, 5- [l, 2-bis (o-anisylphenylphosphino) -ethane] - Rhodium tetrafluoroborate in 30 ml of ethanol are shaken in a Hoke flask at Erwa 27 at and 50 ° C. The hydrogen uptake is essentially complete after 2 hours. The ethanol is driven off from the solution obtained by means of a rotary evaporator. The residue is examined by means of nuclear magnetic resonance, which confirms the presence of the hydrogenation product 2-acetoxy-3-phenylpropanoic acid ethyl ester in the form of an oil. The product is obtained by vacuum distillation. 1.6 g of a distillate with a boiling range of 80 to 83 ° C. at 0.05 Torr are obtained. Magnetic resonance analysis shows that the product contains 97.6% of the desired hydrogenation product and 2.4% of the starting olefin. Gas chromatography confirms this analysis. [a] D20 = -6.91 ° (C = 6.0 in CHC13). Optical purity 79.4%; if corrected according to the analysis, it would be 81.5%.

(B) 2.2721 g of the Z-isomer of ethyl 2-acetoxy-3-phenyl-2-propenate and 0.0202 g of cyclooctadiene-l, 5- [l, 2-bis (o-anisylphenylphosphino) -ethane] - rhodium tetrafluoroborate are hydrogenated in 30 ml of ethanol at 51 ° C under an H2 pressure of 3 at. The ethanol is driven off from the solution obtained by means of a rotary evaporator. The investigation by magnetic nuclear magnetic resonance shows that the hydrogenation is 89% complete after 6 hours. The product,

2-acetoxy-3-phenylpropanoic acid ethyl ester, is obtained by flash distillation; Boiling range 80 to 85 ° C / 0.5 Torr. According to the nuclear magnetic resonance spectrum, the product contains 87.0% of the desired isomer. The observed optical rotation of the product was -0.515 °, [a] D20 = 8.27 ° (C = 6.0 in CHC13). The optical purity, corrected according to the analysis, is 95%.

Example 2

I. Preparation of the Z-isomer of 3-acetoxy-3-phenyl-2-propenoic acid ethyl ester

A solution of 27.8 g (0.145 mol) of 3-oxo-3-phenylpropanoic acid ethyl ester, 29.0 g of 2-acetoxy-l-propene and 100 mg of p-toluenesulfonic acid monohydrate is heated to reflux for 17 hours. The reaction mass is poured at 50 ° C in 50 ml of a saturated NaHC03 solution and the organic phase is extracted with ethyl ether. The ether solution is dried and the solvent is driven off. Distillation of the residue at 0.1 torr gives 8.3 g of a yellow oil with a boiling range of 110 to 120 ° C. It is confirmed by GLC, NMR and UV analysis that the distillate from the Z isomer of 3- Acetoxy-3-phenyl-2-propensäureäthyl ester exists.

II. Preparation of ethyl 3-acetoxy-3-phenyipropanoate

A solution of 2.5 g of the Z-isomer of 3-acetoxy-3-phenyl-2-propenoic acid ethyl ester and 0.0373 g of cyclooctadiene-l, 5- [l, 2-bis (o-anisylphenylphosphino) -ethane] - Rhodium tetra fluoroborate in 30 cc ethanol is hydrogenated at 27 at and 50 ° C in a hoke bomb. After 12 hours, the product is isolated by removing the ethanol using a rotary evaporator. NMR analysis shows that the hydrogenation product to olefin ratio is 89:11. There is also some ethyl 3-phenylpropanoate, which was formed by hydro-genolysis.

2.5 g of the crude product are subjected to distillation. A first fraction from the boiling range 75 to 87 ° C. at 0.1 Torr, which consists of ethyl 3-phenylpropanoate, is collected. The rest of the crude product, which distills at 95 to 110 ° C and 0.1 Torr, is a mixture of 3-aceto-xy-3-phenylpropanoic acid ethyl ester and the Z-isomer of

3-acetoxy-3-phenyl-2-propenoic acid ethyl ester in a ratio of 86:14 (according to NMR). [a] D20 = -4.74 ° C (pure substance, 1 = 1). Corrected according to the NMR analysis, the optical purity is 90.5 '/ c.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

624 088

Example 3

I. Preparation of the E-isomer of 3-acetoxy-3-phenyl-2-propenoic acid ethyl ester

A solution of 5.2 g of the Z-isomer of 3-acetoxy-3-phenyl-2-propenoic acid ethyl ester in 60 ml of CHC13 is irradiated with light of wavelength 3100 A for 72 hours. The solvent is removed using a rotary evaporator. Distillation of the residue at 0.03 Torr gives 1.3 g of a yellow oil with a boiling range of 92 to 98 ° C. It is confirmed by GLC, NMR and UV analysis that the distillate from the E isomer of 3- Acetoxy-3-phenyl-2-propenic acid ethyl ester (purity 86%) exists.

II. Preparation of ethyl 3-acetoxy-3-phenylpropanoate

A solution of 1.1566 g of the E-isomer of 3-aceto-xy-3-phenyl-2-propenoic acid ethyl ester (prepared as in I

described, purity 86%) and 0.027 g of cyclooctadiene-1,5- [l, 2-bis- (o-anisylphenylphosphino) -ethane] -rhodium tetra-fluoroborate in 30 ml of ethanol is hydrogenated for 5 hours at 27 at and 50 ° C. . Then the ethanol is driven off by means of a rotary evaporator and the product is subjected to NMR analysis. The ratio of hydrogenation product to olefin is 76:24. This product mixture is distilled at 95 to 120 ° C and 0.2 torr. Analysis of the distillate by gas chromatography confirms that the ratio of ethyl 3-acetoxy-3-phenylpropanoate to E-isomers of ethyl 3-acetoxy-3-phenyl-2-propionate to ethyl 3-phenylpropanoate is 64:18:18. The mixture has an optical rotation [a] D20 = + 0.515 ° (pure substance, 1 = 1). After correction according to the analysis of the desired hydrogenation product, the optical elongation [a] o20 = + 0.805 ° (pure substance, 1 = 1). The optical purity is 15.4%.

s

Claims (6)

624 088 2nd PATENT CLAIMS 1. Process for the preparation of enantiomorphs with high optical purity of compounds of the formula: R1 C00R2 \ / XCH-CH 0 \ H 3 R 0-C-R (A) 3 "r-c-0 R C00R ^ CH-dH S ^ R1 or 2 (B) R1 COOR2 \ / NC = C 0 / \ Ii 3 R x0-C-RJ (C) or 0 3 II 2 R-C-0. ^ COOR \ = C R R1 (D) asymmetrically hydrogenated under homogeneous catalysis in the presence of a coordination complex of rhodium, iridium and / or ruthenium, which has an optically active bis-phosphine ligand of the formula: A-P-CH0CH0-P-A I 2 2 I D D (I) contains, as a catalyst, wherein A and D, which are different, each represent an optionally substituted alkyl group having 1 to 12 carbon atoms, an optionally substituted cycloalkyl group having 4 to 7 carbon atoms or an optionally substituted aryl group, the substituents being no significant disruption to the steric conditions around the phosphorus atoms may cause. 2. The method according to claim 1, characterized in that a bis-phosphine ligand of the formula: X-P-CH0CH_-P-X I 2 2 I Y Y (II) 10th used, in which X represents an optionally substituted phenyl group and Y represents an optionally further substituted 2-alkoxyphenyl group, the alkoxy group of which contains 1 to 6 carbon atoms, the substituents not being allowed to cause any substantial disturbance of the steric conditions around the phosphorus atoms, and X and Y are different . 3. The method according to claim 1, characterized in that a bis-phosphine ligand of the formula: wherein at least one of the carbon atoms of the represented grouping of the formula: ^ .CH-CÎff is asymmetrical, R, R1 and R2, which are the same or different, each represent hydrogen, an optionally substituted alkyl group having 1 to 5 carbon atoms or an optionally substituted aryl group and R3 is an optionally substituted alkyl group having 1 to 5 carbon atoms or is an optionally substituted aryl group, characterized in that the geometric Z isomer of a corresponding compound of the formula: M-P-CH_CH -P-M i 2 2 i Q Q where M is a group of the formula: ry and Q is a group of the formula: RIM0 (in) means, where R 'and R ", which are the same or different, each represent hydrogen, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 35 6 carbon atoms and R'" is an n-alkyl group having 1 to 6 Carbon atoms means that M and Q are different. 4. The method according to claim 1, characterized in that the bis-phosphine ligand is l, 2-bis (o-anisylphenyl) 40 phosphino) -ethane used. 5. The method according to claim 1, characterized in that rhodium is used as the metal in the catalyst complex. 6. The method according to claim 1, characterized in that the Z isomer of 2-acetoxy-3-phenyl-2-propene acid ethyl ester hydrogenated. 50