CS240663B1 - Method of n-acylamino acids preparation - Google Patents

Description

The invention relates to a process for the preparation of N-aoylamino acids.

It is known that rhodium coordination compounds containing especially chelating bidentate phosphines, phosphinites or aminophosphines as ligands are effective catalysts for the hydrogenation of dehydroamino acids as a route to amino acid production. In terms of the type of rhodium complexes, they can be divided into two groups: neutral complexes such as (Can. J. Chem. 57, 180 (1979)} and cationic, in which the anion is a ClO 4 or BP 4 ion, such as e.g.

Chem. Soc. 98, 214-3 (1976)) It is further known that, using chiral rhodium complexes, the reaction of prochiral dehydroamino acids proceeds to form enantiomers that are formed in amounts significantly different from the equilibrium distribution. This process was carried out with a series of rhodium complexes containing phosphines with chirality on phosphorus (NSR Pat. Nos. 2,210,938 and 2,456,937) or on a carbon substituent attached to a phosphorus atom (NSR Pat. No. 2,161,200) as chiral ligands. ), phosphinites and aminophosphines (Synthesis 1981, 85). Depending on the structure and configuration of the prochiral substrate and the type and structure of the chiral ligand, this asymmetric hydrogenation took place with enantiomeric excesses ranging from 3 to 96% (Synthesis 1981, 85). The high optical yields obtained in the hydrogenation of some dehydroamino acids represent a significant advance in which catalysed asymmetric synthesis has become one of the promising ways to produce optically active amino acids. Its advantage has already been demonstrated, for example, in the synthesis of DOPA by hydrogenation of 3,4-dimethoxy-α-acetamidocinnamic acid (U.S. Pat

849,480) ·

- 3 240 003

The catalyst types used so far based on cationic rhodium complexes have the disadvantage that they exhibit limited solubility in an environment favorable to the reaction of the hydrogenated substance. This disadvantage is overcome by the method according to the invention.

The present invention provides a process for the preparation of N-aoylamino acids of general formula

R ¹ -CR ² H-CH (CO ⁵ ) NR ⁴ CO ⁵ , wherein R is hydrogen, alkyl to C 1-4, preferably methyl, isopropyl, aryl, preferably phenyl, 3,4-dimethoxyphenyl, 3,4,0-methylenophenyl 3-acetoxy, 4-methoxyphenyl, 4-acetoxyphenyl, 4-hydroxyphenyl, R is hydrogen, methyl and COR 4, R-5 is hydroxy, alkoxy to C 1-4, preferably methoxy, ethoxy and isopropyl, phenoxy and amino, R ⁴ denotes hydrogen and methyl and R 1 denotes methyl, phenyl, benzyl and methoxy by hydrogenation of the dehydroamino acids of the general formula

R ¹ -CR ² = C (CO ⁵ ) NR ⁴ CO ⁵ , wherein the substituents R ¹ to R 6 are as defined above, in the presence of rhodium coordination compounds as catalysts at a hydrogen pressure of from 30 kPa to 2 MPa and a temperature of 10 to 80 Deň: 32 ° C. The reaction is carried out in the presence of a rhodium complex of the general formula

Rh (olefin) _m L ² (O ₃ SR), wherein the olefin denotes an alkene with a C 8 to C 8 and a cycloalkene with a C 8 to C 8, preferably ethylene, cyclooctene and further an alkadiene with a C 8 to C 8 g, preferably

1,5-hexadiene, 1,5-cyclooctadiene and norbornadiene L ² represents alkylendifosfiny formula (C ₆ H ₅₎ gFCH (R ⁶⁾ / CH (R *) / _n P (C ₆ H ₅₎ g>

wherein R and R is hydrogen, n equals 1-4, R is methyl or phenyl and is hydrogen, n equals 1 and R ⁶ and ^R? is methyl for n equals 1 and 1,4-diphosphinobutane derivatives, n equals 3, of the formula

O-CH-CH _o P (Cz-Hc) o / b 2 b 5 2

A 1 ^X O-CH-CHgP (C ₆ H ₅ ) g * wherein A represents isopropylidene, cyclopentylidene, cyclohexylidene and cyclooctylidene and R 50 denotes an organosulfonate group in which R represents phenyl, tolyl, naphthyl, m- 240 063

and m is 0 to 1 in the case of dienes and 0 to 2 in the case of alkenes, the p index is 0.5 to 2, wherein the sum of the metal-to-olefin coordinate bonds and the L ligand is four in the presence of organic solvents. The solvent used may be alcohol, suitably methanol, ethanol and isopropanol, mixtures thereof with aromatic hydrocarbons, suitably benzene, or these solvents with the addition of water.

Alkylenediphosphines as defined above also include derivatives in which replacing the hydrogen of a methylene group with a methyl group results in a chiral carbon atom in the molecule of the compound. For the purposes of the invention, the formulas thus represent both the racemic mixture of both enantiomers and the respective optical antipodes. In this sense, for example, the formula

C ₆ h ₅ ) ₂ pch (CH 2) ₂ p (c ₆ h ₅ ) ₂ represents 1,2-bis (diphenylphosphino) propane, (R) - (+) - 1,2-bis (diphenylphosphino) propane and (S) - (-) - 1,2-Bis (diphenylphosphino) propane.

Random catalysts of the above formula can be prepared by reacting dimeric olefin (chlorine) rhodium complexes with silver p

salts of the respective organosulfonate in the presence of phosphine L or by reacting olefin (pentanedioate) rhodium complexes with the appropriate orphan sulfonic acid in the presence of ligand L, i.e. in a manner analogous to known methods for preparing cationic rhodium complexes containing perchlorate or tetrafluoroborate anion. ,

The structure of the rhodium catalyst formed by the above reactions depends on the molar ratio of the reactants. For example, the reaction of Rh (1,5-cyclooctadiene) (2,4-pentanedione) with an equimolar amount of 1 and toluenesulfonic acid yields Rh (1,5p).

-cyclooctadiene) L (O ^SCgH CHCH ^), whereas in the presence of a higher than equimolar amount of phosphine L ² , a coordinated alkadiene is exchanged for an L ² ligand to form Rh (L ² ) ₂ (O ^SCgH ^CH ^), which at a ratio of Rh to L ^{2 of} 1 to 2 becomes the major reaction product.

It was further found that in addition to isolated rhodných complexes with the process of the invention by hydrogenation of dehydroamino even in the presence of catalytic systems prepared oz starting olefinrhodného complex ligand L and organosulfonic acid or its salt by using these components in a molar ratio of Rh to L ² to RSO ^ H (Ag) equal to 1 in 0.5 to 2.5 in

-ϊ 240 063

0.5 to 4, preferably in a ratio of 1 to 0.8 to 1.2 to 0.8 to 1.2 without subsequent isolation or prepared directly in the reaction mixture (in situ catalysts).

It has further been found that hydrogenation can also be carried out with the catalysts in the presence of a target. amines such as triethylamine.

The solvents for the process according to the invention are preferably alcohols, suitably methanol, ethanol and isopropanol, mixtures thereof with aromatic hydrocarbons, suitably benzene, toluene, optionally alcohols with added water. The hydrogenation is carried out both with the solution of the hydrogenated substance and with the hydrogenated substance present in an amount exceeding its solubility limit in the medium, for example according to the method described in U.S. Pat. 185 974, at hydrogen pressures of 50 kPa to 2 MPa and temperatures of 10 to 80 ° C. The choice of optimal reaction conditions depends on the reactivity of the hydrogenated species and the catalytic activity of the selected rhodium catalyst. Although in the case of the reaction temperature its upper limit is limited to the boiling point of the reaction mixture at the selected pressure, it is preferred to carry out the hydrogenation at a temperature where the partial pressure of the solvent reaches at most half the total pressure.

Both hydrogen-depleted hydrogen by conventional purification and unpurified electrolytic hydrogen can be used for hydrogenation.

The process according to the invention can advantageously be used for the hydrogenation of dehydroamino acids and their derivatives of the general formula

wherein R 1 is hydrogen, C 1 -C 4 alkyl, preferably methyl and isopropyl, phenyl, 3,4-dimethoxyphenyl, 3,4-O-methylenophenyl, 3-acetoxy-4-methoxyphenyl, 4-acetoxyphenyl, 4-hydroxyphenyl,

propoxy, phenoxy and amino (R ^{4) are} hydrogen and methyl (R ⁴ )

R 1 is methyl, phenyl, benzyl and methoxy.

The following examples illustrate the methods of carrying out the invention

(240 BB3 of the invention without limiting or limiting it. The weights are given in parts by weight ·

Example 1

10 parts of Z1-acetamidocinnamic acid were introduced into a hydrogenation reactor equipped with a stirrer and a hydrogen inlet and the reactor was evacuated several times and purged with hydrogen. 150 parts of a 1: 1 mixture of benzene-ethanol and a solution of 0.2 parts of Rh (1,5-cyclooctadiene) / (-) - DI0P / 0 ₅ SC ₆ H ₄ CHyP (DIOP is added to the reactor) 2,3-O-isopropylidene-2,3-dihydroxy-1,4-diphenylphosphinobutane) in 50 parts of the same solvent. The hydrogen pressure was adjusted to 91 kPa and the reaction mixture was maintained under constant stirring and constant hydrogen pressure at 25 ° C for 20 minutes. After completion of the reaction, the reaction mixture was evaporated to dryness, dissolved in 200 parts of a 0.5 molar aqueous NaOH solution, freed from the solids by filtration, acidified with hydrochloric acid, and the product was taken up in diethyl ether. After evaporation of the solvent, 9 parts (90%) of (R) - (-) - N-acetylphenylalanine having an optical purity of 81% (MD ⁶ - 37 ° 3 ° (c 1 → ethanol)) were obtained. Example 2

Example 1 was repeated with the difference that instead of Rh (1,5-cyclooctadiene) / (-) - DIOP / (O-SCgH ₄ CH ₄ -p (DIOP is 2,5-O-isopropylidene-2,3-dihydroxy) (1,4-diphenylphosphinobutane) were used as catalysts of rhod complexes of general formula Rh (1,5-cyclooctadiene) L (O-SCgH-CH2-p) and the reaction was carried out for 1 hour. of Example 1, N-acetylphenylalanine was obtained in yields summarized in Table 1.

Table 1 j2 N-acetylphenylalanine chem.-optic fiber,% purity,% (c ₆ h ₅ ) ₂ pch ₂ ch ₂ p (c ₆ h ₅ ) ₂ (C, H,). P (CH), Ρ (Ο, Η,.).

89 (R) 87 (R) 74 (R)

240 803

- / continuation of Table 1

CH-CH ₂ P (C ₆ H ₅ ) ₂ L (2R, 3R)

(r, r) - (o-ch, oc ₆ h ₄ ) c ₆ h ₅ pch ₂ ch ₂ p (c ₆ h ₅ ) (0 ₆ H ₄₀ CH ₃ -O) ^b ₅ θCH 2 O-CH- CH ₂ P (C ₆ H ₅ ) ₂ o-ch-ch ₂ p (o ₆ h ₅ ) ₂ j (2 R, 5 R)

O - CH - CH ₂ P (C ₆ HO ₂

85 (R)

81

82 ^a The reaction was carried out at a hydrogen pressure of 350 kPa. The reaction was carried out at 50 ° C and a hydrogen pressure of 350 kPa.

Example 3

In a hydrogen purged reactor described in Example 1 and purged with hydrogen, 150 parts of ethanol and 10 parts of hydrogenated substance were introduced, and then a catalyst prepared under an inert atmosphere was added by mixing Rh (1,5-cyclooctadiene) (2,4-pentanedione), ₂ Ρ (0Η). ₂ ) ₄ Ρ (0θΗ ^) ₂ and benzenesulfonic acid in a 1 to 1.1 to 1 molar ratio in ethanol-benzene in a 2 to 1 volume ratio in such a quantity that the molar ratio of Rh to hydrogenated substance is 1 to 200. Hydrogenation was carried out at a temperature of 50 ° C and a constant hydrogen pressure of 0.5 MPa for 2 hours. After removal of the catalyst by an ion exchanger according to a known method (J. Amer. Chem. Soc. 100, 5491 (1978)), the amino acids and their derivatives listed in Table 2 were obtained in 85-91% yields.

Example 4

0.07 parts of Rh (norbornadien) (2,4-pentanedionate), 0.1 parts of 1,5-bis (diphenylphosphino) propane and 0.05 parts of methanesulfonic acid in solution were introduced successively into the hydrogenation reactor of Example 1 under hydrogen. of benzene-methanol (1 in 1, total in 50 parts solvent) and the mixture was stirred at normal temperature and hydrogen pressure for 15 min. Then 10 parts of Z-1-acetamidocinnamic acid ethyl ester in 150 parts of methanol were added. While stirring and heating, the hydrogen pressure was raised to 2 MPa and the reaction was carried out at 80 ° C for 10 minutes. Treatment of the reaction mixture of Example 1 afforded the phenylalanine ethyl derivative in 95% yield.

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Example 5

Example 1 was repeated except that the catalyst was prepared from 0.125 parts Rh (ethylene) ₂ (2,4-pentanedione), 0.25 parts (-) - DIOP (DIOP is 2,5-O-isopropylidene-2, 5-dihydroxy-1,4-diphenylphosphinobutane) and 0.08 parts of benzenesulfonic acid in 50 parts of a 1: 1 by volume mixture of benzene-ethanol. Following the procedure of Example 1, (R) - (-) - N-acetylphenylalanine was obtained in a chemical yield of 92% and an optical purity of 81%. The same yields were also obtained using catalyst systems prepared from / Rh (cyclooctene) ₂ Cl / ₂ , (-) - DIOP (DIOP is 2,5-O-isopropylidene-2,5-dihydroxy-1,4-diphenylphosphinobutane) and silver benzenesulfonate in a molar ratio of Rh to DIOP to benzenesulfonate of 1 to 1 to 0,8 to 1, 5.

Example 6

Example 1 was repeated except that 100 parts of N-acetamidocinnamic acid were used for the reaction. After completion of the reaction, the reaction product was filtered from the reaction mixture. Obtained were 65 parts (R) - (-) - N-acetyl-phenylalanine with an optical purity of 99% / ^{W-6 '46} »°° ° ^{ethane 1} · D / · The filtrate was evaporated to dryness, dissolved in 500 parts of 0, The solution was freed from the solids by filtration, acidified with hydrochloric acid and the product was shaken into diethyl ether. After evaporation of the solvent, 50 parts of (R) - (-) - N-acetylphenylalanine with an optical purity of 42% were obtained.

Example 7

Example 1 was repeated with the difference that 0.02 parts of Rh (1,5-cyclooctadiene) / (+) - DIPO / O-SCgH-CH2-p (DIOP is 2,5-O-isopropylidene) were used as catalyst. (2,5-dihydroxy-1,4-diphenylphosphinobutane) and hydrogenabe was performed for 40 min. After working up the reaction mixture as in Example 1, 8.9 parts (89%) of (S) - (+) - N-acetylphenylalanine having an optical purity of 82% were obtained.

Claims (2)

OBJECT OF THE INVENTION 240 883 A process for the preparation of N-acylamino acids of the formula R ¹ -CR ² H-CH (CO ⁵ ) NR ⁴ CO ⁵ , wherein R ¹ is hydrogen, alkyl to C 1-4, preferably methyl, isopropyl, phenyl, J, 4-dimethoxyphenyl, J metylenfenyl 4-0-J-acetoxy-4-methoxyphenyl, 4-acetoxyphenyl, 4-hydroxyphenyl, R ² is hydrogen, methyl, and-COR, R denotes hydroxyl, alkoxy · C, _C to C, preferably methoxy , ethoxy. and isopropoxy, phenoxy and amino, R is hydrogen and methyl and R 1 is methyl, phenyl, benzyl and methoxy, hydrogenation of the dehydroamino acids of formula ^RlLR2 ^ (C0R ⁵⁾ NR ⁴ C0R ⁵ j wherein R ¹ to R ^ are as defined above, in the presence of coordination compounds of rhodium as catalyst at a hydrogen pressure from JO kPa to 2 MPa and temperatures from 10-80 ° C characterized in that the reaction is carried out in the presence of a rhodium complex of the general formula RhColefin (CO 2 SR), wherein the olefin denotes an alkene with C ₂ to C 8 and a cycloalkene with up to Οθ, preferably ethylene, cyclooctene and further an alkadiene with up to C ₆ , preferably 1,5-hexadiene, 1,1-cyclooctadiene and norbornadiene? L ² represents alkylendifosfiny formula (C ₆ H _{$) 2} PCH (R ^S) / CH ^(R?) / _N P (C ₆ H _{5) 2,} X for / c £ R and R * jeYpro n is 1 to 4, R is methyl, phenyl and χ. Λ R ^r is hydrogen, n equals 1 and R and R is methyl, n is 1, and derivatives of 1,4-difosfinobutanu, J n is of the formula 0-0Η-σΗ _ο Ρ (0 _Α Η, -) _{ο a} / ₍ 2,652 ^x o-ch-ch ₂ p (c ₆ h ₅ ) _2; where A represents isopropylidene, cyclopentylidene, cyclohexylidene and cyclooctylidene and RSO 2 denotes an organosulfonate group in which R represents phenyl, tolyl, naphthyl, methyl and ethyl, the m index being 0 to 1 for dienes and 0 to 2 for alkenes, the p index being 0.5 to 2, the sum of the coordination bonds metal atom - 7V " 240,063 to olefin and L ² ligands is equal to four in the presence of an organic solvent · Process according to claim 1, characterized in that the solvents used are alcohols, preferably methanol, ethanol and isopropanol, mixtures thereof with aromatic hydrocarbons, suitably benzene or these solvents with the addition of water.