DD293583A5 - PROCESS FOR THE PREPARATION OF (R) - AND (S) -FURYLALANINE AND THEIR DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of * and * and derivatives thereof by catalytically asymmetric hydrogenation of prochiral ungranulated precursors in the presence of chiral metal complex catalysts. The hydrogenated derivatives can be converted to the furylalanines. The starting materials used are the N-acylfurfurylidene compounds which are obtainable in good yields. They are erfindaesz in high stereoselectivities and activities, wherein the enantioselectivities are between 70 to 90%, hydrogenated to the gesaettigten compounds in good chemical yield. The process leads to price equality in the production of * and * {* * furylalanine derivative; asymmetric hydrogenation; Metal complex catalyst; Didehydroaminosaeurederivat; enantioselectivity; Pharmakaintermediat}

Description

COOR MICW

in the

R, R ¹ and X have the above meanings, in the presence of chiral rhodium catalysts of the general formula III,

OT> TV

"ι

in the

R ¹ a-naphthoxyalkyl, in particular a-naphthoxymethyl, and R ^{3 is} hydrogen or R ² R ^{3 is} a cyclopentane fused in 1,3-position and R ^{4 is} an n- or iso-alkyl group, in a solvent at temperatures between -20 and +50 ⁰ C and a rVDruck of 0.05 to 0.2 MPa are asymmetrically hydrogenated.

2. The method according to claim 1, characterized in that methanol or ethanol is used as the solvent.

Process according to claims 1 and 2, characterized in that at a temperature of 25 ° C and an H ₂ pressure of 0.1 MPa is asymmetrically hydrogenated.

Field of application of the invention

The invention relates to a process for the preparation of (R) - and (S) -furylalanln and its derivatives, in particular the N-acyl-furylalanines and their esters, by catalytically asymmetric hydrogenation of suitably substituted propenoic acid derivatives in the presence of cationic or neutral Rh-I -Complex catalysts with chiral ligands. The resulting optically active furylalanines are intermediates for (R) - and (S) -furylalanine in both antipodes and are valuable intermediates for heterocyclic substituted di- and polypeptides and low molecular weight ACE inhibitors.

Characteristic of the known state of the art

It is known that heterocyclic amino acids such as tryptophan, which are among the essential amino acids, can be prepared by asymmetric chemical synthesis.

It is also known (C. Cativiela et al., J. Org. Chem. 49 [1984] 2502) that N-acyl furylalanine can be prepared by asymmetric hydrogenation in the presence of phosphine-Rh catalysts, wherein but at a small substrate / catalyst ratio, higher temperature, and only the acid, hydrogenation occurred giving a maximum optical yield of 13%.

Furthermore, it is known from DD-A1-253995 that Rh-1-aminophosphine phosphinite complexes can be used for the asymmetric hydrogenation of carbocyclic substituted propenoic acids, and it is also known that norbornanaminophosphine phosphinites in the form of their Rh complexes can be used for carbocyclically substituted unsaturated compounds (DD-A1-253192). In the field of heteroatom-substituted substrates, the chiral complex catalysts in oxygen-bearing prochiral precursors have so far had only poor results. All the known method for the hydrogenation of N-acylcarbocyclic Propensäurederivaten and even more in their application to heterocyclic substituted propenoic acid derivatives used chiral complex catalysts adhere to various disadvantages. In many cases, only one enantiomeric hydrogenation product can be prepared or, as in the case of the furylalanine derivatives, hydrogenation can only be achieved at low substrate catalyst ratios with very poor stereoselectivity.

Object of the invention

It is the object of the invention, in order to avoid the abovementioned disadvantages, to develop a process which can be prepared with suitable chiral metal complex catalysts by asymmetric hydrogenation of unsaturated precursors (R) - and (S) -furylalanine and its derivatives at high speed and with high enantioselectivity.

Explanation of the essence of the invention

The object of the invention is to achieve the preparation of (R) - and (S) -furylalanine and its derivatives in high enantioselectivity by using a complex catalyst available in both enantiomers, optionally from suitable unsaturated precursors

 The object of the invention is achieved by the present invention, a propenoic acid derivative of the general formula II,

I i

CHC

in the

R is hydrogen or an alkyl radical R ^{1 is} hydrogen, an alkyl or aryl radical and X is hydrogen, an alkyl, substituted alkyl or aryl radical, halogen or a nitro group

in the presence of chiral rhodium catalysts of general formula III,

wl

in the

R ^{2 is} a-naphthoxyalkyl, in particular a-naphthoxymethyl, and R ^{3 is} hydrogen or R ³ R ^{3 is} a fused in 1,3-position Cyclopentane and R ^{4 is} an n- or iso-alkyl group, in a solvent at temperatures of about 25 ⁰ C and

an asymmetric hydrogenation of an H ₂ pressure of about 0.1 MPa.

According to the prochiral unsaturated precursors are under mild conditions at high speed and

high stereoselectivity asymmetrically hydrogenated by the chiral catalyst.

The hydrogenation can be carried out in alcoholic solution, preferably in methanolic or ethanolic solution, but also in suspension

respectively. The introduced rhodium complex catalysts allow the process to be carried out at temperatures between -20 and + 50 ° C., preferably at room temperature The hydrogenations are carried out in a pressure range between

0.05 and 2 MPa H ₂ , but preferably at atmospheric pressure, where it seems particularly advantageous to be able to emanate both from an in situ formed as well as previously prepared in substance precatalyst.

The use of copper complexes offers the advantage of a good meterability of the ligand, since it directly with the cocatalyst, z. As the dimeric rhodium (cycloocta-1,5-diene) chloride, the hydrogenation-active complex is formed in situ.

According to the invention, both neutral and cationic precatalysts for hydrogenation can be used without inhibition of the course of the reaction occurring due to the substrate interaction. In this way, higher substrate / catalyst ratios of 1000: 1 to 4000: 1 can be used for the hydrogenation.

Because of the ready accessibility of the ligands in both forms, either (R) or (S) -furylalanine derivatives can be prepared at equal price. The optical yields are between 70 and 90% ee.

embodiments

example 1

(Z) -2-Benzamino-3- (2-furyl) propenoic acid (modified)

(See also C.Cativiela et al., An. Quim. 81c [1985] 56)

12 g of (Z) -2-phenyl-4- (2-furfurylidene) oxazol-5-one are heated for 45 minutes in 100 ml of 0.5N NaOH to 8O ⁰ C, cooled, filtered and the filtrate acidified with 0.2% HCl , The gray product is washed with water and recrystallized from EtOH / water.

Mp. 217 ⁰ C (Lit. 231 ⁰ C), yield 85% (lit. 78%).

δ CH 7.34 (s); NH 9.71 (s); CH _Ph . _nyl 8.09 (m, 2H), 7.52 (m, 3H); CH.7.71 (d); CH "6.56 (q); CH ₀ 6.82 (d): DMSO-D ₆

Example 2

(Z) -2-benzamino-3- (2-furyl) propenoate

0.1 g of sodium in 360 ml of abs. MeOH dissolved and added to 48g (Z) -2-phenyl-4- (2-furylidene) oxazol-5-one. The mixture is heated for 15 minutes to 6O ⁰ C with stirring. Upon cooling, the ester crystallizes. After some time and cooling is filtered off, washed with cold MeOH and recrystallized from MeOH.

Mp 139 ° C, yield 94%.

δ CH ₃ O 3.78 (s); NH 3.33 (s); CH _Phsnyl 7.96 (m, 2H); 7.51 (m, 3H); CH 7.08 (s); CH, 7.56covered; CH _b 6,44 (q); CH _C 6,58 (d): CDCl ₃

Example 3

(Z) -2-phenyl-4- (2- (5-nitro) furfurylidene) oxazol-5-one

4.2 g of freshly distilled 5-nitrofuran aldehyde and 9.6 g of 2-phenyloxazol-5-one are heated to 8O ⁰ C for 5 minutes, resulting in a clear melt, which crystallizes soon. It is crushed under ice water, filtered and washed with EtOH / H ₂ O, dried and crystallized from toluene.

M.p. 178 ⁰ C, yield 73%.

Example 4

(Z) -2-benzamino-3- (2- (5-nitro) furyl) propenoate

3g of the oxazolone according to Example 3 are heated in 100 ml of ethanol in which 0.1 g of sodium was dissolved with stirring at 8O ⁰ C for one hour. The precipitate formed is sucked off after some time, washed with EtOH / water (50/50, v / v), dried and from abs. EtOH recrystallized.

M.p. 182 ⁰ C, yield 67%.

C ₁₈ H ₁₄ O ₆ N ₂ (330,29)

Ber. C 58.18 H 4.27 N 8.48

Gef. C 57.79 H 4.30 N 8.45

δ CH 7.14 (s); NH 10.11 (s); CH _Phenv , 8.13 (m, 2H); 7.58 (m, 3H); CH. 7.12 (d); CH _b 7.63 (d); CH ₂ 4.28 (q); CH ₃ 1.29 (t): DMSO-D ₆

Example 5

(Z) (5-nitro furylpropensäure -2-benzamino-3- (2)

1.14 g of oxazolone in Example 3 are heated on a water bath in a mixture of 30ml water and 30ml of dioxane, were dissolved in 0.86 g of sodium carbonate, for one hour at 85 ⁰ C. After cooling with ice-water is acidified with dilute hydrochloric acid and the precipitate after drying from 90% EtOH recrystallized. Yellow-brown crystals of the m.

215 ⁰ C (dec.), Yield 48%.

C ₁₄ H ₁₀ PCO ₆ N ₂

Ber. C 55.63 H 3.34 N 9.27

Gef. C 55.51 H 3.50 N 9.40

δ CH 7.23 (s); NH10.03 (s); CH _{Ph (} , _ny , 8.13 (m, 2H); 7.59 (m, 3H); CH, 7.08 (d); CH "7.66 (d).

Example 6

1 mmol of propenoic acid prepared according to Example 2 are dissolved in 15 ml of methanol and, after the oxygen has been displaced by argon and this multiple times by hydrogen, in the presence of 0.01 mmol of the rhodium catalyst of formula III (R ² R ³ = fused cyclopentane , R ⁴ = methyl), prepared from the copper complex and (Rh (COD) Cl] ₂ , as indicated in DD-A1 -253192, at 25 ⁰ C and 0.1 MPa H ₂ pressure in a thermostatted, with stirrer

hydrogenated vessel hydrogenated. After completion of the hydrogen uptake is concentrated and the product recrystallized several times from aqueous ethanol until the constancy of the rotation. The optically pure N-benzoylfurylalanine methyl ester melts at 86 to 89 ° C.

[a] _D ^M + 37.1 ° (c = 1, MeOH); [a] _D ^M -104.2 ° (c = 1, CHCl ₃ ).

The configuration is probably (R).

C ₁₅ H ₁₆ O ₄ N (273.3)

Ber. C, 65.92 H, 5.53, N, 5.13

C, 65.91, H, 5.54, N, 5.21

MS: M ⁺ 273; M ⁺ - CH ₃ OH 241; M ⁺ - COOCH ₃ 214; M ⁺ - NH ₂ COC ₆ H ₆ 152; NH ₂ COC ₆ H ₆ 121; C ₆ H ₆ CH -C0105 δ 4.98 (d, t); NH 6.98 (d); OCH ₃ 3.68 (s); CH ₂ 3.23 (d); CH _110n,. 7.72 (m, 2H), 7.33 (m, 3H); CH, 7.39 (1H); CH "6.21 (d, d, 1H); CH _C

Example 7

1 mmol of the propenoic acid prepared according to Example 1 is hydrogenated analogously to Example 6, after the intake of the theoretical amount of hydrogen, the solution is filtered and concentrated to dryness in vacuo. It is recrystallized several times from 20 to 30% ethanol, to give colorless crystals of mp. 132 to 135 ⁰ C. The configuration is probably (R). The rotation of the optically pure compound is [a] _D ^M + 27,6 ° (c = 1, MeOH)

C ₁₄ H ₁₃ O ₄ N (259.25)

Ber. C 64.86 H 5.05 N 5.40

Gef. C 64.72 H 5.33 N 6.20

δ CH 4.74 (d, t); NH 8.71 (d); CH " _om. 7,88 (m, 2H), 7,48 (m, 4H, below CH ₁ ); CH _b 6.32 (d, d, 1H); CH _C 6.19 (d, 1H).

Example 8

Analogously to Example 6, 1 mmol of propenoic acid methyl ester is hydrogenated with the copper complex and [Rh (COD) ₂ ] BF ₄ , the half-life being 10 minutes and the hydrogenation product in presumable (R) configuration being obtained in 74 to 76% enantiomeric excess. Work-up according to Example 6 provides the pure product. As in Examples 6 and 7, the theoretical hydrogen uptake in the hydrogenation is 100%. This also applies to Examples 9 to 15.

Example 9

Analogously to Example 6, 1 mmol of propenoic acid is hydrogenated using the copper complex and [Rh (COD) ₂ ] BF ₄ , the half-life being 7.8 minutes and the hydrogenation product having a presumptive (R) configuration being obtained in 75% enantiomeric excess. Work-up according to Example 7 provides the pure product.

Example 10

1 mmol of the propenoic acid methyl ester prepared according to Example 2 are dissolved in 15 ml of MeOH with 0.01 mmol of the ligand prepared according to formula III (R ² -naphthoxymethyl, R ³ = H and R ⁴ = isopropyl), as described in DD-A1-253947 (R) configuration, after addition of the equivalent amount of [Rh (CODhCl] ₂ , as described in Example 6, hydrogenated, wherein at half-times between 45 and 80 minutes, an enantiomeric excess of 79% with the (S) configuration is achieved Work-up is carried out according to Example 6.

Example 11

1 mmol of propenoic acid prepared according to Example 1 is hydrogenated analogously to Example 10, wherein at a half-life of 13 minutes, an enantiomeric excess of 74% of the (S) configuration is achieved. The workup is carried out according to Example 7.

Example 12

1 mmol of the acid prepared according to Example 1 is analogously to Example 10 with 0.01 mmol of [Rh (COD) ₂ ] BF ₄ and the ligand prepared according to DD-A1 -253947 at 25 ° C and 0.1 MPa H ₂ - Hydrogenated pressure, with a half-life of 8 minutes 81.6% enantiomeric excess with (S) configuration is achieved. The work-up is carried out according to Example 7.

Example 13

lOmmol of the acid prepared according to Example 1 are hydrogenated in 30ml of methanol with 0.01 mmol of of Example 10 applied in crystalline form rhodium complex catalyst at 25 ⁰ C and 0.1 MPa hydrogen pressure, achieved a Entantiomerenüberschuß of 90% at a half-life of 35 minutes becomes. The work-up is carried out according to Example 7 and provides 81% yield of (R) -configured product.

Example 14

10 mmol of the propenoic acid methyl ester are hydrogenated analogously to Example 13 and, given a half-life of 70 minutes, give an enantiomeric excess of 87%. After working up analogously to Example 6, a yield of 83% of (R) -configured product is achieved.

Example 15

Analogously to Example 6, 1 mmol of the ester prepared according to Example 2 is hydrogenated in the presence of 0.01 mmol of the catalyst used in Example 6, but prepared in situ from ligand and [Rh (COD) ₂ ] BF ₄ , wherein at a half-life of 7 Minutes an enantiomeric excess of 73% is achieved. The (R) -configured product is worked up according to Example 6.

Example 16

1 mmol of propenoic acid ethyl ester prepared according to Example 4 is analogously to Example 6 with the catalyst used in Example 13 in 30 ml of ethanol - in this case, only one suspension is formed hydrogenated. After theoretical hydrogen uptake, which is complete after about 23 hours, the procedure is as in Example 6 and worked up from chloroform on silica gel 60 chromatographies. The isolated product has a rotation of [a] _D ²³ -51.2 ° (c = 0.0976, CHCl ₃ ).

Example 17

1 mmol of the propenoic acid prepared according to Example 5 is hydrogenated using the catalyst mentioned in Example 13 in 30 ml of ethanol, wherein the readily soluble product is hydrogenated at a half-life of 30 minutes. For workup, the solvent is removed in vacuo, the residue dissolved in 10 ml of NaHCO ₃ solution (50 g / l), extracted ₃ times with ethyl acetate and washed with 2 ml of water. The combined aqueous solutions are acidified with HCl, extracted again 3 times with ethyl acetate and washed with 2 ml of water and the ethyl acetate phase after drying lampft. The residual residue has a rotation value of [a] _D ²³ -102.1 ° (c = 0.212, CHCl ₃ )

IR: 1350SS, 1490SS, 1525ss, 1635.1 655ss, 1705ss cm " ¹ 2910-3 500cm- '

Claims (1)

claims: 1. A process for the preparation of (R) - and (S) -furylalanine and derivatives thereof of general formula I _1st If in the R is hydrogen or an alkyl radical, R ^{1 is} hydrogen, an alkyl or aryl radical and X represents hydrogen, an alkyl, substituted alkyl or aryl radical, halogen or a nitro group, by catalytic hydrogenation of propenoic acid derivatives in the presence of chiral rhodium catalysts, characterized in that propenoic acid derivatives of the general formula II,