JP2005518339A - Process for producing enantiomerically rich N-acyl-β-amino acid derivatives by enantioselective hydrogenation of the corresponding (Z) enamide - Google Patents

Abstract

Enantio-rich formula (1) wherein R ¹ is an optionally substituted alkyl, aryl or heteroaryl group having 20 or less carbon atoms, R ² is an alkyl group having 20 or less carbon atoms, and R ³ is A method for producing a β-amino acid derivative of H or an alkyl or aryl group having a carbon number of 20 or less, or the opposite enantiomer thereof, wherein n is 0 to 6 , R represents at least one non-hydrogen organic group having 20 or less carbon atoms) and is catalyzed by a cationic rhodium complex of a chiral phosphine ligand (Z)- A method comprising asymmetric hydrogenation of an enamide precursor.

Description

  The present invention relates to a method suitable for large-scale production of enantiomerically enriched N-acyl β-amino acid derivatives. In particular, the present invention relates to enantioselective hydrogenation of the corresponding (Z) -enamide precursor.

  Optically active β-amino acids have been found in many natural substances, such as β-peptides (Gellman, Acc. Chem. Res., 1998, 31, 160 and references cited therein). These and other compounds derived from β-amino acid building blocks have a wide range of biomedical applications, and therefore β-amino acids are important.

  A number of methods for synthesizing β-amino acids with pure or abundant enantiomers have been devised (see E. Juaristi, Enantioselective Synthesis of β-amino Acids, Wiley-VCH: New-York (1997)). Most of them have serious drawbacks and their industrial use is limited. For example, enzymatic separation involves a mass loss of at least 50 percent of the material. Widely used methods based on theoretical chiral auxiliaries yield reliable results on a laboratory scale, but are not economical due to their influence on the mass of chiral auxiliaries, and therefore for large scale applications There is a limit.

A more attractive industrial method of synthesizing β-amino acids is by homogeneous asymmetric hydrogenation, which gives the advantages of fast screening, and then an atomic economic method and easy scale-up. Preferred precursors are β- (acylamino) acrylate esters as either the (E)-or (Z) -isomer, and the N-acyl group provides a binding site for transition metal-based catalysts containing chiral ligands . These materials are readily prepared by standard methods, most of which are prepared from the corresponding β-ketoesters by reaction with ammonia and subsequent N-acylation (Zhu, Chen and Zhang, J. Org. Chem., 1999, 64, 6907) or by reaction with acetamide (Overden, Capon, Lacey, Grill, Friedel and Wadsworth, J. Org. Chem., 64, 1140). These methods give a geometric mixture of (i) where the (Z) -isomer is the major component, or in some cases pure (Z) -i is obtained.

The literature describes the asymmetric hydrogenation of rhodium and ruthenium complexes of chiral diphosphine ligands in β- (acylamino) acrylate esters (i) where R ¹ is alkyl or aryl and R ² and R ³ are alkyl. It has been reported to be an effective catalyst for the conversion. The limit of ruthenium catalysis (Lubell, Kitamura and Noyori, Tetrahedron: Asymmetry, 1991, 2, 543) Is to give. Furthermore, pure (E) -i is quantitatively hydrogenated selectively (87-96 percent ee) in the presence of ruthenium BINAP complex, while hydrogenation of (Z) -i is slightly 5-9 percent ee. Thus, the ruthenium catalyst is an effective method only for (E) -β- (acylamino) acrylate and (E) -i. In contrast, the rhodium complexes of the chiral diphosphine method promote enantiomeric inversion hydrogenation of (E)-and (Z) -i, but with a large difference in reactivity and / or enantioselectivity in choosing (E) -i. Are observed (Zhu, Chen and Zhang, J. Org. Chem., 1999, 64, 6907). FIG. 1 / Table 1 shows ethyl 3-acetamido-2-catalyzed by rhodium complexes of (R, R) -methyl DuPHOS (v) and (R, R) -BICP (vi) using toluene as solvent. The reported results for the hydrogenation of butenoate (iii) are shown. With both catalysts (entries 1 and 2), hydrogenation of (E) -iii proceeded quantitatively at 40 psi to give enantiomerically rich (R) -ethyl 3-acetamidobutanoate (iv). In contrast, the hydrogenation of (Z) -iii (entries 3 and 4) requires a hydrogen pressure of 294 psi to proceed in 24 hours with a 100: 1 substrate: catalyst ratio, Selectivity decreased. In particular, the results of entry 4 suggest that DuPHOS-based catalysts have insufficient selectivity in the hydrogenation of (Z) -β- (acylamino) acrylate esters.

  From conventional literature, asymmetric hydrogenation of (Z) -β- (acylamino) acrylate esters to establish industrially useful processes performed at high substrate: catalyst ratios (typically at least 100: 1) It is clear that there is room for improvement. This factor is preferred in rhodium-based catalysts due to the high cost of metals. In order to be economical, there is also a desire for a method that allows for fast and selective hydrogenation of (Z) / (E) -geometric mixtures of β- (acylamino) acrylate esters.

  For related work published after the priority date of this patent application, see Heller, Holz, Drexler, Lang, Drauz, Krimmer and Borner, J. Org. Chem., 2001, 66, 6816; Lee and Zhang, Org. ., 4, 2429.

  The present invention allows the fast and high enantioselective catalytic hydrogenation of (Z) -enamide precursors of N-acyl β-amino acid derivatives catalyzed by cationic rhodium complexes of chiral phosphine ligands, using alcohol solvents Based on the discovery that This simple method provides the basis for an industrially effective and atomically effective method for this product.

The present invention encompasses the novel process shown in FIG. 2 and is an effective means of obtaining an enantiomerically enriched β-amino acid derivative of formula (1) or its opposite enantiomer from (Z) -enamide precursor (2). I will provide a. In the product (1) and the substrate (2), R ¹ is an optionally substituted alkyl, aryl or heteroaryl group having 20 or less carbon atoms, R ² is an alkyl group having 20 or less carbon atoms, and R ³ Is H or an alkyl or aryl group having 20 or less carbon atoms. This method includes asymmetric hydrogenation of the substrate (2), and is a partial formula (3) as a catalyst (wherein n is 0 to 6 and R is at least one non-hydrogen organic having 20 or less carbon atoms). A distinction is made from conventional methods in the use of alcoholic solvents or cosolvents together with cationic rhodium complexes of chiral phosphine ligands having a group). Two or more R groups may be present, and the R groups may be the same or different, may be bonded to form a ring, and may optionally contain a heteroatom. Ligands having such a structure will be readily identifiable to those skilled in the art.

In the process of the invention, the (Z) -enamide precursor (2) may be used in geometrically pure form or as a mixture with the (E) -enamide precursor (4). In the latter case, (4) is hydrogenated to (1) and becomes the same enantio-rich as that obtained from (2) and is usually obtained at a speed comparable to (2) or faster than (2). For example, the desired product (1) can be obtained by a route with high atomic efficiency by combining with the previous step of synthesis of the (E) / (Z) -enamide mixture by amination-acylation of the corresponding β-ketoester .

In a preferred embodiment of the invention, R ¹ , R ² and R ³ are each independently alkyl, more preferably methyl or n-alkyl, and R ² is typically methyl or ethyl. The alcohol solvent or co-solvent is typically selected from the group comprising methanol, ethanol, isopropanol and trifluoroethanol. The moiety R ² OH and the alcohol may be the same to prevent side reactions of transesterification. However, this is not always essential, and for example, trifluoroethanol can be an effective solvent for the substrate (2) where R ² is methyl or ethyl.

In the catalyst used for carrying out this method, the chiral phosphine ligand usually has the formula (5) or (6), wherein the linker and R ′ are independently a non-hydrogen organic or organometallic group having 30 or less carbon atoms. . Preferably the ligand is a bidentate ligand of formula (6), n is 2, more preferably the ligand is formula (7) or the opposite enantiomer, and the optimal group R is a hydrogenated substrate And can easily be determined by the catalyst. R is a non-hydrogen organic group having 20 or less carbon atoms, and is usually a C _1-8 linear or branched alkyl group.

Cationic rhodium complexes used as catalysts usually have the formula [Rh (6) (COD)] ⁺ BF ₄ , but COD (1,5-cyclooctadiene) can be replaced by other dienes such as NBD (2,5-norbornadiene). It will be understood by those skilled in the art that BF ₄ ⁻ may be replaced with other counter ions, such as PF ₆ ⁻ . In this regard, the term “catalyst” refers to an isolated pre-catalyst that is added to a reaction vessel for hydrogenation and undergoes in situ compositional change to generate one or more catalytically active materials. The catalyst is activated by the generation of a catalyst activator from the chiral ligand (6) and the achiral rhodium containing precursor.

  In one embodiment of the invention, ethyl 3-acetamido-2-butanoate is a fast and high enantioselective asymmetric hydrogen of (Z) -ethyl 3-acetamido-2-butenoate [(Z) -10] under carefully selected conditions. (Fig. 3). Table 2 shows the results of the comparative experiment. Entry 1 (Rh-MeDuPHOS catalyst and toluene solvent) has a low substrate conversion with a high substrate: catalyst ratio and moderate enantioselectivity. Entry 2 shows the significant effect of replacing the solvent with methanol, and the same reaction proceeds to completion in less than 1 minute. Due to the use of a homogeneous catalyst containing EtDuPHOS and iPrDuPHOS ligands, entries 3 and 4 show a significant improvement in enantioselectivity and achieve high reactivity and conversion. In the latter case, an effective method is also achieved at high substrate: catalyst ratios (entry 5). Entries 6-9 show further experiments with the preferred Rh-iPrDuPHOS catalyst and various alcohol solvents. Trifluoroethanol (TFE) gives the best method in terms of both rate and enantioselectivity (entry 8) and is also effective when methanol is used as a co-solvent (entry 9). Entries 10-12 show high-efficiency mirror image conversion hydrogenation of a 1: 1 mixture of (Z) -10 and (E) -10. Entry 13 is a control experiment showing a fast and highly selective asymmetric hydrogenation of pure (E) -10 in TFE.

In another embodiment of the invention, [( ⁱ PrDuPHOS) Rh (COD)] BF ₄ is an effective catalyst for asymmetric hydrogenation of (Z) -ethyl 3-acetamido-2-phenyl-2-propenoate Was formed at 77 percent ee to form ethyl 3-acetamido-2-phenylpropanoate (140 psi H ₂ pressure) and increased to 89 percent ee at 30 psi H ₂ .

In summary, the method of the present invention provides an effective method for the production of a wide range of enantio-rich N-acyl β-amino acid derivatives. To be economical, it is important that the enantiomer of the product obtained by asymmetric hydrogenation is at least 70 percent ee, preferably at least 90 percent ee, or higher. If necessary, the ee deficiency is corrected by standard methods such as selective enzyme-catalyzed hydrolysis of the ester or amide group of the undesired enantiomer of the hydrogenation product.
The following examples of the invention are further illustrated.

Example 1: Preparation of (Z)-and (E) -ethyl 3-acetamido-2-butenoate Conventional acetylation of commercially available ethyl 3-amino-2-butenoate (E: Z mixture) (Py, DCM, AcCl, DMAP catalyst) to give the title compound. The crude material obtained by extraction was purified by crystallization from diethyl ether. The (E) -isomer first crystallized (yield 30-35%, not optimized) and then the (Z) -isomer crystallized (yield 20%, not optimized). ¹ H and ¹³ C-NMR spectra were consistent with reported data (Zhu, Chen and Zhang, J. Org. Chem., 1999, 64, 6907).

Example 2: Small scale hydrogenation of (Z)-and (E) -ethyl 3-acetamido-2-butenoate (see Table 2)
Pre-catalyst (0.01 mmol) and starting material (171 mg, 1.0 mmol) were weighed in a glass liner. Stir cloth was added and the liner was placed in a 50 mL autoclave. The autoclave was purged 4 times with 120-160 psi N ₂ and 7-8 times with H ₂ (same pressure). Methanol (3 mL, reagent grade) was added and the autoclave was purged at least 8 times with 140 psi H ₂ . Vigorous stirring was started. When hydrogen uptake ceased (7-8 psi), the pressure was released and a small portion was immediately taken, diluted with diethyl ether or ethyl acetate and analyzed by chiral GC on a Chirasil Dex-CB column.

Example 3: Hydrogenation of a 1: 1 mixture of (Z)-and (E) -ethyl 3-acetamido-2-butenoate In a glass liner, [Rh (S, S) -i-Pr-DuPHOS (COD)] BF ₄ precatalyst (2.1 mg, 0.0029 mmol) and starting material (each isomer 255 mg, total 3.0 mmol) were weighed. Stir cloth was added and the liner was placed in a 50 mL autoclave. The autoclave was purged 4 times with 120-160 psi N ₂ and 7-8 times with H ₂ (same pressure). Trifluoroethanol (9 mL, reagent grade) was added and the autoclave was purged at least 8 times with 140 psi H ₂ . Vigorous stirring was started. When hydrogen uptake ceased (24 psi, 40 min), the pressure was released and immediately a small amount was taken, diluted with diethyl ether and analyzed by chiral GC. Conversion of the substrate to 95.3 percent ee of (S) -ethyl 3-acetamidobutanoate was 100%.

Example 4: Preparation of (Z) -ethyl 3-acetamido-3-phenyl-2-propenoate Ammonium acetate (21.1 g, 0.273 mol) was added to a solution of ethyl benzoyl acetate (35.0 g, 0.182 mol) in ethanol (200 mL). In addition, the mixture was refluxed for 18 hours. After removing all volatiles in vacuo, the residue was suspended in CHCl ₃ (200 mL). The resulting solid was washed with filter paper elsewhere, CHCl 3 (2 × 100 mL), and the combined filtrate was washed with water (150 mL) and brine (150 mL) and dried over magnesium sulfate. A rotary evaporator removed all volatiles to give crude ethyl 3-amino-3-phenyl-2-propenoate as a yellow oil (94 percent). A pyridine solution (30 mL) of the crude β-amino ester (6.71 g, 0.035 mol) was cooled to −78 ° C., and acetyl chloride (2.5 mL, 0.036 mol) was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was warmed to room temperature and left for 16 hours, during which time a white precipitate appeared. The reaction mixture was diluted with MTBE (30 mL) and the solution was washed with HCl (1.0 M) until the aqueous phase was favored (4 × 40 mL). The organic phase was separated, washed with NaHCO ₃ (saturated, 50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration, all volatiles were removed under reduced pressure. Chromatography of the reaction residue on silica using EtOAc (1: 3) in heptane as eluent gave the (Z) -isomer, by-product, then the (E) -isomer. Upon standing, the (E) isomer crystallized while the (Z) isomer remained an oil.

Example 5: Asymmetric hydrogenation of (Z) -ethyl 3-acetamido-3-phenyl-2-propenoate [Rh (S, S) -i-Pr-DuPHOS (COD)] BF ₄ pre-catalyst ( 3.0 mg, 0.005 mmol) and a magnetic stir bar. This liner was placed in the bottom of a 50 mL Parr pressure vessel and the reactor was assembled, flushed with nitrogen and then purged with hydrogen (5 pressurization / release cycles, 100 psi). A solution of (Z) -ethyl 3-acetamido-2-phenyl-2-propenoate (117 mg, 0.5 mmol) in MeOH (5 mL) was added by syringe through the septum of the reactor. The reactor was purged with hydrogen (3 pressurization / release cycles, 10 psi). Finally, the reactor was pressurized to 140 psi with hydrogen and stirred at room temperature for 2.5 hours. The hydrogen was then released and the solution in the glass liner was transferred to a vial. Samples were prepared and analyzed for conversion and ee by ¹ H NMR and SFC electrophoresis (conversion 98% or higher, 77% ee). In a comparative experiment at 30 psi H ₂ , the same product was obtained at 89 percent ee.

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Claims (22)

Enantio-rich formula (1) wherein R ¹ is an optionally substituted alkyl, aryl or heteroaryl group having 20 or less carbon atoms, R ² is an alkyl group having 20 or less carbon atoms, and R ³ is A method for producing a β-amino acid derivative of H or an alkyl or aryl group having 20 or less carbon atoms, or the opposite enantiomer thereof,
An alcohol catalyzed by a cationic rhodium complex of a chiral phosphine ligand having the partial formula (3), wherein n is 0 to 6 and R represents at least one non-hydrogen organic group having 20 or less carbon atoms A process comprising asymmetric hydrogenation of the (Z) -enamide precursor of formula (2) in a solvent or co-solvent.

  The method of claim 1, wherein the (Z) -enamide precursor (2) is geometrically pure. The process of claim 1, wherein the (Z) -enamide precursor (2) is a mixture with (E) -enamide (4) of the following formula, and the (E) -enamide (4) is hydrogenated: .

R ¹ is alkyl, The method according to any one of claims 1 to 3. The method according to claim 4, wherein R ¹ is methyl or n-alkyl. R ¹ is aryl, A method according to any one of claims 1 to 3. R ² is alkyl, The method according to any one of claims 1-6. The method of claim 7, wherein R ² is methyl or ethyl. R ³ is alkyl, The method according to any one of claims 1-8. R ³ is methyl or n- alkyl, The method of claim 9, wherein.   The method according to any one of claims 1 to 10, wherein the alcohol solvent or co-solvent is selected from the group comprising methanol, ethanol, isopropanol and trifluoroethanol. Moiety R ² OH and alcohol are the same, method of claim 11. Moiety R ² OH and an alcohol are different The method of claim 12, wherein. The chiral phosphine ligand has the following formula (5) or (6) (wherein the linker and R ′ are independently a non-hydrogen organic or organometallic group having 30 or less carbon atoms): The method according to claim 1.

  15. The method of claim 14, wherein the ligand has formula (6) and n is 2. 16. The method of claim 15, wherein the ligand has the following formula (7) or is the opposite enantiomer.

The method according to claim 16, wherein R in the formula (7) is a C _1-8 linear or branched alkyl group.   The method of claim 17, wherein R is isopropyl. The ligand is represented by the formula [Rh (6) (diene)] ⁺ X ⁻ (wherein diene is either COD or NBD, and X ⁻ is BF ₄ ⁻ , PF ₆ ⁻ , TfO ⁻ , tetra [3,5 16. A process according to claim 14 or 15, wherein the bis (trifluoromethyl) phenyl] borate and a halide are selected. The method of claim 19, wherein the diene is COD and X ⁻ is BF ₄ ⁻ .   21. A method according to any one of the preceding claims, wherein the β-amino acid derivative (1) is provided at least 70 percent e.e.   The method of claim 21, wherein the β-amino acid derivative (1) is provided at least 90 percent e.e.

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