KR101286716B1 - A process of preparing enantioselective (D)-alpha amino acids - Google Patents
A process of preparing enantioselective (D)-alpha amino acids Download PDFInfo
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Abstract
The organic catalyst of the present invention has a salt form of a cinchonidine alkaloid compound having a specific structure, and is used in a radical addition reaction for selectively producing D-alpha amino acids, thereby greatly improving yield and selectivity. Significantly improved effects can be obtained in terms of recoverability of organic catalysts and scalability of reaction scale.
Description
The present invention relates to a (D) -alpha amino acid enantioselective production method, and more particularly, to (D) -alpha amino acid enantioselective production method which can selectively obtain (D) -alpha amino acid in a very high yield. It is.
Most amino acids in nature have alpha carbon which shows optical activity and are divided into L-alpha amino acid and D-alpha amino acid according to stereospecificity. Most proteins in nature are composed of L-amino acids, except for microorganisms such as peptidoglycan and peptide antibiotics, and bioactive substances of higher plants. have.
According to the research to date, D-alpha amino acid is an intermediate for synthesizing physiologically active substances such as neurotransmitters, vaccines, synthetic sweeteners, antibiotics and hormones, and is widely used in the food and pharmaceutical fields. Methods of producing these have been developed.
Methods of producing D-alpha amino acids can be broadly divided into chemical synthesis and biocatalyst production. First, as a method for producing D-alpha amino acids using a biocatalyst, a method of purely separating and producing only D-alpha amino acids from a DL-amino acid mixture was studied. The method converts a DL-alpha amino acid mixture into DL-alpha amino acid amide. After the preparation, D-alpha amino acid amide is selectively reacted with D-alpha amino acid amide to produce only D-alpha amino acid amide. Therefore, the use of D-stereospecific amino acid amidase for the production of D-alpha amino acids has the advantage of producing a variety of industrially useful D-amino acids from relatively inexpensive DL-alpha amino acid mixtures. However, the production method of D-alpha amino acid using such a biocatalyst has a problem that the production cost is excessively high and the yield is significantly decreased.
On the other hand, the production of amino acids by chemical synthesis produces a D-alpha amino acid using a chemical catalyst. Since the product is obtained in a racemic mixture of D- or L-alpha amino acids, pure D-alpha amino acids In order to obtain this, not only has to go through another complicated optical purification process, but the chemical catalyst is expensive and the process conditions are too harsh to commercialize.
The present invention has been made to solve the above problems, the first problem to be solved of the present invention is to provide a D-alpha amino acid mirror image selective production method capable of producing a high yield of D-alpha amino acids.
The second problem to be solved of the present invention is to provide a method for producing a mirror image selective alpha amino acid that can selectively control the mirror image of the alpha amino acid prepared according to the type of the mirror image of the organic catalyst to be used.
The present invention provides a mirror image of (D) -alpha amino acid comprising the step of radical addition reaction by mixing the synconidine organic catalyst having a structure of Formula 1, a reactant represented by the following Formula 2 and an alkylating agent to solve the above problems It provides an optional manufacturing method.
[Formula 1]
[Formula 2]
Wherein R is selected from benzyl, benzoyl and anthracene-9-carboxylate groups; X is selected from H 3 PO 2 and PF 6 ; R 1 is C 1 -C 5 lower alkyl group, C 6 -C 20 higher alkyl group, phenyl group, benzyl group, substituted C 1 -C 5 lower alkyl group, substituted C 6 -C 20 higher alkyl group, substituted phenyl group , Substituted benzyl group; R 2 is selected from R 3 CO—, benzoyl group, substituted benzoyl group; R 3 is selected from a phenyl group and a substituted phenyl group; The substituted alkyl group is substituted by one or more substituents selected from halides, nitro groups, acyl groups, hydroxy groups, Ra-O-, and Rb-CO-NH-; The substituted phenyl group and the substituted benzyl group are each independently substituted by one or more substituents selected from halides, nitro groups, acyl groups, hydroxy groups, Ra-O-, Rb-CO-NH- and Rc-; Wherein Ra, Rb, and Rc are each independently C 1 -C 5 lower alkyl group, C 6 -C 20 higher alkyl group, C 1 -C 5 lower alkyl group substituted with one or more halides, C substituted with one or more halides 6- C 20 higher alkyl group.
According to a preferred embodiment of the present invention, R 1 is an ethyl group or a phenyl group; R 2 may be R 3 CO-, a benzoyl group, wherein R 3 is
According to another preferred embodiment of the present invention, the alkylating agent may be a compound represented by the following formula (3).
(3)
R 4 -A
R 4 in the above is a primary, secondary or tertiary alkyl group; The alkyl group is C 1 -C 5 lower alkyl group or C 6 -C 20 higher alkyl group; A represents a halide.
According to another preferred embodiment of the present invention, R 4 is an isopropyl group, cyclohexyl group, 3-hepyl, tert-butyl group, amyl, 3-methyl-3-pentyl, ethyl and 1-adamantyl group Is selected from; A may be selected from I, Br, Cl, and F.
According to another preferred embodiment of the present invention, the manufacturing method may further add R 5 3 B, wherein R 5 may be an alkyl group. The alkyl group may preferably be a lower alkyl group of C 1 -C 5 .
According to another preferred embodiment of the present invention, the preparation method may further add Ph 2 SiH 2 .
According to another preferred embodiment of the present invention, the radical addition reaction may be carried out at a reaction temperature of 0 ℃ to -78 ℃.
According to another preferred embodiment of the present invention, the organic catalyst may be used in an amount of 0.4 to 0.5 equivalents based on 1 equivalent of the reactants.
In order to achieve the second object of the present invention, it provides a method for producing an enantioselective alpha amino acid comprising the step of performing a reaction at 0 ~ -78 ℃ including an organic catalyst having a structure of the following formula (1) or enantiomer thereof .
[Formula 1]
According to another preferred embodiment of the present invention, the organic catalyst and the prepared alpha amino acid may have the same mirror image.
According to another preferred embodiment of the present invention, there is provided a (D)-Cynconidine organic catalyst for producing an alpha amino acid having the structure of formula (1).
[Formula 1]
The organic catalyst of the present invention has a salt form of a cinchonidine alkaloid compound having a specific structure, and is used in a radical addition reaction for selectively producing D-alpha amino acids, thereby greatly improving yield and selectivity. Significantly improved effects can be obtained in terms of recoverability of organic catalysts and scalability of reaction scale.
As described above, the production of amino acids by chemical synthesis results in the production of D-alpha amino acids using a chemical catalyst, since the product is obtained in a racemic mixture of D- or L-alpha amino acids. In order to obtain the alpha amino acid, not only has to undergo another complicated optical purification process, but the chemical catalyst is expensive and the process conditions are too harsh to be commercialized.
Accordingly, the present invention provides a method for enantioselectively preparing (D) -alpha amino acids comprising the step of adding a radical synthesizing mixture of the synconidine organic catalyst having the structure of Formula 1, the reactant represented by the following Formula 2 and the alkylating agent The problem mentioned above was overcome.
[Formula 1]
Wherein R is selected from benzyl, benzoyl and anthracene-9-carbonyl groups; X is selected from H 3 PO 2 and PF 6 .
First, the organic catalyst used in the present invention is characterized in that it is used as a salt of the same formula as the above formula (1), rather than being used as a synconydine alkaloid salt having a special structure represented by the above formula (1), and the organic catalyst is used as it is. Instead of using it, it is very advantageous to remarkably maximize the effect of the present invention when used in the form of a salt of the organic catalyst. On the other hand, preferably, the cicononidine alkaloid salt represented by Formula 1 is preferably R is an anthracene-9-carbonyl group, and X is PF 6 It is very advantageous to improve reaction yield and enantioselectivity.
According to a preferred embodiment of the present invention, the organic catalyst (see Example 2) having the steric arrangement represented by the formula (1) of the present invention (S) is very useful for converting the reactants into D-alpha amino acids in high yield and purity. Effective (see Example 4).
The reactant of the present invention can be used as long as it can be converted into D-alpha amino acid through the organic catalyst of Chemical Formula 1, and preferably, a compound represented by Chemical Formula 2 can be used.
[Formula 2]
Wherein R is selected from benzyl, benzoyl and anthracene-9-carboxylate groups; X is selected from H 3 PO 2 and PF 6 ; R 1 is C 1 -C 5 lower alkyl group, C 6 -C 20 higher alkyl group, phenyl group, benzyl group, substituted C 1 -C 5 lower alkyl group, substituted C 6 -C 20 higher alkyl group, substituted phenyl group , Substituted benzyl group; R 2 is selected from R 3 CO—, benzoyl group, substituted benzoyl group; R 3 is selected from a phenyl group and a substituted phenyl group; The substituted alkyl group is substituted by one or more substituents selected from halides, nitro groups, acyl groups, hydroxy groups, Ra-O-, and Rb-CO-NH-; The substituted phenyl group and the substituted benzyl group are each independently substituted by one or more substituents selected from halides, nitro groups, acyl groups, hydroxy groups, Ra-O-, Rb-CO-NH- and Rc-; Wherein Ra, Rb, and Rc are each independently C 1 -C 5 lower alkyl group, C 6 -C 20 higher alkyl group, C 1 -C 5 lower alkyl group substituted with one or more halides, C substituted with one or more halides 6- C 20 higher alkyl group.
According to a preferred embodiment of the present invention, R 1 is an ethyl group or a phenyl group; R 2 may be R 3 CO-, a benzoyl group, wherein R 3 is
Next, the alkylating agent used for this invention is demonstrated. The alkylating agent serves to impart an alkyl group to the resulting D-alpha amino acid and R 4 represented by the following Chemical Formula 3 is It is added to D-alpha amino acid. According to a preferred embodiment of the present invention, the alkylating agent may be a compound represented by the following formula (3).
(3)
R 4 -A
R 4 in the above is a primary, secondary or tertiary alkyl group; The alkyl group is C 1 -C 5 lower alkyl group or C 6 -C 20 higher alkyl group; A represents a halide, wherein R 4 is selected from isopropyl group, cyclohexyl group, 3-hepyl, tert-butyl group, amyl, 3-methyl-3-pentyl, ethyl and 1-adamantyl group; A may be selected from I, Br, Cl, and F.
Next, R 5 3 B which can be used in the present invention is described. In the present invention, R 5 3 B is a radical initiator and in this case R 5 may be an alkyl group. The alkyl group may preferably be a lower alkyl group of C 1 -C 5 .
According to another preferred embodiment of the present invention, the preparation method may further add Ph 2 SiH 2 as a radical transfer agent.
Next, the reaction conditions of the present invention will be described. According to a preferred aspect of the present invention, the yield and enantioselectivity are remarkably improved when 0.4 to 0.5 equivalents of the organic catalyst, 2 to 4 equivalents of the alkylating agent, and R 5 3 B 2 to 4 equivalents are simultaneously reacted based on 1 equivalent of the reactants. You can. If the amount of the organic catalyst added is less than 0.4 equivalents, there is a problem in that enantioselectivity is reduced, and if it exceeds 0.5 equivalents, there is a problem in that the manufacturing cost is excessively increased (see Table 3).
On the other hand, the solvent used in the reaction is not limited in kind but preferably the reaction can be carried out in alcohol, and most preferably, the reaction yield and enantioselectivity can be significantly improved when the reaction is carried out in methanol.
Meanwhile, according to a preferred embodiment of the present invention, a method of preparing an enantioselective alpha amino acid comprising the step of performing a reaction at 0 to -78 ° C, including an organic catalyst having the structure of Formula 1 or an enantiomer thereof do. Preferably, when the reaction is performed with an organic catalyst represented by the following Chemical Formula 1, D-alpha amino acids are produced (Example 4), and when the reaction is performed with the organic catalyst of the enantiomer of Chemical Formula 1, L-alpha amino acids are selectively selected. (Example 3).
[Formula 1]
Hereinafter, the present invention will be described with reference to Examples, but is not limited thereto.
A. Experimental Materials and Methods
All experiments were performed under argon, and the vitreous instruments used in the experiment were dried in an oven of 120 and then cooled to room temperature. The reagents used in the reaction were Aldrich's product, and when the reagent was a liquid, it was transferred to a glass syringe or microsyringe. Thin-layer chromatography (TLC) was performed using Alcod's precoated silica gel glass plates (Silica Gel 60, F-254, layer thickness 250) and Silica Gel 60 (230-240mesh) from E. Merck for column chromatography separation. And Silica Gel, Merck, Grade 9385 (230-400 mesh) from Aldrich. Plates were baked using a UV lamp (254) or spraying a coloring reagent to identify the material separated on the TLC. The color reagent was used as 10% sulfuric acid solution containing 1% cerium sulfate and molybdic acid or aqueous solution containing K 2 CO 3 and KMnO 4 . High performance liquid chromatography used YoungLin SP930D and asymmetric column used Daicel Chiralpak IA column. Brucker Advance 400 (400MHz) was used for the 1 H NMR spectrum and chemical shifts were expressed in ppm (d) in downfield using tetramethylsilane (TMS) as an internal standard. GC / MS analysis was performed using Hewlett-Packard 5890 GC / 5970 MSD (EI, 70 eV). The specific rotation was measured using the JASCO P-2000 polarimeter and the elemental analysis was performed using the EA1110 elemental analyzer.
Example 1 Synthesis of (R) Organic Catalyst
end. (R)-(( 2R, 4S, 8R )-8- Ethylquinuclidin -2-yl) (quinolin-4-yl) methyl Anthracene-9- Of carboxylate (1a) synthesis
[Reaction Scheme 1]
Provided that R is anthracene-9-carboxylate.
The reaction was carried out as in Scheme 1. Specifically, (-)-cinchonidine (3 g, 10 mmol) and Pd / C (1.1 g, 1.0 mmol) were added together with MeOH (50 ml) in a high temperature and high pressure reactor in which water was removed. 5 bar of H 2 was injected into the high temperature and high pressure reactor, and the mixture was stirred for 3 hours. After removing Pd / C using Celite, the solvent was removed under reduced pressure. After argon gas was sufficiently flowed into the water-reduced two-necked flask, reduced cinchonidine (3 g, 10.1 mmol) and Et 3 N (10 mL, 101 mmol) were put in anhydrous THF (80 mL) solvent, and then, at room temperature. After stirring for an minute, anthracene-9-carbonyl chloride (3.6 g, 15 mmol) was added thereto, and the mixture was heated and refluxed for 24 hours. After completion of the reaction, the mixture was diluted with MC, washed with saturated aqueous NaHCO 3 and saturated aqueous NaCl solution, and then dried over anhydrous MgSO 4 . The solvent was removed under reduced pressure and then separated by silica gel column chromatography (eluent; MeOH: CH 2 Cl 2 = 2: 8). The desired product was obtained in a yield of 89% (4.5 g). Yellow syrup; = -89.0 (c 0.50, CHCl 3 ); 1 H NMR (CDCl 3 ) d 1.55 (t, J = 7.2 Hz, 3H), 1.92-2.26 (m, 3H), 2.36-2.48 (m, 1H), 2.49-2.59 (m, 1H), 2.68-2.96 (m, 3H), 3.36-3.42 (m, 1H), 3.44-3.54 (m, 1H), 3.74-3.88 (m, 1H), 4.02-4.13 (m, 1H), 4.15-4.25 (m, 1H) , 5.13 (dd, J = 10.8, 11.2 Hz, 1H), 8.04 (d, J = 4.4 Hz, 1H), 8.10-8.17 (m, 1H), 8.20-8.30 (m, 5H), 8.35-8.44 (m , 1H), 8.76-8.84 (m, 4H), 9.07-9.15 (m, 3H), 9.42 (d, J = 4.4 Hz, 1H); 13 C NMR (CDCl 3 ) d 174.9, 149.3, 147.2, 146.5, 146.4, 137.9, 136.9, 130.8, 129.4, 128.3, 127.6, 126.4, 126.3, 126.1, 125.0, 124.9, 124.6, 124.2, 124.1, 122.4, 117.8, 115.7, 65.7, 59.54, 55.6, 42.6, 35.0, 26.5, 24.4, 24.1, 17.1, 10.9; IR (neat) 3056, 2956, 1727, 1624, 1445. Anal. calcd for C 34 H 32 N 2 O 2 : C, 81.57; H, 6.44; N, 5.60. Found: C, 81.48; H, 6.34; N, 5.52.
I. (R)-(( 2R, 4S, 8R )-8- Ethylquinuclidin -2-yl) (quinolin-4-yl) methyl Anthracene-9- Carboxy Rate ( 1a) and hexafluorophosphoric acid Salt (1a) HPF 6 ) Synthesis (1b)
[Chemical Formula]
A MeOH solution containing Cinchonidine derivative (1 g, 2.0 mmol) and hexafluorophosphoric acid (0.25 mL, 2.0 mmol, 65% aqueous solution) was stirred at room temperature for 10 minutes, and then concentrated to give a salt (1b) of a cincona derivative and hexafluorophosphoric acid. . yellowish syrup; = -65.6 (c 0.50, EtOH); 1 H NMR (CDCl 3 ) d 1.37 (t, J = 7.2 Hz, 3H), 1.42-1.55 (m, 1H), 1.75-1.92 (m, 2H), 1.98-2.10 (m, 1H), 2.34-2.54 (m, 2H), 2.55-2.66 (m, 1H), 2.67-2.82 (m, 2H), 3.36-3.50 (m, 1H), 3.74-3.87 (m, 1H), 4.03-4.18 (m, 2H) , 4.77-4.90 (m, 1H), 6.84 (s, 1H), 8.15-8.20 (m, 5H), 8.55-8.67 (m, 3H), 8.68-8.78 (m, 3H), 8.93 (d, J = 5.6 Hz, 1H), 9.20 (d, J = 8.4 Hz, 1H), 9.70 (d, J = 8.4 Hz, 1H), 9.87 (d, J = 5.6 Hz, 1H); 13 C NMR (CDCl 3 ) d 169.8, 142.4, 136.4, 133.3, 129.7, 129.6, 128.5, 127.5, 127.4, 126.5, 125.7, 124.6, 124.5, 124.4, 124.1, 120.6, 118.9, 65.6, 59.0, 55.2, 42.5, 33.8, 25.2, 23.3, 23.2, 16.4, 10.3; IR (neat) 3560, 3200, 2963, 1662, 1524, 1142.Anal. calcd for C 34 H 33 F 6 N 2 O 2 P: C, 63.16; H, 5.14; N, 4.33. Found: C, 63.20; H, 5.21; N, 4.23.
Example 2 Synthesis of (S) -Organic Catalyst
end. (S)-(( 2R, 4S, 8R )-8- Ethylquinuclidin -2-yl) (quinolin-4-yl) methyl Anthracene-9- Of carboxylate (1c) synthesis
[Reaction Scheme 2]
Provided that R is anthracene-9-carboxylate.
(+)-Cinchonine (3 g, 10 mmol) and Pd / C (1.1 g, 1.0 mmol) were added together with MeOH (50 ml) in a high temperature, high pressure reactor with no water. 5 bar of H 2 was injected into the high temperature and high pressure reactor, and the mixture was stirred for 3 hours. After removing Pd / C using Celite, the solvent was removed under reduced pressure. After argon gas was sufficiently flowed into the water-reduced two-necked flask, reduced cinchonine (3 g, 10.1 mmol) and Et 3 N (10 mL, 101 mmol) were put in anhydrous THF (80 mL) solvent, and then, at room temperature. After stirring for an minute, anthracene-9-carbonyl chloride (3.6 g, 15 mmol) was added thereto, and the mixture was heated to reflux for 24 hours. After completion of the reaction, the mixture was diluted with MC, washed with saturated aqueous NaHCO 3 and saturated aqueous NaCl solution, and then dried over anhydrous MgSO 4 . The solvent was removed under reduced pressure and then separated by silica gel column chromatography (eluent; MeOH: CH 2 Cl 2 = 2: 8). The desired product was obtained in 82% (4.1 g) yield. yellow oil; = +152.6 (c 0.50, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.87 (t, J = 6.8 Hz, 3H), 1.18-1.30 (m, 4H), 1.35-2.10 (m, 6H), 2.40-2.55 (m, 1H), 2.90-3.05 (m, 2H), 5.12 (d, J = 7.2 Hz, 1H), 7.21-7.55 (m, 7H), 7.82-7.95 (m, 5H), 8.22-8.30 (m, 3H); 13 C NMR (CDCl 3 ) d 167.5, 151.4, 150.7, 148.6, 143.0, 137.4, 129.9, 129.7, 129.2, 128.5, 128.3, 128.2, 126.7, 125.8, 121.4, 118.3, 71.7, 63.5, 55.7, 48.9, 40.5, 29.4, 28.6, 27.3, 19.9, 12.4; IR (neat) 3035, 2938, 1748, 1620, 1466.Anal. calcd for C 34 H 32 N 2 O 2 : C, 81.57; H, 6.44; N, 5.60. Found: C, 81.57; H, 6. 46; N, 5.62.
I. (S)-(( 2R, 4S, 8R )-8- Ethylquinuclidin -2-yl) (quinolin-4-yl) methyl Anthracene-9- Carboxy Rate ( 1c) and hexafluorophosphoric acid Salt (1c HPF 6 ) Synthesis (1d)
[Chemical Formula]
A MeOH solution in which Cinchonine derivatives (1 g, 2.0 mmol) and hexafluorophosphoric acid (0.25 mL, 2.0 mmol, 65% aqueous solution) was dissolved was stirred at room temperature for 10 minutes, and then concentrated to obtain a salt of the syncona derivative and hexafluorophosphoric acid. Yellow syrup; . = +148.2 (c 0.50, EtOH); 1 H NMR (CDCl 3 ) d 0.87 (t, J = 6.8 Hz, 3H), 1.18-1.30 (m, 4H), 1.35-2.10 (m, 6H), 2.40-2.55 (m, 1H), 2.90-3.05 (m, 2H), 5.12 (d, J = 7.2 Hz, 1H), 7.01 (s, 1H), 7.21-7.55 (m, 7H), 7.82-7.95 (m, 5H), 8.22-8.30 (m, 3H ); 13 C NMR (CDCl 3 ) d 171.1, 152.1, 151.1, 148.6, 143.2, 137.9, 130.0, 129.8, 129.2, 128.6, 128.4, 128.2, 126.8, 126.0, 121.8, 118.0, 69.8, 63.5, 55.7, 48.9, 39.0, 29.6, 28.7, 27.2, 20.2, 12.6; IR (neat) 3301, 3196, 2880, 1641, 1538, 1083. Anal. calcd for C 34 H 33 F 6 N 2 O 2 P: C, 63.16; H, 5.14; N, 4.33. Found: C, 63.18; H, 5.17; N, 4.34.
Example 3 (R) Radical Addition Reaction Using an Organic Catalyst
end. Synthesis of Reactant 2a
[Chemical Formula]
However, in the formula, Bz is a benzoyl group.
Aldehyde (1.0 equiv) was added to a two-necked flask, and N- benzoyl hydrazide (0.9 equiv) was dissolved in MeOH (10 mL) together with the amount of Zn (ClO 4 ) 2 and placed in a two-necked flask. And the mixture was stirred at room temperature for 12 hours. After the reaction was completed, filtered and washed with diethyl ether to give the desired product (2a) in a yield of 90% or more.
I. Preparation of L-alpha Amino Acids
Scheme 3
L-alpha amino acid was prepared by performing a radical addition reaction according to Scheme 3. Specifically, the reaction solvent C 2 H 4 Cl 2 was sonicated for 1 hour, and then degassing was performed sequentially using three balloons filled with argon gas while flowing argon gas. The organic catalyst (R) prepared in Example 1 (0.3 eqiuv or 0.5 eqiuv) and reactant 2a (1.0 eqiuv) were added thereto, and the resultant was stirred at −30 for 1 hour. After 1 hour, alkyl halide (3.0 eqiuv), Ph 2 SiH 2 (1.0 equiv) and Et 3 B (3.0 equiv, 1 M solution in n-hexane) were added and air was continuously injected through the needle for one day. After the reaction was completed, the solvent was concentrated to remove the solvent, and then separated by silica gel column chromatography.
All. (S) - Synthesis of ethyl 2- (2- benzoylhydrazinyl) butanoate ( 3a)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3a in 96% yield: (eluent: ethyl acetate / hexane = 1/9); 99% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 31.4 min, tr (minor) = 28.7 min]. yellow oil; = +7.8 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.91 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H), 1.65-1.74 (m, 2H), 3.63 (t, J = 6.0 Hz, 1H), 4.04-4.14 (m, 2H), 5.11 (s, 1H), 7.20-7.71 (m, 5H), 8.70 (s, 1H); 13 C NMR (CDCl 3 ) d 173.3, 167.2, 132.6, 131.7, 128.5, 127.1, 64.3, 60.9, 23.9, 14.1; IR (neat) 3296, 1732, 1301, 1203, 1027. Anal. calcd for C 13 H 18 N 2 O 3 : C, 62.38; H, 7. 25; N, 11.19. Found: C, 62.58; H, 7. 45; N, 11.39.
la. (S) - ethyl 2- (2- benzoylhydrazinyl) -2- cyclohexylacetate (3b)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3b in 82% yield: (eluent: ethyl acetate / hexane = 1/9); 96% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 46.4 min, tr (minor) = 39.9 min]. yellow oil; = +4.0 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 1.24-1.27 (m, 9H), 1.63-1.66 (m, 1H), 1.73-1.75 (m, 4H), 3.54 (d, J = 4.0 Hz, 1H), 4.14-4.24 (m, 2H), 5.09 (s, 1 H), 7.37-7.71 (m, 5 H), 8.02 (s, 1 H); 13 C NMR (CDCl 3 ) d 173.0, 166.9, 132.7, 131.8, 128.6, 126.9, 68.7, 60.9, 39.8, 29.5, 29.0, 26.2, 26.1, 14.2; IR (neat) 3316, 1720, 1331, 1221, 1156.Anal. calcd for C 17 H 24 N 2 O 3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.17; H, 7.81; N, 9.24.
hemp. (S) - ethyl 2- (2- benzoylhydrazinyl) -3- methylbutanoate (3c)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3c in 85% yield: (eluent: ethyl acetate / hexane = 1/9); 96% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 22.2 min, tr (minor) = 20.3 min]. yellow oil; = +1.4 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3) d 1.03-1.06 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H), 2.07-2.16 (m, 1H), 3.55 (d, J = 4.8 Hz, 1H), 4.13 -4.24 (m, 2H), 5.10 (s, 1H), 7.36-7.71 (m, 5H), 8.10 (s, 1H); 13 C NMR (CDCl 3 ) d 172.9, 167.0, 132.7, 131.8, 128.6, 126.9, 69.0, 60.9, 30.0, 18.9, 18.6, 14.3; IR (neat) 3296, 1732, 1300, 1202, 1020. Anal. calcd for C 14 H 20 N 2 O 3 : C, 63.62; H, 7.63; N, 10.60. Found: C, 64.08; H, 7.52; N, 10.85.
bar. (S) - ethyl 2- (2- benzoylhydrazinyl) -3- propylhexanoate (3d)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3d in 78% yield: (eluent: ethyl acetate / hexane = 1/9); 95% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 15.9 min, tr (minor) = 13.7 min]. yellow oil; = +2.5 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.82 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.6 Hz, 3H), 1.22-1.34 (m, 4H), 1.44-1.56 (m, 4H), 1.73-1.87 (m, 1H), 3.69 (m, 1H), 4.21 (s, 1H), 4.95-5.01 (m, 2H), 7.38-7.71 (m, 5H), 7.78 (s, 1 H); 13 C NMR (CDCl 3 ) d 173.4, 167.0, 132.9, 132.1, 128.9, 127.1, 64.7, 36.5, 36.4, 24.2, 18.8, 14.1, 10.3; IR (neat) 3363, 1736, 1253, 1006.Anal. calcd for C 18 H 28 N 2 O 3 : C, 67.47; H, 8.81; N, 8.74. Found: C, 67.18; H, 8.52; N, 9.00.
four. (S) - ethyl 2- (2- benzoylhydrazinyl) -3,3- dimethylbutanoate (3e)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3e in a yield of 81%: (eluent: ethyl acetate / hexane = 1/9); 99% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 16.0 min, tr (minor) = 12.9 min]. mp 89-89.5; = +13.7 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 1.03 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H), 3.43-3.44 (m, 1H), 4.13-4.22 (m, 2H), 5.17 (s, 1H ), 7.34-7.69 (m, 5 H), 7.97-7.98 (m, 1 H); 13 C NMR (CDCl 3 ) d 172.7, 167.3, 132.7, 131.8, 128.6, 126.9, 72.8, 60.7, 33.9, 26.9, 14.3; IR (neat) 3292, 1733, 1308, 1203, 1027. Anal. calcd for C 15 H 22 N 2 O 3 : C, 64.73; H, 7.97; N, 10.06. Found: C, 64.95; H, 7.62; N, 10.09.
Ah. (S) - ethyl 2- (2- benzoylhydrazinyl) -2- adamantylacetate (3f)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3f in a yield of 79%: (eluent: ethyl acetate / hexane = 1/9); 99% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 21.7 min, tr (minor) = 17.7 min]. yellow oil; = +33.5 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.82-1.07 (m, 8H), 1.10-1.39 (m, 6H), 1.51-1.66 (m, 1H), 1.74-1.95 (m, 3H), 3.63-3.68 (m, 1H), 4.16-4.24 (m, 2H), 5.03 (s, 1H), 7.71-7.38 (m, 5H), 7.96 (s, 1H); 13 C NMR (CDCl 3 ) d 173.4, 167.1, 167.0, 132.9, 132.0, 128.8, 127.1, 68.1, 61.1, 61.0, 36.9, 26.4, 26.0, 15.8, 15.2, 14.4, 12.0, 11.9; IR (neat) 3295, 1732, 1301, 1200, 1126. Anal. calcd for C 21 H 28 N 2 O 3 : C, 70.76; H, 7.92; N, 7.86. Found: C, 70.38; H, 7.96; N, 7.38.
character. (S) - ethyl 2- (2- benzoylhydrazinyl) -3,3- dimethylpentanoate (3g)
[Chemical Formula]
Reaction was carried out according to the method described above to give 3 g of a compound in 81% yield: (eluent: ethyl acetate / hexane = 1/9); 99% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 18.5 min, tr (minor) = 13.2 min]. yellow oil; = +19.5 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.92-0.96 (t, J = 7.6 Hz, 3H), 0.99 (s, 3H), 1.03 (s, 3H), 1.25-1.29 (t, J = 7.2 Hz, 3H), 1.37-1.54 (m, 2H), 3.54 (s, 1H), 4.17-4.26 (m, 2H), 5.09 (s, 1H), 7.38-7.68 (m, 6H); 13 C NMR (CDCl 3 ) d 172.9, 167.4, 134.6, 132.9, 128.9, 127.1, 71.3, 60.9, 26.9, 32.6, 29.9, 24.0, 23.8, 14.5, 8.3; IR (neat) 3390, 1733, 1252, 1006. Anal. calcd for C 16 H 24 N 2 O 3 : C, 65.73; H, 8. 27; N, 9.58. Found: C, 65.54; H, 8.06; N, 9.36.
car. (S) - ethyl 2- (2- benzoylhydrazinyl) -3- ethyl -3- methylpentanoate (3h)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3h in 79% yield: (eluent: ethyl acetate / hexane = 1/9); 98% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 15.8 min, tr (minor) = 11.8 min]. yellow oil; = +23.6 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.75-0.97 (m, 9H), 1.20-1.33 (m, 7H), 3.64 (s, 1H), 4.09-4.29 (m, 2H), 5.07 (s, 1H), 7.31 -7.68 (m, 5 H), 7.80 (s, 1 H); 13 C NMR (CDCl 3 ) d 172.9, 167.4, 134.5, 130.4, 128.2, 127.8, 62.0, 33.6, 30.1, 22.9, 14.3, 6.9; IR (neat) 3383, 1738, 1253, 1006.Anal. calcd for C 17 H 26 N 2 O 3 : C, 66.64; H, 8.55; N, 9.14. Found: C, 66.93; H, 8.79; N, 8.90. ]
Ka. (S) - ethyl 2- (2- benzoylhydrazinyl) decanoate (3i)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3i in 64% yield: (eluent: ethyl acetate / hexane = 1/9); 79% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL · min −1 , = 254 nm, tr (major) = 21.8 min, tr (minor) = 18.0 min]. yellow oil; = +3.5 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.83-0.87 (m, 3H), 0.95-0.96 (m, 3H), 1.24-1.30 (m, 11H), 1.68-1.80 (m, 3H), 3.71 (t, J = 6.0 Hz, 1H), 4.14-4.23 (m, 2H), 5.02-5.06 (m, 1H), 7.38-7.72 (m, 5H), 7.98 (s, 1H); 13 C NMR (CDCl 3 ) d 173.7, 167.1, 132.9, 132.1, 128.9, 127.1, 63.5, 61.3, 61.2, 32.0, 31.0, 29.7, 29.5, 29.4, 27.1, 25.8, 22.9, 14.5, 14.4, 14.3; IR (neat) 3292, 1736, 1300, 1026. Anal. calcd for C 19 H 30 N 2 O 3 : C, 68.23; H, 9.04; N, 8.38. Found: C, 68.14; H, 9.03; N, 8.14.
Get on. Experiment result
Table 1 shows the yield and purity of L amino acids prepared in 3-da-ka.
[Table 1]
As can be seen in Table 1, the (R) organic catalyst of the present invention is very useful for preparing L-alpha amino acids in high yield and purity.
Example 4 (S) Radical Addition Reaction Using an Organic Catalyst
end. Preparation of D-alpha Amino Acids
[Reaction Scheme 4]
The radical addition reaction was performed according to Scheme 4 to prepare D-alpha amino acid. Specifically, the reaction solvent C 2 H 4 Cl 2 was sonicated for 1 hour, and then degassing was performed sequentially using three balloons filled with argon gas while flowing argon gas. The (S) organic catalyst (0.3 eqiuv or 0.5 eqiuv) prepared in Example 2 and reactant 2a (1.0 eqiuv) were added thereto and stirred at −30 for 1 hour. After 1 hour, alkyl halide (3.0 eqiuv), Ph 2 SiH 2 (1.0 equiv) and Et 3 B (3.0 equiv, 1 M solution in n-hexane) were added and air was continuously injected through the needle for one day. After the reaction was completed, the solvent was concentrated to remove the solvent, and then separated by silica gel column chromatography.
I. (R) - ethyl 2- (2- benzoylhydrazinyl) butanoate (3j)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3j in 90% yield: (eluent: ethyl acetate / hexane = 1/9); 91% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 28.7 min, tr (minor) = 31.4 min]. yellow oil; = -7.4 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.91 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H), 1.65-1.74 (m, 2H), 3.63 (t, J = 6.0 Hz, 1H), 4.04-4.14 (m, 2H), 5.11 (s, 1H), 7.20-7.71 (m, 5H), 8.70 (s, 1H); 13 C NMR (CDCl 3 ) d 173.3, 167.2, 132.6, 131.7, 128.5, 127.1, 64.3, 60.9, 23.9, 14.1; IR (neat) 3296, 1732, 1301, 1203, 1027. Anal. calcd for C 13 H 18 N 2 O 3 : C, 62.38; H, 7. 25; N, 11.19. Found: C, 62.58; H, 7. 45; N, 11.39.
All. (R) - ethyl 2- (2- benzoylhydrazinyl) -2- cyclohexylacetate (3k)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3k in 82% yield: (eluent: ethyl acetate / hexane = 1/9); 95% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 39.6 min, tr (minor) = 46.0 min]. yellow oil; = -4.0 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 1.24-1.27 (m, 9H), 1.63-1.66 (m, 1H), 1.73-1.75 (m, 4H), 3.54 (d, J = 4.0 Hz, 1H), 4.14-4.24 (m, 2H), 5.09 (s, 1 H), 7.37-7.71 (m, 5 H), 8.02 (s, 1 H); 13 C NMR (CDCl 3 ) d 173.0, 166.9, 132.7, 131.8, 128.6, 126.9, 68.7, 60.9, 39.8, 29.5, 29.0, 26.2, 26.1, 14.2; IR (neat) 3316, 1720, 1331, 1221, 1156.Anal. calcd for C 17 H 24 N 2 O 3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.17; H, 7.81; N, 9.24.
la. (R) - ethyl 2- (2- benzoylhydrazinyl) -3- methylbutanoate (3l)
[Chemical Formula]
Reaction was carried out according to the above-mentioned method, and compound 3l was obtained in a yield of 86%: (eluent: ethyl acetate / hexane = 1/9); 97% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 20.3 min, tr (minor) = 22.3 min]. yellow oil; = -1.4 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3) d 1.03-1.06 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H), 2.07-2.16 (m, 1H), 3.55 (d, J = 4.8 Hz, 1H), 4.13 -4.24 (m, 2H), 5.10 (s, 1H), 7.36-7.71 (m, 5H), 8.10 (s, 1H); 13 C NMR (CDCl 3 ) d 172.9, 167.0, 132.7, 131.8, 128.6, 126.9, 69.0, 60.9, 30.0, 18.9, 18.6, 14.3; IR (neat) 3296, 1732, 1300, 1202, 1020. Anal. calcd for C 14 H 20 N 2 O 3 : C, 63.62; H, 7.63; N, 10.60. Found: C, 64.08; H, 7.52; N, 10.85.
hemp. (R) - ethyl 2- (2- benzoylhydrazinyl) -3- propylhexanoate (3m)
[Chemical Formula]
Reaction was carried out according to the method described above to obtain compound 3m in 75% yield: (eluent: ethyl acetate / hexane = 1/9); 96% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 13.7 min, tr (minor) = 15.9 min]. yellow oil; = -2.6 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.82 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.6 Hz, 3H), 1.22-1.34 (m, 4H), 1.44-1.56 (m, 4H), 1.73-1.87 (m, 1H), 3.69 (m, 1H), 4.21 (s, 1H), 4.95-5.01 (m, 2H), 7.38-7.71 (m, 5H), 7.78 (s, 1 H); 13 C NMR (CDCl 3 ) d 173.4, 167.0, 132.9, 132.1, 128.9, 127.1, 64.7, 36.5, 36.4, 24.2, 18.8, 14.1, 10.3; IR (neat) 3363, 1736, 1253, 1006.Anal. calcd for C 18 H 28 N 2 O 3 : C, 67.47; H, 8.81; N, 8.74. Found: C, 67.18; H, 8.52; N, 9.00.
bar. (R) - ethyl 2- (2- benzoylhydrazinyl) -3,3- dimethylbutanoate (3n)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3n in 80% yield: (eluent: ethyl acetate / hexane = 1/9); 99% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL · min −1 , = 254 nm, tr (major) = 13.0 min, tr (minor) = 16.0 min]. mp 89-89.5; = -13.7 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 1.03 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H), 3.43-3.44 (m, 1H), 4.13-4.22 (m, 2H), 5.17 (s, 1H ), 7.34-7.69 (m, 5 H), 7.97-7.98 (m, 1 H); 13 C NMR (CDCl 3 ) d 172.7, 167.3, 132.7, 131.8, 128.6, 126.9, 72.8, 60.7, 33.9, 26.9, 14.3; IR (neat) 3292, 1733, 1308, 1203, 1027. Anal. calcd for C 15 H 22 N 2 O 3 : C, 64.73; H, 7.97; N, 10.06. Found: C, 64.95; H, 7.62; N, 10.09.
four. (R) - ethyl 2- (2- benzoylhydrazinyl) -2- adamantylacetate (3o)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3o in 73% yield: (eluent: ethyl acetate / hexane = 1/9); 99% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL · min −1 , = 254 nm, tr (major) = 18.0 min, tr (minor) = 22.2 min]. yellow oil; = -33.4 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.82-1.07 (m, 8H), 1.10-1.39 (m, 6H), 1.51-1.66 (m, 1H), 1.74-1.95 (m, 3H), 3.63-3.68 (m, 1H), 4.16-4.24 (m, 2H), 5.03 (s, 1H), 7.71-7.38 (m, 5H), 7.96 (s, 1H); 13 C NMR (CDCl 3 ) d 173.4, 167.1, 167.0, 132.9, 132.0, 128.8, 127.1, 68.1, 61.1, 61.0, 36.9, 26.4, 26.0, 15.8, 15.2, 14.4, 12.0, 11.9; IR (neat) 3295, 1732, 1301, 1200, 1126. Anal. calcd for C 21 H 28 N 2 O 3 : C, 70.76; H, 7.92; N, 7.86. Found: C, 70.38; H, 7.96; N, 7.38.
Ah. (R) - ethyl 2- (2- benzoylhydrazinyl) -3,3- dimethylpentanoate (3p)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3p in 82% yield: (eluent: ethyl acetate / hexane = 1/9); 99% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 13.2 min, tr (minor) = 18.6 min]. yellow oil; = -19.5 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.92-0.96 (t, J = 7.6 Hz, 3H), 0.99 (s, 3H), 1.03 (s, 3H), 1.25-1.29 (t, J = 7.2 Hz, 3H), 1.37-1.54 (m, 2H), 3.54 (s, 1H), 4.17-4.26 (m, 2H), 5.09 (s, 1H), 7.38-7.68 (m, 6H); 13 C NMR (CDCl 3 ) d 172.9, 167.4, 134.6, 132.9, 128.9, 127.1, 71.3, 60.9, 26.9, 32.6, 29.9, 24.0, 23.8, 14.5, 8.3; IR (neat) 3390, 1733, 1252, 1006. Anal. calcd for C 16 H 24 N 2 O 3 : C, 65.73; H, 8. 27; N, 9.58. Found: C, 65.54; H, 8.06; N, 9.36.
character. (R) - ethyl 2- (2- benzoylhydrazinyl) -3- ethyl -3- methylpentanoate (3q)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3q in 80% yield: (eluent: ethyl acetate / hexane = 1/9); 99% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL · min −1 , = 254 nm, tr (major) = 11.8 min, tr (minor) = 15.5 min]. yellow oil; = -23.7 (c 0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.75-0.97 (m, 9H), 1.20-1.33 (m, 7H), 3.64 (s, 1H), 4.09-4.29 (m, 2H), 5.07 (s, 1H), 7.31 -7.68 (m, 5 H), 7.80 (s, 1 H); 13 C NMR (CDCl 3 ) d 172.9, 167.4, 134.5, 130.4, 128.2, 127.8, 62.0, 33.6, 30.1, 22.9, 14.3, 6.9; IR (neat) 3383, 1738, 1253, 1006.Anal. calcd for C 17 H 26 N 2 O 3 : C, 66.64; H, 8.55; N, 9.14. Found: C, 66.93; H, 8.79; N, 8.90.
car. (R) - ethyl 2- (2- benzoylhydrazinyl) decanoate (3r)
[Chemical Formula]
Reaction was carried out according to the method described above to give compound 3r in 62% yield: (eluent: ethyl acetate / hexane = 1/9); 80% ee as determined by HPLC [Daicel Chiralpak IA, hexane / EtOH = 95/5, 0.7 mL.min -1 , = 254 nm, tr (major) = 18.1 min, tr (minor) = 21.9 min]. yellow oil; = -3.6 (c0.10, CHCl 3 ); 1 H NMR (CDCl 3 ) d 0.83-0.87 (m, 3H), 0.95-0.96 (m, 3H), 1.24-1.30 (m, 11H), 1.68-1.80 (m, 3H), 3.71 (t, J = 6.0 Hz, 1H), 4.14-4.23 (m, 2H), 5.02-5.06 (m, 1H), 7.38-7.72 (m, 5H), 7.98 (s, 1H); 13 C NMR (CDCl 3 ) d 173.7, 167.1, 132.9, 132.1, 128.9, 127.1, 63.5, 61.3, 61.2, 32.0, 31.0, 29.7, 29.5, 29.4, 27.1, 25.8, 22.9, 14.5, 14.4, 14.3; IR (neat) 3292, 1736, 1300, 1026. Anal. calcd for C 19 H 30 N 2 O 3 : C, 68.23; H, 9.04; N, 8.38. Found: C, 68.14; H, 9.03; N, 8.14.
Car. Experiment result
Table 2 shows the yield and purity of D-alpha amino acids prepared from 4-na to tea.
[Table 2]
As can be seen in Table 2, the organic catalyst (S) of Example 2 of the present invention is very useful for preparing D-alpha amino acids in high yield and purity.
Example 5 Addition of Proper (S) Organic Catalyst
Scheme 5
In order to confirm the addition amount of the appropriate (S) organic catalyst, 3n D-alpha amino acid of Example 4 was prepared while varying the equivalent of the (S) organic catalyst of Example 2, and the results are shown in Table 3.
[Table 3]
As can be seen from Table 3, when the (S) organic catalyst is added in more than 0.4 equivalents, it was possible to maximize the mirror image purity of D-alpha amino acids.
The present invention is a very useful invention in the biological and pharmaceutical industry because the D-alpha amino acid can be obtained in high yield.
Claims (14)
[Formula 1]
(2)
Wherein R is selected from benzyl, benzoyl and anthracene-9-carboxylate groups; X is selected from H 3 PO 2 and PF 6 ;
R 1 is C 1 -C 5 lower alkyl group, C 6 -C 20 higher alkyl group, phenyl group, benzyl group, substituted C 1 -C 5 lower alkyl group, substituted C 6 -C 20 higher alkyl group, substituted phenyl group , Substituted benzyl group;
R 2 is R 3 CO- or benzoyl group; R 3 is selected from a phenyl group and a substituted phenyl group;
The substituted alkyl group is substituted by one or more substituents selected from halides, nitro groups, acyl groups, hydroxy groups, Ra-O-, and Rb-CO-NH-;
The substituted phenyl group and the substituted benzyl group are each independently substituted by one or more substituents selected from halides, nitro groups, acyl groups, hydroxy groups, Ra-O-, Rb-CO-NH- and Rc-; Wherein Ra, Rb, and Rc are each independently C 1 -C 5 lower alkyl group, C 6 -C 20 higher alkyl group, C 1 -C 5 lower alkyl group substituted with one or more halides, C substituted with one or more halides 6- C 20 higher alkyl group.
R 1 is an ethyl group or a phenyl group;
R 2 is R 3 CO-, a benzoyl group, wherein R 3 is
The alkylating agent is a method of enantioselective preparation of (D) -alpha amino acid, characterized in that the compound represented by the formula (3).
(3)
R 4 -A
R 4 in the above is a primary, secondary or tertiary alkyl group; The alkyl group is C 1 -C 5 lower alkyl group or C 6 -C 20 higher alkyl group; A represents a halide.
The manufacturing method is a method for enantioselectively preparing (D) -alpha amino acid, characterized in that R 5 3 B is further added, wherein R 5 is an alkyl group.
And said alkyl group is a C 1 -C 5 lower alkyl group.
The preparation method is a method for enantioselectively preparing (D) -alpha amino acids, characterized in that further adding Ph 2 SiH 2 .
The radical addition reaction is a mirror selective production method of (D) -alpha amino acid, characterized in that carried out at a reaction temperature of 0 ℃ to -78 ℃.
Method for the enantioselective preparation of (D) -alpha amino acid, characterized in that for using 0.4 to 0.5 equivalents of the organic catalyst based on 1 equivalent of the reactant.
[Formula 1]
Wherein R is selected from benzyl, benzoyl and anthracene-9-carboxylate groups; X is selected from H 3 PO 2 and PF 6 .
The organic catalyst and the alpha amino acid prepared is a mirror image selective production method of alpha amino acid, characterized in that having the same mirror image.
[Formula 1]
Wherein R is selected from benzyl, benzoyl and anthracene-9-carboxylate groups; X is selected from H 3 PO 2 and PF 6 .
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| JPH0770121A (en) * | 1993-06-22 | 1995-03-14 | Sumitomo Chem Co Ltd | Optically active quaternary ammonium salt |
| KR20030057223A (en) * | 2001-12-28 | 2003-07-04 | 주식회사 티지 바이오텍 | A quinoline alkaloide derivative and a pharmaceutical composition comprising the same |
| US7649094B2 (en) * | 2002-01-31 | 2010-01-19 | Daiso Co., Ltd. | Optically active compounds, method for kinetic optical resolution of carboxylic acid derivatives and catalysts therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0770121A (en) * | 1993-06-22 | 1995-03-14 | Sumitomo Chem Co Ltd | Optically active quaternary ammonium salt |
| KR20030057223A (en) * | 2001-12-28 | 2003-07-04 | 주식회사 티지 바이오텍 | A quinoline alkaloide derivative and a pharmaceutical composition comprising the same |
| US7649094B2 (en) * | 2002-01-31 | 2010-01-19 | Daiso Co., Ltd. | Optically active compounds, method for kinetic optical resolution of carboxylic acid derivatives and catalysts therefor |
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