A method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds

Abstract

The present application relates to a kind of 2-amino-3-phenyl-2-methyl butyric acid compound synthesis method, comprising the following steps: (1) N-(benzyl) alanine is reacted with benzaldehyde, and 3-benzyl-4-methyl-2-phenyl oxazolidine-5-ketone is generated;(2) 3-benzyl-4-methyl-2-phenyl oxazolidine-5-ketone is reacted with the compound shown in formula (II) under the action of catalyst to generate the compound shown in formula (III);(3) the compound shown in formula (III) is reacted with potassium trimethylsilanol, and the compound shown in formula (I) is generated, i.e. the 2-amino-3-phenyl-2-methyl butyric acid compound.The synthesis method of the present application fills the blank of the synthesis method of 2-amino-3-phenyl-2-methyl butyric acid compound, and the yield of the synthesis method of the present application is high, and it is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds. Background Technology

[0002] Non-natural amino acids, as a component of amino acids, have been widely used in the research of proteins, nucleosides, and nucleic acids. Incorporating non-natural amino acids into protein sequences to design and synthesize novel proteins is of great significance for studying the folding and function of natural proteins. To date, more than 30 non-natural amino acids have been artificially inserted into naturally synthesized proteins. Furthermore, the presence of non-natural amino acids can limit the conformational flexibility of peptides, provide DNA or ribonucleic acid molecules with stable secondary structures, enhance the stability of peptides to enzymes, and improve pharmacokinetics and biological activity. Therefore, the efficient synthesis of non-natural amino acids has become an important research topic in the fields of chemistry and biochemistry.

[0003] 2-Amino-3-phenyl-2-methylbutyric acid is also a non-natural amino acid; however, there are currently very few literature reports on the synthesis methods of 2-amino-3-phenyl-2-methylbutyric acid compounds. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to fill the gap in the existing technology for the synthesis of 2-amino-3-phenyl-2-methylbutyric acid compounds, and to provide a synthesis method for 2-amino-3-phenyl-2-methylbutyric acid compounds with high yield, and the synthesis method is suitable for industrial production.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds, wherein the structural formula of the 2-amino-3-phenyl-2-methylbutyric acid compounds is shown in formula (I):

[0007]

[0008] The synthesis method includes the following steps:

[0009] (1) React N-(phenylmethyl)alanine with benzaldehyde to generate 3-benzyl-4-methyl-2-phenyloxazolidine-5-one;

[0010] (2) 3-Benzyl-4-methyl-2-phenyloxazolidine-5-one is reacted with the compound shown in formula (II) in the presence of a catalyst to generate the compound shown in formula (III);

[0011] (3) React the compound shown in formula (III) with potassium trimethylsilanolate (KOSiMe3) to generate the compound shown in formula (I), namely the 2-amino-3-phenyl-2-methylbutyric acid compound;

[0012] The structural formula of the compound represented by formula (II) is as follows:

[0013] The structural formula of the compound shown in formula (III) is:

[0014] In the above structural formula, R is H, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a halogen-substituted C1-C4 alkyl group;

[0015] X is a halogen.

[0016] In some specific embodiments, R is selected from H, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, or isopropyl; X is selected from Cl, F, I, or Br.

[0017] In some embodiments, in formulas (I), (II), and (III), R represents the meta or para position on the benzene ring.

[0018] In some specific examples, the compound represented by formula (I) is selected from the following compounds:

[0019]

[0020] In some embodiments, the catalyst in step (2) is a palladium catalyst.

[0021] In some specific embodiments, the catalyst is one or a combination of Pd2dba3 and Pd(OAc)2.

[0022] In some specific embodiments, the molar ratio of the catalyst to 3-benzyl-4-methyl-2-phenyloxazolidine-5-one is 0.001 to 0.005:1.

[0023] In some embodiments, in step (2), the reaction is further carried out in the presence of a strong base, which is one or a combination of several of sodium bis(trimethylsilyl)amino (NaHMDS), lithium bis(trimethylsilyl)amino (LiHMDS), and potassium bis(trimethylsilyl)amino (KHMDS).

[0024] In some embodiments, in step (2), the reaction is carried out in the presence of a solvent, which is one or a combination of tetrahydrofuran (THF), dioxane, and N,N-dimethylformamide (DMF).

[0025] Further, in step (2), the molar ratio of the 3-benzyl-4-methyl-2-phenyloxazolidine-5-one to the compound shown in formula (II) is 1:1 to 2. The molar ratio of the 3-benzyl-4-methyl-2-phenyloxazolidine-5-one to the strong base is 1:0.8 to 1.2.

[0026] In some embodiments, in step (2), the reaction is carried out at -85°C to 40°C.

[0027] In some specific embodiments, in step (2), the reaction is first carried out at -85 to -65°C, and then at 10 to 40°C.

[0028] In some specific embodiments, in step (2), 3-benzyl-4-methyl-2-phenyloxazolidine-5-one and solvent are added to the reactor at -85 to -65°C, and then a strong alkaline solution is added dropwise. After the addition is complete, a catalyst and the compound shown in formula (II) are added, and the reaction is carried out at -85 to -65°C for 0.5 to 2 hours, and then the temperature is raised to 10 to 40°C for 2 to 5 hours.

[0029] In some specific embodiments, in step (2), after the reaction is completed, the reaction solution is post-processed. The post-processing includes adding saturated NH4Cl solution to the reaction solution, removing the solvent, extracting, and then washing with alkaline solution and salt solution in sequence, drying, filtering and removing the solvent, purifying, and obtaining the compound shown in formula (III).

[0030] Further, in step (2), the extraction is performed using ethyl acetate, the alkaline solution is an aqueous solution of sodium bicarbonate and / or sodium hydroxide, and the salt solution is an aqueous solution of sodium chloride.

[0031] In some embodiments, in step (1), N-(phenylmethyl)alanine, base, water and organic solvent are mixed and heated until dissolved. After removing the solvent, organic solvent and benzaldehyde are added and reacted at 15-40°C. The organic solvent used for dissolution is one or a combination of methanol and acetone, and the organic solvent used for reaction is one or a combination of ethanol and diethyl ether.

[0032] Further, in step (1), the molar ratio of N-(phenylmethyl)alanine to benzaldehyde is 1:1 to 2. The molar ratio of N-(phenylmethyl)alanine to alkali is 1:0.8 to 1.2.

[0033] In some specific embodiments, in step (1), after the reaction is completed, the reaction solution is post-treated, which includes rotary evaporation to remove solvent, extraction with water and ethyl acetate, concentration, recrystallization, and filtration to obtain the 3-benzyl-4-methyl-2-phenyloxazolidine-5-one.

[0034] In some embodiments, in step (3), the reaction is carried out in the presence of a solvent, namely tetrahydrofuran; the reaction is carried out at 10–80°C.

[0035] In some specific embodiments, in step (3), the reaction is first carried out at 10–40°C and then at 60–80°C.

[0036] Further, in step (3), the molar ratio of the compound shown in formula (III) to potassium trimethylsilanolate is 1:2 to 4.

[0037] In some specific embodiments, in step (3), after the reaction is completed, the reaction solution is post-treated, which includes vacuum removal of solvent, water washing, and pulping to obtain the compound shown in formula (I).

[0038] The pulping process uses a mixture of ethyl acetate and n-heptane in a volume ratio of 1:5 to 15.

[0039] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0040] The synthesis method of the present invention fills the gap in the synthesis method of 2-amino-3-phenyl-2-methylbutyric acid compounds, and the synthesis method of the present invention has a high yield and is suitable for industrial production. Attached Figure Description

[0041] Figure 1 The NMR spectrum of 2-amino-3-(4-methoxyphenyl)-2-methylbutyric acid from Example 1 is shown. Detailed Implementation

[0042] The technical solutions of the present invention will be described in detail below with reference to specific embodiments, so that those skilled in the art can better understand and implement the technical solutions of the present invention, but the present invention is not limited to the scope of the examples described.

[0043] The raw materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.

[0044] The structure of the compound was determined by nuclear magnetic resonance (¹H-NMR). NMR determination was performed using an ACF-400BRUKER NMR spectrometer. The solvents used were deuterated chloroform (CDCl₃), deuterated dimethyl sulfoxide (DMSO-D₆), or heavy water (D₂O), with TMS as an internal standard. Column chromatography was performed using 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Plant).

[0045] Example 1

[0046] This embodiment provides the synthesis of 2-amino-3-(4-methoxyphenyl)-2-methylbutyric acid.

[0047]

[0048] The synthesis steps include:

[0049] (1) In a flask, add N-(phenylmethyl)alanine (1.79 g, 10 mmol), NaOH (0.4 g, 10 mmol), water (5 mL), and methanol (25 mL). Heat until the solid dissolves for about 10 min. Remove the solvent and evaporate to dryness. Then add ethanol (20 mL) and benzaldehyde (1.59 g, 15 mmol) and stir at room temperature for 3 h. After the reaction is complete, remove the solvent by rotary evaporation. Extract with water and ethyl acetate (EA), concentrate, recrystallize under cooling with petroleum ether, and filter to obtain 3-benzyl-4-methyl-2-phenyloxazolidine-5-one (2.4 g, 90%).

[0050] (2) At -78°C, 3-benzyl-4-methyl-2-phenyloxazolidine-5-one (2.67 g, 10 mmol) and 25 mL THF were added to a flask. Then, a THF solution of NaHMDS (10 mL 1 M THF solution) was added dropwise over 20 min with stirring. After 10 min, Pd2dba3 (3 mmol%) and 1-(1-chloroethyl)-4-methoxybenzene (2.56 g, 15 mmol) were added. The mixture was stirred at -78°C for 1 h, then brought to room temperature and stirred for 3 h. After the reaction was complete, saturated NH4Cl solution was added to the reaction mixture, THF was removed under vacuum, the organic phase was extracted with ethyl acetate, and the organic phase was washed successively with 50 mL NaHCO3 solution (2N concentration) and 50 mL brine (2N concentration). After drying with Na2SO4, filtering and removing the solvent, the product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (V / V = 15 / 1) to give 3-benzyl-4-(1-(4-methoxyphenyl)ethyl)-4-methyl-2-phenyloxazolidine-5-one (3.98 g, 99.1%).

[0051] (3) 3-Benzyl-4-(1-(4-methoxyphenyl)ethyl)-4-methyl-2-phenyloxazolidine-5-one (0.52 g, 1.3 mmol) was dissolved in THF (1 mL), and then added to a dry three-necked flask along with KOSiMe3 (2 M in THF, 2.0 mL, 3.9 mmol) and 5 mL TFA. The mixture was stirred at room temperature for 1 h, then heated to 70 °C and stirred for 2 h. After the reaction was complete, THF was removed under vacuum, and the mixture was washed with water several times. A mixture of ethyl acetate and n-heptane at a volume ratio of 1:10 was then slurried to obtain 2-amino-3-(4-methoxyphenyl)-2-methylbutyric acid (0.27 g, 91.5%).

[0052] MRI results:

[0053] 1 H NMR(400MHz,D2O)δ7.08(m,2H),6.86(m,2H),3.78(s,3H),3.39(qt,1H),1.51(s,3H),1.31(d,3H).

[0054] Example 2

[0055] This embodiment provides the synthesis of 2-amino-3-(3-methoxyphenyl)-2-methylbutyric acid.

[0056]

[0057] In this embodiment, in step (2), 15 mmol of 1-(1-chloroethyl)-3-methoxybenzene was used instead of 1-(1-chloroethyl)-4-methoxybenzene, and the final total yield of 2-amino-3-(3-methoxyphenyl)-2-methylbutyric acid was 81.2%.

[0058] 1 H NMR (400MHz, D2O) δ7.23(t,1H),7.03(m,1H),6.84(dt,1H),6.79(m,1H),3.82(s,3H),3.33(qd,1H),1.50(s,3H),1.35(d,3H).

[0059] Example 3

[0060] This embodiment provides the synthesis of 2-amino-2-methyl-3-phenylbutyric acid.

[0061]

[0062] In this embodiment, in step (2), 15 mmol (1-chloroethyl)benzene was used instead of 1-(1-chloroethyl)-4-methoxybenzene, and the final total yield of 2-amino-2-methyl-3-phenylbutyric acid was 81.6%.

[0063] 1 H NMR (400MHz, D2O) δ7.27(m,5H),3.37(m,1H),1.48(s,3H),1.32(d,3H).

[0064] Example 4

[0065] This embodiment provides the synthesis of 2-amino-2-methyl-3-(p-tolyl)butyric acid.

[0066]

[0067] In this embodiment, in step (2), 15 mmol of 1-(1-chloroethyl)-4-toluene was used instead of 1-(1-chloroethyl)-4-methoxybenzene, and the final total yield of 2-amino-2-methyl-3-(p-tolyl)butyric acid was 81.7%.

[0068] 1 H NMR (400MHz, D2O) δ7.12(m,4H),3.36(q,1H),2.33(d,3H),1.48(s,3H),1.32(d,3H).

[0069] Example 5

[0070] This embodiment provides the synthesis of 2-amino-2-methyl-3-(3-(trifluoromethyl)phenyl)butyric acid.

[0071]

[0072] In this embodiment, in step (2), 15 mmol of 1-(1-chloroethyl)-3-(trifluoromethyl)benzene was used instead of 1-(1-chloroethyl)-4-methoxybenzene, and the final total yield of 2-amino-2-methyl-3-(3-(trifluoromethyl)phenyl)butyric acid was 80.4%.

[0073] 1 H NMR (400MHz, D2O) δ7.47(m,3H),7.23(m,1H),3.36(qd,1H),1.49(s,3H),1.32(d,3H).

[0074] Example 6

[0075] This embodiment provides the synthesis of 2-amino-2-methyl-3-(4-(trifluoromethyl)phenyl)butyric acid.

[0076]

[0077] In this embodiment, in step (2), 15 mmol of 1-(1-chloroethyl)-4-(trifluoromethyl)benzene was used instead of 1-(1-chloroethyl)-4-methoxybenzene, and the final total yield of 2-amino-2-methyl-3-(4-(trifluoromethyl)phenyl)butyric acid was 80.6%.

[0078] 1 H NMR (400MHz, D2O) δ7.62(m,2H),7.26(m,2H),3.36(m,1H),1.48(s,3H),1.32(d,3H).

[0079] Example 7

[0080] This embodiment provides the synthesis of 2-amino-3-(4-methoxyphenyl)-2-methylbutyric acid, which differs from that in Example 1 in that: in step (2), potassium bis(trimethylsilyl)amino (KHMDS) is used instead of sodium bis(trimethylsilyl)amino (NaHMDS).

[0081] At -78°C, 2.67 g (10 mmol) of 3-benzyl-4-methyl-2-phenyloxazolidine-5-one and 25 mL of THF were added to a flask. Then, a solution of KHMDS in THF (10 mL of 1 M THF solution) was added dropwise over 20 min with stirring. After 10 min, Pd2dba3 (3 mmol%) and 1-(1-chloroethyl)-4-methoxybenzene (2.56 g, 15 mmol) were added. The mixture was stirred at -78°C for 1 h, then brought to room temperature and stirred for 3 h. After the reaction was complete, saturated NH4Cl solution was added to the reaction mixture, THF was removed under vacuum, the organic phase was extracted with ethyl acetate, and the organic phase was washed successively with 50 mL of NaHCO3 solution (2N concentration) and 50 mL of brine (2N concentration). After drying with Na2SO4, filtering and removing the solvent, the product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (V / V = 15 / 1) to give 3-benzyl-4-(1-(4-methoxyphenyl)ethyl)-4-methyl-2-phenyloxazolidine-5-one (3.57 g, 89%).

[0082] Example 8

[0083] This embodiment provides the synthesis of 2-amino-3-(4-methoxyphenyl)-2-methylbutyric acid, which differs from that in Example 1 in that: in step (2), lithium bis(trimethylsilyl)amino (LiHMDS) is used instead of sodium bis(trimethylsilyl)amino (NaHMDS).

[0084] At -78°C, 2.67 g (10 mmol) of 3-benzyl-4-methyl-2-phenyloxazolidine-5-one and 25 mL of THF were added to a flask. Then, a THF solution of LiHMDS (10 mL of 1 M THF solution) was added dropwise over 20 min with stirring. After 10 min, Pd2dba3 (3 mmol%) and 1-(1-chloroethyl)-4-methoxybenzene (2.56 g, 15 mmol) were added. The mixture was stirred at -78°C for 1 h, then brought to room temperature and stirred for 3 h. After the reaction was complete, saturated NH4Cl solution was added to the reaction mixture, THF was removed under vacuum, the organic phase was extracted with ethyl acetate, and the organic phase was washed successively with 50 mL of NaHCO3 solution (2N concentration) and 50 mL of brine (2N concentration). After drying with Na2SO4, filtering and removing the solvent, the product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (V / V = 15 / 1) to give 3-benzyl-4-(1-(4-methoxyphenyl)ethyl)-4-methyl-2-phenyloxazolidine-5-one (3.21 g, 80%).

[0085] Example 9

[0086] This embodiment provides the synthesis of 2-amino-3-(4-methoxyphenyl)-2-methylbutyric acid, which differs from Example 1 in that a different catalyst (Pd(OAc)2) is used instead of the palladium catalyst.

[0087] At -78°C, 2.67 g (10 mmol) of 3-benzyl-4-methyl-2-phenyloxazolidine-5-one and 25 mL of THF were added to a flask. Then, a solution of NaHMDS in THF (10 mL of 1 M THF solution) was added dropwise over 20 min with stirring. After 10 min, Pd(OAc)₂ (3 mmol%) and 1-(1-chloroethyl)-4-methoxybenzene (2.56 g, 15 mmol) were added. The mixture was stirred at -78°C for 1 h, then brought to room temperature and stirred for 3 h. After the reaction was complete, saturated NH₄Cl solution was added to the reaction mixture, THF was removed under vacuum, the organic phase was extracted with ethyl acetate, and the organic phase was washed successively with 50 mL of NaHCO₃ solution (2N concentration) and 50 mL of brine (2N concentration). After drying with Na2SO4, filtering and removing the solvent, the product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (V / V = 15 / 1) to give 3-benzyl-4-(1-(4-methoxyphenyl)ethyl)-4-methyl-2-phenyloxazolidine-5-one (2.61 g, 65%).

[0088] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0089] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A method for synthesizing a 2-amino-3-phenyl-2-methylbutyric acid compound, wherein the structural formula of the 2-amino-3-phenyl-2-methylbutyric acid compound is shown in formula (I): Its features are, The synthesis method includes the following steps: (1) React N-(phenylmethyl)alanine with benzaldehyde to generate 3-benzyl-4-methyl-2-phenyloxazolidine-5-one; (2) 3-Benzyl-4-methyl-2-phenyloxazolidine-5-one is reacted with the compound shown in formula (II) in the presence of a catalyst to generate the compound shown in formula (III); the catalyst is Pd2dba3, and the reaction is carried out in the presence of a strong base, the strong base being sodium bis(trimethylsilyl)amino. (3) React the compound shown in formula (III) with potassium trimethylsilanolate to generate the compound shown in formula (I), namely the 2-amino-3-phenyl-2-methylbutyric acid compound; The structural formula of the compound represented by formula (II) is as follows: The structural formula of the compound shown in formula (III) is: In the above structural formula, R is H, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a halogen-substituted C1-C4 alkyl group; X is a halogen.

2. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to claim 1, characterized in that: The R is selected from H, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, isopropyl; and / or the X is selected from Cl, I, Br, F.

3. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to claim 1, characterized in that: The molar ratio of the catalyst to 3-benzyl-4-methyl-2-phenyloxazolidine-5-one is 0.001 to 0.005:

1.

4. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to claim 1, characterized in that: In step (2), the reaction is carried out in the presence of a solvent.

5. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to claim 1, characterized in that: In step (2), the reaction is carried out at -85℃ to 40℃.

6. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to claim 4, characterized in that: The solvent is one or a combination of tetrahydrofuran, dioxane, and N,N-dimethylformamide; and / or, in step (2), the reaction is first carried out at -85 to -65°C, and then at 10 to 40°C.

7. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to any one of claims 1 to 6, characterized in that: In step (2), after the reaction is completed, the reaction solution is post-processed. The post-processing includes adding saturated NH4Cl solution to the reaction solution, removing the solvent, extracting, then washing with alkaline solution and salt solution in sequence, drying, filtering and removing the solvent, purifying, and obtaining the compound shown in formula (III).

8. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to claim 1, characterized in that: In step (1), N-(phenylmethyl)alanine, alkali, water and organic solvent are mixed and heated until dissolved. After removing the solvent, organic solvent and benzaldehyde are added and reacted at 15-40°C. The organic solvent used for dissolution is one or a combination of methanol and acetone, and the organic solvent used for reaction is one or a combination of ethanol and diethyl ether.

9. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to claim 1, characterized in that: In step (3), the reaction is carried out in the presence of a solvent, wherein the solvent is tetrahydrofuran; and / or, in step (3), the reaction is carried out at 10–80 °C.

10. The method for synthesizing 2-amino-3-phenyl-2-methylbutyric acid compounds according to claim 1, characterized in that: In step (3), the reaction is first carried out at 10–40°C and then at 60–80°C.

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