Method for preparing Alpha-methyl-Alpha, Alpha-disubstituted-Alpha-aminophenol and derivatives thereof

Abstract

The invention discloses a method for preparing an Alpha-methyl-Alpha, Alpha-disubstituted-Alpha-aminophenol and derivatives thereof, comprising the following steps of: a) synthesizing S1 / R1: leading proline to react with o-chlorobenzyl chloride; b) synthesizing S2 / R2: leading methylene dichloride solution of S1 / R1 to react with phosphorus trichloride and 2-aminobenzophenone; c) synthesizing S3 / R3: leading S2 / R2 and alanine to react with nickelous nitrate hexahydrate; d) synthesizing S4 / R4: leading the redistilled tetrahydrofuran to react with sodium iodide, sodium hydride and RX / RX; e) synthesizing S5 / R5: leading the methanol solution of S4 / R4 to react with hydrochloric acid and concentrated ammonia liquor; and f) synthesizing S6 / R6: leading S5 / R5 to react with anhydrous sodium carbonate and Fmoc-Osu. The invention uses easily obtained raw materials with low price to obtain the Alpha-methyl-Alpha, Alpha-disubstituted-Alpha-aminophenol and derivatives thereof with extremely high optical activity by a normal six-step organic chemistry method. The method has moderate reaction condition and is easy for operation and amplification.

Description

technical field

[0001] The present invention relates to a preparation method of α-methyl-α,α-disubstituted-α-amino acid and derivatives thereof, in particular to an α-methyl-α,α-disubstituted-α-amino acid and its derivatives Methods of Organic Synthesis of Derivatives. Background technique

[0002] Unnatural amino acids are amino acids encoded by non-protein genes, and have important applications in frontier biotechnology research such as genomics and proteomics. For example, α-unnatural amino acids have been widely used in the study of proteins, nucleosides and nucleic acids: they can limit the flexibility of polypeptide conformation, provide deoxyribonucleic acid or ribonucleic acid molecules with stable secondary structure, enhance the ability of polypeptides to enzymatic β-unnatural amino acids are precursors of β-lactams and key components of many potential enzyme inhibitors, and have quite interesting pharmacological activities. β-unnatural amino acids have become in...

Examples

Embodiment 1

[0059] Example 1: Synthesis of (S)-α-allyl-Fmoc-alanine (R 1 = allyl)

[0060] 1. Synthesis of S1

[0061] 700 mL of isopropanol was heated to 55° C., 145.9 g of potassium hydroxide was added, and after the dissolution was complete, 100 g of L-proline was added. After complete dissolution, 167.5 g of o-chlorobenzyl chloride was added. After stirring evenly, thin layer chromatography showed that the reaction of L-proline had been completed. Adjust the pH of the system to 5-6 with 6N hydrochloric acid, add dichloromethane and let stand for 4 hours, then filter, wash the filter cake with dichloromethane, collect the filtrate, spin dry, and crystallize with acetone. 185.37 g of S1 was precipitated as a white solid with a yield of 89%. H NMR spectroscopy 1 H NMR (CD 3 OD), δ: 2.08-2.80 (m, 4H,); 3.48 (m, 1H); 3.77 (m, 1H,); 4.20 (m, 1H); 4.67, 4.51 (AB, J=13.1Hz, 2H, ); 7.66-8.00 (m, 3H).

[0062] 2. Synthesis of S2

[0063] Dissolve 31.0 g of S1 in 270 mL of dichlorometha...

Embodiment 2

[0072] Embodiment 2: the synthesis of (R)-alpha-(5-pentenyl)-Fmoc-alanine (R 2 =5-pentenyl)

[0073] 1. Synthesis of R1

[0074] Heat 350mL of isopropanol to 55°C, add 73g of potassium hydroxide, and after the dissolution is complete, add 50g of D-proline. Add 84 grams of o-chlorobenzyl chloride after complete dissolution. After stirring evenly, thin-layer chromatography showed that L-proline had reacted completely. Use 6N hydrochloric acid to adjust the pH of the system to 5-6, add dichloromethane and let stand for 4 hours, then filter, wash the filter cake with dichloromethane, collect the filtrate and spin it dry, and crystallize with acetone. 78.1 g of R1 precipitated as a white solid, yield 75%. H NMR spectrum 1 H NMR (CD 3 OD), δ: 2.08-2.80 (m, 4H,); 3.48 (m, 1H); 3.77 (m, 1H); 4.20 (m, 1H); 4.67, 4.51 (AB, J=13.1Hz, 2H,) ; 7.66-8.00 (m, 3H).

[0075] 2. Synthesis of R2

[0076] Dissolve 46.5 grams of R1 in 400 mL of dichloromethane, place in an ice bath, and sl...

Embodiment 3

[0085] Embodiment 3: the synthesis of (S)-alpha-benzyl-Fmoc-alanine (R 1 = benzyl)

[0086] The synthesis of S1, S2 and S3 in this example is the same as Example 1.

[0087] 1. Synthesis of S4

[0088] Add 6.54 g of S3 to a 100 mL three-necked flask in sequence, distill 40 mL of tetrahydrofuran, place the reaction system in an ice bath, cool to 0°C, add 1.8 g of sodium iodide and 0.87 g of sodium hydride under the protection of argon, and stir for 1 hour Afterwards, 5.12 g of benzyl bromide was added dropwise at 0°C, and reacted at 0-10°C for 5 hours. Thin-layer chromatography showed that the reaction of the raw materials was complete, and the reaction was quenched with ice, neutralized with acetic acid, extracted with dichloromethane (50 mL×3), and the organic phases were combined and dried overnight with anhydrous magnesium sulfate. After filtration, the filtrate was collected, and the obtained crude product was spin-dried with ethyl acetate as eluent, and silica gel colu...

technical field

[0001] The present invention relates to a preparation method of α-methyl-α,α-disubstituted-α-amino acid and derivatives thereof, in particular to an α-methyl-α,α-disubstituted-α-amino acid and its derivatives Methods of Organic Synthesis of Derivatives. Background technique

[0002] Unnatural amino acids are amino acids encoded by non-protein genes, and have important applications in frontier biotechnology research such as genomics and proteomics. For example, α-unnatural amino acids have been widely used in the study of proteins, nucleosides and nucleic acids: they can limit the flexibility of polypeptide conformation, provide deoxyribonucleic acid or ribonucleic acid molecules with stable secondary structure, enhance the ability of polypeptides to enzymatic β-unnatural amino acids are precursors of β-lactams and key components of many potential enzyme inhibitors, and have quite interesting pharmacological activities. β-unnatural amino acids have become in...

Examples

Embodiment 1

[0059] Example 1: Synthesis of (S)-α-allyl-Fmoc-alanine (R 1 = allyl)

[0060] 1. Synthesis of S1

[0061] 700 mL of isopropanol was heated to 55° C., 145.9 g of potassium hydroxide was added, and after the dissolution was complete, 100 g of L-proline was added. After complete dissolution, 167.5 g of o-chlorobenzyl chloride was added. After stirring evenly, thin layer chromatography showed that the reaction of L-proline had been completed. Adjust the pH of the system to 5-6 with 6N hydrochloric acid, add dichloromethane and let stand for 4 hours, then filter, wash the filter cake with dichloromethane, collect the filtrate, spin dry, and crystallize with acetone. 185.37 g of S1 was precipitated as a white solid with a yield of 89%. H NMR spectroscopy 1 H NMR (CD 3 OD), δ: 2.08-2.80 (m, 4H,); 3.48 (m, 1H); 3.77 (m, 1H,); 4.20 (m, 1H); 4.67, 4.51 (AB, J=13.1Hz, 2H, ); 7.66-8.00 (m, 3H).

[0062] 2. Synthesis of S2

[0063] Dissolve 31.0 g of S1 in 270 mL of dichlorometha...

Embodiment 2

[0072] Embodiment 2: the synthesis of (R)-alpha-(5-pentenyl)-Fmoc-alanine (R 2 =5-pentenyl)

[0073] 1. Synthesis of R1

[0074] Heat 350mL of isopropanol to 55°C, add 73g of potassium hydroxide, and after the dissolution is complete, add 50g of D-proline. Add 84 grams of o-chlorobenzyl chloride after complete dissolution. After stirring evenly, thin-layer chromatography showed that L-proline had reacted completely. Use 6N hydrochloric acid to adjust the pH of the system to 5-6, add dichloromethane and let stand for 4 hours, then filter, wash the filter cake with dichloromethane, collect the filtrate and spin it dry, and crystallize with acetone. 78.1 g of R1 precipitated as a white solid, yield 75%. H NMR spectrum 1 H NMR (CD 3 OD), δ: 2.08-2.80 (m, 4H,); 3.48 (m, 1H); 3.77 (m, 1H); 4.20 (m, 1H); 4.67, 4.51 (AB, J=13.1Hz, 2H,) ; 7.66-8.00 (m, 3H).

[0075] 2. Synthesis of R2

[0076] Dissolve 46.5 grams of R1 in 400 mL of dichloromethane, place in an ice bath, and sl...

Embodiment 3

[0085] Embodiment 3: the synthesis of (S)-alpha-benzyl-Fmoc-alanine (R 1 = benzyl)

[0086] The synthesis of S1, S2 and S3 in this example is the same as Example 1.

[0087] 1. Synthesis of S4

[0088] Add 6.54 g of S3 to a 100 mL three-necked flask in sequence, distill 40 mL of tetrahydrofuran, place the reaction system in an ice bath, cool to 0°C, add 1.8 g of sodium iodide and 0.87 g of sodium hydride under the protection of argon, and stir for 1 hour Afterwards, 5.12 g of benzyl bromide was added dropwise at 0°C, and reacted at 0-10°C for 5 hours. Thin-layer chromatography showed that the reaction of the raw materials was complete, and the reaction was quenched with ice, neutralized with acetic acid, extracted with dichloromethane (50 mL×3), and the organic phases were combined and dried overnight with anhydrous magnesium sulfate. After filtration, the filtrate was collected, and the obtained crude product was spin-dried with ethyl acetate as eluent, and silica gel colu...

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