CN108948077B - Alpha-phosphorylated alpha-amino acid ester compound and synthesis method thereof - Google Patents

Abstract

The invention discloses an α-phosphorylated α-amino acid ester compound and a synthesis method thereof. The method of the invention comprises the following steps: in the presence of a transition metal catalyst, in an organic solvent, an N -aryl glycinate and a phosphite compound are prepared. The α-phosphorylated α-amino acid ester compounds are obtained by heating reaction, and the structures of these compounds are characterized and confirmed by methods such as ¹ H NMR, ¹³ C NMR and HR-MS. The method of the invention does not require a pre-functionalized reaction substrate, adopts oxygen in the air as a green oxidant, and directly conducts cross-desorption through two carbon-hydrogen bonds in the two reaction substrates, N -arylglycinate and phosphite compounds. Hydrogen coupling to prepare an α-phosphorylated α-amino acid ester compound. The synthesis method of the invention has high atom utilization rate, short synthesis route and environmental friendliness. The synthesis reaction conditions are mild, the operation steps are simple, and the atom economy is high. It can be applied to larger-scale synthesis and has good application prospects.

Description

A kind of α-phosphorylated α-amino acid ester compound and its synthesis method

technical field

The invention belongs to the field of organic synthesis, and relates to the synthesis of α-substituted α-amino acid compounds, in particular to a method for synthesizing α-phosphorylation of α-amino acid derivatives.

Background technique

Dehydrogenative Cross-Coupling (Dehydrogenative Cross-Coupling) is a reaction that directly utilizes two carbon-hydrogen bonds in the reaction substrate to form new carbon-carbon bonds or carbon-hetero bonds under oxidative conditions. The novel organic synthesis reaction has been favored by chemists. Compared with traditional organic synthesis methods, this type of reaction does not require pre-functionalization of the reaction substrate, which makes the synthesis route simpler, the atom utilization rate is higher, and the reaction efficiency is improved. In recent years, transition metal-catalyzed dehydrogenation cross-coupling reactions have developed rapidly in modern synthetic organic chemistry. Phosphorus-containing organic compounds are commonly found in bioactive molecules, flame retardants, extractants and phosphorus-containing ligands. Dehydrogenation and cross-coupling catalyzed by transition metals is undoubtedly the most convenient and effective synthetic method for the construction of carbon-phosphorus.

Alpha-amino acids are widely found in natural products and biologically active molecules in nature. Among them, α-phosphoramidate compounds have very important application value because of their important biological activity and pesticide activity. However, so far, the use of transition metal-catalyzed α-amino acid esters for α-phosphorylation cross-dehydrogenation coupling reactions to construct carbon-phosphorus bonds is rare. In 2013, Yang Shangdong et al. reported the copper-catalyzed oxidative coupling reaction of α-aminoketone and diphenylphosphine to synthesize iminophosphates. In 2016, the research group of Li Chaojun reported the dehydrogenation cross-coupling reaction of N -arylglycine amide and phosphite diester. However, N -arylglycine esters are not effective for cross-dehydrocoupling in this reaction system. To the best of our knowledge, there has not been any patent or literature report on the cross-dehydrogenation coupling reaction of catalyzing α-amino acid esters for α-phosphorylation.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a green synthesis method for preparing α-phosphorylated α-amino acid ester compounds through α-imidization of α-amino acid derivatives catalyzed by transition metals. It is an important method for the new synthesis of α-substituted α-amino acid derivatives. In this method, commercially available transition metal salts are used as catalysts, air is used as terminal oxidant, and the α-phosphorylation products of α-amino acid esters are synthesized in one step through the direct cross-dehydrogenation coupling of α-amino acid esters and phosphites.

In order to solve the above technical problems, the present invention provides a synthesis method for α-phosphorylation of α-amino acid ester compounds, which has good chemical selectivity, high atom economy and environmental friendliness. The synthesis method has mild reaction conditions, simple operation, green environmental protection, high product purity, convenient separation and purification, and can be applied to larger-scale synthesis applications.

The present invention adopts the following technical scheme: a kind of α-phosphorylated α-amino acid ester compound, whose structural formula is shown in formula (I):

(I)

(I)

Wherein, R ¹ can be an electron donating group or an electron withdrawing group. Preferably, the electron donating group may be an alkyl group; the electron withdrawing group may be a phenyl group. R ² is various alkyl groups or allyl groups. When R2 is alkyl, it can be methyl, ethyl, isopropyl, tert ^- butyl or benzyl.

^R3 can be various alkyl or benzyl groups. Preferably, the alkyl group can be, for example without limitation, methyl, ethyl, isopropyl, or tert-butyl.

A method for synthesizing α-phosphorylation of an α-amino acid ester compound of the present invention comprises the following steps: in the presence of a catalyst, in an organic solvent, using N -arylglycine ester (II) and a phosphite diester compound ( III) As a reaction substrate, the reaction was stirred for 12 hours until the reaction was completed by TLC detection, and the α-phosphorylated α-amino acid ester compound (I) could be efficiently prepared by column chromatography after rotary evaporation and concentration. The general reaction formula is as follows:

(II) (III) (I)

In the preparation method of the present invention, the catalyst is CoO, CoCl ₂ , Co(OAc) ₂ , Co(ClO ₄ ) ₂ •6H ₂ O, CuO, CuCl ₂ or Cu(OTf) ₂ , preferably Co (ClO ₄ ) ₂ • 6H ₂ O; the amount of catalyst is 10 mol % of the compound of formula (III) in mol %.

Preferably, the organic solvent in the step is acetonitrile or 1,2-dichloroethane, most preferably acetonitrile.

Preferably, the temperature in the step is room temperature to 100°C, most preferably 80°C.

In the preparation method of the present invention, the molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is preferably 1:1-10, most preferably 1:8.

Compared with the prior art, the present invention has the following advantages and beneficial effects: a synthetic method for the α-phosphorylation of an α-amino acid ester compound of the present invention is a kind of simple and convenient operation, mild reaction conditions, high atom economy and Environmentally friendly and other advantages of the process flow. The method adopts commercially available cobalt salts as catalysts, air as terminal oxidant, simple reaction operation, mild conditions and green environmental protection, easy separation and purification of products, suitable for large-scale preparation, and good application prospects.

Detailed ways

The present invention will be further described in detail below through specific examples, but the embodiments of the present invention are not limited thereto.

Example 1

N -4-Tolylglycine ethyl ester (0.2 mmol), diethyl phosphite (1.6 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with a stirring bar under air atmosphere . Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain pure pale yellow solid 3a with a yield of 83%. The structural characterization data of compound 3a are as follows:

3a

3a

light yellow solid; mp 75.2-76.4 °C; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00 (d, J = 6.4 Hz, 2H), 6.61 (dd, J = 5.4 Hz, J = 1.4 Hz, 2H) ), 4.47 (d, J = 18.4Hz, 1H), 4.27-4.17 (m, 6H), 2.24 (s, 3H), 1.36-1.31 (m, 6H), 1.27 (t, J = 5.6Hz, 3H) ; ¹³ C NMR (100 MHz, CDCl ₃ ): δ 168.5 (d, J = 2.4 Hz), 143.8 (d, J = 9.0 Hz), 129.8, 128.8, 114.2, 64.2 (d, J = 4.5 Hz), 63.6 (d, J = 4.7 Hz), 62.2, 56.8 (d, J = 118.0 Hz), 20.5, 16.5 (d, J = 4.8 Hz), 16.4 (d, J = 5.4 Hz), 14.1; HRMS (ESI) calcd for C ₁₅ H ₂₅ NO ₅ P (M+H) ⁺ 330.1465, found 330.1467.

Example 2

N -4-Tolylglycine ethyl ester (0.2 mmol), dimethyl phosphite (1.6 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with a stirring bar under air atmosphere . Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain pure pale yellow solid 3b with a yield of 95%. The structural characterization data of compound 3b are as follows:

3b

3b

light yellow solid; mp 69.2-70.1 °C; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.01(d, J = 6.4 Hz, 2H), 6.61 (dd, J = 6.8 Hz, 2H), 4.52 (d , J = 19.2 Hz, 1H), 4.30-4.23 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.24 (s, 3H), 1.28 (t, J = 6.4Hz, 3H) ; ¹³ C NMR (100 MHz, CDCl ₃ ): δ 168.3 (d, J = 2.6 Hz), 143.7 (d, J = 9.4 Hz), 129.9, 129.0, 114.3, 62.4, 56.5 (d, J = 119.4 Hz) , 54.5 (d, J = 4.6 Hz), 53.9 (d, J = 5.3 Hz), 20.5, 14.1; HRMS (ESI) calcd for C ₁₃ H ₁₉ NO ₅ P (MH) ^- 300.1006, found 300.1003.

Example 3

N -4-Tolylglycine ethyl ester (0.2 mmol), diisopropyl phosphite (1.6 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with a stirring bar under air atmosphere middle. Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain pure pale yellow solid 3c with a yield of 76%. The structural characterization data of compound 3c are as follows:

3c

3c

light yellow solid; mp 67.9-68.6 °C; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.99 (d, J = 6.4 Hz, 2H), 6.59 (dd, J = 8.8 Hz, J = 2.0 Hz, 2H ), 4.85-4.76 (m, 2H), 4.41 (d, J = 19.2 Hz, 1H), 4.22 (q, J = 6.4 Hz, 2H), 2.23 (s, 3H), 1.36-1.31 (m, 6H) , 1.37-1.29 (m, 12H), 1.26 (t, J = 6.4 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 168.8 (d, J = 1.6 Hz), 144.1 (d, J = 10.6 Hz), 129.8, 128.6, 114.2, 72.9 (d, J = 6.3 Hz), 72.4 (d, J = 5.8 Hz), 61.9, 57.8 (d, J = 119.6 Hz), 24.3 (d, J = 3.3 Hz) ), 24.0 (d, J = 2.9 Hz), 23.8 (d, J = 4.3 Hz), 23.7 (d, J = 3.5 Hz), 20.5, 14.1; HRMS (ESI) calcd for C ₁₇ H ₂₉ NO ₅ P ( M+H) ⁺ 358.1778, found358.1776.

Example 4

N -4-Tolylglycine ethyl ester (0.2 mmol), dibutyl phosphite (1.6 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with a stirring bar under air atmosphere . Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain pure light yellow oily liquid 3d with a yield of 62%. The structural characterization data of the 3d compounds are as follows:

3d

3d

light yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.99 (d, J = 6.4 Hz, 2H), 6.60 (dd, J = 8.8 Hz, J = 2.0 Hz, 2H), 4.48 (d, J = 18.8 Hz, 1H), 4.23 (d, J = 6.4 Hz, 2H), 4.19-4.05 (m, 4H), 2.23 (s, 3H), 1.71-1.61 (m, 4H), 1.46-1.28(m, 4H), 1.26 (t, J = 5.6 Hz, 3H), 0.96-0.89 (m, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 168.6 (d, J = 1.8 Hz), 143.9 (d, J = 10.1 Hz), 129.8, 128.7, 114.2, 67.7 (d, J = 6.1 Hz), 67.1 (d, J = 5.8 Hz), 65.5 (d, J = 5.1 Hz), 62.1, 56.7(d, J = 118.7 Hz), 32.5 (d, J =5.6 Hz), 32.4 (d, J =5.0 Hz), 20.4, 18.7,18.6 (d, J =1.4 Hz), 14.1, 13.5; HRMS (ESI) calcd for C ₁₉ H ₃₁ NO ₅ P (MH) ^- 384.1945, found 384.1942.

Example 5

N -4-Tolylglycine methyl ester (0.2 mmol), diethyl phosphite (1.6 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with a stirring bar under air atmosphere . Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain pure pale yellow solid 3e with a yield of 78%. The structural characterization data of the 3e compound are as follows:

3e

3e

light yellow solid; mp 73.5-74.8 °C; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00(d, J = 6.8 Hz, 2H), 6.60 (d, J = 6.8 Hz, 2H), 4.50 (d , J = 18.8 Hz, 1H), 4.27-4.17 (m, 4H), 3.78 (s, 3H), 2.24 (s, 3H), 1.35 (t, J = 5.2 Hz, 3H), 1.32(t, J = 5.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 169.5 (d, J = 2.4 Hz), 143.8 (d, J = 9.6 Hz), 129.9, 128.9, 114.2, 64.1 (d, J = 4.7 Hz), 63.7 (d, J = 5.4 Hz), 56.6 (d, J = 119.0 Hz), 53.0, 20.4, 16.4 (d, J = 6.4 Hz), 16.3; HRMS(ESI) calcd for C ₁₄ H ₂₃ NO ₅ P (M+H) ⁺ 316.1308, found 316.1311.

Example 6

N -4-Tolylglycine isopropyl ester (0.2 mmol), diethyl phosphite (1.6 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with a stirring bar under air atmosphere middle. Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain pure pale yellow solid 3f with a yield of 69%. The structural characterization data of the 3f compound are as follows:

3f

3f

light yellow solid; mp 76.0-77.5 °C; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00 (d, J = 6.4 Hz, 2H), 6.60 (d, J = 6.0 Hz, 2H), 5.11-5.07 (m, 1H), 4.44 (d, J =18.4 Hz, 1H), 4.25-4.20 (m, 4H), 2.24 (s, 3H), 1.35 (t, J = 5.4 Hz, 3H), 1.32(t, J = 5.6 Hz, 3H), 1.27 (d, J = 5.2 Hz, 3H), 1.27 (d, J = 4.8 Hz, 3H); ¹³ CNMR (100 MHz, CDCl ₃ ): δ 168.0 (d, J = 2.0 Hz), 143.9 (d, J = 9.0 Hz), 129.8, 128.7, 114.3, 70.0, 64.0 (d, J = 6.2 Hz), 63.4 (d, J = 5.7 Hz), 56.9 (d, J =118.1 Hz) , 21.8, 21.6, 20.5, 16.5 (d, J = 4.1 Hz), 16.4 (d, J = 5.2 Hz); HRMS(ESI) calcd for C ₁₆ H ₂₇ NO ₅ P (M+H) ⁺ 344.1621, found 344.1619 .

Example 7

N -4-Tolylglycine tert-butyl ester (0.2 mmol), diethyl phosphite (0.2 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with a stirring bar under air atmosphere middle. Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain 3 g of a pure light yellow oily liquid with a yield of 67%. The structural characterization data of 3g compound are as follows:

3g

3g

light yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00 (d, J = 6.4 Hz, 2H), 6.61 (d, J = 6.0 Hz, 2H), 4.37 (d, J = 18.0 Hz, 1H) ), 4.26-4.12 (m, 4H), 2.24(s, 3H), 1.46 (s, 9H), 1.36 (t, J = 5.8 Hz, 3H), 1.31 (t, J = 5.6 Hz, 3H); ¹³ CNMR (100 MHz, CDCl ₃ ): δ 167.4 (d, J = 1.3 Hz), 144.2 (d, J = 8.2 Hz), 129.8, 128.5, 114.2, 83.1, 63.9 (d, J = 5.9 Hz), 63.3 ( d, J = 6.0 Hz), 57.5 (d, J = 119.2 Hz), 27.9, 20.5, 16.5 (d, J = 4.4 Hz), 16.4 (d, J = 5.4 Hz); HRMS (ESI)calcd for C ₁₇ H ₂₉ NO ₅ P (M+H) ⁺ 358.1778, found 358.1776.

Example 8

N -4-Tolylglycine benzyl ester (0.2 mmol), diethyl phosphite (0.2 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to a dry reaction tube with a stirring bar under air atmosphere . Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain a pure light yellow oily liquid for 3 hours, and the yield was 80%. The structural characterization data of the 3h compound are as follows:

3h

3h

light yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.33-7.30 (m, 5H), 6.98 (d, J = 6.8 Hz, 2H), 6.59 (d, J = 6.8 Hz, 2H), 5.24 -5.16 (m, 2H), 4.54 (d, J =18.8 Hz, 1H), 4.23-4.06 (m, 4H), 2.23 (s, 3H), 1.36-1.31 (m, 6H), 1.26 (t, J = 5.6 Hz, 3H), 1.25 (t, J = 5.6 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 168.5 (d, J = 2.5 Hz), 143.8 (d, J = 10.0 Hz) , 135.1, 129.9, 128.9, 128.5, 128.4, 114.3, 67.8, 64.3 (d, J = 6.1 Hz), 63.7 (d, J = 5.8 Hz), 62.2, 56.8 (d, J = 118.4 Hz), 20.5, 16.4 (d, J = 4.0 Hz), 16.3 (d, J = 3.9 Hz); HRMS (ESI) calcdfor C ₂₀ H ₂₇ NO ₅ P (M+H) ⁺ 392.1621, found 392.1621.

Example 9

Ethyl N -4-(1,1'-biphenyl)glycine (0.2 mmol), diethyl phosphite (0.2 mmol) and cobalt perchlorate hexahydrate (0.02 mmol) were added to the mixture under air atmosphere. Stir the magnetic bar in the dry reaction tube. Then acetonitrile solvent (2 mL) was added to the test tube and the reaction tube was placed in an air atmosphere for 12 hours in an 80 ^o C oil bath. After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure with a rotary evaporator, and the residue was separated and purified by column chromatography to obtain pure light yellow oily liquid 3i with a yield of 65%. The structural characterization data of the 3i compound are as follows:

3i

3i

light yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.52 (dd, J = 6.8 Hz, J =0.8 Hz, 2H), 7.45 (dd, J = 5.2 Hz, J = 1.6 Hz, 2H), 7.39 (t, J = 6.2 Hz, 2H), 7.29-7.26 (m, 1H), 6.76 (dd, J = 5.2 Hz, J = 1.6 Hz, 2H), 4.68 (brs, 1H), 4.56(d, J = 18.4 Hz, 1H), 4.31-4.18 (m, 6H), 2.24 (s, 3H), 1.36-1.31 (m, 6H), 1.36 (t, J = 5.6 Hz, 3H), 1.33 (t, J = 5.6 Hz, 3H), 1.29 (t, J = 5.6 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 168.4 (d, J = 1.6 Hz), 145.6 (d, J = 8.3 Hz), 140.9, 132.4, 128.7, 128.0, 126.5, 114.3, 64.2 (d, J = 4.7 Hz), 63.7 (d, J =6.1 Hz), 62.4, 56.8 (d, J = 117.3 Hz), 20.5, 16.5 (d, J = 5.3 Hz), 16.4,14.2; HRMS (ESI) calcd for C ₂₀ H ₂₇ NO ₅ P (M+H) ⁺ 392.1621, found 392.1627.

Claims (3)

1. a synthetic method of alpha-phosphorylation of alpha-amino acid ester compounds is disclosed, wherein the structural formula of the compounds is shown as the formula (I):

；

wherein R is¹Is methyl or phenyl; r²Is methyl, ethyl, isopropyl, tert-butyl or benzyl; r³Is methyl, ethyl, isopropyl, tert-butyl or benzyl;

the method is characterized by comprising the following steps:

in the presence of a catalyst in an organic solventNAryl glycine ester (II) and phosphite ester compound (III) are used as reaction substrates, stirring is carried out for 12 hours until TLC detection reaction is completed, and the product α -phosphorylated α -amino acid ester compound (I) can be prepared by rotary evaporation concentration and column chromatography separation, and the reaction general formula is as follows:

the catalyst is Co (ClO)₄)₂•6H₂O; the amount of the catalyst is 10 mol percent of the compound shown in the formula (III);

the organic solvent is acetonitrile or 1, 2-dichloroethane.

2. The method for synthesizing alpha-aminoacylation according to claim 1, wherein the temperature in the step (a) is from room temperature to 100 ℃.

3. The method for synthesizing alpha-aminoacylation according to claim 1, wherein the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1: 1-10.