CN114605466B - Synthesis method of acyl phosphate - Google Patents

Abstract

式(2)：

式(3)：

。The present invention provides a kind of synthetic method of acyl phosphate, and described acyl phosphate is the compound shown in formula (3), comprises: by the peroxyaryl anhydride shown in formula (1) and the compound shown in formula (2) The step of carrying out the acylation reaction of phosphite diester in the presence of a catalyst, wherein, in formulas (1) to (3), R ¹ is a substituted or unsubstituted aryl or heteroaryl group, R ² and R ³ can be The same or different, and each independently is a substituted or unsubstituted alkyl group with 1 to 10 carbon atoms, a substituted or unsubstituted aryl group or a heteroaryl group, and the catalyst is a halide, formula (1):

Formula (2):

Formula (3):

.

Description

A kind of synthetic method of acyl phosphate

technical field

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing acyl phosphate.

Background technique

Organophosphates exist as building blocks in various common natural products and pesticides, and possess outstanding biological properties. Meanwhile, acyl phosphates are one of the extremely important organic substances, which have been widely used in organic synthesis intermediates, drugs and functional materials. In addition, acyl phosphates are intermediates in many biochemical acylation reactions. Therefore, the synthetic methods of acyl phosphates have attracted people's continuous attention and extensive research.

The synthesis method of acyl phosphate in the prior art mainly relies on factors such as acid chloride, low temperature system, metal catalyst, etc., which is not friendly to the environment, the synthesis steps are not economical, and the reaction substrate is limited and the operability is not strong. question. Therefore, there is a need to develop an environmentally friendly and low-cost method for the synthesis of acyl phosphates.

Contents of the invention

The inventors of the present application found that by using halides as catalysts, the cost of synthesizing acyl phosphates can be reduced, the environmental burden of the reaction can be reduced, and acyl phosphates can be synthesized with high yield. The purpose of this application is to provide an efficient, environmentally friendly and low-cost synthetic method of acyl phosphates.

The purpose of this application adopts following technical scheme to realize:

The application provides a kind of synthetic method of acyl phosphate, and described acyl phosphate is the compound shown in formula (3), comprises: by the peroxy aryl acid anhydride shown in formula (1) and the compound shown in formula (2) The step of carrying out the acylation reaction of the phosphite diester in the presence of a catalyst,

Formula 1):

Formula (2):

Formula (3):

Wherein, in formulas (1) to (3), R ¹ is a substituted or unsubstituted aryl or heteroaryl group, R ² and R ³ can be the same or different, and each independently is substituted or unsubstituted with 1 An alkyl, substituted or unsubstituted aryl or heteroaryl group of ~10 carbon atoms, and the catalyst is a halide.

According to the method for synthesizing acyl phosphate esters of the present invention, acyl phosphate esters can be synthesized efficiently, at low cost and in an environmentally friendly manner.

In some optional embodiments, R ¹ is an aryl or heteroaryl group substituted with an electron-donating group.

According to the method for synthesizing acyl phosphate of the present invention, acyl phosphate can be synthesized with a higher yield.

In some optional embodiments, R is unsubstituted phenyl, ^1-10 carbon atoms of alkyl, halogen, alkoxy substituted phenyl, substituted or unsubstituted naphthyl and thienyl At least one, and/or each of R2 and ^R3 is at least one of an unsubstituted alkyl group having ¹ to 4 carbon atoms and a substituted or unsubstituted phenyl group.

According to the method for synthesizing acyl phosphate of the present invention, acyl phosphate can be synthesized with a higher yield.

In some optional embodiments, the acyl phosphate is a compound shown in any one of formulas 3a to 3f,

In some optional embodiments, the catalyst is any one of bromide, iodide, chloride or a combination thereof, and/or the solvent for the acylation reaction is acetonitrile, dichloromethane, 1,2 - Any one or combination of dichloroethane and N,N-dimethylformamide.

In some optional embodiments, the catalyst is any one or a combination of sodium bromide, lithium bromide, potassium bromide, ammonium bromide, tetrabutylammonium bromide, sodium iodide and sodium chloride, And/or the solvent is acetonitrile.

According to the method for synthesizing acyl phosphate esters of the present invention, the cost and environmental burden of the reaction for synthesizing acyl phosphate esters can be further reduced.

In some optional embodiments, the molar ratio of the phosphite diester shown in formula (2), the peroxyaryl acid anhydride shown in formula (1) and the catalyst is 1: (1-3): ( 0.1-1.5).

According to the method for synthesizing acyl phosphate esters of the present invention, the cost and environmental burden of the reaction for synthesizing acyl phosphate esters can be further reduced.

In some optional embodiments, the molar ratio of the phosphite diester shown in formula (2), the peroxyaryl acid anhydride shown in formula (1) and the catalyst is 1:(1.5-2):( 0.2-1).

According to the method for synthesizing acyl phosphate esters of the present invention, the cost of the reaction for synthesizing acyl phosphate esters can be further reduced.

In some optional embodiments, the reaction temperature of the acylation reaction is 30°C-50°C, and/or the reaction atmosphere of the acylation reaction is air.

In some optional embodiments, the reaction temperature of the acylation reaction is 40°C.

According to the method for synthesizing acyl phosphate esters of the present invention, the cost and environmental burden of synthesizing acyl phosphate esters can be further reduced.

detailed description

Hereinafter, the present application will be further described in conjunction with specific implementation methods. It should be noted that, on the premise of not conflicting, the various embodiments or technical features described below can be combined arbitrarily to form new embodiments.

The invention provides a method for synthesizing acyl phosphate. Specifically, a kind of synthetic method of the acyl phosphoric acid ester shown in formula (3) comprises: by the peroxyaryl anhydride shown in formula (1) and the phosphite diester shown in formula (2) in catalyst the step of carrying out the acylation reaction in the presence of,

Formula 1):

Formula (2):

Formula (3):

Wherein, in formulas (1) to (3), R ¹ is a substituted or unsubstituted aryl or heteroaryl group, R ² and R ³ can be the same or different, and each independently is substituted or unsubstituted with 1 An alkyl, substituted or unsubstituted aryl or heteroaryl group of ~10 carbon atoms, and the catalyst is a halide.

The method for synthesizing acyl phosphate of the present invention not only reduces the synthesis cost of acyl phosphate, but also reduces the burden on the environment by replacing the metal catalyst (such as metal Na or Ag) in the prior art with halides.

The peroxyaryl anhydride shown in formula (1) is not particularly limited, for example, R in formula ( ¹ ) can be substituted or unsubstituted aryl or heteroaryl. Preferably, R ¹ may be substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thienyl, and the like. The substituents of the substituted aryl and heteroaryl groups are not particularly limited, but are preferably electron-donating groups, more preferably at least one of alkyl, halogen and alkoxy groups having 1 to 10 carbon atoms, and more preferably It is preferably at least one of methyl, Cl, Br and methoxy, most preferably methyl.

The phosphite diester shown in formula (2) is not particularly limited, for example, R ² and R ³ in formula (2) can be the same or different, and R ² and R ³ each independently represent a atom alkyl, substituted or unsubstituted aryl or heteroaryl. Preferably, R ² and R ³ each independently represent at least one of an alkyl group having 1 to 4 carbon atoms and a substituted or unsubstituted phenyl group. The substituents of substituted aryl and heteroaryl are not particularly limited, but are preferably at least one of alkyl, halogen and alkoxy having 1 to 10 carbon atoms, more preferably methyl, Cl, Br and At least one of methoxy, most preferably methyl.

Preferably, according to the method for synthesizing acyl phosphate of the present invention, compounds shown in any one of the following formulas 3a to 3f can be synthesized.

The halide used as catalyst of the present invention is not particularly limited, but is preferably any one of bromide, iodide, chloride or a combination thereof, more preferably sodium bromide, lithium bromide, potassium bromide, ammonium bromide, tetra Any one or a combination of butylammonium bromide, sodium iodide and sodium chloride, most preferably sodium bromide or tetrabutylammonium bromide (TBAB).

The amount of catalyst is not particularly limited, for example, the phosphite diester shown in formula (2), the peroxyaryl acid anhydride shown in formula (1) and the molar ratio of the catalyst is 1: (1-3): (0.1-1.5), preferably, the phosphite diester shown in formula (2), the peroxyaryl acid anhydride shown in formula (1) and the mol ratio of described catalyst are 1: (1.5-2): ( 0.2-1). When the amount of the catalyst used is too low, the acylation reaction cannot be efficiently carried out. On the other hand, excessive catalyst usage will not lead to further improvement of yield or selectivity, but will cause catalyst waste, increase cost and environmental burden.

The acylation reaction of the present invention needs to be carried out in a solvent. The solvent is preferably any one or a combination of acetonitrile, dichloromethane (DCM), dichloroethane (DCE) and N,N-dimethylformamide (DMF), more preferably acetonitrile.

The reaction temperature of the acylation reaction in the present invention is not particularly limited, but is preferably 30°C to 50°C, more preferably 35°C to 45°C. The reaction atmosphere of the acylation reaction of the present invention is not particularly limited, and can be performed, for example, under an air atmosphere.

Example

The present invention is further described below through specific examples, but the present invention is not limited to the following examples.

In Examples, analysis and identification of compounds were performed using ¹ H-NMR and ¹³ C-NMR.

< ¹ H-NMR and ¹³ C-NMR analysis method>

In ¹ H-NMR analysis, JNM-ECP400 manufactured by JEOL Datum Ltd. was used. The integrated value of the NMR measurement value is a theoretical value. ¹ H-NMR and ¹³ C-NMR were recorded on CDCl ₃ at room temperature with TMS as internal standard (400 MHz ¹ H, 101 MHz ¹³ C) in CDCl ₃ , shifts (δ) are expressed in ppm and J values in Hz.

Example 1

Bis(4-methylbenzoyl) peroxide (0.80 mmol), diethyl phosphite (0.4 mmol), NaBr (20 mol%), and acetonitrile (4 mL) were added to a Schlenk tube (50 mL) with a stir bar , closed and stirred at 40° C. under an air atmosphere for 12 hours. After the reaction was complete, the mixture was dissolved in _CH2Cl2 ( ₃ x 5 mL), filtered and concentrated under reduced pressure. The residue was then purified by TLC technique (10:1 (v/v) petroleum ether/ethyl acetate) to give the desired product (diethylphosphoric acid) 4-methylbenzoic anhydride (3a).

Embodiment 2～6

Under the same conditions as in Example 1, the types of compounds of formula (1) and formula (2) were changed to synthesize the following mixtures 3b-3f, respectively. The yields and characterization results are as follows.

(Diethylphosphoric acid) 4-methylbenzoic anhydride (3a): Colorless oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ7.88(d, J=7.6Hz, 2H), 7.22(d, J=7.5Hz, 2H), 4.30(p, J=7.2Hz, 4H), 2.37( s, 3H), 1.36(t, J=7.1Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ160.9(d, J=8.1Hz), 145.6, 130.6, 129.4, 125.3(d, J= 9.1 Hz), 65.2 (d, J=5.1 Hz), 21.7, 16.0 (d, J=7.1 Hz).

(Diethylphosphoric acid)benzoic anhydride (3b): colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ8.01(d, J=7.4Hz, 2H), 7.60(t, J=7.4Hz, 1H), 7.44(t, J=7.8Hz, 2H), 4.33(p, J=7.2Hz, 4H), 1.38(t, J=7.1Hz, 6H). ¹³ C NMR(101MHz, CDCl3) δ161.0 (d, J=8.1 Hz), 134.5, 130.6, 128.7, 128.1 (d, J=8.1 Hz), 65.3 (d, J=6.1 Hz), 16.0 (d, J=7.1 Hz).

(Diethylphosphoric acid) 4-methoxybenzoic anhydride (3c): colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.59 (d, J=7.5Hz, 1H), 7.49 (s, 1H), 7.33(t, J=8.1Hz, 1H), 7.13(dd, J=8.3, 2.3Hz, 1H), 4.31(p, J=7.1Hz, 4H), 3.80(s, 3H), 1.37( t, J = 7.2 Hz, 6H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 161.7 (d, J = 9.1 Hz), 160.5, 130.5, 121.8, 115.7, 66.1, 56.2, 16.9.

(Diethylphosphoric acid) 2-methylbenzoic anhydride (3d): colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.96 (d, J=8.4Hz, 1H), 7.46 (t, J =7.4Hz,1H),7.26(dd,J=8.7,5.5Hz,2H),4.34(p,J=7.1Hz,4H),2.62(s,3H),1.39(t,J=7.0Hz,6H ). ¹³ C NMR (101MHz, CDCl ₃ ) δ161.1(d, J=8.1Hz), 142.8, 133.9, 132.3, 131.9, 126.8(d, J=8.1Hz), 126.2, 65.3(d, J=6.1 Hz), 22.2, 16.2 (d, J=7.1 Hz).

(Diethylphosphoric acid) 2-chlorobenzoic anhydride (3e): colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.95–7.90 (m, 1H), 7.46 (dd, J＝5.8, 2.8 Hz, 2H), 7.32(ddd, J＝8.3, 5.6, 3.2Hz, 1H), 4.33(p, J＝7.1Hz, 4H), 1.36(t, J＝6.6Hz, 6H). ¹³ C NMR (101MHz , CDCl ₃ ) δ 159.5 (d, J=8.1 Hz), 135.5, 134.5, 133.0, 131.9, 131.3, 127.1, 65.8 (d, J=6.1 Hz), 16.3 (d, J=7.1 Hz).

(Diisopropylphosphoric acid) 4-methylbenzoic anhydride (3f): colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.89 (d, J＝8.2Hz, 2H), 7.24–7.21( m, 2H), 4.89(dq, J＝12.5, 6.2Hz, 2H), 2.38(s, 3H), 1.37(dd, J＝9.0, 6.2Hz, 12H). ¹³ C NMR (101MHz, CDCl ₃ ) δ161 .3 (d, J = 9.1 Hz), 145.7, 130.8, 129.7, 125.9 (d, J = 8.1 Hz), 74.5 (d, J = 6.1 Hz), 23.8 (dd, J = 29.3 Hz), 22.0.

Examples 7-17 and Comparative Examples 1-3

Using the same raw materials as in Example 1, the acyl phosphate ester 3a was synthesized under the conditions shown in Table 1 below, and the equivalent number of the catalyst was based on diethyl phosphite. The specific yields are shown in Table 1 below.

Table 1

As shown in Table 1, when NaI, NaCl, NH ₄ Br, LiBr, TBAB, and KBr were used as catalysts, they all showed good acyl phosphate yields. However, when _I2 was used as a catalyst or when no catalyst was used (Comparative Examples 1-2), acyl phosphates could not be obtained. When NaBr was used as catalyst, a yield of 71% could be obtained even when used in a lower amount of 0.2 equivalents (Example 1). On the other hand, when DCM, DCE, and acetonitrile were used as solvents, higher yields were obtained, while when DMF was used, only traces of acyl phosphates were obtained. In terms of reaction temperature, when the reaction is carried out at 30° C. to 50° C., a higher yield can be obtained, while when the reaction temperature is too high or too low, the yield drops significantly.

This application has been elaborated from the viewpoints of purpose of use, performance, progress and novelty, etc., and has complied with the function enhancement and use requirements emphasized by the patent law. The above description of this application is only a preferred embodiment of this application. This application is limited in this way, therefore, all the structures, devices, features, etc. that are similar and identical to the application, that is, all equivalent replacements or modifications made according to the scope of the patent application of the application, should be protected by the patent application of the application. within range.

Claims (7)

1. A method for synthesizing an acyl phosphate, which is a compound represented by formula (3), comprising: a step of acylating a peroxyaryl acid anhydride represented by the formula (1) with a phosphorous acid diester represented by the formula (2) in the presence of a catalyst,

formula (1):

formula (2):

formula (3):

wherein, in the formulae (1) to (3), R ² And R ³ The same or different;

R ¹ is unsubstituted phenyl, alkyl of 1 to 10 carbon atoms, halogen, alkoxy substituted phenyl, at least one of substituted or unsubstituted naphthyl and thienyl, and/or R ² And R ³ Each at least one of an unsubstituted alkyl group having 1 to 4 carbon atoms and a substituted or unsubstituted phenyl group;

the catalyst is any one or the combination of bromide, iodide and chloride, and the solvent for the acylation reaction is any one or the combination of acetonitrile, dichloromethane and 1, 2-dichloroethane;

the reaction temperature of the acylation reaction is 30-50 ℃.

2. The method according to claim 1, wherein the acyl phosphate is a compound represented by any one of formulas 3a to 3f,

3. the synthesis method according to claim 1, wherein the catalyst is any one or combination of sodium bromide, lithium bromide, potassium bromide, ammonium bromide, tetrabutylammonium bromide, sodium iodide and sodium chloride, and/or the solvent is acetonitrile.

4. The method according to claim 1, wherein the molar ratio of the phosphorous acid diester represented by formula (2), the peroxyaryl acid anhydride represented by formula (1), and the catalyst is 1: (1-3): (0.1-1.5).

5. The method according to claim 4, wherein the molar ratio of the phosphorous acid diester represented by formula (2) to the peroxyaryl anhydride represented by formula (1) to the catalyst is 1: (1.5-2): (0.2-1).

6. The synthesis method according to claim 1, wherein the reaction atmosphere of the acylation reaction is air.

7. The synthesis method according to claim 1, wherein the reaction temperature of the acylation reaction is 40 ℃.