Chiral alpha alkyl beta hydroxyl phosphate compound as well as preparation method and application thereof

Abstract

The invention discloses a chiral alpha alkyl beta hydroxyl phosphate compound as well as a preparation method and application thereof, and belongs to the technical field of chemical synthesis. In the presence of a catalyst, carbonyl of a substrate is reduced into hydroxyl to obtain a chiral alcohol compound, alpha-alkyl beta-ketophosphonate is reduced by an asymmetric catalytic hydrogen transfer method, and a reduced product can be used as a core skeleton of various drug molecules, so that the chiral alcohol compound is prepared. The compound has an obvious promotion effect on migration and repair of keratinocytes, and has great application potential in the aspects of wound healing, skin tissue soothing, repair, aging resistance and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and in particular relates to a chiral α-alkyl β-hydroxy phosphate compound, a preparation method and an application thereof. Background Art

[0002] Chiral β-hydroxyphosphonates have garnered widespread attention in recent years due to their ability to mimic the molecular structure of hydroxyphosphonic acid and their significant application in antimicrobial development, enzyme activity regulation, and peptide analog construction. These compounds have been shown to be key intermediates in the synthesis of phosphate-based antibiotics, novel enzyme inhibitors, and bioactive peptide analogs.

[0003] In the prior art, there are few methods for synthesizing chiral β-hydroxyphosphonates via asymmetric catalytic hydrogen transfer. Summary of the Invention

[0004] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0005] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0006] One of the objectives of the present invention is to provide a chiral α-alkyl β-hydroxy phosphate compound, which has a significant promoting effect on keratinocyte migration and repair.

[0007] In order to solve the above technical problems, the present invention provides the following technical solutions: a chiral α-alkyl β-hydroxy phosphate compound, the structural formula of which is shown in Formula I;

[0008] (Formula I);

[0009] Wherein, R is an alkyl group; Ar is an unsubstituted aryl group or an aryl group in which at least one hydrogen is substituted, or a five-membered or more heterocyclic ring.

[0010] As a preferred embodiment of the chiral α-alkyl β-hydroxy phosphate compound of the present invention, wherein: in Formula I, R is selected from methyl, ethyl, and propyl;

[0011] Ar is selected from one of the following groups:

[0012] 、 、 、 、 、 、 、 、 、 .

[0013] As a preferred embodiment of the chiral α-alkyl β-hydroxy phosphate compound of the present invention, the compound represented by Formula I is selected from one of the compounds having the following structures:

[0014] 、 、 、 、 、 、 、 、 、 、 、 .

[0015] Another object of the present invention is to provide a method for preparing the chiral α-alkyl β-hydroxy phosphate compound as described above, comprising reacting a substrate represented by structural formula II with a hydrogen source in the presence of a catalyst to obtain a compound represented by formula I;

[0016] (Formula II);

[0017] Wherein, R and Ar in Formula II correspond to R and Ar in Formula I;

[0018] The catalyst is selected from at least one of the compounds of the following structures:

[0019] 、 、 、 、 .

[0020] As a preferred embodiment of the method for preparing the chiral α-alkyl β-hydroxy phosphate compounds of the present invention, the hydrogen source comprises at least one of HCOOH / Et3N with a molar ratio of 5:2, HCOOH / Et3N with a molar ratio of 3:2, HCOOH / Et3N with a molar ratio of 1:1, HCOOH / DABCO with a molar ratio of 2:1, HCOOH / DBU with a molar ratio of 2:1, HCO2NH4, and HCO2Na;

[0021] The amount of the hydrogen source used is 1.0 to 3.0 molar equivalents of the substrate shown in Formula II.

[0022] As a preferred embodiment of the method for preparing the chiral α-alkyl β-hydroxy phosphate compounds of the present invention, the amount of the catalyst added is 0.00005 to 0.01 molar equivalents of the substrate represented by Formula II, preferably 0.0001 to 0.005 molar equivalents, and more preferably 0.0001 to 0.001 molar equivalents.

[0023] As a preferred embodiment of the method for preparing the chiral α-alkyl β-hydroxy phosphate compounds of the present invention, the reaction is carried out in the absence of an inert gas, and the reaction temperature is 10-80°C, preferably 20-50°C.

[0024] As a preferred embodiment of the method for preparing the chiral α-alkyl β-hydroxy phosphate compounds of the present invention, the reaction is carried out in an organic solvent, and the organic solvent comprises at least one of an alcohol solvent, ethyl acetate, and tetrahydrofuran.

[0025] As a preferred embodiment of the method for preparing the chiral α-alkyl β-hydroxy phosphate compounds of the present invention, the organic solvent is an alcohol solvent, such as methanol, ethanol, propanol, etc., or a mixed solvent of two thereof, preferably methanol.

[0026] As a preferred embodiment of the method for preparing the chiral α-alkyl β-hydroxy phosphate compounds of the present invention, the substrate represented by formula II is synthesized by heating reaction using a styrene compound and a phosphite as raw materials and CuSO4 as a catalyst.

[0027] Another object of the present invention is to provide the use of the chiral α-alkyl β-hydroxy phosphate compound described above in promoting keratinocyte migration and repair.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] This invention reduces α-alkyl β-ketophosphonates via asymmetric catalytic hydrogen transfer. The reduced products can serve as core backbones for a variety of drug molecules. The products obtained by this synthesis method exhibit excellent yields and enantioselectivity. The synthesized compounds significantly promote keratinocyte migration and repair, demonstrating great potential for wound healing, skin tissue soothing, repair, and anti-aging applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0031] Figure 1 This is the single crystal diffraction pattern of the target product I-i prepared in the present invention;

[0032] Figure 2 The figure shows the comparison of the wound healing rates of keratinocytes treated with different compounds at 0 hour and 24 hours in Example 13 of the present invention. DETAILED DESCRIPTION

[0033] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0034] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0035] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0036] Unless otherwise specified, the raw materials used in the examples were purchased commercially.

[0037] The catalysts used in the present invention are Cat.A, Cat.B, Cat.C, Cat.D, and Cat.E reported in the literature (Phansavath P, Ratovelomanana-Vidal V, Echeverria PG, et al. Tethered Rh(III)-N-(p-Tolylsulfonyl)-1,2-Diphenylethylene-1,2-Diamine Complexes: Efficient Catalysts for Asymmetric Transfer Hydrogenation[J]. SynOpen, 2022. DOI:10.1055 / s-0040-1719914.), and their structural formulas are shown below:

[0038] 、 、 、 、 ;

[0039] The synthesis method of the catalyst is also referred to this document.

[0040] The synthesis method of the substrate α-amino β-ketophosphonate derivative used in the present invention is based on patent CN106279274A. The synthesis reaction formula is:

[0041]

[0042] Taking the synthesis of α-amino β-ketophosphonate derivative II-a as an example, the specific steps are:

[0043] β-Methylstyrene (0.118 g, 1 mmol), diethyl phosphite (0.276 g, 2 mmol), CuSO4·5H2O (0.026 g, 0.1 mmol), and 10 mL of acetonitrile were placed in a 25-mL three-necked flask and heated to 60°C in an oil bath. The reaction was continued at this temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was extracted with dichloromethane (15 x 3 mL). The organic phases were combined and dried over Na2SO4. The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether / ethyl acetate, v / v = 1:1) to obtain the target compound as a yellow oil in a 70% yield.

[0044] The synthesis methods of other substrates are the same as above and will not be repeated here.

[0045] Example 1 Synthesis of Diethyl (1-hydroxy-1-phenylpropan-2-yl)phosphonate:

[0046] α-Amino β-ketophosphonate derivative II-a (135 mg, 0.5 mmol) was added to the reaction flask, along with catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), and methanol (1 mL). The mixture was reacted at 25 °C for 16 h. After completion of the reaction, the solvent was dried to obtain crude product I-a, which was subsequently separated and purified by column chromatography to obtain clean product I-a.

[0047] The reaction formula is:

[0048]

[0049] The above target product Ⅰ-a was characterized:

[0050] 1H NMR (500 MHz, CDCl3) δ 7.33 – 7.26 (m, 4H), 7.19 (dd, J = 8.3, 5.4Hz, 1H), 5.24 (dt, J = 9.9, 2.3 Hz, 1H), 4.16 – 4.05 (m, 4H), 3.56 (d, J =2.5 Hz, 1H), 2.19 – 2.06 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1Hz, 3H), 0.97 (dd, J = 18.4, 7.4 Hz, 3H). 31 P NMR (203 MHz, CDCl3) δ 33.3. 13 CNMR (126 MHz, CDCl3) δ 141.7 (d, J = 16.1 Hz), 128.2, 127.3, 125.9, 71.0 (d,J = 3.7 Hz), 62.4 (d, J = 6.9 Hz), 62.1 (d, J = 7.1 Hz), 39.3, 38.2, 17.5 –14.5 (m), 6.4 (d, J = 3.2 Hz).

[0051] The product is a yellow oil with a yield of 98%, a diastereoselectivity ratio of >20:1, and an enantiomeric excess of >99%.

[0052] Example 2 Synthesis of Diethyl (1-(4-fluorophenyl)-1-hydroxypropan-2-yl)phosphonate:

[0053] α-Aminoβ-ketophosphonate derivative II-d (144 mg, 0.5 mmol) was added to the reaction flask, along with catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), and methanol (1 mL). The mixture was reacted at 25°C for 16 h. After completion of the reaction, the solvent was evaporated to give the crude product I-d, which was subsequently separated and purified by column chromatography to obtain the clean product I-d.

[0054] The reaction formula is:

[0055]

[0056] The target product I-d was characterized as follows:

[0057] 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.29 (m, 2H), 7.03 (t, J = 8.7 Hz, 2H), 5.27 (dd, J = 9.9, 2.6 Hz, 1H), 4.24 – 4.09 (m, 4H), 3.66 (d, J = 2.3Hz, 1H), 2.20 – 2.07 (m, 1H), 1.37 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 1.01 (dd, J = 18.3, 7.4 Hz, 3H).

[0058] 31 P NMR (162 MHz, CDCl3) δ 33.0.

[0059] 19 F NMR (376 MHz, CDCl3) δ -115.7.

[0060] 13 C NMR (101 MHz, CDCl3) δ 162.1 (d, J = 245.0 Hz), 137.4 (dd, J =16.1, 3.1 Hz), 127.5 (d, J = 8.1 Hz), 115.0 (d, J = 21.3 Hz), 70.5 (d, J =3.6 Hz), 62.5 (d, J = 6.9 Hz), 62.1 (d, J = 6.9 Hz), 39.3, 38.2, 16.6 (t, J =6.2 Hz), 6.4 (d, J = 3.2 Hz).

[0061] The product is a yellow oil with a yield of 98%, a diastereoselectivity ratio of >20:1, and an enantiomeric excess of >99%.

[0062] Example 3 Synthesis of Diethyl (1-hydroxy-1-(3-(trifluoromethyl)phenyl)propan-2-yl)phosphonate:

[0063] α-Amino β-ketophosphonate derivative II-e (144 mg, 0.5 mmol) was added to the reaction flask, along with catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), and methanol (1 mL). The mixture was reacted at 25 °C for 16 h. After completion of the reaction, the solvent was dried to obtain crude product I-e, which was subsequently separated and purified by column chromatography to obtain clean product I-e.

[0064] The reaction formula is:

[0065]

[0066] The above target product I-e was characterized:

[0067] 1 H NMR (500 MHz, CDCl3) δ 7.60 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.46(d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 5.26 (d, J = 9.8 Hz, 1H), 4.30– 4.23 (m, 1H), 4.13 – 4.04 (m, 4H), 2.19 – 2.09 (m, 1H), 1.27 (dd, J = 14.7,7.3 Hz, 7H), 0.97 (dd, J = 18.3, 7.4 Hz, 3H).

[0068] 31 P NMR (203 MHz, CDCl3) δ 32.6.

[0069] 19 F NMR (471 MHz, CDCl3) δ -62.6.

[0070] 13C NMR (126 MHz, CDCl3) δ 143.3 (d, J = 15.9 Hz), 130.5 (q, J = 32.1Hz), 129.4, 128.6, 125.3, 123.4 (dd, J = 152.7, 3.9 Hz), 70.5 (d, J = 3.5Hz), 63.7 (d, J = 5.8 Hz), 62.5 (d, J = 6.8 Hz), 62.0 (d, J = 7.0 Hz), 39.2,38.1, 16.4 (dd, J = 5.9, 4.5 Hz), 6.5 (d, J = 3.4 Hz).

[0071] The product is a yellow oil with a yield of 95%, a diastereoselectivity ratio of >20:1, and an enantiomeric excess of >99%.

[0072] Example 4 Synthesis of Diethyl (1-hydroxy-1-(p-tolyl)propan-2-yl)phosphonate:

[0073] α-Amino β-ketophosphonate derivative II-f (142 mg, 0.5 mmol) was added to the reaction flask, along with catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), and methanol (1 mL). The mixture was reacted at 25 °C for 16 h. After completion of the reaction, the solvent was dried to obtain crude product I-f, which was subsequently separated and purified by column chromatography to obtain clean product I-f.

[0074] The reaction formula is:

[0075]

[0076] The above target product I-f was characterized:

[0077] 1H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 7.8 Hz, 2H), 7.15 (d, J = 7.8Hz, 2H), 5.27 (d, J = 9.8 Hz, 1H), 4.25 – 4.11 (m, 4H), 3.47 (s, 1H), 2.34(s, 3H), 2.21 – 2.12 (m, 1H), 1.37 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 1.03 (dd, J = 18.4, 7.4 Hz, 3H).

[0078] 31 P NMR (203 MHz, CDCl3) δ 33.5.

[0079] 13 C NMR (126 MHz, CDCl3) δ 138.6 (d, J = 16.2 Hz), 136.9, 129.0,125.8, 70.9 (d, J = 3.8 Hz), 62.5 (d, J = 6.9 Hz), 62.2 (d, J = 6.9 Hz), 39.3, 38.2, 29.8, 21.2, 17.3 – 15.5 (m), 6.4 (d, J = 3.2 Hz).

[0080] The product is a yellow oil with a yield of 97%, a diastereoselectivity ratio of >20:1, and an enantiomeric excess of >99%.

[0081] Example 5 Synthesis of Diethyl (1-(4-ethylphenyl)-1-hydroxypropan-2-yl)phosphonate:

[0082] α-Amino β-ketophosphonate derivative II-g (149 mg, 0.5 mmol) was added to the reaction flask, along with catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), and methanol (1 mL). The mixture was reacted at 25 °C for 16 h. After completion of the reaction, the solvent was dried to obtain crude product I-g, which was subsequently separated and purified by column chromatography to obtain clean product I-g.

[0083] The reaction formula is:

[0084]

[0085] The target product I-g was characterized as follows:

[0086] 1 H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 7.7 Hz, 2H), 7.08 (d, J = 7.8Hz, 2H), 5.18 (d, J = 9.7 Hz, 1H), 4.10 – 4.00 (m, 4H), 3.47 – 3.42 (m, 1H), 2.54 (q, J = 7.6 Hz, 2H), 2.14 – 2.02 (m, 1H), 1.27 (t, J = 7.0 Hz, 3H), 1.23(t, J = 7.0 Hz, 3H), 1.13 (t, J = 7.6 Hz, 3H), 0.95 (dd, J = 18.4, 7.4 Hz, 3H).

[0087] 31 P NMR (203 MHz, CDCl3) δ 33.4.

[0088] 13 C NMR (126 MHz, CDCl3) δ 142.3, 138.0 (d, J = 15.9 Hz), 126.7,124.9, 69.9 (d, J = 3.7 Hz), 61.4 (d, J = 6.9 Hz), 61.1 (d, J = 7.1 Hz), 38.3, 37.2, 27.6, 15.6 (t, J = 6.3 Hz), 14.7, 5.5 (d, J = 3.2 Hz).

[0089] The product is a yellow oil with a yield of 96%, a diastereoselectivity ratio of >20:1, and an enantiomeric excess of >99%.

[0090] Example 6 Synthesis of Diethyl (1-(4-(benzyloxy)phenyl)-1-hydroxypropan-2-yl)phosphonate:

[0091] α-Amino β-ketophosphonate derivative II-i (188 mg, 0.5 mmol) was added to the reaction flask, along with catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), and methanol (1 mL). The mixture was reacted at 25 °C for 16 h. After completion of the reaction, the solvent was dried to obtain crude product I-i, which was subsequently separated and purified by column chromatography to obtain clean product I-i.

[0092] The reaction formula is:

[0093]

[0094] Characterization of the above target product Ⅰ-i:

[0095] 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.1 Hz, 2H), 7.39 – 7.34 (m,2H), 7.34 – 7.29 (m, 1H), 7.27 – 7.24 (m, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.24(d, J = 10.0 Hz, 1H), 5.04 (s, 2H), 4.20 – 4.08 (m, 4H), 3.51 (d, J = 2.3 Hz,1H), 2.19 – 2.07 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H),1.03 (dd, J = 18.4, 7.4 Hz, 3H).

[0096] 31 P NMR (162 MHz, CDCl3) δ 33.4.

[0097] 13 C NMR (101 MHz, CDCl3) δ 158.1, 137.2, 134.0 (d, J = 16.1 Hz), 128.7, 128.1, 127.6, 127.1, 114.6, 70.7 (d, J = 3.7 Hz), 70.2, 62.3 (dd, J =27.9, 7.0 Hz), 39.5, 38.1, 29.8, 16.6 (t, J = 5.9 Hz), 6.5 (d, J = 2.9 Hz).

[0098] The product is a yellow oil with a yield of 92%, a diastereoselectivity ratio of >20:1, and an enantiomeric excess of >99%.

[0099] Example 7 Synthesis of Diethyl (1-(4-chlorophenyl)-1-hydroxypentan-2-yl)phosphonate:

[0100] α-Amino β-ketophosphonate derivative II-1 (166 mg, 0.5 mmol), catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), and methanol (1 mL) were added to the reaction flask and reacted at 25 °C for 16 h. After the reaction was completed, the solvent was dried to obtain crude product I-1, which was subsequently separated and purified by column chromatography to obtain clean product I-1.

[0101] The reaction formula is:

[0102]

[0103] The above target product I-1 was characterized:

[0104] 1 H NMR (500 MHz, CDCl3) δ 7.31 (d, J = 1.1 Hz, 4H), 5.22 (d, J = 14.1Hz, 1H), 4.19 – 4.06 (m, 4H), 3.98 (d, J = 3.6 Hz, 1H), 2.08 (ddt, J = 21.1,7.3, 2.8 Hz, 1H), 1.63 – 1.51 (m, 1H), 1.47 – 1.40 (m, 1H), 1.37 – 1.34 (m,3H), 1.34 – 1.30 (m, 1H), 1.28 (d, J = 7.1 Hz, 3H), 1.07 (dq, J = 9.9, 6.5Hz, 1H), 0.74 – 0.69 (m, 3H).

[0105] 31 P NMR (203 MHz, CDCl3) δ 32.9.

[0106] 13C NMR (126 MHz, CDCl3) δ 140.5 (d, J = 14.9 Hz), 132.9, 128.3,127.4, 70.9 (d, J = 3.8 Hz), 62.3 (dd, J = 14.6, 7.0 Hz), 44.5, 43.4, 24.9(d, J = 2.7 Hz), 22.0 (d, J = 5.5 Hz), 16.6 (d, J = 5.9 Hz), 16.5 (d, J = 5.9Hz), 14.0.

[0107] The product is a yellow oil with a yield of 90%, a diastereoselectivity ratio of >20:1, and an enantiomeric excess of >99%.

[0108] Example 8 Synthesis of other substrates

[0109] Example 8 is basically the same as Example 1, except that the substrate is different, and other conditions remain the same as Example 1. The experimental results are shown in Table 1 below.

[0110] Table 1

[0111]

[0112] Example 9 Optimization of catalyst conditions

[0113] Example 9 is basically the same as Example 1, except that the catalyst is different, and other conditions remain the same as Example 1. The experimental results are shown in Table 2 below.

[0114] Table 2

[0115] catalyst Molar weight Yield (%) Cat. A 1 mol% 20 Cat. B 1 mol% 15 Cat. C 1 mol% 26 Cat. D 1 mol% 33 Cat. E 1 mol% 99 Cat. E 0 0 Cat. E 0.01 mol% 90 Cat. E 0.1 mol% 94 Cat. E 5 mol% 99

[0116] It can be seen from Table 2 that at the same dosage (1 mol%), the catalytic activities of various catalysts vary significantly. Among them, Cat.E has much higher activity than other catalysts, with a yield of 99%, while the yields of other catalysts (AD) are lower (15%-33%).

[0117] For Cat.E, which performed best, the relationship between its molar weight and yield was further examined. In the absence of a catalyst (0 mol%), the yield was 0, indicating that the reaction depended on the presence of a catalyst. Moreover, at a low dosage (0.01 mol%), a high yield of 90% could be achieved, demonstrating the high catalytic efficiency of Cat.E. When the dosage reached 1 mol% and above (5 mol%), the yield stabilized at 99% and no longer increased with increasing dosage, indicating that 1 mol% is an economical and efficient dosage of Cat.E.

[0118] Example 10 Optimization of hydrogen source conditions

[0119] Example 10 is substantially the same as Example 1, except that the hydrogen source is different, and other conditions remain the same as Example 1. The experimental results are shown in Table 3 below.

[0120] Table 3

[0121] Hydrogen source Molar weight Yield (%) <![CDATA[HCOOH / Et3N(5:2)]]> 2.0 equiv 99 HCOOH / Et3N (3:2) 2.0 equiv 70 <![CDATA[HCOOH / Et3N(1:1)]]> 2.0 equiv 77 HCOOH / DABCO (2:1) 2.0 equiv 80 HCOOH / DBU (2:1) 2.0 equiv 81 <![CDATA[HCO2NH4]]> 2.0 equiv 5 <![CDATA[HCO2Na]]> 2.0 equiv 3 <![CDATA[HCOOH / Et3N(5:2)]]> 1.0 equiv 89 <![CDATA[HCOOH / Et3N(5:2)]]> 3.0 equiv 99

[0122] As can be seen from Table 3, different hydrogen sources and their ratios affect the reaction yield. Among them, the HCOOH / Et3N (5:2) combination has the best effect, with a yield of 99%, which is the best performance among all hydrogen sources. In the same HCOOH / Et3N system, the change in ratio has a significant impact on the yield: 5:2>1:1 (77%)>3:2 (70%), indicating that the efficiency is highest when the ratio of formic acid to triethylamine is controlled at 5:2. When HCOOH is combined with other organic bases (DABCO, DBU) in a 2:1 ratio, the yield is 80%-81%, which is higher than some HCOOH / Et3N ratios, but still lower than the optimal 5:2 combination. When single formate salts (HCO2NH4, HCO2Na) are used as hydrogen sources, the yield is extremely low (3%-5%) and can hardly effectively promote the reaction, indicating that simple formate salts are not suitable as hydrogen sources for this reaction.

[0123] For the best-performing hydrogen source combination (HCOOH / Et3N (5:2)), our dosage was further investigated. At 1.0 equiv, the yield was 89%; at 2.0 equiv, the yield significantly increased to 99%; and at 3.0 equiv, the yield remained at 99%. Further increasing the dosage would not improve the yield but might instead result in waste of raw materials.

[0124] Example 11 Optimization of solvent conditions

[0125] Example 11 is substantially the same as Example 1, except that the solvent is different, and other conditions remain the same as Example 1. The experimental results are shown in Table 4 below.

[0126] Table 4

[0127] solvent Yield (%) Methanol 99 ethanol 95 Isopropyl alcohol 90 Ethyl acetate 85 Tetrahydrofuran 86

[0128] Table 4 shows that solvent type significantly affects reaction yield. Alcohols generally perform better. Reaction yields (90%-99%) for methanol, ethanol, and isopropanol are all higher than those for non-alcoholic solvents (ethyl acetate 85% and tetrahydrofuran 86%), indicating that this reaction is more suitable for alcoholic environments. Of all the solvents tested, methanol achieved the highest yield (99%), making it the optimal choice for this reaction.

[0129] Example 12 Optimization of reaction temperature conditions

[0130] Example 12 is substantially the same as Example 1, except for the reaction temperature. Other conditions remain the same as Example 1. The experimental results are shown in Table 5 below.

[0131] Table 5

[0132] Reaction temperature Yield (%) 10℃ 98 25℃ 99 50℃ 97 80℃ 80

[0133] As can be seen from Table 5, the yield remains high and stable when the temperature is in the range of 10-50°C. The yield is 98% at 10°C and 97% at 50°C. The difference with the highest yield at 25°C is very small (only 1-2 percentage points), indicating that the reaction can be carried out efficiently in a wide medium-low temperature range (10-50°C) and has good tolerance to temperature fluctuations.

[0134] When the temperature rose to 80°C, the yield dropped sharply to 80%. It is speculated that the high temperature may have triggered side reactions (such as product decomposition, raw material isomerization, etc.) or destroyed the stability of the reaction system (such as catalyst deactivation), resulting in a decrease in the efficiency of the main reaction.

[0135] Example 13 Bioactivity Test of Compounds on Cell Migration and Repair

[0136] To analyze the activity of these compounds on cell migration and repair, a human keratinocyte (HaCaT) scratch assay was performed. First, cells were passaged and seeded into 12-well plates. When the cell density reached 60%-70%, a scratch was performed. Two perpendicular lines were drawn in the 12-well plate. After the scratch, the plate was gently rinsed 2-3 times with PBS to remove cell debris. After rinsing, fresh culture medium was added. After the scratch, the corresponding concentration of compound was added to the corresponding wells. Then, photos were taken and data was collected at 0h and 24h after the scratch. The scratch area of ​​the keratinocytes in the blank group and the sample group was measured, and the healing rate was calculated. The healing rate calculation formula is as follows:

[0137]

[0138] The test results are as follows Figure 2 shown. Figure 2The DE scratch healing rates of keratinocytes at 0 and 24 hours after treatment with different compounds (I-a, I-e, I-i, and I-f) are shown. Compared to the blank control group, the cells in the experimental groups gradually began to migrate and connect with each other over time after treatment with these compounds, resulting in a significant reduction in the scratch area. These compounds significantly promoted HaCaT cell migration. Calculation of the change in scratch area and healing rate revealed a significant increase in the healing rate of HaCaT cell scratches in the treated groups, accelerating wound repair, with statistically significant differences (*P < 0.05).

[0139] The stratum corneum, the outermost layer of the skin, is primarily composed of multiple layers of keratinocytes. Skin damage can trigger stress responses such as inflammation, activating the regeneration and migration of keratinocytes. Compounds such as I-a, I-e, I-i, and I-f significantly promote keratinocyte migration and repair, demonstrating great potential for wound healing, skin tissue soothing, repair, and anti-aging applications.

[0140] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A chiral α-alkyl β-hydroxy phosphate compound, characterized in that: Its structural formula is shown in Formula I; (Formula I); Wherein, R is an alkyl group; Ar is an unsubstituted aryl group or an aryl group in which at least one hydrogen is substituted, or a five-membered or more heterocyclic ring.

2. The chiral α-alkyl β-hydroxy phosphate compound according to claim 1, characterized in that: In formula I, R is selected from methyl, ethyl, and propyl; Ar is selected from one of the following groups: 、 、 、 、 、 、 、 、 、 。 3. The chiral α-alkyl β-hydroxy phosphate compound according to claim 2, characterized in that: The compound represented by formula I is selected from one of the compounds having the following structures: 、 、 、 、 、 、 、 、 、 、 、 。 4. The method for preparing a chiral α-alkyl β-hydroxy phosphate compound according to any one of claims 1 to 3, characterized in that: The method comprises reacting a substrate represented by structural formula II with a hydrogen source in the presence of a catalyst to obtain a compound represented by formula I; (Formula II); Wherein, R and Ar in Formula II correspond to R and Ar in Formula I; The catalyst is selected from at least one of the compounds of the following structures: 、 、 、 、 。 5. The method for preparing a chiral α-alkyl β-hydroxy phosphate compound according to claim 4, wherein: The hydrogen source comprises at least one of HCOOH / Et3N with a molar ratio of 5:2, HCOOH / Et3N with a molar ratio of 3:2, HCOOH / Et3N with a molar ratio of 1:1, HCOOH / DABCO with a molar ratio of 2:1, HCOOH / DBU with a molar ratio of 2:1, HCO2NH4, and HCO2Na; The amount of the hydrogen source used is 1.0 to 3.0 molar equivalents of the substrate shown in Formula II.

6. The method for preparing a chiral α-alkyl β-hydroxy phosphate compound according to claim 4, wherein: The amount of the catalyst added is 0.00005-0.01 molar equivalent of the substrate shown in formula II.

7. The method for preparing a chiral α-alkyl β-hydroxy phosphate compound according to claim 4, wherein: The reaction is carried out in the absence of an inert gas at a reaction temperature of 10-80°C.

8. The method for preparing a chiral α-alkyl β-hydroxy phosphate compound according to claim 4, wherein: The reaction is carried out in an organic solvent, which includes at least one of an alcohol solvent, ethyl acetate, and tetrahydrofuran.

9. The method for preparing a chiral α-alkyl β-hydroxy phosphate compound according to claim 4, wherein: The substrate represented by formula II is synthesized by heating reaction using styrene compound and phosphite as raw materials and CuSO4 as catalyst.

10. Use of the chiral α-alkyl β-hydroxy phosphate compound according to any one of claims 1 to 3 in promoting keratinocyte migration and repair.

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