Chiral alpha-alkyl beta-hydroxyl phosphate compounds, and preparation method and application thereof

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical synthesis, and particularly relates to a chiral alpha-alkyl beta-hydroxyl phosphate compound, a preparation method and application thereof. BACKGROUND

[0002] Chiral beta-hydroxyl phosphonate has been widely concerned in recent years, because it not only has the molecular characteristics of simulating the structure of hydroxyl phosphonate, but also shows important application value in the fields of antibacterial agent development, enzyme activity regulation, and peptide analogue construction. This kind of compound has been proved to be a key intermediate for synthesizing phosphonic acid antibiotics, novel enzyme inhibitors, and bioactive peptide analogues.

[0003] In the prior art, there are few methods for synthesizing chiral beta-hydroxyl phosphonate through asymmetric catalytic hydrogen transfer. SUMMARY

[0004] This section aims to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification to avoid obscuring the purpose of this section, the abstract and the title. Such simplifications or omissions cannot be used to limit the scope of the present application.

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

[0006] One of the purposes of the present application is to provide a chiral alpha-alkyl beta-hydroxyl phosphate compound, which has obvious promoting effect on keratinocyte migration and repair.

[0007] To solve the above technical problems, the present application provides the following technical scheme: a chiral alpha-alkyl beta-hydroxyl phosphate compound, the structural formula of which is shown as formula I;

[0008] (Formula I);

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

[0010] As a preferred scheme of the chiral alpha-alkyl beta-hydroxyl phosphate compound of the present application, 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 scheme of the chiral α-alkyl β-hydroxyl phosphate compound of the present application, the compound of formula I is selected from one of the following compounds:

[0014] 、 、 、 、 、 、 、 、 、 、 、 .

[0015] Another object of the present application is to provide a preparation method of the chiral α-alkyl β-hydroxyl phosphate compound as described above, comprising, in the presence of a catalyst, reacting a substrate of formula II with a hydrogen source to obtain a compound of formula I;

[0016] (Formula II);

[0017] wherein R and Ar in formula II are consistent with R and Ar in formula I;

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

[0019] 、 、 、 、 .

[0020] As a preferred scheme of the preparation method of the chiral α-alkyl β-hydroxyl phosphate compound of the present application, 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, HCO2Na.

[0021] The amount of the hydrogen source is 1.0-3.0 molar equivalents of the substrate of formula II.

[0022] As a preferred scheme of the preparation method of the chiral alpha alkyl beta hydroxyl phosphate compound of the present application, the amount of the catalyst added is 0.00005-0.01 mole equivalent of the substrate of formula II, preferably 0.0001-0.005 mole equivalent, and more preferably 0.0001-0.001 mole equivalent.

[0023] As a preferred scheme of the preparation method of the chiral alpha alkyl beta hydroxyl phosphate compound of the present application, the reaction is carried out in the absence of inert gas, and the reaction temperature is 10-80 DEG C, preferably 20-50 DEG C.

[0024] As a preferred scheme of the preparation method of the chiral alpha alkyl beta hydroxyl phosphate compound of the present application, the reaction is carried out in an organic solvent, and the organic solvent includes at least one of alcohol solvent, ethyl acetate, and tetrahydrofuran.

[0025] As a preferred scheme of the preparation method of the chiral alpha alkyl beta hydroxyl phosphate compound of the present application, the organic solvent is alcohol solvent, such as methanol, ethanol, and propanol, or a mixture of two of them, and is preferably methanol.

[0026] As a preferred scheme of the preparation method of the chiral alpha alkyl beta hydroxyl phosphate compound of the present application, the substrate of formula II is synthesized by heating reaction using styrene compound and phosphite as raw materials and CuSO4 as catalyst.

[0027] Another object of the present application is to provide the use of the chiral alpha alkyl beta hydroxyl phosphate compound as described above in promoting keratinocyte migration and repair.

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

[0029] The present application reduces alpha alkyl beta ketone phosphonate by asymmetric catalytic hydrogen transfer method, and the reduced product can be used as the core skeleton of various drug molecules. The product obtained by the synthesis method has excellent yield and enantiomeric selectivity, and the synthesized compound has obvious promoting effect on keratinocyte migration and repair, and shows great application potential in wound healing, skin tissue soothing, repair, and anti-aging. BRIEF DESCRIPTION OF DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor. Among them:

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

[0032] Figure 2 Comparison of the scratch healing rate of keratinocytes treated with different compounds for 0 hours and 24 hours in Example 13 of the present application. DETAILED DESCRIPTION

[0033] In order to make the above-mentioned purposes, features and advantages of the present application more obvious and easy to understand, the specific embodiments of the present application will be described in detail below with reference to the description examples.

[0034] In the following description, a large number of specific details are set forth in order to facilitate a thorough understanding of the present application, but the present application can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without departing from the concept of the present application, therefore the present application is not limited to the specific examples disclosed below.

[0035] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. "In one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an embodiment that is separate or alternative to other embodiments.

[0036] Unless otherwise specified, the raw materials used in the examples are commercially available.

[0037] The catalyst used in the present application is 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.) The structural formulas thereof are as follows:

[0038] , , , , ;

[0039] The synthesis method of the catalyst also refers to the literature.

[0040] The synthesis method of the substrate α-amino β-ketone phosphonate derivative used in the present application refers to the patent CN106279274A. The synthesis reaction formula is as follows:

[0041]

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

[0043] β-methylstyrene (0.118 g, 1 mmol), diethyl phosphite (0.276, 2 mmol), CuSO4·5H2O (0.026 g, 0.1 mmol), acetonitrile 10 mL in a 25 mL three-necked flask, heated to 60°C in an oil bath, continue to react at this temperature for 2 h, detect the reaction progress with TLC plate, after the reaction is completed, extract with dichloromethane (15x 3 mL), combine the organic phase, dry with Na2SO4, remove the solvent under reduced pressure, separate by column chromatography (petroleum ether / ethyl acetate, V / V = 1:1), and the target compound in yellow oil is obtained, with a yield of 70 %.

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

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

[0046] In a reaction bottle, add α-amino β-ketone phosphonate derivative II-a (135 mg, 0.5 mmol), add catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), methanol (1 mL), react at 25°C for 16 h, after the reaction is completed, spin dry the solvent, and obtain the crude product I-a, which is then purified by column chromatography to obtain the clean product I-a.

[0047] The reaction formula is as follows:

[0048]

[0049] The above target product I-a is characterized as follows:

[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 was a yellow oil with a yield of 98%, a diastereoselectivity ratio >20:1, and an enantiomeric excess >99%.

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

[0053] In a reaction bottle, the α-amino β-keto phosphonate derivative II-d (144 mg, 0.5 mmol) was added, a catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), methanol (1 mL) were added, and the reaction was carried out at 25 °C for 16 h. After the reaction was completed, the solvent was spin-dried to obtain the crude product I-d, which was then separated and purified by column chromatography to obtain the pure product I-d.

[0054] The reaction formula is:

[0055]

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

[0057] 1H NMR (400 MHz, CDC13) 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 = 2.3 Hz, 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, CDC13) δ 33.0.

[0059] 19 F NMR (376 MHz, CDC13) δ -115.7.

[0060] 13 C NMR (101 MHz, CDC13) 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 was a yellow oil in 98% yield with a diastereomeric ratio >20:1 and an enantiomeric excess >99%.

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

[0063] In a reaction bottle, add the α-amino β-ketophosphonate derivative II-e (144 mg, 0.5 mmol), add the catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), methanol (1 mL), and react at 25 °C for 16 h. After the reaction is completed, spin dry the solvent to obtain the crude product I-e, which is then purified by column chromatography to obtain the pure product I-e.

[0064] The reaction formula is:

[0065]

[0066] The above target product I-e is characterized as follows:

[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 was a yellow oil with a yield of 95% with a diastereomeric ratio >20:1 and an enantiomeric excess >99%.

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

[0073] In a reaction vial, add the aminophosphonate derivative II-f (142 mg, 0.5 mmol), add the catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), methanol (1 mL), and react at 25 °C for 16 h. After the reaction is complete, spin dry the solvents to obtain the crude product I-f, which is then purified by column chromatography to obtain the pure product I-f.

[0074] The reaction scheme is:

[0075]

[0076] The target product I-f is characterized as follows:

[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 was a yellow oil with a yield of 97%, a diastereoselectivity ratio > 20:1, and an enantiomeric excess > 99%.

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

[0082] In a reaction bottle, the α-amino β-keto phosphonate derivative II-g (149 mg, 0.5 mmol) was added, a catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), methanol (1 mL) were added, and the reaction was carried out at 25 °C for 16 h. After the reaction was completed, the solvent was spin-dried to obtain the crude product I-g, which was then separated and purified by column chromatography to obtain the pure product I-g.

[0083] The reaction formula is:

[0084]

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

[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 was a yellow oil in 96% yield with a diastereomeric ratio >20:1 and an enantiomeric excess >99%.

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

[0091] In a reaction bottle, add the α-amino β-keto phosphonate derivative II-i (188 mg, 0.5 mmol), add the catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), methanol (1 mL), and react at 25 °C for 16 h. After the reaction is completed, spin dry the solvent to obtain the crude product I-i, which is then purified by column chromatography to obtain the pure product I-i.

[0092] The reaction formula is:

[0093]

[0094] The above target product I-i is characterized:

[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 was a yellow oil with a yield of 92%, a diastereoselectivity ratio >20:1, and an enantiomeric excess >99%.

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

[0100] In a reaction bottle, add the aminophosphonate derivative II-l (166 mg, 0.5 mmol), add the catalyst Cat.E (0.4 mg, 0.005 mmol), HCOOH / Et3N (5:2) (127 μL, 1.0 mmol), methanol (1 mL), and react at 25 °C for 16 h. After the reaction is complete, spin dry the solvent to obtain the crude product I-l, which is then purified by column chromatography to obtain the pure product I-l.

[0101] The reaction formula is:

[0102]

[0103] The target product I-l is characterized as follows:

[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 was a yellow oil with a yield of 90% and a diastereoselectivity ratio of >20:1 and an enantiomeric excess of >99%.

[0108] Example 8 Synthesis of other substrates

[0109] Example 8 was basically the same as Example 1, except that the substrate was different, and other conditions were consistent with Example 1. The experimental results are shown in Table 1 as follows.

[0110] Table 1

[0111]

[0112] Example 9 Optimization of catalyst conditions

[0113] Example 9 was basically the same as Example 1, except that the catalyst was different, and other conditions were consistent with Example 1. The experimental results are shown in Table 2 as follows.

[0114] Table 2

[0115] Catalyst Molar amount 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] As can be seen from Table 2, under the same amount (1 mol%), the catalytic activities of various catalysts are significantly different, among which the activity of Cat.E is much higher than that of other catalysts, and the yield reaches 99%, and the yields of other catalysts (A-D) are lower (15%-33%).

[0117] For the best-performing Cat.E, further investigate the relationship between its molar amount and yield. Without catalyst (0 mol%), the yield is 0, indicating that the reaction depends on the presence of the catalyst; and at a low dosage (0.01 mol%), a high yield of 90% can be achieved, which reflects the high catalytic efficiency of Cat.E; when the dosage reaches 1 mol% and above (5 mol%), the yield is stable at 99% and no longer increases with the dosage, indicating that 1 mol% is the economic and efficient dosage of Cat.E.

[0118] Example 10 Condition optimization of hydrogen source

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

[0120] Table 3

[0121] Hydrogen source Molar amount Yield (%) HCOOH / Et3N (5:2) 2.0 equiv 99 HCOOH / Et3N (3:2) 2.0 equiv 70 HCOOH / Et3N (1 :1) 2.0 equiv 77 HCOOH / DABCO (2:1) 2.0 equiv 80 HCOOH / DBU (2:1) 2.0 equiv 81 HCO2NH4 2.0 equiv 5 [HC02Na] 2.0 equiv 3 HCOOH / Et3N (5:2) 1.0 equiv 89 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 which the HCOOH / Et3N (5:2) combination has the best effect, with a yield of 99%, which is the best among all hydrogen sources; the same HCOOH / Et3N system, the ratio change has a significant effect on the yield: 5:2 > 1:1 (77%) > 3:2 (70%), indicating that the ratio of formic acid to triethylamine needs to be controlled at 5:2 for the highest efficiency; when HCOOH is combined with other organic bases (DABCO, DBU) at a ratio of 2:1, the yield is 80%-81%, which is higher than some HCOOH / Et3N ratios, but still lower than the optimal 5:2 combination; when formate (HCO2NH4, HCO2Na) is used as a hydrogen source alone, the yield is very low (3%-5%), which is almost impossible to effectively promote the reaction, indicating that pure formate salt is not suitable as a hydrogen source for this reaction.

[0123] For the best-performing hydrogen source (HCOOH / Et3N (5:2) combination), further investigation of its dosage shows that when 1.0 equiv is used, the yield is 89%; when 2.0 equiv is used, the yield is significantly improved to 99%; when 3.0 equiv is used, the yield remains at 99%, and increasing the dosage will not improve the yield, but may cause waste of raw materials.

[0124] Example 11 Condition optimization of solvent

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

[0126] Table 4

[0127] Solvent Yield (%) Methanol 99 Ethanol 95 Isopropanol 90 Ethyl acetate 85 Tetrahydrofuran 86

[0128] As can be seen from Table 4, the type of solvent has a significant effect on the reaction yield, among which alcohol solvents overall perform better, with the reaction yield of methanol, ethanol, and isopropanol (90%-99%) being higher than that of non-alcohol solvents (ethyl acetate 85%, tetrahydrofuran 86%), indicating that the reaction is more suitable in an alcohol environment. Among all the tested solvents, methanol has the highest yield (99%) and is the best choice for this reaction.

[0129] Example 12 Condition optimization of reaction temperature

[0130] Example 12 is substantially the same as Example 1, except that the reaction temperature is different, and other conditions remain the same as Example 1. The experimental results are shown in Table 5 as follows.

[0131] Table 5

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

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

[0134] When the temperature is raised to 80℃, the yield is greatly reduced to 80%, which is speculated to be caused by side reactions (such as product decomposition, raw material isomerization, etc.) or destruction of the stability of the reaction system (such as catalyst deactivation) caused by high temperature, resulting in a decrease in the efficiency of the main reaction.

[0135] Example 13 Biological activity 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 test was performed. First, the cells were subcultured and inoculated into a 12-well plate, and when the cell density reached 60%-70%, two perpendicular straight lines were drawn in the 12-well plate, and after the scratch was completed, the cells were gently washed with PBS for 2-3 times to remove cell debris. After washing, fresh culture medium was added, and after the scratch was completed, the corresponding concentrations of compounds were added to the corresponding wells, and then the data was collected by photographing at 0h and 24h after the scratch. The scratch area of the keratinocytes in the blank and sample groups was measured and the healing rate was calculated, and the healing rate calculation formula is as follows:

[0137]

[0138] The test results are shown in Table 6 as follows. Figure 2 Figure 2 ​The scratch healing rate of keratinocytes treated with different compounds (I-a, I-e, I-i, I-f) at 0 hour and 24h DE was shown. It can be found that, compared with the blank group, the cells in the experimental group gradually began to migrate and connect with each other as time went on after adding different compounds, which led to a significant decrease in the scratch area, and all of them could significantly promote the migration of HaCaT cells. The calculation of the area change and healing rate of the scratch showed that the healing rate of the scratch of the HaCaT cells in the treatment group increased significantly, which accelerated the repair of the scratch, and the difference was statistically significant (*P<0.05).

[0139] The stratum corneum is the outermost layer of the skin, mainly composed of multiple layers of squamous cells. Skin damage can cause inflammatory stress response to be activated, and the regeneration and migration ability of keratinocytes plays a crucial role in the repair process of skin wounds. The compounds I-a, I-e, I-i, I-f have obvious promoting effect on the migration and repair of keratinocytes, which shows great application potential in wound healing, skin tissue soothing, repair, anti-aging and the like.

[0140] It should be noted that the above examples are only used to illustrate the technical solutions of the present application and are not limiting. Although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present application, which should be covered in the scope of the claims of the present application.

Claims

1. A chiral α-alkyl β-hydroxy phosphate compound, characterized in that: The structural formula is shown as formula I; (Formula I); R is methyl; Ar is selected from one of the following groups: 、 、 、 、 。 2. The method of claim 1, wherein the chiral α-alkyl β-hydroxyphosphonate compound is prepared by the process comprising: reacting a chiral α-hydroxy phosphonate compound with an alkylating agent in the presence of a base to form the chiral α-alkyl β-hydroxyphosphonate compound. The method comprises the following steps: reacting a substrate shown as formula II with a hydrogen source in the presence of a catalyst to obtain a compound shown as formula I; (Formula II); R and Ar in formula II are consistent with R and Ar in formula I; The catalyst is selected from at least one of the following compounds: 、 、 、 、 ； The hydrogen source is selected from at least one of the following: 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, and HCOOH / DBU with a molar ratio of 2:

1.

3. The method of claim 2, wherein the chiral α-alkyl β-hydroxyphosphonate compound is prepared by the process comprising: reacting a chiral α-hydroxy phosphonate compound with an alkylating agent in the presence of a base to form the chiral α-alkyl β-hydroxyphosphonate compound. The amount of the hydrogen source is 1.0-3.0 molar equivalents of the substrate shown as formula II.

4. The method for preparing chiral α-alkyl β-hydroxy phosphate compounds as described in claim 2, characterized in that: The amount of the catalyst is 0.00005-0.01 molar equivalents of the substrate shown as formula II.

5. The method for preparing chiral α-alkyl β-hydroxy phosphate compounds as described in claim 2, characterized in that: The reaction is carried out in the absence of inert gas, and the reaction temperature is 10-80℃.

6. The method for preparing chiral α-alkyl β-hydroxy phosphate compounds as described in claim 2, characterized in that: The reaction is carried out in an organic solvent, and the organic solvent is at least one of an alcohol solvent, ethyl acetate, and tetrahydrofuran.

7. Use of the chiral alpha-alkyl beta-hydroxyl phosphate compound of claim 1 in the preparation of a drug for promoting keratinocyte migration and repair.

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