阅读说明：本技术 呋喃酮基氨基酸类化合物及其制备方法和用作凝血药物的应用 (Furanone amino acid compound, preparation method thereof and application of furanone amino acid compound as blood coagulation medicine ) 是由 汪朝阳 王能 林建云 杨凯 罗时荷 于 2020-12-14 设计创作，主要内容包括：本发明公开了一种呋喃酮基氨基酸类化合物及其制备方法和用作凝血药物的应用。本发明的呋喃酮基氨基酸类化合物的结构式为：式中,X选自-Cl、-Br中的一种,R～1选自C-3～C-(10)的烷基、C-6～C-(10)的芳基中的一种,R～2选自中的一种。本发明的呋喃酮基氨基酸类化合物的制备方法包括以下步骤：进行氨甲环酸、氨甲苯酸或氨基己酸与2(5H)-呋喃酮化合物的反应,即得呋喃酮基氨基酸类化合物。本发明的呋喃酮基氨基酸类化合物具有优异的凝血性能,凝血时间短,且其制备方法简单、反应条件温和、后处理操作简单,有望作为凝血和消炎止痛多功能药物应用于临床。(The invention discloses a furanone amino acid compound, a preparation method thereof and application of the furanone amino acid compound as a blood coagulation medicament. The structural formula of the furanone amino acid compound is as follows: in the formula, X is selected from one of-Cl and-Br, R 1 Is selected from C 3 ～C 10 Alkyl of (C) 6 ～C 10 One of the aryl groups of (1), R 2 Is selected from One kind of (1). Preparation of Furanonyl amino acids of the present inventionThe method comprises the following steps: reacting tranexamic acid, aminomethylbenzoic acid or aminocaproic acid with 2(5H) -furanone compound to obtain furanone amino acid compound. The furanone amino acid compound has excellent blood coagulation performance, short blood coagulation time, simple preparation method, mild reaction condition and simple post-treatment operation, and is expected to be used as a multifunctional medicine for blood coagulation, inflammation diminishing and pain relieving in clinic.)

1. A furanone-based amino acid compound having the structural formula:

in the formula, X is selected from one of-Cl and-Br, R¹Is selected from C₃～C₁₀Alkyl of (C)₆～C₁₀One of the aryl groups of (1), R²Is selected fromOne kind of (1).

2. The furanone-based amino acid of claim 1, wherein: the R is¹Selected from isopropyl, n-butyl, cyclohexyl,One kind of phenyl.

3. The furanone-based amino acid of claim 2, wherein: the furanone amino acid compound is

4. A process for the production of a furanone-based amino acid compound according to any one of claims 1 to 3, comprising the steps of: reacting tranexamic acid, aminomethylbenzoic acid or aminocaproic acid with 2(5H) -furanone compound to obtain furanone amino acid compound.

5. A process for the preparation of furanone-based amino acids according to claim 4, comprising the steps of: adding tranexamic acid, aminomethylbenzoic acid or aminocaproic acid into a reaction kettle, adding an alkali catalyst, a 2(5H) -furanone compound and a solvent, discharging air in the reaction kettle, filling nitrogen, and reacting to obtain the furanone amino acid compound.

6. The method for producing a furanone-based amino acid compound according to claim 4 or 5, wherein: the molar ratio of the 2(5H) -furanone compound to the tranexamic acid is 1: 1-1: 3; the molar ratio of the 2(5H) -furanone compound to the aminomethylbenzoic acid is 1: 1-1: 3; the molar ratio of the 2(5H) -furanone compound to the aminocaproic acid is 1: 1-1: 3.

7. The method for producing a furanone-based amino acid compound according to claim 5, wherein: the molar ratio of the 2(5H) -furanone compound to the base catalyst is 1: 1-1: 4.

8. The method for producing a furanone-based amino acid compound according to claim 5 or 7, wherein: the alkali catalyst is at least one of triethylene diamine, sodium tert-butoxide, potassium tert-butoxide, 1, 8-diazabicycloundece-7-ene, sodium hydroxide, potassium fluoride and potassium carbonate.

9. The method for producing a furanone-based amino acid compound according to claim 5 or 7, wherein: the solvent is at least one of water, dichloromethane, methanol, ethanol and tetrahydrofuran.

10. Use of the furanone-based amino acid compound of any one of claims 1 to 3 in the preparation of a blood coagulation medicament.

Technical Field

The invention relates to the technical field of blood coagulation materials, in particular to a furanone-based amino acid compound, a preparation method thereof and application thereof as a blood coagulation medicament.

Background

Bleeding is a clinical manifestation of many diseases and poses a serious threat to human health. Research on blood coagulation drugs has been one of the hot spots in drug development. Due to the specific molecular structure and properties of the small-molecule hemostatic drug, the small-molecule hemostatic drug has the advantages of quick response, predictable pharmacokinetic properties, high safety and the like, and is particularly concerned.

Currently, small molecule coagulation drugs commonly used in clinic include etamsylate, carbachol, tranexamic acid, aminomethylbenzoic acid, aminocaproic acid, and the like. The methods of using the etamsylate and carbachol are various, including the chemical modification and reuse of the etamsylate, the selection of a suitable drug carrier for loading and reuse, and the combination with other types of hemostatic drugs [ Luo Y, ZHao X, Releken Y, et al.J.Arthroplasty,2020,35(1), 61-68; the pediatrics pharmacology journal, 2015,21(7), 30-33. Although the existing blood coagulation medicines can effectively act on one or more links in the blood coagulation process to further achieve the blood coagulation effect, the problems of simple molecular structure and single and few types of functional groups generally exist, so that the medicine has single performance, and the clinical application is limited to a certain extent.

Disclosure of Invention

An object of the present invention is to provide a furanone-based amino acid compound.

Another object of the present invention is to provide a process for producing the furanone-based amino acid compound.

The invention also aims to provide the application of the furanone-based amino acid compound in the preparation of blood coagulation medicaments.

The technical scheme adopted by the invention is as follows:

a furanone-based amino acid compound of the formula:

in the formula, X is selected from one of-Cl and-Br, R¹Is selected from C₃～C₁₀Alkyl of (C)₆～C₁₀One of the aryl groups of (1), R²Is selected fromOne kind of (1).

Preferably, said R is¹Selected from isopropyl, n-butyl, cyclohexyl,One kind of phenyl.

Preferably, the furanone-based amino acid compound is

The preparation method of the furanone amino acid compound comprises the following steps: reacting tranexamic acid, aminomethylbenzoic acid or aminocaproic acid with 2(5H) -furanone compound to obtain furanone amino acid compound.

Preferably, the method for preparing the furanone-based amino acid compound comprises the following steps: adding tranexamic acid, aminomethylbenzoic acid or aminocaproic acid into a reaction kettle, adding an alkali catalyst, a 2(5H) -furanone compound and a solvent, discharging air in the reaction kettle, filling nitrogen, and reacting to obtain the furanone amino acid compound.

Preferably, the molar ratio of the 2(5H) -furanone compound to the tranexamic acid is 1: 1-1: 3.

Preferably, the molar ratio of the 2(5H) -furanone compound to aminomethylbenzoic acid is 1:1 to 1: 3.

Preferably, the molar ratio of the 2(5H) -furanone compound to the aminocaproic acid is 1: 1-1: 3.

Preferably, the molar ratio of the 2(5H) -furanone compound to the base catalyst is 1: 1-1: 4.

Preferably, the base catalyst is at least one of triethylene diamine, sodium tert-butoxide, potassium tert-butoxide, 1, 8-diazabicycloundece-7-ene, sodium hydroxide, potassium fluoride and potassium carbonate.

Preferably, the solvent is at least one of water, dichloromethane, methanol, ethanol and tetrahydrofuran.

Preferably, the reaction is carried out at 25-40 ℃ for 15-30 h.

The reactions involved in the present invention are as follows:

in the formula, X is selected from one of-Cl and-Br, R¹Is selected from C₃～C₁₀Alkyl of (C)₆～C₁₀One of the aryl groups of (1), R²Is selected from One kind of (1).

The invention has the beneficial effects that: the furanone amino acid compound has excellent blood coagulation performance, short blood coagulation time, simple preparation method, mild reaction condition and simple post-treatment operation, and is expected to be used as a multifunctional medicine for blood coagulation, inflammation diminishing and pain relieving in clinic.

Specifically, the method comprises the following steps:

1) the furanone-based amino acid compound has better blood coagulation performance than tranexamic acid, aminomethylbenzoic acid and aminocaproic acid, has shorter blood coagulation time, and has the effects of resisting bacteria, diminishing inflammation, relieving pain and the like because the molecular structure still retains complete furanone groups;

2) under the condition of not using metal catalyst and organic ligand, the invention cuts off the carbon-halogen bond through mild reaction conditions, the synthesis and post-treatment processes are simple and efficient to operate, and the C-N bond is effectively constructed based on C_sp2The construction of the C-N bond of the X-type compound provides a new idea;

3) the ends of the furanone amino acid compound of the invention all retain active carboxyl, and can be further subjected to derivatization reaction to construct more complex and diversified functional molecules.

Drawings

FIG. 1 is a graph showing the results of a blood coagulation performance test.

FIG. 2 is a diagram of the results of in vitro pig liver model coagulation experiments with 5-bornyloxy-3-bromo-2 (5H) furanosyl tranexamic acid.

Detailed Description

The invention will be further explained and illustrated with reference to specific examples.

The structural formulae and yields of the main compounds referred to in examples 1 to 10 are as follows:

example 1:

synthesis of 5-menthoxy-3-bromo-2 (5H) furanonylaminocaproic acid (Compound D):

0.3961g (2.00mmol) of aminocaproic acid and 0.1257g (2.24mmol) of potassium hydroxide are added into a 50mL two-neck flask, 5mL of absolute ethyl alcohol is added for stirring and dissolving, vacuum pumping is carried out to discharge the air in the two-neck flask, nitrogen is filled for protection, stirring is started, 0.3961g (1mmol) of 5-menthoxy-3-bromo-2 (5H) furanone is dissolved by 5mL of dichloromethane, then the dissolved 5-menthoxy-3-bromo-2 (5H) furanone is dripped into the two-neck flask through a constant pressure dropping funnel, 1 drop is added every 20s and 30min is finished, stirring is carried out at room temperature for 24H, after the reaction is finished, hydrochloric acid with the mass fraction of 15% is used for adjusting the pH of the reaction liquid to 3, ethyl acetate is used for extraction for 3 times (20 mL of ethyl acetate is used for each time), liquid separation is carried out, anhydrous sodium sulfate is used for drying, the crude product is separated, 0.3442g of 5-menthoxy-3-bromo-2 (, melting point 144.3-145.9 deg.C, 77.1% yield).

The NMR data of 5-menthoxy-3-bromo-2 (5H) furanosyl amino caproic acid are as follows:

¹H NMR(600MHz,CDCl₃-TMS),δ,ppm:0.81(3H,d,J＝6.0Hz,CH₃-12),0.84-0.87(1H,m,CH-13),0.93(3H,d,J＝6.0Hz,CH₃-14),0.95(3H,d,J＝6.0Hz,CH₃-15),0.99-1.14(2H,m,CH₂-9),1.21-1.28(2H,m,CH₂-18),1.40-1.46(2H,m,CH-8,CH-11),1.63-1.72(6H,m,CH₂-10,CH₂-17,CH₂-19),2.10-2.26(2H,m,CH₂-7),2.39(2H,t,J＝6.0Hz,CH₂-20),3.37-3.56(2H,m,NCH₂-16),3.57-3.75(1H,m,OCH-6),4.77(1H,s,NH),5.74(1H,s,CH-5)。

the results show that the compound prepared in this example has the formula:

example 2:

synthesis of 5-menthoxy-3-bromo-2 (5H) furanosyl tranexamic acid (Compound E):

0.1570g (1.00mmol) of tranexamic acid and 0.1042g (1.12mmol) of potassium hydroxide are added into a 50mL two-neck flask, 7mL of absolute ethanol is added for stirring and dissolution, the two-neck flask is vacuumized to discharge the air in the two-neck flask, nitrogen is charged for protection, stirring is started, 0.1980g (0.50mmol) of 5-menthoxy-3, 4-dibromo-2 (5H) furanone is dissolved by 5mL of dichloromethane and then is dripped into the two-neck flask through a constant pressure dropping funnel, 1 drop is added every 60s and 20min is added, stirring is carried out at room temperature for 28H, after the reaction is finished, hydrochloric acid with the mass fraction of 15% is used for adjusting the pH of the reaction liquid to 5, ethyl acetate is used for extraction for 3 times (20 mL of ethyl acetate each time), liquid separation is carried out, anhydrous sodium sulfate is used for drying, the crude product is separated by column chromatography, 0.1948g of 5-menthoxy-3-bromo-2 (5H) furaminecarboxylic acid (white solid is obtained, melting point 115.3-116.5 ℃, yield 82.5%).

The NMR data of 5-menthoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹H NMR(150MHz,CDCl₃-TMS),δ,ppm:0.79(3H,d,J＝6.0Hz,CH₃-12),0.80-0.84(1H,m,CH-13),0.88(3H,d,J＝6.0Hz,CH₃-14),0.96(3H,d,J＝6.0Hz,CH₃-15),1.00-1.03(2H,m,CH₂-9),1.31-1.40(1H,m,CH-17),1.42-1.45(2H,m,CH-8,11),1.47-1.66(4H,m,CH₂-18,22),1.67-1.73(2H,m,CH₂-10),1.87-1.91(2H,m,CH₂-7),2.10-2.25(4H,m,CH₂-19,21),2.29-2.33(1H,m,CH-20),3.23-3.37(2H,m,NCH₂-16),3.66-3.74(1H,m,OCH-6),5.12(1H,t,J＝6.0Hz,NH),5.87(1H,s,CH-5)。

the NMR spectrum data of 5-menthoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹³C NMR(150MHz,CDCl₃-TMS),δ,ppm:15.8(C-12),20.9(C-14),22.3(C-15),23.1(C-10),25.3(C-13),28.1(C-19,21),29.3(C-18,22),31.4(C-8),34.2(C-9),38.2(C-17),39.8(C-7),42.4(C-20),42.9(C-16),48.0(C-11),78.2(C-6),81.9(C-3),94.5(C-5),167.8(C-4),171.3(C-2),181.5(C-23)。

the high resolution mass spectral data of 5-menthoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

ESI-HRMS,m/z:Calcd for C₂₂H₃₅Br₂NO₅[M+H]⁺:472.1693,Found:472.1739。

the results show that the compound prepared in this example has the formula:

example 3:

synthesis of 5-menthoxy-3-chloro-2 (5H) furanosyl tranexamic acid (Compound F):

0.1059g (0.674mmol) of tranexamic acid and 0.0424g (0.7549mmol) of potassium hydroxide are added into a 50mL two-neck flask, 5mL of absolute ethanol is added for stirring and dissolution, the two-neck flask is vacuumized to discharge the air in the two-neck flask, nitrogen is filled for protection, stirring is started, 0.1034g (0.337mmol) of 5-menthoxy-3, 4-dichloro-2 (5H) furanone is dissolved by 5mL of dichloromethane and then is dripped into the two-neck flask through a constant pressure dropping funnel, 1 drop is added every 60s, 20min is added, stirring is carried out at room temperature for 28H, the pH of the reaction solution is adjusted to 5 by 15 percent of hydrochloric acid after the reaction is finished, ethyl acetate is used for 3 times (20 mL of ethyl acetate is used for each time), liquid separation is carried out, anhydrous sodium sulfate is used for drying, the crude product is separated by column chromatography, 0.1175g of 5-menthoxy-3-chloro-2 (5H) furanone based tranexamic acid (white solid is obtained, melting point 108.4-109.7 deg.C, yield 81.6%).

The NMR data of 5-menthoxy-3-chloro-2 (5H) furanosyl tranexamic acid are as follows:

¹H NMR(600MHz,DMSO-d₆),δ,ppm:0.77(3H,d,J＝6.0Hz,CH₃-12),0.79-0.84(1H,m,CH-13),0.87(3H,d,J＝6.0Hz,CH₃-14),0.91(3H,d,J＝6.0Hz,CH₃-15),0.94-1.00(2H,m,CH₂-9),1.18-1.24(1H,m,CH-17),1.27-1.38(2H,m,CH-8,11),1.39-1.65(4H,m,CH₂-18,22),1.68-1.77(2H,m,CH₂-10),1.89-1.93(2H,m,CH₂-7),1.96-2.33(4H,m,CH₂-19,21),2.97-3.11(1H,m,CH-20),3.35-3.39(2H,m,NCH₂-16),3.60-3.70(1H,m,OCH-6),6.15(1H,s,CH-5),7.58(1H,b,NH),12.03(1H,b,COOH)。

the NMR spectrum data of 5-menthoxy-3-chloro-2 (5H) furanosyl tranexamic acid are as follows:

¹³C NMR(150MHz,DMSO-d₆),δ,ppm:16.4(C-12),21.5(C-14),22.6(C-15),22.8(C-10),25.6(C-13),28.7(C-19,21),29.3(C-18,C-22),31.4(C-8),34.1(C-9),37.7(C-17),40.5(C-7),42.5(C-20),43.0(C-16),48.2(C-11),79.6(C-6),84.3(C-3),96.9(C-5),160.1(C-4),167.2(C-2),177.1(C-23)。

the high resolution mass spectral data of 5-menthoxy-3-chloro-2 (5H) furanosyl tranexamic acid are as follows:

ESI-HRMS,m/z:Calcd for C₂₂H₃₅ClNO₅[M+H]⁺:428.2198,Found:428.2267。

the results show that the compound prepared in this example has the formula:

example 4:

synthesis of 5-bornyloxy-3-bromo-2 (5H) furanosyl tranexamic acid (Compound G):

0.1572g (1.00mmol) of tranexamic acid and 0.0628g (1.12mmol) of potassium hydroxide are added into a 50mL two-neck flask, 5mL of absolute ethanol is added for stirring and dissolution, the two-neck flask is vacuumized to discharge the air in the two-neck flask, nitrogen is filled for protection, stirring is started, 0.1971g (0.5mmol) of 5-bornyloxy-3, 4-dibromo-2 (5H) furanone is dissolved by 5mL of dichloromethane and then is dripped into the two-neck flask through a constant pressure dropping funnel, 1 drop is added every 60s, 20min is completed, stirring is carried out at room temperature for 28H, the pH of a reaction solution is adjusted to 5 by 15% of hydrochloric acid after the reaction is finished, ethyl acetate is used for 3 times (20 mL of ethyl acetate is used for each time), liquid separation is carried out, anhydrous sodium sulfate is used for drying, a crude product is separated by column chromatography, 0.2084g of 5-bornyloxy-3-bromo-2 (5H) furanone group tranexamic acid (white solid is obtained, melting point 157.3 ℃ -158.2 ℃ yield 88.6%).

The NMR data of 5-bornyloxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹H NMR(600MHz,CDCl₃-TMS),δ,ppm:0.87(3H,s,CH₃-14),0.89(3H,s,CH₃-15),0.92(3H,s,CH₃-12),1.05-1.20(2H,m,CH₂-9),1.23-1.28(2H,m,CH₂-8),1.30-1.33(1H,m,CH-17),1.47-1.53(2H,m,CH₂-11),1.54-1.74(4H,m,CH₂-18,22),1.78-1.98(4H,CH₂-19,21),2.12-2.14(1H,m,CH-10),2.29-2.32(1H,m,CH-20),3.22-3.42(2H,m,NCH₂),3.96-4.18(1H,m,OCH-6),4.88(1H,t,J＝6.0Hz,NH),5.74(1H,s,CH-5)。

the NMR spectrum data of 5-bornyloxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹³C NMR(150MHz,CDCl₃-TMS),δ,ppm:14.2(C-12),18.8(C-14),19.6(C-15),26.7(C-9),28.0(C-19),28.1(C-21),28.4(C-8),29.3(C-18),29.4(C-22),37.1(C-11),38.1(C-17),42.8(C-20),44.9(C-10),47.7(C-13),47.9(C-16),49.5(C-7),84.2(C-6),87.7(C-3),99.2(C-5),151.6(C-4),167.6(C-2),181.3(C-23)。

the high resolution mass spectral data of 5-bornyloxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

ESI-HRMS,m/z:Calcd for C₂₂H₃₃BrNO₅[M+H]⁺:470.1537,Found:470.1566。

the results show that the compound prepared in this example has the formula:

example 5:

synthesis of 5-menthoxy-3-bromo-2 (5H) furanonylaminomethylbenzoic acid (Compound H):

1.009g (6.68mmol) of aminomethylbenzoic acid and 0.419g (7.48mmol) of potassium hydroxide were put into a 50mL two-necked flask, and 15mL of absolute ethanol was added thereto, and the mixture was stirred and dissolved, then the air in the two-necked flask was evacuated, nitrogen gas was introduced and the stirring was turned on, 1.323g (3.34mmol) of 5-menthoxy-3, 4-dibromo-2 (5H) furanone was dissolved in 15mL of dichloromethane, and then the resulting solution was dropped into the two-necked flask through a constant pressure dropping funnel, 1 drop was added per 120s and 45min was completed, the mixture was stirred at room temperature for 20 hours, after completion of the reaction, the pH of the reaction solution was adjusted to 2.5 with 15% by mass of hydrochloric acid, 3 times (20 mL of ethyl acetate per time) of ethyl acetate, liquid separation was carried out, drying was carried out over anhydrous sodium sulfate, and the crude product was separated by column chromatography to obtain 1.1043g of 5-menthoxy-3-bromo-2 (5H) furanosylaminomethylbenzoic acid (white solid, melting point 109.5 ℃ to 110.7 ℃ and yield 70.9%).

The NMR data of 5-menthoxy-3-bromo-2 (5H) furanosyl aminomethylbenzoic acid are as follows:

¹H NMR(600MHz,CDCl₃-TMS),δ,ppm:0.71(3H,d,J＝6.0,CH₃-12),0.83-0.93(7H,m,CH-13,CH₃-14,CH₃-15),0.96-1.19(2H,m,CH₂-9),1.26-1.44(2H,m,CH-8,CH-11),1.62-1.71(2H,m,CH₂-10),2.00-2.25(2H,m,CH₂-7),3.56-3.71(1H,m,OCH-6),4.67-4.89(2H,m,NCH₂-16),5.45(1H,b,NH),5.80(1H,s,CH-5),7.38-7.44(2H,m,ArH-18,22),8.10-8.16(2H,m,ArH-19,21)。

the NMR data for 5-menthoxy-3-bromo-2 (5H) furanosyl aminomethylbenzoic acid are as follows:

¹³C NMR(150MHz,CDCl₃-TMS),δ,ppm:15.8(C-12),21.0(C-14),22.1(C-15),22.8(C-10),25.3(C-13),31.6(C-8),33.9(C-9),42.4(C-7),47.9(C-11),48.1(C-16),78.4(C-6),82.2(C-3),98.7(C-5),127.0(C-18,22),129.1(C-20),130.9(C-19,21),143.3(C-17),159.4(C-4),167.7(C-2),171.4(C-23)。

the mass spectrum data of 5-menthoxy-3-bromo-2 (5H) furanosyl aminomethylbenzoic acid with high resolution are as follows:

ESI-HRMS,m/z:Calcd for C₂₂H₂₉BrNO₅[M+H]⁺:466.1224,Found:466.1260。

the results show that the compound prepared in this example has the formula:

example 6:

synthesis of 5-phenoxy-3-bromo-2 (5H) furanosyl aminomethylbenzoic acid (Compound I):

0.3023g (2mmol) of tranexamic acid and 0.1257g (2.24mmol) of potassium hydroxide are added into a 50mL two-neck flask, 5mL of absolute ethanol is added for stirring and dissolving, vacuum pumping is carried out to discharge air in the two-neck flask, nitrogen is filled for protection, stirring is started, 0.3340g (1mmol) of 5-phenoxy-3, 4-dibromo-2 (5H) furanone is dissolved by 5mL of dichloromethane and then is dripped into the two-neck flask through a constant pressure dropping funnel, 1 drop is added every 60s and 20min is finished, stirring is carried out at room temperature for 28H, after the reaction is finished, hydrochloric acid with the mass fraction of 15% is used for adjusting the pH of the reaction liquid to 5, ethyl acetate is used for extraction for 3 times (20 mL of ethyl acetate is used for each time), column chromatography is carried out, anhydrous sodium sulfate is used for drying, a crude product is separated, 0.4043g of 5-phenoxy-3-bromo-2 (5H) furanone aminomethylbenzoic acid (white solid) is obtained, melting point 164.5-165.7 ℃, yield 29.7%).

The NMR data of 5-phenoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹H NMR(600MHz,DMSO-d₆),δ,ppm:4.41-5.00(2H,m,NCH₂-12),6.47-6.77(1H,m,ArH-9),6.90(1H,s,CH-5),7.06-7.36(4H,m,ArH-7,8,10,11),7.45(2H,d,J＝6.0Hz,ArH-14,18),7.97(2H,d,J＝6.0Hz,ArH-15,17),8.31-8.74(1H,m,NH),12.96(1H,b,COOH)。

NMR carbon spectrum data for 5-phenoxy-3-bromo-2 (5H) furanosyl aminomethylbenzoic acid are as follows:

¹³C NMR(150MHz,DMSO-d₆),δ,ppm:47.5(C-12),79.6(C-3),95.1(C-5),116.7(C-7),117.2(C-11),123.9(C-9),127.5(14,18),130.0(C-8,10),130.2(C-15,17),130.4(C-16),143.9(C-13),158.5(C-6),161.6(C-4),167.6(C-2),176.1(C-19)。

the high resolution mass spectral data for 5-phenoxy-3-bromo-2 (5H) furanosyl aminomethylbenzoic acid are as follows:

ESI-HRMS,m/z:Calcd for C₁₈H₁₅BrNO₅[M+H]⁺:404.0128,Found:404.0177。

the results show that the compound prepared in this example has the formula:

example 7:

synthesis of 5-butoxy-3-bromo-2 (5H) furanosyl aminomethylbenzoic acid (Compound J):

0.3023g (2mmol) of tranexamic acid and 0.1257g (2.24mmol) of potassium hydroxide are added into a 50mL two-necked flask, 5mL of absolute ethanol is added for stirring and dissolution, vacuum pumping is carried out to discharge the air in the two-necked flask, nitrogen is filled for protection, stirring is started, 0.3139g (1mmol) of 5-butoxy-3, 4-dibromo-2 (5H) furanone is dissolved by 5mL of dichloromethane and then is dripped into the two-necked flask through a constant pressure dropping funnel, 1 drop is added every 60s and 20min is finished, stirring is carried out at room temperature for 28H, after the reaction is finished, the pH of the reaction solution is adjusted to 5 by using hydrochloric acid with the mass fraction of 15%, extraction is carried out for 3 times by using ethyl acetate (20 mL of ethyl acetate every time), column chromatography is carried out, drying is carried out by using anhydrous sodium sulfate, and a crude product is separated to obtain 0.4140g of 5-butoxy-3-bromo-2 (5H) furan tranexamic acid (white solid, melting point 164.4-165.9 ℃, yield 41.4%).

NMR data for 5-butoxy-3-bromo-2 (5H) furanosyltranexamic acid are as follows:

¹H NMR(600MHz,DMSO-d₆),δ,ppm:0.64-0.96(3H,m,CH₃-9),1.13-1.56(4H,m,CH₂-7,8),3.52-3.71(2H,m,OCH₂-6),4.38-4.90(2H,m,NCH₂-10),6.13(1H,s,CH-5),7.43(2H,d,J＝6.0Hz,ArH-12,16),7.95(2H,d,J＝6.0Hz,ArH-13,15),8.29(1H,s,NH),12.92(1H,s,COOH)。

NMR data for 5-butoxy-3-bromo-2 (5H) furanosylaminomethylbenzoic acid were as follows:

¹³C NMR(150MHz,DMSO-d₆),δ,ppm:14.0(C-9),19.0(C-8),31.3(C-7),47.2(C-10),68.3(C-6),72.9(C-3),97.5(C-5),127.4(12,16),129.9(C-13,15),130.1(C-14),144.4(C-11),161.8(C-4),167.6(C-2),170.8(C-17)。

the mass spectral data for 5-butoxy-3-bromo-2 (5H) furanosyl aminomethylbenzoic acid are as follows:

ESI-HRMS,m/z:Calcd for C₁₆H₁₉BrNO₅[M+H]⁺:384.0441,Found:384.0472。

the results show that the compound prepared in this example has the formula:

example 8:

synthesis of 5-phenoxy-3-bromo-2 (5H) furanosyl tranexamic acid (Compound K):

0.1572g (1mmol) of tranexamic acid and 0.0628g (1.12mmol) of potassium hydroxide are added into a 50mL two-neck flask, 5mL of absolute ethanol is added for stirring and dissolution, the two-neck flask is vacuumized to discharge the air in the two-neck flask, nitrogen is charged for protection, stirring is started, 0.1669g (1mmol) of 5-phenoxy-3, 4-dibromo-2 (5H) furanone is dissolved by 5mL of dichloromethane and then is dripped into the two-neck flask through a constant pressure dropping funnel, 1 drop is added every 60s, 20min is completed, stirring is carried out at room temperature for 28H, after the reaction is finished, the pH of the reaction liquid is adjusted to 5 by 15% of hydrochloric acid in mass fraction, extraction is carried out for 3 times by ethyl acetate (20 mL of ethyl acetate is used for each time), column chromatography is carried out for liquid separation, anhydrous sodium sulfate is dried, the crude product is separated, 0.1487g of 5-phenoxy-3-bromo-2 (5H) furanone based tranexamic acid (white solid is obtained, melting point 140.7-141.8 ℃, yield 37.0%).

The NMR data of 5-phenoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹H NMR(600MHz,CDCl₃-TMS),δ,ppm:1.23-1.32(1H,m,CH-13),1.43-1.68(4H,m,CH₂-14,18),1.89-2.12(4H,m,CH₂-15,17),2.21-2.33(1H,m,CH-16),3.22-3.46(2H,m,NCH₂-12),5.05(1H,b,NH),6.20(1H,s,CH-5),7.09-7.16(3H,m,ArH-7,9,11),7.35-7.38(2H,m,ArH-8,10)。

NMR data for 5-phenoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹³C NMR(150MHz,CDCl₃-TMS),δ,ppm:28.1(C-15,17),29.3(C-14),29.4(C-18),38.2(C-13),42.6(C-16),45.9(C-12),83.1(C-3),95.8(C-5),116.7(C-7,11),124.1(C-9),130.0(C-8,10),155.7(C-6),160.1(C-4),163.8(C-2),180.0(C-19)。

the high resolution mass spectral data for 5-phenoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

ESI-HRMS,m/z:Calcd for C₂₂H₃₅ClNO₅[M+H]⁺:428.2198,Found:428.2247。

the results show that the compound prepared in this example has the formula:

example 9:

synthesis of 5-cyclohexyloxy-3-bromo-2 (5H) furanosyl tranexamic acid (Compound L):

0.1572g (1.00mmol) of tranexamic acid and 0.0628g (1.12mmol) of potassium hydroxide are added into a 50mL two-neck flask, 7mL of absolute ethanol is added for stirring and dissolution, the two-neck flask is vacuumized to discharge the air in the two-neck flask, nitrogen is filled for protection, stirring is started, 0.1700g (1mmol) of 5-cyclohexyloxy-3, 4-dibromo-2 (5H) furanone is dissolved by 5mL of dichloromethane and then is dripped into the two-neck flask through a constant pressure dropping funnel, 1 drop is added every 60s and 20min is finished, stirring is carried out at room temperature for 28H, after the reaction is finished, the pH of the reaction solution is adjusted to 5 by 15% of hydrochloric acid, ethyl acetate is used for extraction for 3 times (20 mL of ethyl acetate is used for each time), separation is carried out, anhydrous sodium sulfate is used for drying, the crude product is separated by column chromatography, 0.1728g of 5-cyclohexyloxy-3-bromo-2 (5H) furaminecarboxylic acid (white solid, melting point 140.7-141.8 deg.C, yield 84.4%).

The NMR data of 5-cyclohexyloxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹H NMR(600MHz,CDCl₃-TMS),δ,ppm:1.00-1.06(1H,m,CH-13),1.19-1.44(6H,m,CH₂-8,9,10),1.45-1.63(4H,m,CH₂-14,18),1.73-1.92(4H,m,CH₂-15,17),1.96-2.15(4H,m,CH₂-7,11),2.23-2.33(1H,m,CH-16),3.10-3.51(2H,m,NCH₂-12),3.79-3.82(1H,m,OCH-6),5.00(1H,b,NH),5.83(1H,s,CH-5)。

the NMR spectrum data of 5-cyclohexyloxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹³C NMR(150MHz,CDCl₃-TMS),δ,ppm:23.9(C-8),24.0(C-10),25.3(C-9),28.0(C-15,17),29.3(C-14),29.4(C-18),32.0(C-7),33.3(C-11),38.1(C-13),42.8(C-16),49.6(C-12),78.7(C-6),84.5(C-3),96.5(C-5),160.2(C-4),167.7(C-2),181.3(C-19)。

the high resolution mass spectral data of 5-cyclohexyloxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

ESI-HRMS,m/z:Calcd for C₁₈H₂₈BrNO₅[M+H]⁺:416.1067,Found:416.1093。

the results show that the compound prepared in this example has the formula:

example 10:

synthesis of 5-isopropoxy-3-bromo-2 (5H) furanosyl tranexamic acid (Compound M):

0.1572g (1mmol) of tranexamic acid and 0.0628g (1.12mmol) of potassium hydroxide are added into a 50mL two-neck flask, 5mL of absolute ethanol is added for stirring and dissolution, the two-neck flask is vacuumized to discharge the air in the two-neck flask, nitrogen is charged for protection, stirring is started, 0.1499g (0.5mmol) of 5-isopropoxy-3, 4-dibromo-2 (5H) furanone is dissolved by 5mL of dichloromethane and then is dripped into the two-neck flask through a constant pressure dropping funnel, 1 drop is added every 60s and 20min is finished, stirring is carried out at room temperature for 28H, after the reaction is finished, the pH of the reaction solution is adjusted to 5 by 15% of hydrochloric acid, ethyl acetate is used for extraction for 3 times (20 mL of ethyl acetate is used for each time), separation is carried out, anhydrous sodium sulfate is used for drying, the crude product is separated by column chromatography, 0.1866g of 5-isopropoxy-3-bromo-2 (5H) furanone tranexamic acid (light yellow solid, melting point 93.8-94.5 ℃, yield 91.4%).

The NMR data of 5-isopropoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹H NMR(600MHz,CDCl₃-TMS),δ,ppm:1.24-1.30(7H,m,CH-10,CH₃-7,8),1.43-1.63(4H,m,CH₂-11,15),1.86-2.13(4H,m,CH₂-12,14),2.28-2.33(1H,m,CH-13),3.20-3.38(2H,m,NCH₂-9),4.10-4.15(1H,m,OCH-6),4.96(1H,t,J＝6.0Hz,NH),5.79(1H,s,CH-5)。

NMR data for 5-isopropoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

¹³C NMR(150MHz,CDCl₃-TMS),δ,ppm:22.0(C-7),23.3(C-8),28.1(C-12,14),29.3(C-11),29.4(C-15),38.2(C-10),42.7(C-13),49.6(C-9),73.2(C-6),85.4(C-3),96.5(C-5),164.8(C-4),167.5(C-2),180.6(C-16)。

the high resolution mass spectral data for 5-isopropoxy-3-bromo-2 (5H) furanosyl tranexamic acid are as follows:

ESI-HRMS,m/z:Calcd for C₁₅H₂₃BrNO₅[M+H]⁺:376.0754,Found:376.0742。

the results show that the compound prepared in this example has the formula:

and (3) performance testing:

1) blood coagulation performance test of furanone amino acid compounds:

reference [ Lin J Y, Luo S H, Chen S H, et al. Polym.J.,2020,52(6), 615-; according to the experimental method in Lokhande G, Carrow J K, Thakur T et al, acta Biomate, 2018,70,35-47, the coagulation performance of the compounds D to M prepared in examples 1 to 10 was examined by measuring the chicken blood coagulation time (unit: min) with the target compound, and compared with the coagulation performance of aminocaproic acid (compound A), aminomethylbenzoic acid (compound B) and tranexamic acid (compound C), and the coagulation performance test result chart is shown in FIG. 1.

As can be seen from fig. 1:

a) by adjusting the concentration of calcium ions in the calcium chloride solution and selecting the using amount of the sodium citrate anticoagulated blood, the negative Blank control group (Blank) has a slightly blood coagulation phenomenon at the 2 nd min, the blood coagulation phenomenon is slightly increased at the 3 rd min, the blood coagulation amounts are sequentially increased at the 4 th min and the 5 th min, and the blood is basically completely coagulated at the 6 th min;

b) the positive control A, B, C showed a small amount of clotting within 1min, with the amount of clotting increasing with time. All A coagulated at 5min, all B coagulated at 4min, and all C coagulated at 3 min. It can be seen that the positive control group A, B, C has blood coagulation ability, and the blood coagulation ability is different, the tranexamic acid has slightly strong blood coagulation ability, and the tranexamic acid and the aminocaproic acid have the second highest;

c) coagulation phenomena also appear in the target compound groups D-M within 1min, compared with a negative Blank control group (Blank), accelerated coagulation phenomena exist in the groups D-M, and the coagulation performance of the target product groups D-M after structure modification is superior to that of the corresponding raw material groups A-C; specifically, the coagulation performance of the furanone amino caproic acid product D is better than that of the amino caproic acid A (the initial coagulation time is shortened from 4min to 1 min); the blood coagulation performance of the furanone group tranexamic acid product groups E-G, K-M is superior to that of tranexamic acid C (the initial blood coagulation time is shortened by 2min compared with that of C); the coagulation performance of the furanone aminomethylbenzoic acid groups H-J is superior to that of aminomethylbenzoic acid B (the initial coagulation time is shortened by 3min compared with that of B);

d) in the same series, comparing the target compounds E and F, it can be found that the influence of different halogens at the No. 3 position of the furanone group 2(5H), the blood coagulation effect of the furanone group tranexamic acid compound E (obvious blood coagulation at the 1 st min) is better than that of the furanone group tranexamic acid compound F (obvious blood coagulation at the 2 nd min, but more blood coagulation amount than that of the comparative sample C) at the time of bromine;

e) in the same series, the influence of steric hindrance of the group at the 2(5H) furanone group 5 position is examined, and compared with the amount of blood coagulation in the same time period, it can be found that the compound groups D to M with modified structures have slightly different blood coagulation properties and different speeds. In the aminomethylbenzoic acid-modified target compound group H, I, J, the aminomethylbenzoic acid compound having butoxy group (J) at the 5-position of furanone is slightly weaker in blood coagulation than the aminomethylbenzoic acid compound having phenoxy group (I) or menthoxy group (H) with larger steric hindrance at the 5-position; for a target compound group E, G, K, L, M modified by tranexamic acid, the blood coagulation effect is better when the group at the No. 5 position of furanone is a menthoxy (E), a borneoxy (G), a phenoxy (K) and a cyclohexyloxy (L) with larger steric hindrance;

f) in general, the modified target compounds have relatively better blood coagulation performance of the tranexamic acid target compounds, and the blood coagulation performance of the aminomethylbenzoic acid target compounds is inferior to that of the aminoadipic acid target compounds. Meanwhile, the effect of the 5-position substituent and the 3-position halogen is combined to show that the 5-bornyloxy-3-bromo-2 (5H) furylcarbamic acid G has the best blood coagulation effect (obvious blood coagulation at 1min, and more blood coagulation amount than E, H, I and the like).

2) In vitro porcine liver model coagulation assay of 5-bornyloxy-3-bromo-2 (5H) furanosyl tranexamic acid:

reference [ Lin J Y, Luo S H, Chen S H, et al. Polym.J.,2020,52(6), 615-; according to the experimental method in Lokhande G, Carrow J K, Thakur T et al, acta Biomate, 2018,70,35-47, 5-bornyloxy-3-bromo-2 (5H) furanone group tranexamic acid (compound G) is selected to carry out in-vitro pig liver model coagulation experiments, and the test result chart is shown in figure 2.

Experimental phenomena:

a) cutting freshly prepared pig liver, the section is shown as I in figure 2;

b) when the target compound G is sprayed to the left side of the section of the pork liver for 2min, the sample reacts with the cut section wound, the sample at the thinner edge reacts with blood, and other thicker sample positions also react with blood, but mainly exist in the form of solid powder, as shown in II in figure 2 (the left side is applied, and the right side is not applied);

c) at 4min after spraying target compound G, the sample further acted on the cut wound, at which time more of the sample acted on the blood and appeared as a transparent film, as shown in III in FIG. 2 (left applied and right non-applied control);

d) at 6min after spraying target compound G, the sample had a relatively complete effect on the cut wound, and most of the sample had already acted on the blood and appeared as a transparent film, similar to a scab, as shown in IV in FIG. 2 (left side applied and right side not applied); after 6min, the cut wound application was accompanied by a wrinkled film similar to the phenomenon shown in IV in FIG. 2 (left applied and right non-applied contrast);

e) on the upper part of the pig liver after the target compound G is applied to the cut surface wound for 6min, the pressure of 3N is applied by a weight, and the bleeding of the wound of the sprayed sample G is basically stopped (shown in the left side of V in FIG. 2), while the bleeding of the right side of the unwanted sample is still observed under the applied pressure of 3N (shown in the right circle of V in FIG. 2);

f) continuously keeping the weight on the upper part of the pig liver to continuously apply 3N pressure, and at the 10 th min, no bleeding occurs in the section hole of the blood vessel on the position where the sample is sprayed (shown in the left side of VI in figure 2), while blood seepage is obvious in the section hole of the blood vessel on the right side of the pig liver where the sample is not sprayed (shown in the right circle of VI in figure 2).

As can be seen from fig. 2: 5-borneol oxygen-3-bromine-2 (5H) furanone group tranexamic acid can effectively participate in blood coagulation, accelerate the blood coagulation speed, and form a scab-like folded membrane in a short time, which is beneficial to promoting the ordered proceeding of the blood coagulation process and reducing the loss of blood.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.