CN108191888A8 - A kind of 1,4- sulphur azatropylidene medicinal compounds and its preparation method and application for skin ulcer nursing - Google Patents

Abstract

The invention discloses a kind of Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compounds and its preparation method and application for skin ulcer nursing, belong to medical synthesis technical field.Technical scheme of the present invention main points are：A kind of Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compound for skin ulcer nursing, structural formula are：

Description

A kind of 1,4-thiazepine drug compound for skin ulcer care and its preparation method and application

technical field

The invention belongs to the technical field of medical synthesis, in particular to a kind of 1,4-thiazepine drug compound for skin ulcer care and its preparation method and application.

Background technique

Skin ulcer is common skin secondary damage, and skin defect or damage reaches dermis or below dermis, and single or multiple acute stage ulcer expands rapidly, and surface is covered with necrotic tissue, exudate, incrustation, and ulcer peripheral skin is red and swollen , has the characteristics of complex etiology, long course of disease, and easy recurrence. After bandaging the patient's skin ulcer, if the ulcer is not relieved well, it will cause the bandage to adhere to the ulcer wound. During the dressing change process, changing the bandage will cause great pain to the patient. Therefore, how to treat the patient's skin ulcer Effective care has always been a matter of great concern to medical staff. At present, in order to reduce the pain of patients in the nursing process, medical staff generally use silver ion dressings in clinical applications. By using silver ions, which have a bactericidal effect, the ulcers can be quickly scabbed, reducing the stickiness of the bandage and the wound, which can reduce the number of patients. For pain during bandage changing, the more typical silver ion dressing is silver sulfadiazine.

Nitrogen-containing sulfur-containing heterocyclic compounds play an important role in human health and agricultural production such as medicine and pesticides because of their good biological activity. In particular, thiazepines are an important class of seven-membered heterocyclic compounds. This type of compound has attracted much attention due to its unique medicinal value and broad-spectrum biological activity. This type of compound can improve myocardial blood supply and reduce myocardial consumption. Oxygen, used to treat angina pectoris, has minimal side effects, such as diltiazem; this type of compound is also a G protein-coupled receptor antagonist, and compounds with such structural units also have sedative and hypnotic effects, such as diazepam and clothiapine ; This type of compound can also promote the secretion of growth hormone, which can be used to treat children with slow growth; this type of compound is also a class of anti-ulcer active compounds, which can be used to protect gastric mucosa and be used for the treatment of chronic gastric ulcer; Zorb is also a class of compounds with better antibacterial activity, all showing a good inhibitory effect on Staphylococcus aureus and some fungi; recent research shows that thiazepine compounds have a certain effect in the treatment of AIDS, and are HIV reversal agents. Recording enzyme inhibitors, researchers are modifying its structure in order to find drugs with better anti-AIDS effects.

Contents of the invention

Summary of the invention The technical problem that the present invention solves is to provide a kind of synthetic method simple, novel molecular structure and remarkable bactericidal effect for skin ulcer nursing 1,4-thiazepine drug compound and its preparation method and application.

The present invention adopts following technical scheme for solving the problems of the technologies described above, a kind of 1,4-thiazepine drug compound for skin ulcer care, is characterized in that this 1,4-thiazepine drug compound The structural formula is: ^S' *:: ^ m ; «:

A kind of preparation method of the 1,4-thiazepine drug compound that is used for skin ulcer care, is characterized in that concrete steps are:

(1) under nitrogen protection, compound is joined in N, in the N-dimethylformamide, temperature of reaction HS enters N6 ^ and is cooled to 10 ℃ and adds N-chlorine succinimide in batches After the addition, return to room temperature for reaction. After monitoring the complete reaction of the raw materials, add ethyl acetate, then wash the reaction solution with saturated sodium chloride solution until the organic phase does not contain N,N-dimethylformamide, and the organic phase is anhydrous After drying and concentrating over magnesium sulfate, adding n-hexane, cooling, stirring and beating, and drying with suction to obtain compound Br;

(2) compound 2-chloroethylamine and basic compound are joined in tetrahydrofuran, wherein basic 1r, compound is sodium hydride or potassium hydride, heats backflow reaction after reaction system gas is replaced with nitrogen, drops to after raw material reaction is complete Add dichloroethane at room temperature, filter the reaction solution after stirring, add water and hydrochloric acid solution after the filtrate is concentrated under reduced pressure, extract the reaction solution with a mixed solution of ethyl acetate and n-hexane to remove impurities, and adjust the water phase with saturated sodium hydroxide solution pH*n, then extracted with chloroform, dried with anhydrous sodium sulfate and concentrated to obtain compound Br;

(3) compound and sodium bicarbonate are joined in water and methylene dichloride, be cooled to 0 ℃ after stirring Br, drop the methylene chloride solution that is dissolved with benzyl chloroformate, dropwise at room temperature React until the raw materials are completely reacted, separate the organic phase, extract the water phase with dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain compound W; wide N-N

(4) compound B and sulfonic acid compound are joined in toluene, wherein sulfonic acid Br compound is methanesulfonic acid or p-toluenesulfonic acid, is heated to 70 ℃, then adds paraformaldehyde, adds Then react under the condition of 70 rc until the reaction of the raw materials is complete, cool to room temperature, filter the reaction solution, and the filtrate is washed with saturated sodium bicarbonate solution to separate the organic ©bz\ phase, and after drying over anhydrous sodium sulfate, filter and concentrate, and then Obtain compound Br through column chromatography separation and purification; Add catalyst Pd(dppf)cl2S Pd(OAc) after entering nitrogen replacement reaction system gas three times , pass into hydrogen replacement reaction system gas three times again and be heated to 100 DEG C to react, after monitoring raw material reaction complete, reaction system is cooled to At room temperature, add ethyl acetate, wash with saturated sodium chloride solution for several times, then dry the organic phase with anhydrous magnesium sulfate, concentrate and separate and purify by column chromatography to obtain compound s n taste..

(6) under nitrogen protection, compound poly-N is joined in the mixed solution of 1,4-dioxane and deionized water, then add 2-chloro-4-formic acid methyl pyridine and potassium phosphate , add catalyst Pd (dppf) C12 after passing through nitrogen replacement reaction system gas three times, pass through nitrogen replacement reaction system gas three times again and be heated to 90 ℃ to react until raw material reaction is complete, after reaction temperature is cooled to room temperature, add ethyl acetate Ester extraction reaction solution, after merging the organic phases, wash with saturated sodium chloride solution, then dry with anhydrous sodium sulfate and concentrate, then separate and purify by column chromatography to obtain compound H0W (£). _4]⑺Under nitrogen protection, the compound B) The mixed solvent is a mixed solution composed of tetrahydrofuran, methanol and deionized water with a volume ratio of 2:2:1, then lithium hydroxide is added, and the temperature is raised to 50°C to react until the raw material is completely reacted, and the reaction solution is cooled After reaching room temperature, filter the reaction solution and concentrate in vacuo, then add dichloroethane, cool, stir and beat, and filter and dry to obtain compound 1 N 1 WH q ;

(8) Under nitrogen protection, compound 4 is added in SJ anhydrous tetrafuran, then WH o adds (8-2-(diethylamino) propyl-1-amine, TU and DIEA, heated to reflux Reaction, react until the raw materials are completely reacted, then add ethyl acetate, wash the reaction solution with saturated sodium chloride solution several times, separate the organic phase and dry it with anhydrous sodium sulfate, concentrate and separate and purify by column chromatography to obtain the target compound s N

Further preferably, the molar ratio of compounding and basic compound described in step (2) is Br 3:4.

Further preferably, the Br molar ratio of compounding and sulfonic acid compounds described in step (4) is 5:1. Gbz

Further preferably, compound I described in step (5) and the charging capacity mass ratio S Br of catalyzer are 50:1.

A kind of 1 for skin ulcer nursing, the 4-thiazepine pharmaceutical composition is characterized in that this is used for the 1 of skin ulcer nursing, and the 4-thiazepine pharmaceutical composition is by mass ratio Compound sw of 5:4:12:4:0-5:20:1.5:5:3:3:2:40 monoglyceride, ipp, white petrolatum, propylparaben, propylene glycol, alcohol, Medicinal ointment prepared from Nepal gold methyl ester, glycerin, MAP emulsifier, essence, peppermint oil and water.

Further preferably, described skin ulcer is caused by bacillus anthracis or/and staphylococcus aureus.

The comprehensive thiazepines compound of the present invention has advantages such as sedation, growth hormone secretion promotion, anti-ulcer and sterilization, synthesized a kind of 1,4-thiazepines drug compound for skin ulcer care and carried out The antibacterial activity test was carried out, and it was found that this kind of compound has good inhibitory activity against Bacillus anthracis and Staphylococcus aureus, which are easy to cause skin ulcers. Then it was made into ointment for clinical nursing experiment, and the nursing effect was found to be more obvious.

detailed description

Below by embodiment above-mentioned content of the present invention is described in further detail, but this should not be interpreted as the scope of the above-mentioned theme of the present invention is only limited to following embodiment, all technology that realizes based on above-mentioned content of the present invention all belongs to the present invention range.

Embodiment 1

Under nitrogen protection, compound J^3Lf:150g (1mol) is joined in N.N-dimethylformamide HS^N^w 2000mL, after reaction temperature is cooled to 10 ℃, add N- Chlorosuccinimide 65g, a total of 195g (1.5mol), return to room temperature reaction 12h after adding, LCMS monitoring raw material reaction is complete, add ethyl acetate 10000mL, after stirring 10min, use saturated sodium chloride solution Wash the reaction solution until the organic phase does not contain N,N-dimethylformamide, dry the organic phase over 300 g of anhydrous magnesium sulfate, add 1000 mL of n-hexane after concentration, stir and beat at 0° C., filter with suction and dry to obtain the compound The yield is 87.3%, -HRMS (⑴-ESI): m/z = 23 1 .097 1 Br (calcd.231.0975for CeHsBrNsS, [M+H]+).

Embodiment 2 wide n-n,,

In reaction flask, join the sodium hydride 8g (0.2mol) of compound 35g (0.15mol), 2-chloroethylamine 17.4g (0.15mol) and m 60wt% content in THF 100mL, use The gas in the reaction system was replaced with nitrogen three times, and then heated to reflux for 10 h. TLC monitored the reaction of the raw materials and then dropped to room temperature. Added 200 mL of dichloroethane to the reaction system. After stirring for 10 min, the reaction solution was filtered. After the filtrate was concentrated under reduced pressure, 1 water was added. 0 mL, then add 20 mL of hydrochloric acid solution, extract the reaction solution twice with 100 mL of a mixed solution of ethyl acetate and n-hexane with a volume ratio of 1:1, adjust the pH of the aqueous phase to 11 through saturated sodium hydroxide solution, and then use 100 mL of chloroform Extracted 3 times, combined organic phase, concentrated after drying with anhydrous sodium sulfate to obtain compound 33g, yield was 81%; 4 NMR (CDC13, 400MHz) S8.43-8.42 (m, 1H), 7 • 83 ir (d , J=12.0, lH), 7.29 (d, J=12.0, lH), 5.39 (s, 2H), 3.57-3.55 (m, 2H), 3.04 (d, J = 8.0, 2H)〇

Embodiment 3

In reaction flask, compound 35g (0.15mol), 2-chloroethylamine 17.4g (0.15mol) * Br potassium hydride 8g (0.2mol) is added in tetrahydrofuran 100mL, with nitrogen displacement reaction system gas three times, Heating and reflux reaction 10h then, after TLC monitoring raw material reaction completes, drop to room temperature, add ethylene dichloride 200mL in reaction system, filter reaction solution after stirring 10min, add water 100mL after filtrate is concentrated under reduced pressure, then add hydrochloric acid solution 20mL, use 100 mL of a mixed solution of ethyl acetate and n-hexane with a volume ratio of 1:1 was used to extract the reaction solution twice, and the aqueous phase was adjusted to a pH of 11 by saturated sodium hydroxide solution, then extracted three times with 100 mL of chloroform, and the organic Phase, concentrated after drying with anhydrous sodium sulfate to obtain compound H2N~35 5g, yield is 87% 4 NMR (CDC13, 400MHz) S8 43-8 42 (m, 1H), 7 83 Sr (d, J=12.0, lH), 7.29 (d, J=12.0, lH), 5.39 (s, 2H), 3.57-3.55 (m, 2H), 3.04 (d, J=8.0, 2H)

Embodiment 4

In reaction flask, compound 35g (0.13mol) and sodium bicarbonate 16.8g Br (0.2mol) are joined in water 100mL and monochloromethane 200mL, be cooled to 0 after stirring evenly °C, slowly dropwise add 100mL of monochloromethane solution that is dissolved with octyl chloroformate 24g (0·14mol), react at room temperature for 2h after the dropwise addition, after TLC monitors that the raw material has reacted completely, separate the organic phase and the aqueous phase Extract twice with 100 mL of methyl chloride, combine the organic phases, dry and concentrate over anhydrous sodium sulfate to obtain 49 g of compound Q ketone, with a yield of 93%. Br

Embodiment 5 1-N-N\,

In reaction flask, compound 20g (0.05mol) and methyl benzyl acid 1 g Br (0.01mol) are joined in the toluene 500mL, slowly heated to 70 DEG C, then slowly add more 15g (0.5mol) of polyoxymethylene, reacted at 70°C for 10h after the addition, TLC monitored the complete reaction of the raw materials, cooled to room temperature, filtered the reaction solution, and the filtrate was washed with 100mL of saturated sodium bicarbonate solution for 1 Once, the organic phase was separated, dried by anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (VpE: VEA=10:1) to obtain compound ^^^5^14§, with a yield of 70%. -1113((+)-£31):111/2 Bf = 420.3023 (calcd.420.301 lfor Ci7Hi6BrN402S, [M+H]+)

Embodiment 6, broad

In reaction flask, compound 20g (0.05mol) and p-toluenesulfonic acid 2g Br (0.01mol) are joined in toluene 500mL, slowly heated to 7 ℃. (:, then slowly add paraformaldehyde 15g (0.5mol), react 10h under the condition of 70 ℃ after adding, TLC monitoring raw material reaction is complete, cool to room temperature, filter reaction solution, filtrate is passed through saturated sodium bicarbonate 100 mL of the solution was washed once, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography (VpE·Cbzv VEA=H): D to separate 17 g of the extracted compound, and the yield was 85%.If

Embodiment 7

Under the protection of nitrogen, compound 280g (1mol) and DMS02800mL are added to reaction flask soil, then add biboronic acid pinacol ester 510g (2mol) and _Potassium 3008 (3mol), pass into the nitrogen replacement reaction system=7^(dPPf)Cl2 5_eg for three times, pass through the hydrogen replacement reaction system gas again after three times and slowly heat to imrc into the lamp reaction, after the reaction lcms monitoring raw material reaction is complete, and reaction system is cooled to room temperature, adds ethyl acetate 2400mL, after stirring for 30mm, wash reaction solution 4 times with saturated sodium chloride solution, then dry organic phase with anhydrous sodium sulfate, after concentrating After separation and purification by column chromatography (Vpe: Vea=5:D), the compound 220g yield was 72_6 ❹ surface (CDCl3, 400MHz) S8.65(d, h80, m), 8i4(d, j=i2 〇, iH), 3. (12.0 2H) 3^53-3.51 (m, 2H), 2.97 (dJ = 8.0) 2H) 7_122 ( 2H)_

Embodiment 8 Cbz-8] under the protection of nitrogen, compound (2280gO1) will be added to Br280g (2mG:0 and potassium acetate 3GGg (3mol), feed nitrogen Suspend the reaction system; 5.6 times pass nitrogen into the reaction system to replace the gas for three times, then slowly heat the reaction system. After the reaction is over, the reaction should be completed. Although the cake is warm, add ethyl acetate to 1400mL and stir. After 30min, wash the reaction liquid with sodium chloride solution 800mL for several times, then dry the TXxj organic phase with anhydrous sulfuric acid mirror, concentrate and separate and purify by column chromatography (VpE: Vea=5:1) Obtain compound s270g, yield, OV' 81.8%.

Embodiment 9

[托_0] Under nitrogen protection, compound b>, O (1mol) was added to 1,4-dioxane 2500mL and 500mL of deionized water was added, and then 2-chloro-4-formic acid methyl ester was added Pyridine (400g, 1.2mol) and potassium phosphate 424g (2mol), add catalyst Pd (dppf) Cl after passing through nitrogen displacement reaction system gas three times 1: 3g, pass through nitrogen replacement reaction system gas three times again and slowly Heating to 90°C for reaction, after 3 hours of reaction, monitor the raw material reaction by LCMS, add ethyl acetate 3000mL to extract the reaction solution 3 times after the reaction temperature is cooled to room temperature, wash 1 time with saturated sodium chloride solution after merging the organic phases, and then Concentrate after drying with anhydrous sodium sulfate, separate and purify by column chromatography (Vpe:Vea=5:1) to obtain compound TO.*

Embodiment 10 DtO

Under hot air protection, compound 34g (0.1mol) is joined in the mixed solvent of THF0 400mL, methyl alcohol 400mL and deionized water 200mL, then add Lithium Hydroxide 5g (0.2mol), slowly be warming up to 50 °C to react, after 2 hours of reaction, LCMS monitors the complete reaction of the raw materials, cools the reaction solution to room temperature, filters the reaction solution and concentrates in vacuum, then adds 400mL of dichloroethane, stirs and beats at 0 °C, and vacuum-dries to obtain Compound S W 29g, yield is 88.7%; NMR (CDCl3, 400MHz) S9.34 (d, J = 8_0, 1H) CN ° H o 8-26 (d, J = 8.0, 1H), 8.01 (d, J = 8.0, lH), 7.87 (s, lH), 7.64 (s, lH), 4.22 (d, J = 8.0, lH), 3.82 (s, 2H), 3.09 (d, J = 8.0, 2H), 2.85(d, J = 8.0,2H) •

Embodiment 11, OW

Under nitrogen protection, compound \-^ ..33g (0.1mol) is joined in 800mL anhydrous WH m tetrahydrofuran, then add (R)-2-(diethylamino) propylamine 2. g (0.15mol), add HATU42g (0.11mol) and DIEA 39g (0.3mol) after stirring for 10min, slowly heat to reflux reaction, after reacting 2h, LCMS monitoring raw material reaction is complete, then add ethyl acetate 2000mL, stir After 1h, wash the reaction solution 2 times with saturated sodium chloride solution 1000mL, separate the organic phase and dry it with anhydrous sodium sulfate. After concentration, separation and purification by column chromatography obtains the target compound, 41g, and the yield is 93- ( m, 2H) , 4.22(d, J = 8.0, 1H) , 3.72 (d, Ji = 12.0, J2 = 8.0, 2H) , 3.42 (s, lH) , 3.14 (d, J^8.4, 2H) , 3.01 (d, J = 8.4, 2H), 2.37-2.35 (m, 4H), 1.25 (s, 3H), 1.05-1.02 (m, 6H); MS m/z = 440.5697 (Calcd 440.5689forC22H29N70S+ H). Anal. Calcd for C22H29N70S: C, 60.11; H, 6.65; N, 22.30. Found: C, 60.24; H, 6.71; N, 22.35

Embodiment 12

The present embodiment selects Bacillus anthracis and Staphylococcus aureus as antibacterial activity test object. First, prepare liquid culture medium (put 1g of peptone, 0.5g of yeast extract, 1g of sodium chloride, and 100mL of distilled water into a 250mL Erlenmeyer flask, heat while stirring on the electric stove, and stop heating when the mixture is clear and uniform. , seal the bottle mouth with gauze and kraft paper successively for later use) and solid medium (put peptone 1g, yeast extract 0.5g, sodium chloride 1g, agar 2g, distilled water 100mL in a 250mL Erlenmeyer flask, put it on the electric furnace and stir Heating while heating, when the mixture is clear and uniform, stop heating, seal the mouth of the bottle with gauze and kraft paper in turn for use); then sterilize the culture medium through an autoclave. Next is the preparation of the bacterium liquid, after Escherichia coli and Staphylococcus aureus strains are activated, pipette 100 g of the activated bacterium liquid with a pipette gun, place in sterilized 100mL distilled water and mix well. Finally, the plate is sterilized by ultraviolet light, and then the culture medium is quickly poured into the plate while it is hot, with a thickness of about 0.15cm, spread evenly, let it stand still, let it solidify slowly, and put it into an incubator at 37°C after solidification Cultivate for one day to do the free bacteria test.

Configure synthesized target compound and reference compound solution respectively with DMF, be placed in volumetric flask for use. Use a puncher to punch holes in the filter paper with a pore size of 5 mm, then sterilize the filter paper and soak it in the sample solution with a concentration of 0.1 mg/mL for use.

On ultra-clean workbench, light alcohol lamp, get 10 µm of diluted nutrient solution with pipette gun and add to solid medium surface, and coat evenly. Use sterile tweezers to take the soaked round filter paper and spread it on the surface of the culture medium. 4 slices were placed on each plate, and 3 parallel experiments were performed, one of which was used as a blank control. The flat plate with the tablet is placed in a 37°C incubator and cultivated for 24h to observe the phenomenon. The antibacterial activity of each sample can be seen by measuring the diameter of the antibacterial zone through the appearance of different sizes of transparent rings-inhibition zone on the agar medium.

^ ~ ~ "growth inhibition rate (%) | inhibition -: 1N > numbering structural formula ..... Bacillus anthracicus ___ grape bran_ Mongolian DO 3 one. one -... ................................................. 187 〇

Embodiment 13

Under 10 ℃ of conditions, add water 40g and propylene glycol 20g in stirring container, then add glycerol 5g and Peppermint Oil 2g, start stirring, add compound and then add monoglyceride 4g successively; :: ^: 5g, IPP 12g, white petrolatum 4g, propyl-Nepalate 0.5g, methyl-Nepalate 1.5g, MAP emulsifier 3g and essence 3g, keep stirring at a temperature of 10°C for 2h to obtain a medicinal ointment.

Embodiment 14

Use the medicine ointment prepared by embodiment 13, carry out nursing treatment to the skin ulcer that 30 routine diabetics cause because of pressure sore. Skin ulcers are mostly located on the front of the shin, the lower part of the calf, the dorsum of the foot and the toes. The largest ulcer area is 4.0cm X 5 • 0cm, the smallest is 1. Ocm X 1 • 5cm, and the depth is 0 • 2-1 • 0cm. There are different degrees of purulent or purulent secretions and a small amount of necrotic tissue at the base of some ulcers.

First carry out conventional iodophor disinfection, such as wound infection, first clean its concentrated secretion with 3wt% hydrogen peroxide and then debride the wound according to the program, the wound with too many necrotic tissues should adopt a small amount of multiple debridement methods. The Chinese medicine nurses in the treatment group applied the ointment to the wound, covered it with sterile gauze, fixed it, and changed the dressing every two days, and changed the dressing once a day for those with severe infections until healed. The blank control group used vaseline oil gauze, soaked with 1wt% gentamicin, covered the wound, and changed the dressing once a day.

Therapeutic effect is seen by ulcer surface healing speed, and the 7th day average healing speed of treatment group is (0.42 ± 0.15) cm / day, obviously faster than blank control group (0 • 33 ± 0 • 15) cm / day .

Above-mentioned embodiment has described fundamental of the present invention, main feature and advantage, and those skilled in the art should understand that the present invention is not limited by above-mentioned embodiment, what described in above-mentioned embodiment and specification sheet just illustrates the present invention Principle, without departing from the scope of the principle of the present invention, the present invention also has various changes and improvements, and these changes and improvements all fall within the protection scope of the present invention.

Claims (7)

1. a 1,4-thiazepine drug compound for skin ulcer care, is characterized in that the structural formula of this 1,4-thiazepine drug compound is: D55—S N ^ 0:B: 2. a kind of preparation method of the 1,4-thiazepine drug compound that is used for skin ulcer nursing according to claim 1, is characterized in that concrete steps are: (1) under nitrogen protection, compound i is added In N,N-dimethylformamide, add N-chlorosuccinimide in batches after the reaction temperature is cooled to 10°C, return to room temperature reaction after adding, add ethyl acetate after monitoring the raw material reaction completely, Then wash the reaction solution with saturated sodium chloride solution until the organic phase does not contain n,N-dimethylformamide, dry the organic phase over anhydrous magnesium sulfate, concentrate, add n-hexane, cool, stir and beat, and dry after suction filtration to obtain Compound B "; (2) Add 2-chloroethylamine and a basic compound into tetrahydrofuran, wherein the basic compound W is sodium hydride or potassium hydride, replace the reaction system gas with nitrogen, and then heat and reflux the reaction, and the raw material reacts After complete cooling to room temperature, add dichloroethane, filter the reaction solution after stirring, add water and hydrochloric acid solution after the filtrate is concentrated under reduced pressure, extract the reaction solution with a mixed solution of ethyl acetate and n-hexane to remove impurities, and wash the water phase with saturated hydrogen The sodium oxide solution adjusted the pH to 11, then extracted with chloroform, dried with anhydrous sodium sulfate, and concentrated to obtain compound Bf; (3) Add the compound and sodium bicarbonate to water and methylene chloride, stir evenly, and lower the temperature of Br to 0° C, add dropwise the dichloromethane solution dissolved with benzyl chloroformate, react at room temperature until the raw materials are completely reacted after the dropwise addition, separate the organic phase, extract the aqueous phase with dichloromethane, and then wash the organic phase with anhydrous sodium sulfate Obtain compound fr after drying and concentrating; (#^! Toluenesulfonic acid, heated to 70 ° C, then added paraformaldehyde, after the addition, reacted under 70°C until the raw materials were completely reacted, cooled to room temperature, filtered the reaction solution, and the filtrate was washed with saturated sodium bicarbonate solution, separated The organic phase was taken out, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated and purified by column chromatography to obtain compound I :: fine: 1: (5) under nitrogen protection, the compound and DMSO were added to the reaction flask, and then Add biboronic acid pinacol ester and potassium acetate, add catalyst Pd(dppf)Cl2 or Pd (OAc) after passing through nitrogen replacement reaction system gas three times, then pass through hydrogen replacement reaction system gas three times and heat to iqq° c to carry out the reaction, monitor the complete reaction of the raw materials, cool the reaction system to room temperature, add ethyl acetate, wash with saturated sodium chloride solution for several times, then dry the organic phase with anhydrous magnesium sulfate, concentrate and separate by column chromatography Purify to obtain compound s u \ HOT (6) Under the protection of nitrogen, the compound is added to 1,4-dioxane and deionized water ..., in the mixed solution, then add 2-chloro-4-formic acid methyl pyridine and Potassium Phosphate, add catalyst Pd (dppf) C12 after feeding nitrogen replacement reaction system gas three times, feed nitrogen again Replace the gas in the reaction system three times and then heat to 900°C for reaction until the raw materials are completely reacted. After the reaction temperature is cooled to room temperature, ethyl acetate is added to extract the reaction solution. After merging the organic phases, wash with saturated sodium chloride solution, and then use Concentrate after drying over sodium sulfate, then separate and purify through column chromatography to obtain compound O1 (7) Under the protection of hot air, compound S^O is added in the mixed solvent, wherein the mixed O bath agent is made up of a volume of 2: 2: 1 mixed solution of tetrahydrofuran, methanol and deionized water, then add lithium hydroxide, heat up to 50°C to react until the raw material reaction is complete, the reaction solution is cooled to room temperature, vacuum concentration after filtering the reaction solution, and then add Dichloroethane, cooled and stirred for beating, and dried by suction to obtain the compound: s: (8) Under the protection of nitrogen, the compound was added to anhydrous tetrahydrofuran, and then % (R)-2-(diethylamino)propyl -1-amine, HATU and DIEA, heated to reflux reaction, reacted until the raw materials reacted completely, then added ethyl acetate, washed the reaction solution with saturated sodium chloride solution several times, separated the organic phase and dried it with anhydrous sodium sulfate, After concentration, separation and purification by column chromatography to obtain the target compounds are H ^ -N ^ UN , 3. the preparation method of the 1,4-thiazepines drug compound that is used for skin ulcer care according to claim 2, is characterized in that: the molar ratio of compound described in step (2) and basic compound It is 3:4. Br 4. the preparation method of the 1 for skin ulcer care according to claim 2, the 4-thiazepines drug compound, it is characterized in that: the compound ^ described in step (4) and the sulfonic acid compound feed intake ratio Br The ratio is 5:1. 5. the preparation method of the 1,4-thiazepine drug compound that is used for skin ulcer care according to claim 2 <3:bz, method, it is characterized in that: the compound described in step (5) and catalyst feed intake Quantity mass ratio is 50: Br 1〇 6. A 1,4-thiazepine pharmaceutical composition for skin ulcer care, characterized in that the 1,4-thiazepine pharmaceutical composition for skin ulcer care is composed of a mass ratio of 5:4:12:4:0_5:20:1.5:5:3:3:2:40 Compound S according to claim 1: monoglyceride, IPP, white petrolatum, Nepal O, gold propyl ester, propylene glycol , Nepal gold methyl ester, glycerol, MAP emulsifier, essence, peppermint oil and water to prepare the medicinal ointment. 7. the 1,4-thiazepine pharmaceutical composition for skin ulcer care according to claim 6, is characterized in that: described skin ulcer is caused by bacillus anthracis or/and staphylococcus aureus.