CN105399684A - Pleuromutilin compound, preparation method of pleuromutilin compound, polymorphism and preparation method of polymorphism - Google Patents

Abstract

The invention discloses a preparation method of a pleuromutilin compound, a polymorphism and a preparation method of the polymorphism. The pleuromutilin compound comprises a 14-O-[(4-amino-6-hydroxy-pyrimidine-2-yl) thio acetyl] matrix shown in a structural formula (i) and/or a 14-O-[(4-amino-6-one-pyrimidine-2-yl) thio acetyl] matrix shown in a structural formula (ii). The novel pleuromutilin compound disclosed by the invention has obvious inhibiting effects on multiple drug resistant bacteria such as methicillin resistant staphylococcus aureus and staphylococcus epidermidis as well as common pathogenic bacteria such as escherichia coli and streptococcus mastitidis in veterinary clinics, so that the pleuromutilin compound can be applied to preparation of antibacterial drugs and particularly anti-drug resistant bacterium drugs.

Description

A kind of pleuromutilin compound, preparation method, polymorphic form and preparation method of polymorphic form

technical field

The invention relates to a pleuromutilin compound, a preparation method, a polymorph and a preparation method of the polymorph, and belongs to the field of drug synthesis.

Background technique

The discovery of antibiotics has played an important role in human history. However, the overuse of antibiotics has led to serious drug resistance in many bacteria. Drug-resistant bacteria, especially Staphylococcus pneumoniae, Streptococcus pneumoniae, Mycobacterium tuberculosis, etc., cause more than two million deaths every year, seriously threatening human health. Therefore, it is particularly important to develop new anti-drug-resistant fungal drugs.

Pleuromutilin (see formula i for chemical structure) is a diterpene compound with antibacterial activity isolated from the higher fungi Pleurotusmultilus (Fr.) Sacc. and Pleurotus Passecke-rianusPilat for the first time in the 1950s. The compound consists of a 5-6-8 three-membered ring skeleton containing 8 chiral centers and a side chain of glycolate. Studies have shown that pleuromutilin and its derivatives inhibit bacterial protein synthesis at the ribosome level. This type of compound acts on the 23S RNA of the 50S subunit of the bacterial ribosome, and the binding site is at the peptidyl transferase (PTC) V domain. Its ternary mother nucleus is combined in the active pocket of the A site, and the side chain partially covers the P site where the tRNA binds to the ribosome, and achieves the purpose of antibacterial by inhibiting the synthesis of bacterial proteins. Because of this special mechanism of action, pleuromutilin and its derivatives have good activity against positive drug-resistant bacteria in vivo and in vitro, as well as good pharmacokinetic properties and low drug resistance .

Formula i is the molecular structural formula of pleuromutilin.

The side chain of the ester group structure of pleuromutilin C14 is the main site for chemical modification. The research on the structure modification of the side chain of pleuromutilin C14 at home and abroad is generally carried out at the C22 position under the premise of retaining the ester group structure. Transformation, which can greatly improve its antibacterial activity and bioavailability. The structure-activity relationship shows that when the C-14 side chain is connected to a thioether side chain with a basic center, the activity of the derivative will be decisively improved. Recent studies have shown that in addition to the thioether group, the heterocycle in the side chain can also greatly improve the antibacterial activity of this type of compound.

Pleuromutilin and its derivatives mainly inhibit protein synthesis by inhibiting the activity of peptidyl transferase, so as to achieve antibacterial effect. Since this type of compound has different targets from the commonly used antibacterial drugs currently on the market, there will be no cross-resistance between this type of drug and other drugs, especially for drug-resistant Staphylococcus aureus, Streptococcus pneumoniae and Mycobacterium tuberculosis, etc. have a good inhibitory effect.

Contents of the invention

The technical problem to be solved by the present invention is to overcome existing defects and provide a pleuromutilin compound, a preparation method, a polymorph and a preparation method of the polymorph.

In order to solve the problems of the technologies described above, the present invention provides the following technical solutions:

An object of the present invention is to provide a pleuromutilin compound, including 14-O-[(4-amino-6-hydroxyl-pyrimidin-2-yl)thioacetyl]mer shown in structural formula (i) Lin, and/or its another conformation is 14-O-[(4-amino-6-keto-pyrimidin-2-yl) mercaptoyl] macroline shown in structural formula (ii)

Formula (i) Formula (ii).

Antibacterial activity studies in vitro show that the compound has significant inhibition of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Epidermidis (MRSE), cereus Bacillus cereus ( B. cereus ), Escherichia coli (E.coli), mycoplasma, and Streptococcus pneumoniae isolated from clinical practice, etc. It can effectively protect mice infected with MRSA in vivo, with an ED ₅₀ of 2.35mg/kg, And the ED ₅₀ of tiamulin under this model is 5.95mg/kg.In addition, the acute toxicity of this compound is low, and LD ₅₀ reaches 3320.3mg/kg.The above studies show that this compound is very likely to be developed into a new Drugs against resistant bacteria.

Another object of the present invention is to provide the preparation method of the described pleuromutilin compound, the C-22 hydroxyl of pleuromutilin is activated by p-toluenesulfonyl chloride to generate sulfonated pleuromutilin without separation and direct The pleuromutilin compound is prepared by nucleophilic reaction with the sodium salt of 4-amino-6-hydroxyl-2-mercaptopyrimidine under alkaline conditions, and the specific reaction scheme is as follows:

In the above-mentioned scheme, it is preferred that the reaction temperature of the p-toluenesulfonyl chloride activation reaction is 50-65 ^o C, and the reaction time is 0.5-1.5h.

In any of the above schemes, preferably, the reaction temperature of the nucleophilic reaction is 50-65 ^o C, and the reaction time is 5-6h.

In any of the above schemes, it is preferred that the preparation method of the sodium salt of 4-amino-6-hydroxyl-2-mercaptopyrimidine is to dissolve NaOH in methanol and add 4-amino-6-hydroxyl-2-mercaptopyrimidine dropwise , stirring to obtain, the stirring time is preferably 30min. The sodium salt of 4-amino-6-hydroxyl-2-mercaptopyrimidine prepared by this method can make the yield of the product higher.

The process for preparing the compound of the present invention has the following advantages: 1) The synthesis process is simple: the one-pot method is adopted, and the original two-step reaction is carried out in one reactor, and the reaction solvent does not need to be replaced in the middle. Only need to add the reaction raw material and another solvent; 2) The post-treatment method is simple: after the reaction, just evaporate the reaction solvent to dryness, add a certain amount of water and organic solvent to wash away the impurities, filter through the Buchner funnel, dry and pulverize ;3) Mild reaction conditions: the nucleophilic reaction temperature is 50-65 ^o C, the reaction time is 5-6h, no high pressure and anaerobic conditions are required; 4) High reaction yield: the reaction yield is more than 90%, and the obtained 14 The content of -O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]mpirin reached above 98%.

Another object of the present invention is to provide various crystal forms of the pleuromutilin compound, and methods for preparing each crystal form.

The first crystal form of the pleuromutilin compound provided by the present invention, the crystal form is named I crystal form, and the I crystal form uses the Cu-Kα X-ray diffraction method, and the 2θ angle expressed in degrees There are obvious characteristic absorption peaks at about 8.3526, 9.7560, 13.1360, 13.4535, 19.5221, and 25.1412.

In any of the above schemes, preferably, the X-ray diffraction pattern of the I crystal form is shown in FIG. 1 .

The preparation method of the I crystal form of the pleuromutilin compound provided by the present invention: take 1 g of the above-mentioned pleuromutilin compound (14-O-[(4-amino-6-hydroxyl-pyrimidin-2-yl ) Mercaptoyl] Mutilin and its other conformation), add 20-30ml ethyl acetate, filter, add the same volume of saturated sodium bicarbonate to the filtrate, stir and mix, after standing for 2-3h, the two-phase White needle-like crystals appear between them, and they can be obtained by filtering.

The second crystal form of the pleuromutilin compound provided by the present invention is named as the II crystal form, and the II crystal form uses the Cu-Kα X-ray diffraction method, and the 2θ angle expressed in degrees There are obvious characteristic absorption peaks at about 4.9419, 8.7925, 10.1075, 13.2779, 14.3767, 15.8227, 16.5973, 17.5199, 20.2718, 21.8264, 26.5106.

In any of the above schemes, preferably, the X-ray diffraction pattern of the II crystal form is shown in FIG. 2 .

The preparation method of the II crystal form of the pleuromutilin compound provided by the present invention: take 1 g of the above-mentioned pleuromutilin compound (14-O-[(4-amino-6-hydroxyl-pyrimidin-2-yl ) mercaptoacetyl] Mutilin and its other conformation), added to 20-30ml of dichloromethane, filtered, the solvent evaporated naturally, and the white powder of crystal type II was obtained.

The third crystal form of the pleuromutilin compound provided by the present invention is named as the III crystal form, and the III crystal form uses the Cu-Kα X-ray diffraction method, and the 2θ angle expressed in degrees There are obvious characteristic absorption peaks at about 6.6028, 8.3183, 10.0373, 12.1114, 13.0598, 13.2175, 13.5046, 16.5052, and 21.8365.

In any of the above schemes, preferably, the X-ray diffraction pattern of the III crystal form is shown in FIG. 3 .

The preparation method of the III crystal form of the pleuromutilin compound provided by the present invention: take 1 g of the above-mentioned pleuromutilin compound (14-O-[(4-amino-6-hydroxyl-pyrimidin-2-yl ) Thioacetyl] Mutilin and its other conformation), add 20-30ml of ethyl acetate, filter, and volatilize naturally to obtain the white powder of crystal form III.

The amorphous state of the pleuromutilin compound provided by the present invention, the X-ray diffraction pattern of the amorphous state is shown in FIG. 4 .

The preparation method of the amorphous state of the pleuromutilin compound provided by the present invention: take 1g of the above-mentioned pleuromutilin compound (14-O-[(4-amino-6-hydroxyl-pyrimidine-2- Base) thioacetyl] Mutilin and another conformation), add 10-25ml ethanol, filter, and volatilize naturally to obtain an amorphous white powder.

The pleuromutilin compound of the present invention has inhibitory effect on methicillin-resistant Staphylococcus aureus and Epidermidis, Escherichia coli and Streptococcus agalactiae.

The pleuromutilin compound of the present invention is used in the preparation of antibacterial drugs, especially anti-drug-resistant bacteria drugs.

Beneficial effects of the present invention: the novel pleuromutilin compound of the present invention is effective against a variety of drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus and Epidermidis, as well as common pathogenic bacteria in veterinary clinics such as Escherichia coli and agalactia Streptococcus and the like have significant inhibitory effect, therefore, the pleuromutilin compound of the present invention can be used in the preparation of antibacterial drugs, especially anti-drug-resistant bacteria drugs.

The advantages of the present invention are:

1. The synthesis process is simple: the original two-step reaction is carried out in one reactor by adopting a one-pot method, and there is no need to replace the reaction solvent in the middle. Only the reaction starting materials and another solvent need be added.

2. The post-treatment method is simple: after the reaction, just evaporate the reaction solvent to dryness, add a certain amount of water and an organic solvent to wash away impurities, filter through a Buchner funnel, dry, and pulverize.

3. Mild reaction conditions: the nucleophilic reaction temperature is 50-60 ^o C, the reaction time is 5-6 hours, no high pressure and oxygen-free conditions are required.

4. High reaction yield: the reaction yield is more than 90%, and the obtained APTM content is more than 98%.

Description of drawings

Fig. 1 is the X-ray powder diffraction spectrogram of the embodiment of the present invention 6;

Fig. 2 is the X-ray powder diffraction spectrogram of embodiment 9 of the present invention;

Fig. 3 is the X-ray powder diffraction spectrogram of embodiment 12 of the present invention;

Fig. 4 is an X-ray powder diffraction spectrum diagram of Example 14 of the present invention.

detailed description

Preferred embodiments of the present invention are described below, and it should be understood that the preferred embodiments described here are only used to illustrate and explain the present invention, and are not intended to limit the present invention.

Embodiment 1: A kind of pleuromutilin compound

A pleuromutilin compound, which is 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] Mutilin formula (i), and 14-O-[(4 -Amino-6-keto-pyrimidin-2-yl)thioacetyl]Multiline (formula ii), wherein 14-O-[(4-amino-6-keto-pyrimidin-2-yl)thioacetyl] Mutilin (formula ii) is another conformation of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl] Mutilin formula (i).

Example 2:

The preparation method of pleuromutilin compounds described in Example 1: 4.45 g of pleuromutilin (0.01 mol) with a purity of 85%, 2.10 g of p-toluenesulfonyl chloride (0.01 mol) and 40 mL of methyl iso Butanone (methylisobutylketone, MIBK) was added into a 100mL three-necked flask, heated and stirred to dissolve pleuromutilin and p-toluenesulfonyl chloride. When the temperature rose to 60°C, 2.2mL of 10N NaOH aqueous solution was added dropwise, and the reaction 30min; then the pH value of the reaction solution was adjusted to 8-9 with 5N hydrochloric acid, and 1.65g of 4-amino-6-hydroxy-2-mercaptopyrimidine sodium salt (0.01mol) (4-amino-6-hydroxy-2-mercapto The preparation method of the sodium salt of pyrimidine is to dissolve NaOH in methanol, add dropwise 4-amino-6-hydroxy-2-mercaptopyrimidine, and stir for 30 minutes to obtain), continue the reaction at 60°C for 5 hours, and evaporate to dryness under reduced pressure Add 20mL of water and 20mL of tert-butyl methyl ether to MIBK, stir to suspend the crude product, then use a Buchner funnel to suction filter, and wash the filter cake three times with 10mL of water and tert-butyl methyl ether respectively. After drying and weighing, 4.58 g of the target compound was obtained, with a yield of 91%.

The structural identification data of the reaction product: IR (KBr) 3368, 2930, 1729, 1629, 1575, 1542, 1457, 1286, 1117, 1019, 981, 809 cm-1; 1HNMR (400MHz, CDCl3) δ6.47 (dd, J= 17.4,11.1Hz,1H),5.74(d,J=8.3Hz,1H),5.32(d,J=11.0Hz,1H),5.24-5.13(m,2H),4.79(s,2H),4.11( q,J=7.1Hz,1H),3.85(d,J=16.5Hz,1H),3.69(d,J=16.5Hz,1H),3.35(d,J=6.2Hz,1H),2.24(ddd, J=27.4,15.6,8.1Hz,3H),2.12-1.93(m,3H),1.75(d,J=14.1Hz,1H),1.63(dd,J=21.3,11.1Hz,2H),1.54-1.30 (m,6H),1.26(dd,J=14.5,7.2Hz,3H),1.13(s,4H),0.86(d,J=6.8Hz,3H),0.71(d,J=6.9Hz,3H) ;13CNMR(100MHz,CDCl3)δ216.93,166.90,165.97,162.65,160.33,139.23,117.16,84.04,74.59,70.10,60.39,58.10,45.43,43.94,41.85,36.69,36.00,33.25,30.39,26.88,26.34,24.81 ,21.03,16.79,14.89,11.45;LRMS(ES)calcd[M+H]+forC26H37N3O5S504.2526,found504.2520.

Example 3:

The preparation method of pleuromutilin compounds described in Implementation 1: 4.45 g of pleuromutilin (0.01 mol) with a purity of 85%, 2.10 g of p-toluenesulfonyl chloride (0.01 mol) and 40 mL of methyl isobutyl Add ketone (methylisobutylketone, MIBK) into a 100mL three-necked flask, heat up, and stir to dissolve pleuromutilin and p-toluenesulfonyl chloride. When the temperature rises to 50°C, add 2.2mL of 10N NaOH aqueous solution dropwise, and react for 60min ; Then the reaction solution was adjusted to pH 8-9 with 5N hydrochloric acid, and 1.65 g of 4-amino-6-hydroxyl-2-mercaptopyrimidine sodium salt (0.01mol) was added (4-amino-6-hydroxyl-2-mercaptopyrimidine The preparation method of the sodium salt is to dissolve NaOH in methanol, dropwise add 4-amino-6-hydroxy-2-mercaptopyrimidine, and stir for 30 minutes to obtain), continue to react at 50°C for 6 hours, and evaporate MIBK to dryness under reduced pressure , add 20mL of water and 20mL of tert-butyl methyl ether, stir to suspend the crude product, then use a Buchner funnel to suction filter, and the filter cake is washed three times with 10 mL of water and tert-butyl methyl ether respectively. After drying and weighing, 4.56 g of the target compound was obtained, with a yield of 90.6%.

Example 4:

The preparation method of pleuromutilin compounds described in Implementation 1: 4.45 g of pleuromutilin (0.01 mol) with a purity of 85%, 2.10 g of p-toluenesulfonyl chloride (0.01 mol) and 40 mL of methyl isobutyl Add ketone (methylisobutylketone, MIBK) into a 100mL three-necked flask, heat up, and stir to dissolve pleuromutilin and p-toluenesulfonyl chloride. When the temperature rises to 65°C, add 2.2mL of 10N NaOH aqueous solution dropwise, and react for 90min ; Then the reaction solution was adjusted to pH 8-9 with 5N hydrochloric acid, and 1.65 g of 4-amino-6-hydroxyl-2-mercaptopyrimidine sodium salt (0.01mol) was added (4-amino-6-hydroxyl-2-mercaptopyrimidine The preparation method of the sodium salt is to dissolve NaOH in methanol, dropwise add 4-amino-6-hydroxy-2-mercaptopyrimidine, and stir for 30 minutes to obtain), continue to react at 60°C for 5 hours, and evaporate MIBK to dryness under reduced pressure , add 20mL of water and 20mL of tert-butyl methyl ether, stir to suspend the crude product, then use a Buchner funnel to suction filter, and the filter cake is washed three times with 10 mL of water and tert-butyl methyl ether respectively. After drying and weighing, 4.56 g of the target compound was obtained, with a yield of 90.6%.

Example 5: Crystal Form I of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]Multiline

The crystal form I uses Cu-Kα X-ray diffraction method, and the 2θ angle expressed in degrees has obvious characteristic absorption peaks at about 8.3526, 9.7560, 13.1360, 13.4535, 19.5221, and 25.1412.

Example 6: Preparation of crystal form I of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] monoclonal

Take 1g of the compound of Example 1 (14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] Mutilin and its other conformation), add in 20ml ethyl acetate, filter , add 20mL of saturated sodium bicarbonate to the filtrate, stir and mix evenly, after standing for 2h, white needle-like crystals appear between the two phases, and obtain it by filtration. The X-ray diffraction pattern of the crystal form I is shown in Figure 1.

The data of X-ray powder diffraction method using Cu-Kα for the crystal form I of the pleuromutilin compounds are shown in Table 1.

Table 1: X-ray Diffraction Data of Form I

Example 7: Preparation of crystal form I of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]murolin I

Take 1g of the compound of Example 1 (14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] Mutilin and another conformation thereof), add in 30ml ethyl acetate, filter , add 30mL of saturated sodium bicarbonate to the filtrate, stir and mix well, after standing for 3 hours, white needle-like crystals appear between the two phases, and obtain it by filtration.

Example 8: 14-O-[(4-Amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]Murtilin II crystal form

The crystal form II uses the X-ray diffraction method of Cu-Kα, and the 2θ angles expressed in degrees are clearly characterized at about 4.9419, 8.7925, 10.1075, 13.2779, 14.3767, 15.8227, 16.5973, 17.5199, 20.2718, 21.8264, 26.5106 absorption peak.

Example 9: Preparation of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] monoclonal II crystal form

Take 1g of the compound of Example 1 (14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] Mutilin and its other conformation), add it to 20ml of dichloromethane, filter , the solvent volatilized naturally, and the white powder of crystalline form II was obtained, and the X-ray diffraction pattern of the crystalline form II is shown in FIG. 2 .

The data of the X-ray powder diffraction method using Cu-Kα for the crystal form II of the pleuromutilin compound is shown in Table 2.

Table 2: X-ray Diffraction Data of Form II

Example 10: Preparation of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]Murtilin II Crystal Form

Take 1g of the compound of Example 1 (14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] Mutilin and another conformation thereof), add in 30ml of dichloromethane, filter , the solvent is naturally volatilized, and the white powder of crystal type II is obtained.

Example 11: Crystal Form III of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]Murtilin

The crystal form III uses the Cu-Kα X-ray diffraction method, and the 2θ angle expressed in degrees has obvious characteristic absorption peaks at about 6.6028, 8.3183, 10.0373, 12.1114, 13.0598, 13.2175, 13.5046, 16.5052, and 21.8365.

Example 12: Preparation of crystal form III of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)mercaptoacetyl]myrobolin III

Take 1g of the compound of Example 1 (14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] Mutilin and its other conformation), add in 20ml ethyl acetate, filter , naturally volatilized, that is, the white powder of the III crystal form is obtained, and the X-ray diffraction pattern of the III crystal form is shown in FIG. 3 .

The data of the X-ray powder diffraction method using Cu-Kα for the crystal form III of the pleuromutilin compound is shown in Table 3.

Table 3: X-ray Diffraction Data of Form III

Example 13: Preparation of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]Murtilin III crystal form

Take 1g of the compound of Example 1 (14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] Mutilin and another conformation thereof), add in 30ml ethyl acetate, filter , natural volatilization, namely to obtain the white powder of crystal type III, that is.

Example 14: 14-O-[(4-Amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]Multiline Amorphous Powder

The X-ray diffraction pattern of the amorphous state is shown in FIG. 4 .

Example 15: Preparation of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] macromeridin crystal amorphous powder

Get 1g of the compound of Example 1 (14-O-[(4-amino-6-hydroxyl-pyrimidin-2-yl) mercaptoacetyl] Mutilin and another conformation thereof), add in 10ml ethanol, filter, and naturally Volatilize to obtain an amorphous white powder, the X-ray diffraction pattern of the amorphous powder is shown in Figure 4.

Example 16: Preparation of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)mercaptoacetyl]macrolimus crystal amorphous powder

Get 1g of the compound of Example 1 (14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) mercaptoacetyl] Mutilin and another conformation thereof), add in 25ml ethanol, filter, and naturally Volatilize to obtain an amorphous white powder.

The compound of Example 1 used in Examples 5-16 can be prepared by the method of Example 2.

Finally, it should be noted that: the above is only a preferred embodiment of the present invention, and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, for those skilled in the art, it still The technical solutions recorded in the foregoing embodiments may be modified, or some technical features thereof may be equivalently replaced. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (18)

1. A pleuromutilin compound, comprising 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]murtilin represented by structural formula (i), and/or Its other conformation is 14-O-[(4-amino-6-keto-pyrimidin-2-yl)thioacetyl]murtilin shown in structural formula (ii) Formula (i) Formula (ii). 2. The preparation method of the pleuromutilin compound according to claim 1, characterized in that: the C-22 hydroxyl of pleuromutilin is activated by p-toluenesulfonyl chloride to generate sulfonated pleuromutilin without separation Directly react with the sodium salt of 4-amino-6-hydroxyl-2-mercaptopyrimidine under alkaline conditions to prepare the pleuromutilin compounds through nucleophilic reaction, the specific reaction scheme is as follows: 3. The preparation method of pleuromutilin compounds according to claim 2, characterized in that: the reaction temperature of the p-toluenesulfonyl chloride activation reaction is 50-65 ^o C, and the reaction time is 0.5-1.5h. 4. The preparation method of pleuromutilin compounds according to claim 2 or 3, characterized in that: the reaction temperature of the nucleophilic reaction is 50-65 ^o C, and the reaction time is 5-6h. 5. The crystal form I of pleuromutilin compounds according to claim 1, characterized in that: the crystal form I uses the Cu-Kα X-ray diffraction method, and the 2θ angle expressed in degrees is between about 8.3526 and 9.7560 , 13.1360, 13.4535, 19.5221, 25.1412 have obvious characteristic absorption peaks. 6 . The crystal form I of pleuromutilin compounds according to claim 5 , wherein the X-ray diffraction pattern of the crystal form I is shown in FIG. 1 . 7. The I crystal form of the pleuromutilin compound according to claim 5 or 6, characterized in that: the preparation method of the I crystal form: take 1 g of the pleuromutilin compound according to claim 1, add 20-30ml of ethyl acetate, filter, add the same volume of saturated sodium bicarbonate to the filtrate, stir and mix well, after standing for 2-3h, white needle-like crystals appear between the two phases, filter to obtain. 8. The II crystal form of pleuromutilin compounds according to claim 1, characterized in that: the II crystal form uses the Cu-Kα X-ray diffraction method, and the 2θ angle expressed in degrees is between about 4.9419 and 8.7925 , 10.1075, 13.2779, 14.3767, 15.8227, 16.5973, 17.5199, 20.2718, 21.8264, 26.5106 have obvious characteristic absorption peaks. 9 . The II crystal form of pleuromutilin compounds according to claim 8 , wherein the X-ray diffraction pattern of the II crystal form is shown in FIG. 2 . 10. The II crystal form of the pleuromutilin compound according to claim 8 or 9, characterized in that: the preparation method of the II crystal form: take 1 g of the pleuromutilin compound according to claim 1, add 20-30ml of dichloromethane, filtered, the solvent evaporates naturally, and the white powder of the crystalline form II is obtained. 11. The III crystal form of pleuromutilin compound according to claim 1, characterized in that: the III crystal form uses the Cu-Kα X-ray diffraction method, and the 2θ angle expressed in degrees is between about 6.6028 and 8.3183 , 10.0373, 12.1114, 13.0598, 13.2175, 13.5046, 16.5052, 21.8365 have obvious characteristic absorption peaks. 12 . The III crystal form of pleuromutilin compounds according to claim 11 , wherein the X-ray diffraction pattern of the III crystal form is shown in FIG. 3 . 13. The III crystal form of the pleuromutilin compound according to claim 11 or 12, characterized in that: the preparation method of the III crystal form: take 1 g of the pleuromutilin compound according to claim 1, add In 20-30ml of ethyl acetate, filter and volatilize naturally to obtain the white powder of crystal form III. 14. The amorphous state of the pleuromutilin compound according to claim 1, characterized in that: the X-ray diffraction pattern of the amorphous state is shown in Figure 4. 15. The amorphous state of the pleuromutilin compound according to claim 14, characterized in that: the preparation method of the amorphous state: take 1g of the pleuromutilin compound according to claim 1, add 10-25ml of ethanol, filter and volatilize naturally to obtain an amorphous white powder. 16. The pleuromutilin compound according to claim 1 has inhibitory effect on methicillin-resistant Staphylococcus aureus and Epidermidis, Escherichia coli and Streptococcus agalactiae. 17. The application of the pleuromutilin compound according to claim 1 in the preparation of antibacterial drugs. 18. The application of the pleuromutilin compound according to claim 1 in the preparation of anti-drug-resistant bacteria drugs.