CN116082195B - Pleuromutilin urea compounds, and preparation method and application thereof - Google Patents

Pleuromutilin urea compounds, and preparation method and application thereof Download PDF

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CN116082195B
CN116082195B CN202111316531.8A CN202111316531A CN116082195B CN 116082195 B CN116082195 B CN 116082195B CN 202111316531 A CN202111316531 A CN 202111316531A CN 116082195 B CN116082195 B CN 116082195B
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吴松
李天磊
吴光旭
朱子豪
罗新宇
李吉顺
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Abstract

The invention belongs to the field of pharmacy, and relates to a pleuromutilin urea compound shown in a general formula (I), a preparation method and application thereof, and a composition containing the compound shown in the general formula (I) as an active ingredient.

Description

Pleuromutilin urea compounds, and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmacy, and in particular relates to a pleuromutilin compound with thiourea or urea side chains, and a preparation method and application thereof.
Background
Pleuromutilin (pleuromutilin) is a tricyclic diterpenoid antibiotic obtained by separating strains of Pleurotus pleurotus mutilis and pleurotus passeckeranius of higher fungus Basidiomycetes, and the main skeleton is formed by splicing five-membered rings, six-membered rings and eight-membered rings, and has a tricyclic rigid structure. The pleuromutilin and the derivatives thereof have better inhibition activity on gram-positive bacteria and mycoplasma pathogens, and have better application prospects in veterinary and human antibiotics. Pleuromutilins antibiotics inhibit the activity of peptide-based transferases by selectively binding to the ribosomes of prokaryotic microorganisms, thereby preventing the protein synthesis of prokaryotic cells from producing an antibacterial effect. Due to the specific combination of the pleuromutilin and the bacterial ribosome, the pleuromutilin has higher antibacterial activity and higher selectivity, and is not easy to generate drug resistance compared with other antibiotics. At present, cross drug resistance of pleuromutilins to mupirocin, beta-lactams, macrolide antibiotics or quinolones and other drugs is not found.
Pleuromutilin-type antibiotics have been marketed for nearly 60 years, and the veterinary pleuromutilin-type antibiotics on the market are tiamulin (approved in 1979) and valnemulin (endorsed in European Union 1999), mainly used for preventing and treating swine dysentery, and have a broad antibacterial spectrum; ritamalin (retapamulin) is a 1% topical ointment (sold under the trade name Altabax) developed by the company glazin smith, and is mainly used for treating skin infection diseases such as cytosepsis. In 2007, marketed by the U.S. FDA approved, the same year as european drug administration (EMA) for short-term treatment of secondary epidermoid infections, ritamiline was the first new topical prescription antibiotic; lefamulin (BC-3781) is a semisynthetic antibiotic developed by Austria Nabriva Therapentics for the treatment of community-acquired pneumonia (CABP), and is marketed in FDA approval in 2019, and the new drug is an FDA approved antibiotic with innovative action mechanism in the last 20 years, thus providing a new treatment choice for treating CABP.
The urea/thiourea structure has wider application in pharmaceutical chemistry, such as construction of a diversity small molecule compound library in combinatorial chemistry based on special chemical reactivity of urea or thiourea and high-efficiency linking characteristics thereof. Among the existing marketed drugs, such as anti-infective drugs (SPR 719 and SPR720 of clinical studies, boceprevir, a marketed drug for treating hepatitis C) all contain structural fragments of urea. In addition, in the antibody-drug conjugate, the urea connection mode has been widely applied, and in vivo experiments prove that the structural fragment has better compatibility. Wang Yuliang et al in 2013 applied the urea structure modified valnemulin analogue to anti-infection study for the first time, and the structural characteristics are as follows: the thioether backbone fragment of valnemulin was linked to a different phenylurea fragment (Letters in Drug Design & Discovery,2013,10,219-225). The current research results show that the thioether structure is easy to be oxidized and converted into sulfoxide metabolites in vivo, and the antibacterial activity of the sulfoxide metabolites of valnemulin and derivatives thereof is obviously reduced, and the metabolic problems of the compounds limit the intensive development of the structure in clinic.
The pleuromutilin medicines have few varieties on the market, and meanwhile, the medicines have the advantages of unique antibacterial mechanism, difficult drug resistance, less cross drug resistance and the like, so that the pleuromutilin medicines have deep research value. The invention provides a novel pleuromutilin compound (structure shown as formula I), which is structurally characterized in that: the thiourea or urea is connected with the 22-amino of the pleuromutilin, so that the thioether structure easy to metabolize is avoided, and meanwhile, the antibacterial activity of the compound is obviously improved. Compared with the prior art, the invention has the following advantages: the pleuromutilin compound provided by the invention is a new compound reported for the first time, compared with the pleuromutilin parent nucleus antibacterial activity of the compound, the antibacterial activity of most compounds is obviously improved, and most compounds are superior to that of the marketed drugs, so that the pleuromutilin compound can be used as a novel antibacterial drug for treating bacterial infection of animals or humans.
Disclosure of Invention
In order to solve the defects existing in the prior art, the main purpose of the invention is to provide a pleuromutilin compound with a thiourea or urea side chain structure.
Another object of the present invention is to provide a method for preparing the above pleuromutilin compound having a thiourea or urea side chain structure.
It is a further object of the present invention to provide a pharmaceutical composition comprising a pleuromutilin compound having thiourea or urea side chains as a biologically active ingredient.
It is a further object of the present invention to provide the use of a pleuromutilin compound having thiourea or urea side chains for the manufacture of a medicament for infectious diseases, in particular infectious diseases caused by drug resistant staphylococcus aureus, or multi-drug resistant bacteria.
The aim of the invention is achieved by the following technical scheme:
a pleuromutilin compound having a thiourea or urea side chain, the pleuromutilin compound having a structure as shown in formula (I):
when x=s, R is selected from C 1-18 Alkyl, C 3-8 Cycloalkyl, substituted or unsubstituted phenyl, naphthyl, C 2-6 Alkanoyl, benzoyl, halobenzoyl;
when x=o, R is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, substituted or unsubstituted phenyl, naphthyl;
the substituents are selected from halogen, C 1-6 Alkyl, C of (2) 3-6 Cycloalkyl, C 1-6 Alkoxy, phenyl;
wherein x=s, preferably R is C 3-8 Cycloalkyl, phenyl, o, m, p-substituted halophenyl, o, m, p-substituted methoxy, ethoxy substituted benzene, o, m, p-substituted methyl, trifluoromethyl, ethyl substituted benzene, C 2-6 Alkanoyl.
Wherein x=o, preferably R is C 1-6 Alkyl, C 3-8 Cycloalkyl, phenyl, naphthyl, o-, m-, p-substituted halophenyl, o-, m-, p-substituted methoxy-substituted benzene, o-, m-, p-substituted methyl, trifluoromethyl, ethyl-substituted benzene.
Wherein "halogen" means fluorine, chlorine, bromine, iodine.
More preferably, x=s, R is cyclohexyl, phenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, acetyl, the specific information of which is shown in table-1:
TABLE-1 thiourea representative pleuromutilin compounds
More preferably, x=o, R is ethyl, propyl, cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-methoxyphenyl, 3, 5-dichlorophenyl, 2, 4-difluorophenyl, naphthyl, the specific information being as shown in table-2:
table-2 Urea representative pleuromutilin Compounds
The preparation method of the pleuromutilin compound with the thiourea or urea side chain comprises the following operation steps:
(1) Reacting pleuromutilin with p-toluenesulfonyl chloride to obtain an intermediate with a structure shown as a formula (II):
(2) Using the intermediate (II) as a raw material, and reacting with sodium azide to obtain an intermediate with a structure shown as a formula (III):
(3) The intermediate (III) is used as a raw material, is further activated by reaction with triphenylphosphine, and a certain amount of sodium hydroxide is added to obtain the intermediate with the structure shown in the formula (IV):
(4) The Intermediate (IV) is used as a raw material, and is reacted with an isothiocyanate compound or an isocyanate compound to obtain the pleuromutilin compound with the structure shown in the formula (I) and a thiourea or urea side chain;
the reaction in the step (1) adopts dichloromethane as a solvent, and the reaction is carried out for 12-16 hours at normal temperature, wherein the mol ratio of the p-toluenesulfonyl chloride to the pleuromutilin is 1.1:1;
the reaction in the step (2) adopts N, N-dimethylformamide as a solvent, firstly, an intermediate (II) is dissolved in an aprotic solvent, then sodium azide is added, heating reflux is carried out for 1.5-2h, and the molar ratio of the intermediate (II) to the sodium azide is 1:1.1;
the reaction in the step (3) adopts tetrahydrofuran as a solvent, firstly, an intermediate (III) is dissolved in an aprotic solvent, triphenylphosphine is added, and the reaction is carried out for 8-10 hours at normal temperature, wherein the molar ratio of the intermediate (III) to the triphenylphosphine is 1:1; dissolving alkali in water, adding the alkali into the reaction solution, and continuing to react for 4 hours at normal temperature; the alkali is sodium hydroxide;
the reaction in the step (4) adopts aprotic solvent as solvent, isothiocyanate compounds or isocyanate compounds are added, and the mixture reacts with the Intermediate (IV) for 6 to 8 hours at normal temperature, so that the target compound of the formula (I) is obtained, and the target compound can be purified by recrystallization or column chromatography. The aprotic solvent is acetonitrile. The molar ratio of the isothiocyanate compound or the isocyanate compound to the Intermediate (IV): 1.5 to 1.1:1.
The synthetic route is shown in the following formula:
the beneficial technical effects are as follows:
the invention provides a novel pleuromutilin compound (structure shown as formula I), which is connected with 22-amino of pleuromutilin through thiourea or urea, so that a thioether structure easy to metabolize is avoided, and meanwhile, the antibacterial activity of the compound is obviously improved. Most of the compounds have better antibacterial activity than the medicines on the market, and can be used as novel antibacterial medicines for treating bacterial infection of animals or people.
Detailed Description
The present invention is further described below with reference to examples, but embodiments of the present invention are not limited thereto. The following compounds 1-32 were synthesized:
intermediate II preparation:
10g (26 mmol) of pleuromutilin are dissolved in 60mL of dichloromethane and 5.5g (28.9 mmol) of p-toluenesulfonyl chloride and 7.3mL (98.8 mmol) of triethylamine are added. After stirring the mixture at room temperature for 12h, 50mL of purified water was added to quench the mixture. The reaction solution was then poured into a separating funnel, 40mL of dichloromethane was added, extraction was performed multiple times with saturated NaCl solution, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried under vacuum. The obtained mixture is redissolved by methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times of that of the mixture is added for fully mixing, the crude product-silica gel powder mixture is subjected to column purification by flash column chromatography (petroleum ether: ethyl acetate=2:1 is a mobile phase) after decompression concentration, and the yield of the intermediate II is 99%. ESI-MS (m/z): 533.69[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ 1 H-NMR(500MHz,Chloroform-d)δ7.85(d,J＝8.2Hz,2H),7.39(d,J＝8.0Hz,2H),6.45(dd,J＝17.4,11.0Hz,1H),5.81(d,J＝8.5Hz,1H),5.37(d,J＝11.0Hz,1H),5.23(d,J＝17.4Hz,1H),4.52(s,2H),3.38(s,1H),2.49(s,3H),2.35-2.17(m,3H),2.15-2.04(m,2H),1.79(dq,J＝14.9,3.0Hz,1H),1.73-1.61(m,3H),1.45(s,3H)。
Intermediate III preparation:
intermediate I2g (3.8 mmol) was dissolved in 10mL of N, N-dimethylformamide and 268.9mg (4 mmol) of sodium azide was added. After stirring at 80℃for 1.5h, the reaction was cooled to room temperature and quenched with 30mL of purified water. The reaction solution was poured into a separating funnel, 60mL of ethyl acetate was added, the mixture was washed with a saturated NaCl solution several times, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate iii in 98% yield. ESI-MS (m/z): 404.52[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ6.52(dd,J＝17.5,11.0Hz,1H),5.89(d,J＝8.5Hz,1H),5.41(d,J＝11.0Hz,1H),5.26(d,J＝17.4Hz,1H),3.81(s,2H),3.40(d,J＝6.5Hz,1H),2.38(d,J＝7.0Hz,1H),2.32-2.23(m,2H),2.21-2.12(m,2H),1.87-1.78(m,1H),1.76-1.66(m,3H),1.60(dd,J＝13.4,3.6Hz,1H),1.51(s,6H),1.37(d,J＝16.1Hz,1H),1.22(s,4H),0.93(d,J＝7.0Hz,3H),0.77(d,J＝7.0Hz,3H)。
Intermediate IV preparation:
2g (4.9 mmol) of intermediate II are dissolved in 20mL of tetrahydrofuran/water (5:1) and 1.3g (4.9 mmol) of triphenylphosphine are added, and the reaction is stirred at ambient temperature for 8h. After 8h of reaction, 8mL of 20% NaOH solution was added, and the reaction was continued at room temperature for 4h. The reaction solution was poured into a separating funnel, 40mL of methylene chloride was added, washed with a saturated NaCl solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product is redissolved by methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (methylene dichloride: methanol=10:1 is a mobile phase) to obtain an intermediate IV with the yield of 80 percent. ESI-MS (m/z): 378.53[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ6.57(dd,J＝17.5,10.9Hz,1H),5.82(d,J＝8.5Hz,1H),5.40(d,J＝11.0Hz,1H),5.25(d,J＝17.3Hz,1H),3.39(dd,J＝14.6,8.4Hz,2H),2.40(d,J＝7.0Hz,1H),2.26(dq,J＝19.4,9.3,8.9Hz,2H),2.17-2.07(m,2H),1.82(dd,J＝14.5,3.5Hz,1H),1.70(q,J＝11.3Hz,2H),1.65-1.53(m,4H),1.49(s,4H),1.41(dd,J＝14.0,3.8Hz,1H),1.34(d,J＝16.1Hz,1H),1.21(s,3H),0.93(d,J＝7.0Hz,3H),0.75(d,J＝7.1Hz,3H)。
Example 1: preparation of Compound 1 (14-O- [ (octadecyl aminomethylsulfonyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 90mg (0.33 mmol) of octadecyl isothiocyanate was added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. Re-dissolving the crude product with dichloromethane, adding 3 times of 100-200 mesh silica gel, mixing thoroughly, concentrating under reduced pressure, purifying the crude product-silica gel powder mixture with flash column chromatography (petroleum ether: ethyl acetate=4:1 as mobile phase) to obtain product with yield of 65％。ESI-MS(m/z):689.79[M+H] + . 1 H NMR(500MHz,Chloroform-d)δ6.51(dd,J＝17.4,11.2Hz,1H),5.79(dd,J＝8.6,2.8Hz,1H),5.36(dd,J＝11.1,4.0Hz,1H),5.24(d,J＝17.4Hz,1H),3.93(d,J＝6.5Hz,2H),3.40(d,J＝6.4Hz,1H),3.18(dd,J＝7.2,3.3Hz,2H),2.39-2.19(m,3H),2.12(d,J＝18.1Hz,2H),1.83-1.77(m,1H),1.74-1.64(m,2H),1.50(d,J＝24.3Hz,8H),1.43-1.37(m,2H),1.28(s,34H),1.22-1.12(m,3H),0.91(d,J＝6.6Hz,3H),0.75(d,J＝7.0Hz,3H)。
Example 2: preparation of Compound 2 (14-O- [ (cyclohexylaminomethylsulfonyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 41mg (0.28 mmol) of cyclohexylisothiocyanate was added, and the reaction was allowed to react at room temperature for 7h. The reaction was dried under vacuum to give a mixture. The crude product was redissolved in methylene chloride, 3 times of 100-200 mesh silica gel was added to the crude product and mixed thoroughly, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=4:1 as mobile phase) after concentrating under reduced pressure to give the product in 72% yield. ESI-MS (m/z):519.37[M+H] + . 1 H NMR(500MHz,Chloroform-d)δ6.50(dd,J＝17.5,11.0Hz,1H),5.78(d,J＝8.5Hz,1H),5.35(d,J＝11.0Hz,1H),5.23(d,J＝17.4Hz,1H),3.93(d,J＝7.1Hz,2H),3.39(d,J＝6.4Hz,1H),3.19-3.12(m,5H),2.35(t,J＝7.1Hz,1H),2.30-2.18(m,2H),2.16-2.07(m,2H),1.79(dd,J＝14.5,3.5Hz,1H),1.68(d,J＝11.4Hz,2H),1.54(dd,J＝7.5,3.3Hz,5H),1.48(s,4H),1.38(t,J＝17.5Hz,2H),1.19(s,3H),0.95(d,J＝2.8Hz,4H),0.91(d,J＝7.0Hz,3H),0.75(d,J＝7.0Hz,3H)。
example 3: preparation of Compound 3 (14-O- [ (phenylsulfamoyl) -glycyl ] -mutilin)
Intermediate III 60mg (0.16 mmol) was dissolved in 5mL acetonitrile and 23mg (0.28 mmol) phenylisothiocyanate was added and the reaction was allowed to react at ambient temperature for 8h. The reaction was dried under vacuum to give a mixture. Re-dissolving the crude product with dichloromethane, adding 100-200 mesh silica gel 3 times of the crude product, mixing thoroughly, concentrating under reduced pressure, purifying the crude product-silica gel powder mixture by flash column chromatography (petroleum ether: ethyl acetate=4:1 is mobile phase)) The product was obtained in 68% yield. ESI-MS (m/z): 513.42[ M+H ]]+. 1 H NMR(500MHz,Chloroform-d)δ8.42(s,1H),7.47(t,J＝7.6Hz,2H),7.33(d,J＝4.9Hz,2H),6.72(s,1H),6.44(dd,J＝17.4,11.0Hz,1H),5.79(d,J＝8.4Hz,1H),5.39-5.29(m,1H),5.22(d,J＝17.4Hz,1H),4.37(d,J＝3.4Hz,2H),3.40(s,1H),2.34-2.27(m,2H),2.27-2.17(m,2H),2.15-2.05(m,2H),1.78(dd,J＝14.5,3.3Hz,1H),1.68(dt,J＝20.0,10.1Hz,3H),1.45(s,5H),1.38(d,J＝16.1Hz,2H),1.19(s,3H),0.90(d,J＝6.9Hz,3H),0.72(d,J＝7.0Hz,3H)。
Example 4: preparation of Compound 4 (14-O- [ ((4-fluorophenyl) aminomethyl sulfonyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 45mg (0.29 mmol) of 4-fluorophenyl isothiocyanate was added, and the reaction was reacted at room temperature for 6 hours. The reaction was dried under vacuum to give a mixture. The crude product was redissolved in methylene chloride, added with 3 times of 100-200 mesh silica gel, fully mixed and concentrated under reduced pressure, and the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=3:1 as mobile phase) to obtain the product with a yield of 63%. ESI-MS (m/z):531.41[M+H] + . 1 H NMR(500MHz,Chloroform-d)δ8.16(s,1H),7.18(t,J＝8.4Hz,2H),6.50(t,J＝4.7Hz,1H),6.43(dd,J＝17.3,11.0Hz,1H),5.79(d,J＝8.5Hz,1H),5.32(d,J＝10.8Hz,1H),5.23(d,J＝17.4Hz,1H),4.40-4.28(m,2H),3.40(s,1H),2.36-2.28(m,2H),2.27-2.17(m,1H),2.11(dd,J＝18.4,5.9Hz,2H),1.81-1.75(m,1H),1.73-1.63(m,2H),1.53(dt,J＝12.1,6.5Hz,1H),1.51-1.42(m,5H),1.42-1.34(m,2H),1.35(s,1H),1.19(s,3H),0.90(d,J＝6.9Hz,3H),0.72(d,J＝7.0Hz,3H)。
example 5: preparation of Compound 5 (14-O- [ ((2-methylphenyl) aminomethyl-sulfonyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 43.5mg (0.29 mmol) of p-toluenesulphonate was added, and the reaction was carried out at room temperature for 6 hours. The reaction was concentrated under reduced pressure to give a crude product. Re-dissolving the crude product with dichloromethane, adding 3 times of 100-200 mesh silica gel, mixing thoroughly, and quickly mixing the crude product-silica gel powder mixture after the solvent is volatilizedColumn chromatography column purification (petroleum ether: ethyl acetate=4:1 as mobile phase) gave the product in 76% yield. ESI-MS (m/z):527.79[M+H] + . 1 H NMR(500MHz,Chloroform-d)δ7.72(s,1H),7.36(d,J＝4.5Hz,1H),7.32(dd,J＝5.9,3.4Hz,2H),6.43(dd,J＝17.5,11.0Hz,1H),5.77(d,J＝8.5Hz,1H),5.32(d,J＝11.0Hz,1H),5.22(d,J＝17.4Hz,1H),4.37-4.28(m,2H),3.38(d,J＝6.4Hz,1H),2.34(s,3H),2.32-2.14(m,3H),2.14-1.99(m,2H),1.82-1.74(m,1H),1.66(q,J＝10.9,10.4Hz,3H),1.55-1.43(m,2H),1.41(s,3H),1.39-1.33(m,2H),1.28(s,1H),1.20-1.09(m,3H),0.88(d,J＝7.0Hz,3H),0.69(d,J＝7.0Hz,3H)。
example 6: preparation of Compound 6 (14-O- [ ((4-methoxyphenyl) aminomethyl sulfonyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 48mg (0.29 mmol) of 4-methoxyphenyl isothiocyanate was added, and the reaction was carried out at room temperature for 8 hours. The reaction was concentrated under reduced pressure to give a mixture. The crude product was redissolved in methylene chloride, 3 times of 100-200 mesh silica gel was added to the crude product and mixed thoroughly, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=4:1 as mobile phase) after concentrating under reduced pressure to give the product in 82% yield. ESI-MS (m/z): 543.64[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.23(d,J＝8.3Hz,2H),6.98(dd,J＝9.0,3.3Hz,2H),6.42(dd,J＝12.0,5.1Hz,1H),5.77(dd,J＝8.6,3.4Hz,1H),5.33(s,1H),5.24(d,J＝3.3Hz,1H),5.20(d,J＝3.3Hz,1H),4.35(t,J＝4.0Hz,2H),3.86(d,J＝3.0Hz,3H),3.39(dd,J＝10.2,6.5Hz,1H),2.31(dd,J＝16.5,5.9Hz,2H),2.21(ddd,J＝17.8,11.7,8.9Hz,1H),2.14-2.06(m,2H),1.83-1.74(m,2H),1.70-1.65(m,2H),1.58(dd,J＝13.4,9.8Hz,1H),1.52-1.41(m,5H),1.37(d,J＝16.2Hz,2H),1.19(d,J＝2.9Hz,3H),0.92-0.85(m,3H),0.71(dd,J＝7.0,2.6Hz,3H)。
Example 7: preparation of Compound 7 (14-O- [ ((4-trifluoromethylphenyl) aminomethylsulfonyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 59.2mg (0.29 mmol) of 4- (trifluoromethyl) phenylisothiocyanate was added, and the reaction was reacted at room temperature for 7 hours. The reaction is carried outSpin-drying in vacuo to give a mixture. The crude product was redissolved in methylene chloride, 3 times of 100-200 mesh silica gel was added to the crude product and mixed thoroughly, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=2:1 as mobile phase) after concentrating under reduced pressure to give the product in 70% yield. ESI-MS (m/z): 581.60[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ8.47(s,1H),7.71(d,J＝8.2Hz,2H),7.47(d,J＝8.2Hz,2H),6.89(t,J＝4.9Hz,1H),6.44(dd,J＝17.5,11.0Hz,1H),5.82(d,J＝8.5Hz,1H),5.40-5.29(m,1H),5.23(d,J＝17.4Hz,1H),4.52-4.29(m,2H),3.41(dd,J＝10.1,6.3Hz,1H),2.35-2.29(m,2H),2.28-2.20(m,1H),2.14(q,J＝8.3Hz,2H),1.84-1.77(m,1H),1.74-1.63(m,3H),1.56-1.47(m,6H),1.40(d,J＝16.2Hz,2H),1.21(s,3H),0.91(d,J＝7.0Hz,3H),0.75(d,J＝7.1Hz,3H)。
Example 8: preparation of Compound 8 (14-O- [ (naphthalen-2-yl-aminomethylsulfonyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 53.9mg (0.29 mmol) of 2-naphthyl isothiocyanate was added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product was redissolved in methylene chloride, 3 times of 100-200 mesh silica gel was added to the crude product and mixed thoroughly, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=3:1 as mobile phase) after concentrating under reduced pressure to give the product in 70% yield. ESI-MS (m/z): 563.54[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ8.20(s,1H),8.08-8.04(m,1H),7.97-7.91(m,2H),7.62(dd,J＝9.7,5.4Hz,2H),7.59(s,1H),7.56(t,J＝5.4Hz,1H),6.37(dd,J＝17.4,11.0Hz,1H),5.71(d,J＝8.4Hz,1H),5.34(s,1H),5.27(d,J＝11.0Hz,1H),5.18(d,J＝17.4Hz,1H),4.33(dd,J＝7.9,4.9Hz,2H),3.43-3.25(m,1H),2.29-2.14(m,3H),2.10-1.98(m,2H),1.80-1.70(m,2H),1.63(td,J＝12.1,11.5,5.2Hz,2H),1.52(d,J＝10.4Hz,1H),1.46(dt,J＝13.2,4.3Hz,2H),1.33(d,J＝9.6Hz,5H),1.16(s,3H),0.87(d,J＝7.0Hz,3H),0.63(d,J＝7.1Hz,3H)。
Example 9: compound 9 (14-O- [ (acetamidomethylsulfanyl) -glycyl)]Preparation of Mutirelin 100mg (0.27 mmol) of intermediate III are dissolved in 5mL of acetonitrile and 29 are added2mg (0.29 mmol) of acetyl isothiocyanate, the reaction being carried out at room temperature for 8h. The reaction was dried under vacuum to give a mixture. The crude product was redissolved in dichloromethane, 3 times of 100-200 mesh silica gel was added to the crude product and thoroughly mixed, and after concentrating under reduced pressure, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=4:1 as mobile phase) to give a white product with a yield of 72%. ESI-MS (m/z): 479.52[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ6.49(dd,J＝17.4,11.0Hz,1H),6.06(s,1H),5.79(d,J＝8.5Hz,1H),5.37(d,J＝11.0Hz,1H),5.24(d,J＝17.4Hz,1H),3.96(d,J＝4.6Hz,2H),3.39(d,J＝6.4Hz,1H),2.38-2.17(m,3H),2.09(d,J＝35.3Hz,5H),1.83-1.77(m,1H),1.68(q,J＝11.2Hz,2H),1.61-1.44(m,6H),1.43-1.31(m,2H),1.33(s,1H),1.20(s,3H),0.91(d,J＝6.9Hz,3H),0.74(d,J＝7.0Hz,3H)。
Example 10: preparation of Compound 10 (14-O- [ (benzoylaminomethylsulfonyl) -glycyl ] -mutilin)
Benzoyl chloride 0.16mL (1.4 mmol) was added to a 5mL acetonitrile solution, followed by 130mg (1.4 mmol) of potassium isothiocyanate, and the mixture was reacted at room temperature for 2 hours. The solids were removed by filtration and the solution was dried in vacuo. 5mL of acetonitrile solution and 100mg (0.27 mmol) of intermediate III were added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product was redissolved in methylene chloride, 3 times of 100-200 mesh silica gel was added to the crude product and mixed thoroughly, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=2:1 as mobile phase) after concentrating under reduced pressure to give the product in 74% yield. ESI-MS (m/z): 541.64[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ9.18(s,1H),7.91(d,J＝7.6Hz,2H),7.68(t,J＝7.4Hz,1H),7.56(t,J＝7.6Hz,2H),6.55(dd,J＝17.3,11.0Hz,1H),5.93(d,J＝8.4Hz,1H),5.41(d,J＝11.0Hz,1H),5.27(d,J＝17.3Hz,1H),4.43(d,J＝4.5Hz,2H),3.41(s,1H),2.42-2.36(m,1H),2.27(dq,J＝19.3,10.2,9.1Hz,2H),2.17(q,J＝10.3,9.6Hz,2H),1.82(d,J＝14.1Hz,1H),1.70(dt,J＝24.4,11.0Hz，3H),1.63-1.56(m,1H),1.53(d,J＝7.6Hz,4H),1.44(t,J＝11.8Hz,2H),1.30(s,1H),1.23(s,3H),0.92(d,J＝6.9Hz,3H),0.81(d,J＝6.9Hz,3H)。
Example 11: preparation of Compound 11 (14-O- [ ((4-bromobenzoyl) aminomethyl-sulfonyl) -glycyl ] -mutilin)
200mg (0.92 mmol) of 4-bromobenzoyl chloride was added to a 5mL acetonitrile solution, followed by 130mg (1.4 mmol) of potassium isothiocyanate, and the mixture was reacted at room temperature for 2 hours. The solids were removed by filtration and the solution was dried in vacuo. 5mL of acetonitrile solution and 100mg (0.27 mmol) of intermediate III were added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product was redissolved in methylene chloride, 3 times of 100-200 mesh silica gel was added to the crude product and mixed thoroughly, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=4:1 as mobile phase) after concentrating under reduced pressure to give the product in 64% yield. ESI-MS (m/z): 619.64[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ11.11(t,J＝4.7Hz,1H),9.08(s,1H),7.77(d,J＝8.2Hz,2H),7.70(d,J＝8.3Hz,2H),6.54(dd,J＝17.4,11.0Hz,1H),5.92(d,J＝8.4Hz,1H),5.40(d,J＝11.0Hz,1H),5.26(d,J＝17.4Hz,1H),4.41(d,J＝4.7Hz,2H),3.40(d,J＝6.5Hz,1H),2.36(q,J＝11.1,9.0Hz,1H),2.25(dt,J＝19.6,10.9Hz,2H),2.15(q,J＝9.8Hz,2H),1.81(dd,J＝14.6,3.5Hz,1H),1.76-1.62(m,2H),1.62-1.47(m,6H),1.43(dd,J＝15.7,5.8Hz,3H),1.25-1.12(m,3H),0.91(d,J＝6.9Hz,3H),0.79(d,J＝7.0Hz,3H)。
Example 12: preparation of Compound 12 (14-O- [ ((4-chlorobenzoyl) aminomethyl-sulfonyl) -glycyl ] -mutilin)
200mg (1.14 mmol) of 4-chlorobenzoyl chloride was added to a 5mL acetonitrile solution, and 130mg (1.4 mmol) of potassium isothiocyanate was added thereto, and the mixture was reacted at room temperature for 2 hours. The solids were removed by filtration and the solution was dried in vacuo. 5mL of acetonitrile solution and 100mg (0.27 mmol) of intermediate III were added, and the reaction was carried out at room temperature for 7 hours. The reaction was dried under vacuum to give a mixture. The crude product was redissolved in methylene chloride, 3 times of 100-200 mesh silica gel was added to the crude product and mixed thoroughly, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=4:1 as mobile phase) after concentrating under reduced pressure to give the product in 64% yield. ESI-MS (m/z): 575.60[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ11.11(s,1H),9.03(s,1H),7.84(d,J＝8.2Hz,2H),7.54(d,J＝8.3Hz,2H),6.54(dd,J＝17.4,11.1Hz,1H),5.92(d,J＝8.4Hz,1H),5.41(d,J＝11.0Hz,1H),5.26(d,J＝17.3Hz,1H),4.41(d,J＝4.6Hz,2H),3.46-3.33(m,1H),2.37(t,J＝7.0Hz,1H),2.26(h,J＝9.9,8.7Hz,2H),2.15(d,J＝5.7Hz,2H),1.81(d,J＝14.7Hz,1H),1.69(q,J＝10.9Hz,2H),1.59(d,J＝13.3Hz,1H),1.51(s,5H),1.43(d,J＝15.9Hz,2H),1.19(d,J＝24.0Hz,4H),0.91(d,J＝6.9Hz,3H),0.79(d,J＝6.9Hz,3H)。
Example 13: preparation of Compound 13 (14-O- [ ((4-fluorobenzoyl) aminomethyl sulfonyl) -glycyl ] -mutilin)
200mg (1.27 mmol) of 4-fluorobenzoyl chloride was added to a 5mL acetonitrile solution, 130mg (1.4 mmol) of potassium isothiocyanate was further added, and the mixture was reacted at room temperature for 2 hours. The solids were removed by filtration and the solution was dried in vacuo. 5mL of acetonitrile solution and 100mg (0.27 mmol) of intermediate III were added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product was redissolved in methylene chloride, 3 times of 100-200 mesh silica gel was added to the crude product and mixed thoroughly, the crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=3:1 as mobile phase) after concentrating under reduced pressure to give the product in 75% yield. ESI-MS (m/z): 559.53[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ11.14(t,J＝4.7Hz,1H),9.08(s,1H),7.93(dd,J＝8.6,5.1Hz,2H),7.24(t,J＝8.5Hz,2H),6.54(dd,J＝17.4,11.0Hz,1H),5.92(d,J＝8.5Hz,1H),5.41(d,J＝11.0Hz,1H),5.26(d,J＝17.4Hz,1H),4.41(d,J＝4.7Hz,2H),3.40(d,J＝6.4Hz,1H),2.38(t,J＝6.9Hz,1H),2.30-2.23(m,2H),2.19-2.12(m,2H),1.82(dd,J＝14.6,3.3Hz,1H),1.76-1.64(m,2H),1.60(dd,J＝13.7,3.6Hz,1H),1.52(s,5H),1.47-1.41(m,2H),1.29(s,1H),1.22(s,3H),0.92(d,J＝6.9Hz,3H),0.80(d,J＝7.0Hz,3H)。
Example 14: preparation of Compound 14 (14-O- [ (ethylcarbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, and 20.6mg (0.29 mmol) of ethyl isocyanate was added thereto, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. Re-dissolving the crude product with dichloromethane, adding 3 times of 100-200 mesh silica gel, mixing thoroughly, and volatilizing the solventThe crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=2:1 as mobile phase) to give the product in 73% yield. ESI-MS (m/z): 449.54[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ6.48(dd,J＝17.4,11.0Hz,1H),5.76(d,J＝8.4Hz,1H),5.35-5.28(m,1H),5.21(d,J＝17.4Hz,1H),5.07(t,J＝5.5Hz,1H),3.90(qd,J＝18.3,5.4Hz,2H),3.21(p,J＝7.0Hz,2H),2.37-2.30(m,1H),2.28-2.16(m,2H),2.16-2.04(m,2H),1.78(dd,J＝14.7,3.1Hz,1H),1.67(td,J＝11.9,10.5,7.3Hz,3H),1.57-1.43(m,5H),1.36(t,J＝16.1Hz,2H),1.27(d,J＝2.7Hz,1H),1.18(s,3H),1.13(t,J＝7.2Hz,4H),0.90(d,J＝6.9Hz,3H),0.73(d,J＝7.1Hz,3H)。
Example 15: preparation of Compound 15 (14-O- [ (propylcarbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, and 16.9mg (0.29 mmol) of propyl isocyanate was added thereto, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=4:1 is a mobile phase) to obtain the product with the yield of 80 percent. ESI-MS (m/z): 463.54[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ6.47(ddd,J＝17.4,11.0,2.7Hz,1H),5.81(d,J＝8.4Hz,1H),5.41-5.29(m,1H),5.24(d,J＝17.4Hz,1H),4.33(d,J＝15.3Hz,2H),3.40(d,J＝6.4Hz,1H)，2.28(ddd,J＝32.9,19.6,8.6Hz,3H),2.16-2.07(m,2H),2.06-1.99(m,2H),1.84-1.72(m,3H),1.72-1.60(m,3H),1.48(s,5H),1.43-1.34(m,3H),1.24(d,J＝37.6Hz,6H),0.91(d,J＝7.0Hz,3H),0.75(d,J＝7.0Hz,3H)。
Example 16: preparation of Compound 16 (14-O- [ (cyclohexylcarbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 24.7mg (0.29 mmol) of cyclohexyl isocyanate was added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. Re-dissolving the crude product with dichloromethane, adding 3 times of 100-200 mesh silica gel, and mixing thoroughly until the solvent is volatilizedAfter that, the above crude product-silica gel powder mixture was purified by flash column chromatography (petroleum ether: ethyl acetate=3:1 as mobile phase) to give the product in 65% yield. ESI-MS (m/z): 503.78[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ6.46(dd,J＝17.4,11.0Hz,1H),5.75(d,J＝8.4Hz,1H),5.42(t,J＝5.4Hz,1H),5.30(d,J＝11.1Hz,1H),5.20(d,J＝17.5Hz,1H),5.13(d,J＝8.1Hz,1H),4.12(q,J＝7.2Hz,1H),3.88(dd,J＝8.1,5.4Hz,2H),3.54-3.32(m,2H),2.34-2.17(m,3H),2.12(s,1H),2.10-2.02(m,2H),1.91(d,J＝12.1Hz,3H),1.82-1.74(m,2H),1.68(dt,J＝13.8,7.4Hz,4H),1.45(s,4H),1.37-1.31(m,4H),1.26(t,J＝7.1Hz,1H),1.16(s,3H),0.89(d,J＝6.9Hz,3H),0.72(d,J＝7.0Hz,3H)。
Example 17: preparation of Compound 17 (14-O- [ (phenylcarbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, and 24.7mg (0.29 mmol) of phenyl isocyanate was added thereto, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=4:1 is a mobile phase) to obtain the product with the yield of 80 percent. ESI-MS (m/z): 497.55[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.33(d,J＝7.2Hz,3H),7.25(s,1H),7.11(t,J＝6.7Hz,1H),6.46(dd,J＝17.5,11.0Hz,1H),5.79(d,J＝8.4Hz,1H),5.71(t,J＝5.4Hz,1H),5.28(d,J＝11.0Hz,1H),5.21(d,J＝17.5Hz,1H),4.00(t,J＝5.3Hz,2H),3.39(dd,J＝10.0,6.3Hz,1H),2.32(dq,J＝10.2,5.1,2.8Hz,2H),2.27-2.19(m,1H),2.15-2.07(m,2H),1.79(d,J＝14.6Hz,2H),1.68(dt,J＝13.3,9.8Hz,2H),1.57-1.44(m,6H),1.38(dd,J＝16.7,5.6Hz,2H),1.19(s,3H),0.90(d,J＝7.0Hz,3H),0.76(d,J＝7.1Hz,3H)。
Example 18: preparation of Compound 18 (14-O- [ ((4-chlorophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, and 44.4mg (0.29 mmol) of 4-chlorophenyl isocyanate was added thereto, and the reaction was carried out at room temperature for 8 hours. Spin-drying the reaction under vacuum to obtainTo a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=4:1 is a mobile phase) to obtain the product with the yield of 76%. ESI-MS (m/z): 531.41[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.32-7.27(m,2H),7.23(d,J＝8.5Hz,2H),6.51-6.42(m,1H),5.76(dd,J＝13.2,8.7Hz,1H),5.34-5.28(m,1H),5.22(d,J＝17.3Hz,1H),4.02-3.88(m,2H),3.39(d,J＝6.3Hz,1H),2.36-2.16(m,3H),2.15-2.06(m,2H),1.83-1.75(m,2H),1.67(q,J＝11.1,10.0Hz,2H),1.56-1.43(m,5H),1.38(t,J＝13.4Hz,2H),1.28(s,1H),1.21-1.11(m,3H),0.91(d,J＝6.6Hz,3H),0.75(d,J＝6.8Hz,3H)。
Example 19: preparation of Compound 19 (14-O- [ ((2-chlorophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 44.4mg (0.29 mmol) of o-chlorophenyl isocyanate was added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=5:1 is a mobile phase) to obtain the product with the yield of 66 percent. ESI-MS (m/z): 531.54[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ8.08(dd,J＝8.3,1.6Hz,1H),7.37(dd,J＝8.0,1.5Hz,1H),7.28-7.24(m,1H),7.01(td,J＝7.7,1.6Hz,1H),6.96(s,1H),6.51(dd,J＝17.4,11.0Hz,1H),5.82(d,J＝8.5Hz,1H),5.38-5.32(m,1H),5.24(dd,J＝17.5,1.6Hz,1H),4.03(s,2H),3.40(d,J＝6.4Hz,1H),2.35(q,J＝6.2,5.4Hz,1H),2.24(dq,J＝19.3,10.2,9.2Hz,2H),2.16-2.06(m,2H),1.80(dd,J＝14.5,3.3Hz,1H),1.74-1.63(m,2H),1.58-1.46(m,6H),1.40(t,J＝16.1Hz,2H),1.33-1.27(m,1H),1.21(s,3H),0.92(d,J＝7.0Hz,3H),0.77(d,J＝7.1Hz,3H)。
Example 20: preparation of Compound 20 (14-O- [ ((3-chlorophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III are dissolved in 5mL of acetonitrile and added44.4mg (0.29 mmol) of m-chlorophenyl isocyanate was added, and the reaction was reacted at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=3:1 is a mobile phase) to obtain the product with the yield of 78%. ESI-MS (m/z): 531.48[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.40(s,1H),7.20(d,J＝5.3Hz,2H),7.03(dt,J＝5.8,2.3Hz,1H),6.47(dd,J＝17.4,11.0Hz,1H),5.80(d,J＝8.5Hz,1H),5.28(d,J＝11.0Hz,1H),5.21(d,J＝17.4Hz,1H),4.07-3.93(m,2H),3.40(d,J＝6.4Hz,1H),2.28(ddp,J＝28.8,19.4,9.3,8.6Hz,3H),2.17-2.07(m,2H),1.83-1.75(m,1H),1.74-1.64(m,2H),1.49(s,5H),1.39(dd,J＝15.7,10.2Hz,2H),1.36(s,1H),1.29(q,J＝5.5,3.5Hz,1H),1.20(s,3H),0.91(d,J＝7.0Hz,3H),0.76(d,J＝7.1Hz,3H)。
Example 21: preparation of Compound 21 (14-O- [ ((4-fluorophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 39.7mg (0.29 mmol) of 4-fluorobenzene isocyanate was added, and the reaction was carried out at normal temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=2:1 is a mobile phase) to obtain the product with the yield of 73 percent. ESI-MS (m/z): 515.53[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.50(s,1H),7.26(dd,J＝8.7,4.8Hz,2H),6.96(t,J＝8.5Hz,2H),6.44(dd,J＝17.4,10.9Hz,1H),5.76(d,J＝8.4Hz,1H),5.24(d,J＝11.2Hz,1H),5.19(d,J＝17.4Hz,1H),3.95(dd,J＝12.1,5.5Hz,2H),3.39(dd,J＝9.7,6.1Hz,1H),2.27(ddd,J＝22.1,16.6,8.5Hz,3H),2.15-2.02(m,3H),1.84-1.73(m,1H),1.72-1.60(m,3H),1.50-1.43(m,5H),1.36(dd,J＝15.9,5.3Hz,2H),1.17(s,3H),0.89(d,J＝6.9Hz,3H),0.73(d,J＝7.1Hz,3H)。
Example 22: preparation of Compound 22 (14-O- [ ((2-fluorophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 39.7mg (0.29 mmol) of o-fluorobenzene isocyanate was added, and the reaction was carried out at normal temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=3:1 is a mobile phase) to obtain the product with the yield of 74%. ESI-MS (m/z): 515.72[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ8.00(t,J＝8.1Hz,1H),7.16-7.08(m,2H),7.04(dq,J＝13.9,7.5,6.1Hz,2H),6.50(dd,J＝17.4,11.0Hz,1H),5.82(d,J＝8.5Hz,1H),5.69(t,J＝5.3Hz,1H),5.31(d,J＝11.0Hz,1H),5.22(d,J＝17.4Hz,1H),4.03(t,J＝4.7Hz,2H),3.41(d,J＝6.4Hz,1H),2.40-2.33(m,1H),2.32-2.18(m,2H),2.18-2.06(m,2H),1.85-1.76(m,1H),1.69(q,J＝10.8Hz,2H),1.61-1.46(m,6H),1.40(t,J＝14.8Hz,2H),1.30(t,J＝7.1Hz,1H),1.20(s,3H),0.92(d,J＝6.9Hz,3H),0.77(d,J＝7.0Hz,3H)。
Example 23: preparation of Compound 23 (14-O- [ ((3-fluorophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 39.7mg (0.29 mmol) of m-fluorobenzene isocyanate was added, and the reaction was carried out at normal temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=5:1 is a mobile phase) to obtain the product with the yield of 72 percent. ESI-MS (m/z): 515.64[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.22(dt,J＝10.3,2.8Hz,2H),7.02(dd,J＝8.1,2.0Hz,1H),6.76(td,J＝8.4,2.5Hz,1H),6.47(dd,J＝17.4,11.0Hz,1H),5.81(d,J＝8.5Hz,1H),5.28(d,J＝11.0Hz,1H),5.22(d,J＝17.4Hz,1H),4.08-3.93(m,2H),3.41(d,J＝6.4Hz,1H),2.38-2.17(m,3H),2.17-2.06(m,2H),1.84-1.75(m,1H),1.74-1.64(m,2H),1.50(s,6H),1.43-1.35(m,2H),1.30(t,J＝7.1Hz,1H),1.20(s,3H),0.91(d,J＝7.0Hz,3H),0.77(d,J＝7.0Hz,3H)。
Example 24: preparation of Compound 24 (14-O- [ ((4-bromophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 57.4mg (0.29 mmol) of 4-bromophenylisocyanate was added, and the reaction was carried out at room temperature for 6 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=3:1 is a mobile phase) to obtain the product with the yield of 67%. ESI-MS (m/z): 575.36[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.31(d,J＝8.8Hz,1H),7.22(d,J＝8.4Hz,1H),6.39(dd,J＝17.5,11.0Hz,1H),5.71(d,J＝8.4Hz,1H),5.24(d,J＝11.0Hz,1H),5.15(d,J＝17.5Hz,1H),3.94–3.79(m,2H),3.34(d,J＝6.5Hz,1H),2.28(q,J＝6.0,5.1Hz,1H),2.24-2.13(m,2H),2.11(s,1H),2.03(dd,J＝16.0,8.4Hz,1H),1.74(dd,J＝14.9,3.5Hz,1H),1.66–1.56(m,2H),1.51-1.47(m,1H),1.41(s,4H),1.32(d,J＝16.2Hz,2H),1.22(s,1H),1.12(s,3H),0.85(d,J＝7.0Hz,3H),0.69(d,J＝7.0Hz,3H)。
Example 25: preparation of Compound 25 (14-O- [ ((2-bromophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III is dissolved in 5mL of acetonitrile and 57.4mg (0.29 mmol) of o-bromophenylisocyanate is added, and the reaction is carried out at room temperature for 6 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=4:1 is a mobile phase) to obtain the product with the yield of 71%. ESI-MS (m/z): 575.58[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ8.05(dd,J＝8.3,1.6Hz,1H),7.54(dd,J＝8.0,1.5Hz,1H),7.03-6.92(m,2H),6.51(dd,J＝17.4,11.0Hz,1H),5.82(d,J＝8.5Hz,1H),5.34(d,J＝11.0Hz,1H),5.24(dd,J＝17.4,1.6Hz,1H),4.03(s,2H),3.52(d,J＝7.0Hz,1H),2.35(q,J＝6.0,5.0Hz,1H),2.29-2.20(m,2H),2.18-2.06(m,2H),1.80(dd,J＝14.5,3.2Hz,1H),1.69(ddd,J＝16.5,11.7,7.9Hz,2H),1.59-1.47(m,5H),1.40(t,J＝14.8Hz,2H),1.29(s,1H),1.24(s,1H),1.21(s,3H),0.92(d,J＝7.0Hz,3H),0.77(d,J＝7.1Hz,3H)。
Example 26: preparation of Compound 26 (14-O- [ ((3-bromophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 57.4mg (0.29 mmol) of m-bromobenzyl isocyanate was added, and the reaction was carried out at room temperature for 6 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=2:1 is a mobile phase) to obtain the product with the yield of 72 percent. ESI-MS (m/z): 575.50[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.53(t,J＝1.9Hz,1H),7.35(s,1H),7.24(d,J＝7.9Hz,1H),7.17(d,J＝7.9Hz,1H),7.12(t,J＝7.9Hz,1H),6.46(dd,J＝17.4,11.0Hz,1H),5.79(d,J＝8.6Hz,1H),5.27(d,J＝11.0Hz,1H),5.20(d,J＝17.4Hz,1H),3.99(d,J＝13.2Hz,2H),3.39(d,J＝6.4Hz,1H),2.31(dd,J＝13.6,7.0Hz,1H),2.27-2.19(m,1H),2.11(d,J＝27.3Hz,4H),1.83-1.75(m,1H),1.73-1.64(m,2H),1.49(s,5H),1.37(d,J＝16.1Hz,2H),1.29(s,1H),1.19(s,3H),0.90(d,J＝7.0Hz,3H),0.76(d,J＝7.0Hz,3H)。
Example 27: preparation of Compound 27 (14-O- [ ((4-methoxyphenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III is dissolved in 5mL of acetonitrile, 43.2mg (0.29 mmol) of 4-methoxyphenyl isocyanate is added, and the reaction is carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=4:1 is a mobile phase) to obtain the product with the yield of 71%. ESI-MS (m/z): 526.54[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.24(d,J＝8.4Hz,2H),6.87(d,J＝8.4Hz,2H),6.45(dd,J＝17.4,11.0Hz,1H),5.76(d,J＝8.5Hz,1H),5.27(d,J＝11.0Hz,1H),5.22-5.16(m,1H),3.96(d,J＝3.1Hz,2H),3.81(s,3H),3.38(d,J＝6.4Hz,1H),2.35-2.17(m,3H),2.14-2.03(m,2H),1.83-1.72(m,1H),1.72-1.61(m,2H),1.52-1.41(m,5H),1.36(dd,J＝16.3,9.7Hz,2H),1.28(t,J＝7.2Hz,1H),1.17(s,3H),0.89(d,J＝7.0Hz,3H),0.73(d,J＝7.0Hz,3H)。
Example 28: preparation of Compound 28 (14-O- [ ((3-methylphenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 38.6mg (0.29 mmol) of m-tolyl isocyanate was added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=3:1 is a mobile phase) to obtain the product with the yield of 74%. ESI-MS (m/z): 511.69[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.93(dd,J＝8.8,5.8Hz,1H),6.91(s,1H),6.86(t,J＝8.6Hz,2H),6.49(dd,J＝17.4,11.0Hz,1H),5.81(d,J＝8.5Hz,1H),5.31(d,J＝11.0Hz,1H),5.22(d,J＝17.4Hz,1H),4.08-3.96(m,2H),3.41(d,J＝6.4Hz,1H),2.37(s,4H),2.31-2.20(m,2H),2.18-2.06(m,2H),1.84-1.76(m,1H),1.76-1.65(m,2H),1.57-1.45(m,5H),1.41(d,J＝12.6Hz,2H),1.36(s,1H),1.31(s,1H),1.21(s,3H),0.92(d,J＝6.9Hz,3H),0.77(d,J＝7.0Hz,3H)。
Example 29: preparation of Compound 29 (14-O- [ ((3, 5-dichlorophenyl) carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 53.9mg (0.29 mmol) of 3, 5-dichlorobenzyl isocyanate was added, and the reaction was carried out at room temperature for 6 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=5:1 is a mobile phase) to obtain the product with the yield of 62 percent. ESI-MS (m/z): 565.53[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.03(t,J＝1.9Hz,1H),6.94(s,1H),6.51(dd,J＝17.4,11.0Hz,1H),5.83(d,J＝8.5Hz,1H),5.55(s,1H),5.33(d,J＝11.0Hz,1H),5.24(d,J＝17.4Hz,1H),4.01(q,J＝18.3Hz,2H),3.42(d,J＝6.4Hz,1H),2.40-2.21(m,3H),2.21-2.13(m,2H),1.90-1.78(m,1H),1.71(dt,J＝20.3,8.1Hz,3H),1.58(d,J＝14.4Hz,1H),1.52(s,4H),1.44(d,J＝18.6Hz,2H),1.39(s,1H),1.26-1.15(m,3H),0.93(d,J＝6.9Hz,3H),0.80(d,J＝7.0Hz,3H)。
Example 30: preparation of Compound 30 (14-O- [ ((2, 4-difluorophenyl) carbamoyl chloride) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III is dissolved in 5mL of acetonitrile, 45mg (0.29 mmol) of 2, 4-difluorophenyl isocyanate is added, and the reaction is carried out at room temperature for 8h. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=2:1 is a mobile phase) to obtain the product with the yield of 65 percent. ESI-MS (m/z): 533.59[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.24(t,J＝7.8Hz,1H),7.18(s,1H),7.13(d,J＝8.0Hz,1H),6.97(d,J＝7.5Hz,1H),6.49(dd,J＝17.4,11.0Hz,1H),5.81(d,J＝8.4Hz,1H),5.31(d,J＝11.0Hz,1H),5.23(d,J＝17.4Hz,1H),4.01(s,2H),3.40(d,J＝6.4Hz,1H),2.35(q,J＝6.7Hz,1H),2.27(dq,J＝19.6,9.9Hz,2H),2.19-2.06(m,2H),1.86-1.76(m,1H),1.69(dt,J＝13.7,9.8Hz,2H),1.59-1.46(m,6H),1.39(t,J＝14.2Hz,2H),1.31(d,J＝7.7Hz,1H),1.21(s,3H),0.91(d,J＝7.0Hz,3H),0.77(d,J＝7.0Hz,3H)。
Example 31: preparation of Compound 31 (14-O- [ (1, 1' -biphenyl-2-carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III is dissolved in 5mL of acetonitrile, 56.6mg (0.29 mmol) of 2-biphenylisocyanate is added, and the reaction is carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=4:1 is a mobile phase) to obtain the product with the yield of 78%. ESI-MS (m/z): 573.75[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ7.90(d,J＝8.1Hz,1H),7.49(t,J＝7.5Hz,2H),7.46-7.36(m,4H),7.30(s,1H),7.23(t,J＝7.5Hz,1H),6.51(dd,J＝17.4,11.0Hz,1H),6.31(s,1H),5.79(d,J＝8.5Hz,1H),5.42-5.33(m,1H),5.25(d,J＝17.4Hz,1H),3.94(d,J＝3.1Hz,2H),3.40(d,J＝6.4Hz,1H),2.44-2.18(m,3H),2.16-2.05(m,2H),1.87-1.77(m,1H),1.75-1.66(m,3H),1.55(dd,J＝13.3,3.4Hz,1H),1.48(s,4H),1.43-1.38(m,2H),1.35(s,1H),1.26-1.12(m,3H),0.92(d,J＝6.9Hz,3H),0.75(d,J＝7.0Hz,3H)。
Example 32: preparation of Compound 32 (14-O- [ (naphthyl-1-carbamoyl) -glycyl ] -mutilin)
100mg (0.27 mmol) of intermediate III was dissolved in 5mL of acetonitrile, 49.1mg (0.29 mmol) of 1-naphthyl isocyanate was added, and the reaction was carried out at room temperature for 8 hours. The reaction was dried under vacuum to give a mixture. The crude product is redissolved in methylene dichloride, 100-200 meshes of silica gel with the amount being 3 times that of the crude product is added for fully mixing, and after the solvent is volatilized, the crude product-silica gel powder mixture is purified by a flash column chromatography (petroleum ether: ethyl acetate=3:1 is a mobile phase) to obtain the product with the yield of 66 percent. ESI-MS (m/z): 547.71[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ8.16(dd,J＝6.4,3.3Hz,1H),7.96-7.85(m,1H),7.81(d,J＝8.3Hz,1H),7.71(d,J＝7.5Hz,1H),7.61-7.48(m,4H),6.35(dd,J＝17.4,11.0Hz,1H),5.72(d,J＝8.5Hz,1H),5.19-5.15(m,1H),5.13(s,1H),4.01(s,2H),3.35(d,J＝6.4Hz,1H),2.25(ddd,J＝18.6,10.0,4.7Hz,3H),2.11-2.01(m,2H),1.74(dd,J＝14.6,3.2Hz,1H),1.65(dt,J＝7.6,3.3Hz,2H),1.47(dd,J＝13.7,3.5Hz,2H),1.41(s,3H),1.36-1.26(m,3H),1.15(s,3H),0.85(d,J＝6.9Hz,3H),0.69(d,J＝7.1Hz,3H)。
In vitro bacteriostasis experiment
Experimental method
The in vitro antibacterial activity of the compound on sensitive/drug-resistant strains is evaluated by adopting a trace broth dilution method, and the in vitro antibacterial activity of the compound on different strains is tested by adopting the following specific operation steps: the sterilized 96-well plate was placed in an ultra clean bench, 200. Mu.L of the diluted bacterial liquid was added to the first column, and 100. Mu.L of the bacterial liquid was added to each column from the second column. A test solution dissolved in DMSO at a concentration of 5mg/mL was taken in 4. Mu.L and added to each well of the first column in sequence, and a blank control group (no sample addition) and a positive drug group (levofloxacin at a concentration of 5 mg/mL) were set simultaneously, and each sample was repeated three times. After the sample addition, 128 mu L of samples are sequentially taken from the front row by using an 8-channel micropipette, added into the rear row for 2-time gradient dilution, and when the samples are added into the last hole, 100 mu L of liquid is sucked after the samples are uniformly mixed, and the compound concentrations in all the holes after dilution are 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 and 0.06 mu g/mL respectively. The 96-well plate was placed in an incubator at 37℃for 18 hours, and the growth of bacteria in each well was observed. For each compound, the concentration of the compound corresponding to the first well in which no bacteria were growing was counted from the well to which the sample was added, i.e., the lowest inhibitory concentration (Minimal Inhibitory Concentration, MIC) of the compound. The strains used in the experiments were staphylococcus aureus ATCC29213, methicillin-resistant staphylococcus aureus ATCC43300, enterococcus faecium ATCC19434.
The following table shows MIC test results
Table-3 in vitro antibacterial data for compounds
The urea compounds have better antibacterial activity on staphylococcus aureus and methicillin-resistant staphylococcus aureus than thiourea compounds, and the antibacterial activity of most urea compounds on staphylococcus aureus and methicillin-resistant staphylococcus aureus is close to or better than that of the veterinary drug tiamulin with wide application, wherein the antibacterial activity of compound 26 and compound 27 on staphylococcus aureus and methicillin-resistant staphylococcus aureus is obviously better than that of the veterinary drug tiamulin.
The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (9)

1. A compound having a thiourea or urea side chain of formula (i) or a pharmaceutically acceptable salt thereof:
when x=s, R is selected from C 1-18 Alkyl, C 3-8 Cycloalkyl, substituted or unsubstituted phenyl, naphthyl, C 2-6 Alkanoyl, benzoyl, halobenzoyl;
when x=o, R is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, substituted or unsubstituted phenyl, naphthyl;
the substituents are selected from halogen, C 1-6 Alkyl, C of (2) 3-6 Cycloalkyl, C 1-6 Alkoxy, phenyl.
2. The compound having a thiourea or urea side chain of claim 1 or a pharmaceutically acceptable salt thereof:
when x=s, R is selected from C 3-8 Cycloalkyl, phenyl, o, m, p-halophenyl, o, m, p-substituted methoxy substituted phenyl, o, m, p-substituted ethoxy substituted phenyl, o, m, p-substituted methyl substituted phenyl, o, m, p-substituted trifluoromethyl substituted phenyl, o, m, p-substituted ethyl substituted phenyl, C 2-6 Alkanoyl of (a);
when x=o, R is selected from C 1-6 Alkyl of C 3-8 Cycloalkyl, phenyl, naphthyl, o-, m-, p-substituted halophenyl, o-, m-, p-substituted methoxy-substituted phenyl, o-, m-, p-and p-Methyl substituted phenyl, trifluoromethyl substituted phenyl of ortho, meta and para substitution, ethyl substituted phenyl of ortho, meta and para substitution.
3. A pleuromutilin compound having a thiourea or urea side chain as claimed in claim 1,
when x=s, R is selected from cyclohexyl, phenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, acetyl;
when x=o, R is selected from ethyl, propyl, cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-methoxyphenyl, 3, 5-dichlorophenyl, 2, 4-difluorophenyl, naphthyl.
4. A compound having thiourea or urea side chains or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein said compound is selected from the group consisting of:
5. the method for producing a compound having a thiourea or urea side chain according to any one of claims 1 to 4, comprising the steps of:
(1) Reacting pleuromutilin with p-toluenesulfonyl chloride to obtain an intermediate with a structure shown as a formula (II):
(2) The intermediate (II) is used as a raw material, and is reacted with sodium azide to obtain a structural intermediate shown as a formula (III):
(3) The intermediate (III) is used as a raw material, is further activated by reaction with triphenylphosphine, and a certain amount of sodium hydroxide is added to obtain the intermediate with the structure shown in the formula (IV)
(4) The Intermediate (IV) is used as a raw material, and is reacted with an isothiocyanate compound or an isocyanate compound to obtain the pleuromutilin compound with the structure shown in the formula (I) and a thiourea or urea side chain;
the reaction in the step (1) adopts dichloromethane as a solvent, and the reaction is carried out for 12-16 hours at normal temperature, wherein the mol ratio of the p-toluenesulfonyl chloride to the pleuromutilin is 1.1:1;
the reaction in the step (2) adopts N, N-dimethylformamide as a solvent, firstly, an intermediate (II) is dissolved in an aprotic solvent, then sodium azide is added, heating reflux is carried out for 1.5-2h, and the molar ratio of the intermediate (II) to the sodium azide is 1:1.1;
the reaction in the step (3) adopts tetrahydrofuran as a solvent, firstly, an intermediate (III) is dissolved in an aprotic solvent, triphenylphosphine is added, and the reaction is carried out for 8-10 hours at normal temperature, wherein the molar ratio of the intermediate (III) to the triphenylphosphine is 1:1; dissolving alkali in water, adding the alkali into the reaction solution, and continuing to react for 4 hours at normal temperature; the alkali is sodium hydroxide;
the reaction in the step (4) adopts aprotic solvent as solvent, isothiocyanate compounds or isocyanate compounds are added, and the mixture reacts with the Intermediate (IV) for 6 to 8 hours at normal temperature, so that the target compound of the formula (I) is obtained, and the target compound can be purified by recrystallization or column chromatography;
the synthetic route is shown in the following formula:
r is as defined in any one of claims 1 to 4.
6. The preparation method according to claim 5, wherein the solvent adopted in the reaction in the step (4) is acetonitrile, and the reaction is carried out for 6-8 hours at normal temperature; the molar ratio of the isothiocyanate compound or the isocyanate compound to the Intermediate (IV): 1.5 to 1.1:1.
7. A pharmaceutical composition comprising the compound having a thiourea or urea side chain or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 as an active ingredient.
8. Use of a compound having a thiourea or urea side chain as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a bacterial infectious disease.
9. The use according to claim 8, wherein the bacterial infectious disease is selected from staphylococcus aureus infectious diseases.
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CN106543054A (en) * 2016-09-30 2017-03-29 华南农业大学 A kind of pleuromutilin derivative with 2 amino second mercapto alcohol side chains and its production and use
CN111574395A (en) * 2020-06-18 2020-08-25 华南农业大学 Pleuromutilin derivative with amide side chain, preparation and application thereof

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CN104447450A (en) * 2014-07-08 2015-03-25 南通大学 Cysteine amide type pleuromutilin derivative as well as preparation method and medical application thereof
CN106543054A (en) * 2016-09-30 2017-03-29 华南农业大学 A kind of pleuromutilin derivative with 2 amino second mercapto alcohol side chains and its production and use
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