CN108912147A - A kind of sulphur azatropylidene medicinal compound and preparation method thereof for human burn skin nursing - Google Patents
A kind of sulphur azatropylidene medicinal compound and preparation method thereof for human burn skin nursing Download PDFInfo
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- DICUBYSIEMXTIG-UHFFFAOYSA-N Oc1nc2c[n]3ncc(Br)c3nc2cc1 Chemical compound Oc1nc2c[n]3ncc(Br)c3nc2cc1 DICUBYSIEMXTIG-UHFFFAOYSA-N 0.000 description 1
- FFQNZBILWSCARV-UHFFFAOYSA-N Sc1nc2c[n]3ncc(Br)c3nc2cc1 Chemical compound Sc1nc2c[n]3ncc(Br)c3nc2cc1 FFQNZBILWSCARV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of sulphur azatropylidene medicinal compounds and preparation method thereof for human burn skin nursing, belong to medical synthesis technical field.Technical solution of the present invention main points are：A kind of sulphur azatropylidene medicinal compound for human burn skin nursing, structural formula are：
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of sulphur azatropylidene for human burn skin nursing
Medicinal compound and preparation method thereof.
Background technique
Burn mainly damages the mucous membrane and skin of people, is high temp objects directly to be contacted due to body or by strong hot spoke
Caused tissue damage is penetrated, is a kind of common injury, children, old man and labourer are Yi Fa group, and male is common.Serious person
Such as joint, bone, the muscle even sub-mucosal tissues and subcutaneous tissue of internal organ can also be injured.During burning postoperative care,
Some patients are often accompanied by other chronic diseases, and burn infectious-related complication is more, and case fatality rate is higher, increase very to burn treating and nursing
Big difficulty.There are the following problems in the clinical treatment nursing of fire victim：1, wound exudate and the disinfectant of dressing
Water is easy that wound is made to be bonded together with bandage for dressing, can bring larger pain to patient when more changing a bandage；2, large area is burnt
Hurt that patient's course of disease is long, and bacterium infection often occurs in the surface of a wound.Therefore, how the patient skin surface of a wound is effectively nursed, all the time
It is all medical staff's very concern.Ideal care drug is with the following functions：1, the excessive sepage of the surface of a wound, dimension are absorbed
Hold the microenvironment of wound wetting；2, easy to use, it is not adhered, mitigates patient's pain；3, there is extensive bactericidal effect, can press down
The growth of bacterium and microorganism processed；4, the healing of the surface of a wound can be promoted.
Nitrogenous sulfur heterocyclic compound plays an important role due to it is with good bioactivity in field of medicaments.
Especially sulphur azatropylidene is exactly a kind of important seven member ring heterocyclic compounds object, such compound due to unique medical value and
Wide spectrum biological activity and paid close attention to by people, such compound can improve myocardial blood supply, myocardial oxygen consumption be reduced, for treating
Angina pectoris has minimum side effect, such as diltiazem；Such compound or g protein coupled receptor antagonist have this
The compound of class formation unit also has the effects that calm, hypnosis, such as stable and clotiapine；Such compound can also promote
Growth hormone secretion can be used to treat the children growth phase slow；The compound of such compound or a kind of antiulcer activity,
It can be used to protect stomach lining, for the treatment of chronic gastric ulcer；Furthermore sulphur azatropylidene or one kind have preferable antibacterial activity
Compound, good inhibiting effect is shown to Staphylococcus aureus and some fungies；It has recently been demonstrated that sulphur azepine
Tall and erect compound has certain effect in terms for the treatment of AIDS, is hiv reverse transcriptase inhibitor, and researcher carries out it
Structural modification, to find the drug of more preferable anti-AIDS effect.
Summary of the invention
That the technical problem to be solved by the present invention is to provide a kind of synthetic methods is simple, molecular structure is novel and bactericidal effect is aobvious
The sulphur azatropylidene medicinal compound and preparation method thereof for human burn skin nursing write.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of sulphur for human burn skin nursing
Azatropylidene medicinal compound, it is characterised in that the structural formula of the sulphur azatropylidene medicinal compound is：
Wherein R is phenyl, pyridyl group or piperidyl.
A kind of preparation method of the sulphur azatropylidene medicinal compound for human burn skin nursing, it is characterised in that tool
Body step is：
(1) under nitrogen protection, compoundIt is added in n,N-Dimethylformamide, reaction temperature
Degree is separately added into N-bromosuccinimide in three batches after being cooled to 10 DEG C, add after restoring to room temperature reaction to raw material fully reacting
Enter ethyl acetate, stirring 2h is free of n,N-Dimethylformamide into organic phase with saturated sodium chloride solution washing reaction liquid, has
Machine is mutually dry through anhydrous magnesium sulfate, and n-hexane is added after concentration, dilute hydrochloric acid solution is slowly added dropwise, stirring to pulp under the conditions of 0 DEG C,
It is dried to obtain after suction filtrationHydrochloride, obtainedHydrochloride is added to the water, and uses carbon
Sodium hydroxide saturated solution adjusts reaction solution pH to 8, multiple with chloroform extraction reaction solution, merges organic phase, obtains after concentration pure
Product
(2) compoundIt is added in tetrahydrofuran with 3,3- dimethoxy methyl propionate, mixing is equal
The THF solution of alkali compounds is added after even under the conditions of 0 DEG C, medium alkaline compound is sodium hydride or hydrofining, is dripped
After be warming up to 25 DEG C the reaction was continued, be then cooled to 5 DEG C and the sodium citrate aqueous solution that mass percentages are 20% be added, stirring
After separate organic phase, methylene chloride is added after concentration, is washed with water repeatedly, then with anhydrous sodium sulfate it is dry after be concentrated to get chemical combination
Object
(3) under the conditions of 0~5 DEG C, dissolved with compoundDichloromethane solution drop
It is added in the concentrated sulfuric acid, 60 DEG C is warming up to after dripping, be concentrated in vacuo reaction solution after being stirred to react, be cooled to 0 DEG C, it is mixed that ice water is added
Object is closed, there are a large amount of solids to be precipitated after stirring, filters reaction solution, filter cake is washed with water and the tert-butyl alcohol respectively, dries filter cake
Close object
(4) compoundBe added in toluene, add lawesson reagent, be heated to 100 DEG C into
Row reaction, concentration of reaction solution after raw material fully reacting, concentrate are added chloroform, are washed repeatedly, had with saturated sodium bicarbonate solution
Machine be mutually concentrated after through the isolated compound of silica gel column chromatography
(5) in reaction flask, compound2-chloroethyl amine and alkali compounds are added to tetrahydro
In furans, medium alkaline compound is sodium hydride or hydrofining, with heating reflux reaction after reaction system with nitrogen gas, original
It is down to room temperature after material fully reacting, dichloroethanes is added, water and hydrochloric acid is added after filtrate decompression concentration in filtering reacting liquid after stirring
Solution is extracted with ethyl acetate reaction solution and removes impurity, and it is 10~11 that water phase, which adjusts pH through saturation sodium hydroxide solution, then uses chlorine
Imitative extraction, is concentrated to get compound after being dried with anhydrous sodium sulfate
(6) compoundIt is added in water and methylene chloride, stirs with sodium bicarbonate
It is cooled to 0 DEG C after uniformly, the dichloromethane solution dissolved with benzyl chloroformate is added dropwise, is reacted at room temperature after dripping anti-to raw material
Organic phase should be separated completely, water phase is extracted with dichloromethane repeatedly, is dried over anhydrous sodium sulfate after merging organic phase, after concentration
Obtain compound
(7) compoundIt is added in toluene with sulfonic compound,
Wherein sulfonic compound is methane sulfonic acid or p-methyl benzenesulfonic acid, is heated to 70 DEG C, adds paraformaldehyde, at 70 DEG C after adding
Under the conditions of reaction to raw material fully reacting, be cooled to room temperature, filtering reacting liquid, filtrate is washed more through saturated sodium bicarbonate solution
It is secondary, organic phase is separated, rear filtering and concentrating is dried over anhydrous sodium sulfate, then purifies to obtain compound through column chromatography for separation
(8) under nitrogen protection, compoundIt is added in reaction flask with dimethyl sulfoxide,
Connection boric acid pinacol ester and potassium acetate are added, reaction system with nitrogen gas is passed through and catalyst Pd is added afterwards three times
(dppf)Cl2, it is passed through hydrogen displacement reaction system gas again and is heated to 100 DEG C afterwards three times and is reacted, reacts anti-to raw material
Should completely, reaction system is cooled to room temperature, and ethyl acetate is added, and it is multiple with saturated sodium chloride solution washing reaction liquid after stirring,
Again with the dry organic phase of anhydrous magnesium sulfate, purify to obtain compound through column chromatography for separation after concentration
(9) under nitrogen protection, compoundIt is added to 1,4- dioxane and goes
In ionized water, potassium phosphate and chlorobenzene or 4- chloropyridine are added, reaction system with nitrogen gas is passed through and catalysis is added afterwards three times
Agent Pd (dppf) Cl2, it is passed through reaction system with nitrogen gas is again heated to 90 DEG C afterwards three times and reacted, reaction to original
Material fully reacting, addition ethyl acetate extraction reaction solution is multiple after reaction temperature is cooled to room temperature, and uses and is saturated after merging organic phase
Sodium chloride solution washing, then with being concentrated after anhydrous sodium sulfate drying, purify to obtain target compound through column chromatography for separation
Further preferably, compound described in step (2)Molar ratio with alkali compounds is
1:1.5。
Further preferably, the mass ratio of ice and water is 5 in mixture of ice and water described in step (3):1.
Further preferably, compound described in step (6)With feeding intake mole for alkali compounds
Than being 3:4.
The comprehensive sulphur azatropylidene class compound of the present invention has calm, promotion growth hormone secretion, antiulcer and sterilization etc. excellent
Point, synthesized it is a kind of for human burn skin nursing sulphur azatropylidene medicinal compound and carried out antibacterial activity test,
It was found that such compound all has preferable inhibitory activity to the bacillus anthracis and Staphylococcus aureus that easily cause skin ulcer,
And then ointment is made and carries out clinical care experiment, discovery therapeutic effect is obvious.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
Under nitrogen protection, compound13.5g (0.1mol) is added to N,N-dimethylformamide
In 200mL, reaction temperature be cooled to after 10 DEG C be separately added into three batches N-bromosuccinimide 6.5g (total 19.5g,
0.11mol), restore that ethyl acetate 500mL is added after monitoring raw material fully reacting to room temperature reaction 12h, LCMS, stirring 2h is used
Saturated sodium chloride solution 300mL washing reaction liquid is free of n,N-Dimethylformamide into organic phase, and organic phase is through anhydrous slufuric acid
Magnesium is dry, and n-hexane 200mL is added after concentration, dilute hydrochloric acid solution 100mL is slowly added dropwise, and stirring to pulp under the conditions of 0 DEG C filters
After be dried to obtainHydrochloride, obtainedHydrochloride is added in water 100mL, uses
Hydrocarbon sodium oxide molybdena saturated solution adjusts reaction solution pH to 8, is extracted reaction solution 3 times with chloroform 50mL, merges organic phase, after concentration
It arrivesSterling 17.8g, yield 84%；212.9863 (Calcd of-HRMS ((+)-ESI) m/z=
212.9849for C6H5BrN4+H)。
Embodiment 2
In reaction flask, compound21g (0.1mol) and 3,3- dimethoxy methyl propionate 18g
(0.12mol) is added in tetrahydrofuran 80mL, and the sodium hydride 6g that mass fraction is 60% is added under the conditions of 0 DEG C after mixing
In the THF solution 50mL of (0.15mol), 30min is reacted after dripping, 25 DEG C is warming up to the reaction was continued 5h, be then cooled to 5
DEG C, the sodium citrate aqueous solution 60mL of 20wt% is added, separates organic phase after stirring 30min, methylene chloride is added after concentration
100mL, then washed twice with water 50mL, then be concentrated to get compound after being dried with anhydrous sodium sulfate22g, yield 67%；1H NMR(CDCl3,400MHz)δ9.75(s,1H),9.33 (d,J
=8.0,1H), 7.80-7.79 (m, 1H), 7.29 (d, J=8.0,1H), 4.56 (s, 1H), 3.66-3.64 (m, 6H), 2.43-
2.41(m,2H)。
Embodiment 3
In reaction flask, compound21g (0.1mol) and 3,3- dimethoxy methyl propionate 18g
(0.12mol) is added in tetrahydrofuran 80mL, and the THF of hydrofining 6g (0.15mol) is added under the conditions of 0 DEG C after mixing
In solution 50mL, 30min is reacted after dripping, 25 DEG C is warming up to the reaction was continued 5h, be then cooled to 5 DEG C, be added 20wt%'s
Sodium citrate aqueous solution 60mL separates organic phase after stirring 30min, methylene chloride 100mL is added after concentration, then with water 50mL
It washes twice, then is concentrated to get compound after being dried with anhydrous sodium sulfate29g, yield are
88.4%；1H NMR(CDCl3, 400MHz) and δ 9.75 (s, 1H), 9.33 (d, J=8.0,1H), 7.80-7.79 (m, 1H), 7.29
(d, J=8.0,1H), 4.56 (s, 1H), 3.66-3.64 (m, 6H), 2.43-2.41 (m, 2H).
Embodiment 4
In reaction flask, under the conditions of 0-5 DEG C, dissolved with compound330g(1mol)
Dichloromethane solution 2000mL, be slowly dropped in concentrated sulfuric acid 3000mL, be warming up to 60 DEG C after dripping, stir true after 2h
Empty concentration of reaction solution is cooled to 0 DEG C, and ice 5000g and water 1000g is added, and has a large amount of solids to be precipitated after stirring 2h, filters reaction
Liquid, filter cake washed once with water 2000mL and tert-butyl alcohol 2000mL respectively, and drying filter cake obtains compound190g, yield 72%；1H NMR(CDCl3,400MHz)δ12.69(s,1H),9.23(s, 1H),
8.19 (d, J=8.0,1H), 7.76 (s, 1H), 7.01 (d, J=4.0,1H)；13C NMR(CDCl3,400MHz)δ161.2,
156.9,133.2,132.7,122.6,118.4,115.9,99.3,86.7。
Embodiment 5
In reaction flask, compound26g (0.1mol) is added to toluene 200mL
In, lawesson reagent 40g (0.1mol) is added, 100 DEG C is heated to and is reacted, after TLC monitors raw material fully reacting, concentration is anti-
Liquid is answered, concentrate is added chloroform 300mL, is washed three times with saturated sodium bicarbonate solution 200mL, through silicagel column after organic phase concentration
Chromatography obtains compound18g, yield 64%；1H NMR(CDCl3,400 MHz)δ12.74
(s, 1H), 8.96 (s, 1H), 8.01-8.00 (s, 1H), 7.79 (s, 1H), 7.16 (d, J=4.0,1H).
Embodiment 6
In reaction flask, compound42g (0.15mol), 2-chloroethyl amine 12g (0.15mol)
It is added in tetrahydrofuran 150mL with the sodium hydride 8g (0.2mol) of 60wt% content, with reaction system with nitrogen gas three
Secondary, then heating reflux reaction 15h, is down to room temperature after TLC monitoring raw material fully reacting, dichloroethanes is added into reaction system
300mL stirs filtering reacting liquid after 10min, water 150mL is added after filtrate pressurization concentration, adds hydrochloric acid solution 22mL, uses second
Acetoacetic ester 120mL extracts reaction solution twice, and it is 10~11 that water phase, which adjusts pH through saturation sodium hydroxide solution, then with chloroform 150mL
Extraction 3 times merges organic phase, is concentrated to get compound after being dried with anhydrous sodium sulfate
32g, yield 66%；1H NMR(CDCl3,400MHz)δ8.83(s,1H),8.04 (s,1H),7.86-7.85(m,1H),
7.24 (d, J=8.0,1H), 5.33 (s, 2H), 3.57-3.55 (m, 2H), 2.81-2.79 (m, 2H)；Anal.Calcd for
C11H10BrN5S:C,40.75；H,3.11；N,21.60.Found:C,40.93；H,3.09；N, 21.55.
Embodiment 7
In reaction flask, compound42g (0.15mol), 2-chloroethyl amine 12g (0.15mol)
It is added in tetrahydrofuran 150mL with hydrofining 8g (0.2mol), three times with reaction system with nitrogen gas, then heats back
It is down to room temperature after stream reaction 12h, TLC monitoring raw material fully reacting, dichloroethanes 300mL, stirring are added into reaction system
Filtering reacting liquid after 10min is added water 150mL after filtrate pressurization concentration, adds hydrochloric acid solution 24mL, use ethyl acetate
120mL extracts reaction solution twice, and it is 10~11 that water phase, which adjusts pH through saturation sodium hydroxide solution, then extracts 3 with chloroform 150mL
It is secondary, merge organic phase, is concentrated to get compound after being dried with anhydrous sodium sulfate41g, yield
It is 84.8%；1H NMR(CDCl3,400MHz)δ8.83(s,1H), 8.04(s,1H),7.86-7.85(m,1H),7.24(d,J
=8.0,1H), 5.33 (s, 2H), 3.57-3.55 (m, 2H), 2.81-2.79 (m, 2H)；Anal.Calcd for
C11H10BrN5S:C,40.75；H,3.11；N,21.60.Found:C,40.93；H,3.09；N, 21.55.
Embodiment 8
In reaction flask, compound42g (0.13mol) and sodium bicarbonate 16.8g
(0.2mol) is added in water 100mL and methylene chloride 200mL, is cooled to 0 DEG C after mixing evenly, is slowly added dropwise dissolved with chloro-carbonic acid
The dichloromethane solution 100mL of benzyl ester 23.7g (0.139mol) reacts 2h at room temperature after dripping, it is anti-that TLC monitors raw material
After answering completely, organic phase is separated, water phase is extracted twice with methylene chloride 100mL, it is dried over anhydrous sodium sulfate after merging organic phase,
Compound is obtained after concentration52g, yield 87.5%.
Embodiment 9
In reaction flask, compound23g (0.05mol) and methane sulfonic acid 2g
(0.02mol) is added in toluene 500mL, is slowly heated to 70 DEG C, is slow added into paraformaldehyde 15g (0.5mol), is added
10h is reacted under the conditions of 70 DEG C afterwards, TLC monitors raw material fully reacting, is cooled to room temperature, filtering reacting liquid, filtrate is through saturated carbon
Sour hydrogen sodium solution 100mL washed once, and separate organic phase, be dried over anhydrous sodium sulfate rear filtering and concentrating, then chromatograph (PE through column:
EA=10:1) separating-purifying obtains compound15g, yield 65%；1H NMR(CDCl3,
400MHz) δ 8.78 (s, 1H), 8.30 (d, J=8.0,1H), 7.92 (s, 1H), 7.56-7.54 (m, 2H), 7.31-7.28 (m,
3H),5.17-5.15(m,2H),4.27(d,J1=4.0,2H), 3.34-3.32 (m, 2H), 3.11-3.10 (m, 2H).
Embodiment 10
In reaction flask, compound23g (0.05mol) and p-methyl benzenesulfonic acid
3.8g (0.02mol) is added in toluene 500mL, is slowly heated to 70 DEG C, is slow added into paraformaldehyde 15g (0.5mol), adds
10h is reacted after complete under the conditions of 70 DEG C, TLC monitors raw material fully reacting, is cooled to room temperature, filtering reacting liquid, filtrate is through being saturated
Sodium bicarbonate solution 100mL washed once, and separate organic phase, be dried over anhydrous sodium sulfate rear filtering and concentrating, then chromatograph through column
(PE:EA=10:1) separating-purifying obtains compound19.3g, yield 84%.
Embodiment 11
Under nitrogen protection, compound47g (0.1mol) and DMSO 1500mL add
Enter into reaction flask, add connection boric acid pinacol ester 51g (0.2mol) and potassium acetate 30g (0.3mol), is passed through nitrogen displacement
Catalyst Pd (dppf) Cl is added in reaction system gas afterwards three times22.5g is passed through hydrogen displacement reaction system gas three times again
After be slowly heated to 100 DEG C and reacted, react after 2h through LCMS monitoring raw material fully reacting, reaction system is cooled to room
Ethyl acetate 1400mL is added in temperature, uses saturated sodium chloride solution 500mL washing reaction liquid four times after stirring 30min, then with anhydrous
Magnesium sulfate dries organic phase, chromatographs (V petroleum ether through column after concentration:Ethyl acetate=15 V:1) separating-purifying obtains compound32g, yield 84%；1H NMR(CDCl3,400MHz)δ9.15 (s,1H),8.89(s,
1H), 8.51 (d, J=8.0,1H), 4.24 (d, J1=4.0,2H), 3.77-3.75 (m, 2H), 2.98-2.96 (m, 2H),
1.29(s,12H)。
Embodiment 12
Under nitrogen protection, compound38g (0.1mol) is added to 1,4- dioxy
In six ring 1000mL and deionized water 100mL, chlorobenzene 13g (0.12mol) and potassium phosphate 42g (0.2mol) are added, nitrogen is passed through
Gas replaces reaction system gas and catalyst Pd (dppf) Cl is added afterwards three times22g is passed through reaction system with nitrogen gas again
It is slowly heated to 90 DEG C afterwards three times to be reacted, raw material fully reacting is monitored by LCMS after reaction 3h, reaction temperature is cooled to
Ethyl acetate 800mL is added after room temperature to extract reaction solution 3 times, washs one with saturated sodium-chloride 500mL solution after merging organic phase
It is secondary, then with being concentrated after anhydrous sodium sulfate drying, (V methanol is chromatographed through column:Methylene chloride=3 V:1) separating-purifying obtains25g, yield 75%；1H NMR(CDCl3,400MHz)δ8.82(dd,J1=12.0, J2=
12.0,1H), 8.75 (s, 1H), 8.34 (d, J=8.0,1H), 7.91 (dd, J1=4.0, J2=4.0,2H), 7.23-7.21
(m,2H),7.15(s,1H),3.77-3.75(m,2H),2.86-2.85(m,2H),2.66(s,2H)；MS m/z=
334.4985(Calcd 334.4976for C18H15N5S+H).Anal.Calcd for C18H15N5S:C,64.84；H,4.53；
N, 21.01.Found:C,64.71；H,4.39；N,21.26.
Embodiment 13
Under nitrogen protection, compound38g (0.1mol) is added to 1,4- dioxy
In six ring 1000mL and deionized water 100mL, 4- chloropyridine 18g (0.12mol) and potassium phosphate 42g (0.2mol) are added, is led to
Enter reaction system with nitrogen gas and catalyst Pd (dppf) Cl is added afterwards three times22g is passed through reaction system with nitrogen again
Gas three times, is slowly heated to 90 DEG C, reacts after 3h by LCMS monitoring raw material fully reacting, after reaction temperature is cooled to room temperature
Ethyl acetate 800mL is added to extract reaction solution 3 times, washed once after merging organic phase with saturated sodium chloride solution 600mL, then use
It is concentrated after anhydrous sodium sulfate is dry, chromatographs (V methanol through column:Methylene chloride=3 V:1) separating-purifying obtains compound22g, yield 66%；1H NMR(CDCl3,400MHz)δ8.75(dd,J1=12.0, J2=
12.0,2H), 8.69 (d, J=8.0,1H), 8.34 (s, 1H), 7.98 (dd, J1=12.0, J2=12.0,2H), 4.23-4.21
(m, 2H), 3.04 (s, 2H), 2.98-2.97 (m, 2H), 2.87 (d, J=8.0,2H)；MS m/z=335.4246 (Calcd
335.4251for C17H14N6S+H).Anal.Calcd for C17H14N6S:C,61.06；H,4.22；N,25.13. Found:
C,60.93；H,4.19；N,24.97.
Embodiment 14
Under nitrogen protection, compound38g (0.1mol) is added to 1,4- dioxy
In six ring 1000mL and deionized water 100mL, 4- Chloperastine 14g (0.12mol) and potassium phosphate 42g (0.2mol) are added, is led to
Enter reaction system with nitrogen gas and catalyst Pd (dppf) Cl is added afterwards three times22g is passed through reaction system with nitrogen again
Gas three times, is slowly heated to 90 DEG C, reacts after 3h by LCMS monitoring raw material fully reacting, after reaction temperature is cooled to room temperature
Ethyl acetate 1200mL is added to extract reaction solution 3 times, washed once after merging organic phase with saturated sodium chloride solution 800mL, then
With being concentrated after anhydrous sodium sulfate drying, (V methanol is chromatographed through column:Methylene chloride=7 V:1) separating-purifying obtains compound19g, yield 56%；1H NMR(CDCl3, 400MHz) and δ 8.99 (d, J=12.0,1H),
8.52 (d, J=12.0,1H), 7.45 (s, 1H), 4.23-4.21 (m, 2H), 3.04 (s, 2H), 2.98-2.97 (m, 2H),
2.85 (s, 1H), 2.62 (d, J=8.0,2H), 2.54-2.53 (m, 2H), 2.07-2.06 (m, 2H), 1.87-1.85 (m, 2H)；
MS m/z=341.5167 (Calcd 341.5170for C17H20N6S+H).Anal.Calcd for C17H20N6S:C,
59.97；H, 5.92；N,24.69.Found:C,60.06；H,5.99；N,24.76.
Embodiment 15
The present embodiment selects bacillus anthracis and golden yellow glucose coccus as antibacterial activity test object.It is preparation solution first
Peptone 1g, yeast extract 0.5g, sodium chloride 1g, distilled water 100mL (are placed in 250mL conical flask, are placed on electric furnace by body culture medium
On heat while stirring, it is to be mixed clarification it is uniform when, stop heating, bottleneck gauze and brown paper are successively sealed for use) and
Peptone 1g, yeast extract 0.5g, sodium chloride 1g, agar 2g, distilled water 100mL (are placed in 250mL conical flask by solid medium
In, it is placed on electric furnace and heats while stirring, when clarification to be mixed is uniform, stop heating, successively by bottleneck gauze and brown paper
Sealing is stand-by)；Then sterilization treatment is carried out to culture medium by high-pressure sterilizing pot.The followed by preparation of bacterium solution, bacillus anthracis
After Staphylococcus aureus actication of culture, the bacterium solution after 100 μ L are activated is pipetted with liquid-transfering gun, is placed in sterilized 100mL distillation
It is uniformly mixed in water.It sterilizes, then culture medium is quickly poured into plate while hot, thickness to plate finally by ultraviolet lamp
About 0.15cm is uniformly paved, and is stood, is allowed its slow solidification, is put into cultivate one day in 37 DEG C of incubator after solidification and does no miscellaneous bacteria
Detection.
Synthesized target compound and control compound solution are respectively configured with DMF, is placed in volumetric flask stand-by.With beating
Hole device punches on filter paper, aperture 5mm, is immersed in the sample solution that concentration is 0.1mg/mL after then filter paper sterilizes
For use.
On superclean bench, alcolhol burner is lighted, takes the 10 diluted culture solutions of μ L to be added to solid culture base table with liquid-transfering gun
Face, and be coated with uniform.The garden filter paper impregnated is taken to be taped against media surface with aseptic nipper.Each plate puts 4, carries out 3
Secondary parallel laboratory test, wherein a piece of carry out blank control.The plate for being placed with tablet is placed in 37 DEG C of insulating boxs and is cultivated for 24 hours, observation
Phenomenon.It, can by measurement antibacterial circle diameter by occurring different size of transparent ring-inhibition zone on agar medium respectively
To find out the bacteriostatic activity size of each sample.
Embodiment 16
Under the conditions of 10 DEG C, water 40g and propylene glycol 20g is added in stirring container, adds glycerine 5g and peppermint oil
2g starts stirring, is added5g, sequentially add monoglyceride 4g, IPP12g, albolene 4g,
Nepal gold propyl ester 0.5g, nepal Gold methyl ester 1.5g, MAP emulsifier 3g and essence 3g, are stirred at a temperature of being maintained at 10 DEG C
2h to get arrive drug ointment.
Embodiment 17
Under the conditions of 10 DEG C, water 40g and propylene glycol 20g is added in stirring container, adds glycerine 5g and peppermint oil
2g starts stirring, is added5g, sequentially add monoglyceride 4g, IPP12g, albolene 4g,
Nepal gold propyl ester 0.5g, nepal Gold methyl ester 1.5g, MAP emulsifier 3g and essence 3g, are stirred at a temperature of being maintained at 10 DEG C
2h to get arrive drug ointment.
Embodiment 18
Under the conditions of 10 DEG C, water 40g and propylene glycol 20g is added in stirring container, adds glycerine 5g and peppermint oil
2g starts stirring, is added5g, sequentially add monoglyceride 4g, IPP12g, albolene 4g,
Nepal gold propyl ester 0.5g, nepal Gold methyl ester 1.5g, MAP emulsifier 3g and essence 3g, are stirred at a temperature of being maintained at 10 DEG C
2h to get arrive drug ointment.
Embodiment 19
For the fresh surface of a wound just burnt, give to use Iodophor or Povidone-Iodine Solution liquid disinfectant after being admitted to hospital, and remove the dirt on the surface of a wound
Object has bubble low level to break releasing hydrops, retains bubble skin.If peptone formation gives to steep skin and peptone is all removed.It is free
Or the downright bad Beancurd sheet of Zou's folding is removed, and it is primary to remove clean rear re-disinfection.Apply the drug of the invention for obtaining clinical care of burns
Ointment, dressing in 24 hours is primary, continuous dressing 3 times, and when each dressing should give surface of a wound debridement.
The drug ointment prepared using embodiment 16 handles 50 I degree burn patients, which is leg
Portion or arm or hand are burnt by boiled water or open fire or hot oil, and burn surface area 15%-25%, burn site is red and swollen, and blistering is broken
Skin phenomenon, serious person are rotted, the shapes such as wound deterioration infection, after drug ointment prepared by embodiment 16,75% disease
People fully recovers after 3 days, and 25% patient fully recovers after 7 days.
The drug ointment prepared using embodiment 17 handles 50 I degree burn patients, which is leg
Portion or arm or hand are burnt by boiled water or open fire or hot oil, and burn surface area 15%-25%, burn site is red and swollen, and blistering is broken
Skin phenomenon, serious person are rotted, the shapes such as wound deterioration infection, after drug ointment prepared by embodiment 17,75% disease
People fully recovers after 7 days, and 25% patient fully recovers after 10 days.
The ointment prepared using embodiment 18 handles 50 I degree burn patients, 50 patients be leg or
Arm or hand are burnt by boiled water or open fire or hot oil, and burn surface area 15%-25%, burn site is red and swollen, and it is existing broken skin occur for blistering
As serious person is rotted, and the shapes such as wound deterioration infection, after drug ointment prepared by embodiment 18,75% patient is 3
It fully recovers after it, 25% patient fully recovers after 6 days.
Embodiment 20
China certain, male, the age 24 years old, step was burnt, burn surface area 15%, apply the embodiment of the present invention 18 prepared by medicine
It after object ointment, fully recovers after 3 days, and preventing from scar after healing.
Embodiment 21
Gold certain, male, the age 32 years old, shank was burned, burn surface area 25%, apply the embodiment of the present invention 17 prepared by medicine
It after object ointment, fully recovers after 7 days, and preventing from scar after healing.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (5)
1. a kind of sulphur azatropylidene medicinal compound for human burn skin nursing, it is characterised in that the sulphur azatropylidene class medicine
The structural formula of compounds is：
Wherein R is phenyl, pyridyl group or piperidyl.
2. the preparation side of the sulphur azatropylidene medicinal compound according to claim 1 for human burn skin nursing
Method, it is characterised in that the specific steps are：
(1) under nitrogen protection, compoundIt is added in n,N-Dimethylformamide, reaction temperature is cooling
N-bromosuccinimide is separately added into after to 10 DEG C in batches, acetic acid second is added after restoring to room temperature reaction to raw material fully reacting
Ester, stirring a period of time is free of n,N-Dimethylformamide into organic phase with saturated sodium chloride solution washing reaction liquid, organic
It is mutually dry through anhydrous magnesium sulfate, n-hexane is added after concentration, dilute hydrochloric acid solution is slowly added dropwise, stirring to pulp under the conditions of 0 DEG C is taken out
It is dried to obtain after filterHydrochloride, obtainedHydrochloride is added to the water, and use is hydrocarbon
Sodium oxide molybdena saturated solution adjusts reaction solution pH to 8, multiple with chloroform extraction reaction solution, merges organic phase, obtains sterling after concentration
(2) compoundIt is added in tetrahydrofuran with 3,3- dimethoxy methyl propionate, after mixing
The THF solution of alkali compounds is added under the conditions of 0 DEG C, medium alkaline compound is sodium hydride or hydrofining, is risen after dripping
The reaction was continued to 25 DEG C for temperature, is then cooled to 5 DEG C and the sodium citrate aqueous solution that mass percentages are 20% is added, after stirring point
Methylene chloride is added after concentration in organic phase out, is washed with water repeatedly, then be concentrated to get compound after being dried with anhydrous sodium sulfate
(3) under the conditions of 0-5 DEG C, dissolved with compoundDichloromethane solution be added drop-wise to it is dense
In sulfuric acid, it is warming up to 60 DEG C after dripping, is concentrated in vacuo reaction solution after being stirred to react, is cooled to 0 DEG C, mixture of ice and water is added,
There are a large amount of solids to be precipitated after stirring, filter reaction solution, filter cake is washed with water and the tert-butyl alcohol respectively, and drying filter cake obtains compound
(4) compoundIt is added in toluene, adds lawesson reagent, be heated to 100 DEG C and carry out instead
It answers, concentration of reaction solution after raw material fully reacting, chloroform is added in concentrate, is washed repeatedly with saturated sodium bicarbonate solution, organic phase
Through the isolated compound of silica gel column chromatography after concentration
(5) in reaction flask, compound2-chloroethyl amine and alkali compounds are added to tetrahydrofuran
In, medium alkaline compound is sodium hydride or hydrofining, and with heating reflux reaction after reaction system with nitrogen gas, raw material is anti-
It is down to room temperature after answering completely, dichloroethanes is added, filtering reacting liquid after stirring is added water after filtrate decompression concentration and hydrochloric acid is molten
Liquid removes impurity with the mixed solution of ethyl acetate and n-hexane extraction reaction solution, and water phase is adjusted through saturation sodium hydroxide solution
PH is 10~11, then is extracted with chloroform, is concentrated to get compound after being dried with anhydrous sodium sulfate
(6) compoundIt is added in water and methylene chloride, stirs evenly with sodium bicarbonate
After be cooled to 0 DEG C, the dichloromethane solution dissolved with benzyl chloroformate is added dropwise, reacts to raw material and has reacted at room temperature after dripping
Entirely, organic phase is separated, water phase is extracted with dichloromethane repeatedly, is dried over anhydrous sodium sulfate after merging organic phase, obtains after concentration
Compound
(7) compoundIt is added in toluene with sulfonic compound, wherein sulphonic acids
Close object be methane sulfonic acid or p-methyl benzenesulfonic acid, be heated to 70 DEG C, add paraformaldehyde, reacted under the conditions of 70 DEG C after adding to
Raw material fully reacting, is cooled to room temperature, filtering reacting liquid, and filtrate is washed repeatedly through saturated sodium bicarbonate solution, separates organic phase,
It is dried over anhydrous sodium sulfate rear filtering and concentrating, then purifies to obtain compound through column chromatography for separation
(8) under nitrogen protection, compoundIt is added in reaction flask with dimethyl sulfoxide, then
Connection boric acid pinacol ester and potassium acetate is added, is passed through reaction system with nitrogen gas and catalyst Pd (dppf) is added afterwards three times
Cl2, it is passed through hydrogen displacement reaction system gas again and is heated to 100 DEG C afterwards three times and is reacted, reaction to raw material fully reacting,
Reaction system is cooled to room temperature, and ethyl acetate is added, multiple with saturated sodium chloride solution washing reaction liquid after stirring, then with anhydrous
Magnesium sulfate dries organic phase, purifies to obtain compound through column chromatography for separation after concentration
(9) under nitrogen protection, compoundIt is added to 1,4- dioxane and deionization
In water, potassium phosphate and chlorobenzene or 4- chloropyridine are added, reaction system with nitrogen gas is passed through and catalyst is added afterwards three times
Pd(dppf)Cl2, it is passed through reaction system with nitrogen gas is again heated to 90 DEG C afterwards three times and reacted, reaction to raw material
Fully reacting, addition ethyl acetate extraction reaction solution is multiple after reaction temperature is cooled to room temperature, and uses saturation after merging organic phase
Sodium chloride solution washing, then with being concentrated after anhydrous sodium sulfate drying, purify to obtain target compound through column chromatography for separation
3. the preparation side of the sulphur azatropylidene medicinal compound according to claim 2 for human burn skin nursing
Method, it is characterised in that：Compound described in step (2)With feeding intake mole for alkali compounds
Than being 1:1.5.
4. the preparation side of the sulphur azatropylidene medicinal compound according to claim 2 for human burn skin nursing
Method, it is characterised in that：The mass ratio of ice and water is 5 in mixture of ice and water described in step (3):1.
5. the preparation side of the sulphur azatropylidene medicinal compound according to claim 2 for human burn skin nursing
Method, it is characterised in that：Compound described in step (6)Molar ratio with alkali compounds is 3:4.
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| CN106543102A (en) * | 2016-10-28 | 2017-03-29 | 石家庄学院 | 1,5 benzothiazepines analog derivatives and its application |
| CN108191888A (en) * | 2018-02-09 | 2018-06-22 | 河南科技大学第附属医院（河南省显微外科研究所） | A kind of 1,4- sulphur azatropylidene medicinal compounds nursed for skin ulcer and its preparation method and application |
| CN108329334A (en) * | 2018-02-09 | 2018-07-27 | 河南科技大学第附属医院 | A kind of pyrazolo [1,5-a] pyridines drug molecule and its preparation method and application for skin ulcer nursing |
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| CN108191888A (en) * | 2018-02-09 | 2018-06-22 | 河南科技大学第附属医院（河南省显微外科研究所） | A kind of 1,4- sulphur azatropylidene medicinal compounds nursed for skin ulcer and its preparation method and application |
| CN108329334A (en) * | 2018-02-09 | 2018-07-27 | 河南科技大学第附属医院 | A kind of pyrazolo [1,5-a] pyridines drug molecule and its preparation method and application for skin ulcer nursing |
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