CN108997381A - A kind of pyrazolo [1,5-a] pyridines drug and preparation method thereof, composition and the application in skin ulcer patient nursing - Google Patents
A kind of pyrazolo [1,5-a] pyridines drug and preparation method thereof, composition and the application in skin ulcer patient nursing Download PDFInfo
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- 0 O*C(C1)CN1c1nc(-c(cn[n]2cc3)c2nc3-c2ccc[s]2)c(C=CC(N2)=O)c2c1 Chemical compound O*C(C1)CN1c1nc(-c(cn[n]2cc3)c2nc3-c2ccc[s]2)c(C=CC(N2)=O)c2c1 0.000 description 3
- BUSYZQYFRXBDPV-UHFFFAOYSA-N COC(C1)CN1c1nc(Cl)cc(N)c1 Chemical compound COC(C1)CN1c1nc(Cl)cc(N)c1 BUSYZQYFRXBDPV-UHFFFAOYSA-N 0.000 description 2
- OWSZVYUWTXSQOB-UHFFFAOYSA-N Brc(cn[n]1cc2)c1nc2-c1ccc[s]1 Chemical compound Brc(cn[n]1cc2)c1nc2-c1ccc[s]1 OWSZVYUWTXSQOB-UHFFFAOYSA-N 0.000 description 1
- AGJSLAFYCCABCG-DLYPDAMKSA-N C=C/C(/N(C1)CC1O)=N\C(\Cl)=C/CC(O)=O Chemical compound C=C/C(/N(C1)CC1O)=N\C(\Cl)=C/CC(O)=O AGJSLAFYCCABCG-DLYPDAMKSA-N 0.000 description 1
- GUNAPCKFWCGWBX-UHFFFAOYSA-N CC1(C)OB(c(cn[n]2cc3)c2nc3-c2ccc[s]2)OC1(C)C Chemical compound CC1(C)OB(c(cn[n]2cc3)c2nc3-c2ccc[s]2)OC1(C)C GUNAPCKFWCGWBX-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses a kind of pyrazolo [1,5-a] pyridines drug and preparation method thereof, composition and the applications nursed in skin ulcer patient, belong to medical synthesis technical field.Technical solution of the present invention main points are as follows: a kind of pyrazolo [1,5-a] pyridines drug molecule has following molecular structure:
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of pyrazolo [1,5-a] pyridines drug and its system
Preparation Method, composition and the application in skin ulcer patient nursing.
Background technique
Skin ulcer is common skin secondary lesion, and defect of skin or destruction reach corium or corium once, single-shot or more
Hair, acute stage ulcer expand rapidly, and surface is covered with necrotic tissue, exudate, incrustation, and ulcer margin red swelling of the skin has the cause of disease
It is complicated, the course of disease is long, easily repeatedly the features such as.After wrapping up patient skin ulcer spot, if ulcer alleviation is bad, it can lead
Bandage for dressing and ulcer wound is caused to bond, during dressing, very big pain can be brought to patient by more changing a bandage, therefore, how
Patient skin ulcer is effectively nursed, is all medical staff's very concern all the time.Currently, in order to reduce disease
Pain of the people in nursing process, medical staff generally use silver ion dressing to apply in clinic, have by using silver ion
There is bactericidal effect, ulcer spot is made quickly to be formed a scab, reduces the viscosity of bandage and wound, it is possible to reduce patient is more changing a bandage
Pain in the process is flamazine than more typical silver ion dressing.
Nitrogen-containing heterocycle compound is due to good bioactivity in human healths and the agricultural production such as medicine and pesticide
In play an important role.Especially pyrazoles and pyridine are exactly two kinds of important nitrogen-containing heterocycle compounds, and pyrazoles possesses a variety of
Physiological action, including analgesic, anti-inflammatory, bring down a fever, anti-arrhythmia, calmness, relaxed muscle, mental excitation, anti-spasm, monoamine
Oxidase inhibitor, anti-diabetic and antibacterial.Pyrazoles can be used as the intermediate of certain medicine, pesticide, in the research of medicine, pesticide
Occupy highly important status in exploitation.Pyrazole compound is due to its action spectrum is wide, drug effect is strong the features such as by increasingly
More concerns.Pyrazole compound has curative effect to many diseases in medical applications；On pesticides application, pyrazoles chemical combination
Object has desinsection, sterilization and activity of weeding, and shows efficient, less toxic and structure diversity.Therefore, pyrazoles drug has
Wide research and development prospect.Quinoline group is very important nitrogen-containing benzoheterocycle, has apparent removing to oxygen radical
Effect acts on clearly in terms of preparing anti-infective and anti-ulcer medicament, such as anti-ulcer medicament Rebamipide.Therefore it prepares
Drug molecule that is some while having pyrazoles, pyridine and quinoline has wide prospect in medicine.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of molecular structure novelty and antibacterial activity is significantly used for skin
Pyrazolo [1,5-a] pyridines drug molecule of ulcer care and preparation method thereof, pyrazolo [1,5-a] the pyridines drug point
Son can be used for preparing the pharmaceutical composition for skin ulcer nursing.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of pyrazolo for skin ulcer nursing
[1,5-a] pyridines drug molecule, it is characterised in that pyrazolo [1,5-a] the pyridines drug molecule has following molecule knot
Structure:
The preparation method of pyrazolo [1,5-a] pyridines drug molecule of the present invention for skin ulcer nursing,
It is characterized in that specific steps are as follows:
(1) under inert gas protection, compoundIt is added in Isosorbide-5-Nitrae-dioxane, adds
Ionized water, 2- thienyl boric acid and alkali compounds, the alkali compounds are potassium phosphate, potassium carbonate or saleratus, are set with nitrogen
It changes gas in reaction system three times, adds catalyst Pd (dppf) Cl2, continue with the air in reaction system with nitrogen
After be heated to 90 DEG C and reacted, reaction to raw material fully reacting is cooled to room temperature, and it is more that ethyl acetate extraction reaction solution is added
It is secondary, merge organic phase, organic phase is washed with saturated sodium chloride solution, then dry with anhydrous magnesium sulfate, through column chromatography point after concentration
Compound is obtained from purification
(2) under inert gas protection, compoundIt is added in n,N-Dimethylformamide,
N-bromosuccinimide is added portionwise under the conditions of 10 DEG C, 15~35 DEG C of reactions are warming up to after adding until after raw material fully reacting
Ethyl acetate is added, is free of N, N- dimethyl formyl into organic phase with saturated sodium chloride solution washing reaction liquid after mixing evenly
Amine, organic phase is dry through anhydrous magnesium sulfate, n-hexane is added after concentration, in the cooling condition stirring to pulp, dry after suction filtration
To compound
(3) under inert gas protection, compoundIt is added in reaction flask with dimethyl sulfoxide,
Connection boric acid pinacol ester and potassium acetate are added, hydrogen displacement reaction system gas is passed through and catalyst Pd is repeatedly added afterwards
(dppf)Cl2, be passed through again hydrogen displacement reaction system gas it is multiple after be heated to 100 DEG C and reacted, react anti-to raw material
Should completely, reaction system is cooled to room temperature, and ethyl acetate is added, more with saturated sodium chloride solution washing reaction liquid after mixing evenly
It is secondary, then organic phase is dried with anhydrous magnesium sulfate, it purifies to obtain compound through column chromatography for separation after concentration
(4) under nitrogen protection, the chloro- 4- methyl formate yl pyridines of 2,6- bis-, solvent N-methyl pyrilidone and 3- first
Oxygroup azetidine hydrochloride is added in reaction flask, is reacted at room temperature to raw material fully reacting, acetic acid second is added
Ester, after mixing evenly with saturated sodium chloride solution washing reaction liquid until without containing N-Methyl pyrrolidone, separation in organic phase
Organic phase is placed under cooling condition with methyl tertiary butyl ether(MTBE) is added after anhydrous sodium sulfate drying and is stirred mashing, filtered drying
Obtain the chloro- 4- methyl formate base -6- of 2- (3- methoxyl group azetidinyl) pyridine；
(5) under nitrogen protection, the chloro- 4- methyl formate base -6- of 2- (3- methoxyl group azetidinyl) pyridine is added
Into the mixed solution of tetrahydrofuran, methanol and deionized water, lithium hydroxide is added, 20~50 DEG C is warming up to and carries out reacting straight
To raw material fully reacting, reaction solution is cooled to room temperature, is concentrated in vacuo after filtering reacting liquid, dichloroethanes is added, in 0 DEG C of item
Stirring to pulp under part filters drying and obtains the chloro- 4- carboxyl -6- of 2- (3- methoxyl group azetidinyl) pyridine；
(6) the chloro- 4- carboxyl -6- of 2- (3- methoxyl group azetidinyl) pyridine and aminated compounds are added to toluene
In, which is triethylamine, ethylenediamine or diisopropylethylamine, be heated to 40~80 DEG C be stirred to react after open it is true
Sky obtains solution A after the one third of toluene additional amount is evaporated off；Benzylalcohol is added in toluene, toluene additional amount is evaporated off in normal pressure
1/5th obtain solution B；Under the conditions of solution A is placed in 10 DEG C, the toluene solution dropwise addition dissolved with diphenyl phosphate azide
Into solution A, it is warming up to room temperature after dripping, continues to be stirred to react to raw material fully reacting, be washed with saturated sodium bicarbonate solution
Solution A reaction solution is washed, the solid of washing process generation is filtered to remove, retains filtrate A；Solution B is heated to 85 DEG C, is protected in nitrogen
Under shield, filtrate A is added dropwise, adds toluene after dripping, the reaction was continued, saturation sodium hydroxide solution is then added into reaction solution,
10 DEG C are cooled to, there are a large amount of solids to be precipitated in whipping process, filter cake drying after water and methanol washing obtains compound after suction filtration
(7) in a high pressure reaction kettle, compoundIt is added in methanol, adds saturation
The palladium carbon that sodium hydroxide solution and mass percentage are 5%, it is multiple with gas in nitrogen displacement reaction flask, then replaced with hydrogen
Gas is multiple in reaction flask, and being passed through hydrogen makes pressure in reaction kettle reach 0.1MPa, carries out reaction at room temperature until former
Expect fully reacting, filtering reacting liquid, then active carbon is added into filtrate, filtered after stirring, concentration filtrate obtains compound
(8) compoundIt is added in tetrahydrofuran, mixes with 3,3- dimethoxy methyl propionate
Close uniformly after under the conditions of 0 DEG C be added sodium hydride THF it is molten in, reacted after dripping, then heating to 25 DEG C, the reaction was continued, then
It is cooled to 5 DEG C and the sodium citrate aqueous solution that mass percentage is 20% is added, separate organic phase after mixing evenly, add after concentration
Enter methylene chloride, be washed with water, then is concentrated to get compound after being dried with anhydrous sodium sulfate
(9) under 0~5 DEG C of reaction condition, dissolved with compoundMethylene chloride
Solution is added drop-wise in acid solution, which is the mixed acid of the concentrated sulfuric acid or the concentrated sulfuric acid and concentrated phosphoric acid, is heated up after dripping
It is concentrated in vacuo reaction solution after being reacted to 60 DEG C, is then cooled to 0 DEG C, ice and water is added, there are a large amount of solids to analyse after stirring
Out, reaction solution is filtered, filter cake is washed with water and the tert-butyl alcohol respectively, and drying filter cake obtains compound
(10) under nitrogen protection, compoundIt is added to 1,4- dioxane and deionization
In water, compound is addedAnd potassium phosphate, it is passed through reaction system with nitrogen gas and adds afterwards three times
Enter catalyst Pd (dppf) Cl2, it is passed through reaction system with nitrogen gas again it is heated to 90 DEG C afterwards three times and reacted, is reacted
To raw material fully reacting, reaction temperature be cooled to room temperature after be added ethyl acetate extraction reaction solution, merge organic phase after through being saturated
Sodium chloride solution washing with being concentrated after anhydrous sodium sulfate drying, purifies to obtain target product through column chromatography for separation again
Further preferably, compound described in step (1)Molar ratio with alkali compounds is
1:1.5。
Further preferably, compound described in step (3)Connection boric acid pinacol ester and potassium acetate
Molar ratio be 1:1:3.
Further preferably, the chloro- 4- methyl formate yl pyridines of 2,6- bis- described in step (4) and solvent N-methyl pyrilidone
Feed intake mass ratio be 1:5~15, preferably 1:10.
Further preferably, the chloro- 4- carboxyl -6- of 2- described in step (6) (3- methoxyl group azetidinyl) pyridine and amine
The molar ratio of class compound is 1:1.5；The chloro- 4- carboxyl -6- of 2- (the 3- methoxyl group azetidinyl) pyridine and folded
The molar ratio of nitrogen diphenyl phosphate is 1:1.
Further preferably, in the concentrated sulfuric acid described in step (9) and the mixed acid of concentrated phosphoric acid the concentrated sulfuric acid and concentrated phosphoric acid quality
Than for 1:2；The compoundThe mass ratio that feeds intake with acid solution is 1:20~40.
Pharmaceutical composition of the present invention for skin ulcer nursing, it is characterised in that the pharmaceutical composition is by matter
Amount is than the compound for 5:4:12:4:0.5:20:1.5:5:3:3:2:40Monoglyceride,
IPP, albolene, Nepal's gold propyl ester, propylene glycol, nepal Gold methyl ester, glycerine, MAP emulsifier, essence, peppermint oil and
The drug ointment that water is configured to.
Further preferably, the skin ulcer is as caused by staphylococcus epidermis or/and Staphylococcus aureus.
The comprehensive sulphur azatropylidene class compound of the present invention has calm, promotion growth hormone secretion, antiulcer, sterilization etc. excellent
Point, synthesized it is a kind of for skin ulcer nursing pyrazolo [1,5-a] pyridines drug molecule and carried out antibacterial activity survey
Examination, it is found that such compound all has preferable suppression to the staphylococcus epidermis and Staphylococcus aureus that easily cause skin ulcer
System activity, and then drug ointment is made and carries out clinical care experiment, discovery nursing efficacy 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, compound15g (0.1mol) is added in Isosorbide-5-Nitrae-dioxane 150mL,
Deionized water 30g, 2- thienyl boric acid 15g (0.12mol) and potassium phosphate 32g (0.15mol) are added, with nitrogen displacement reactant
Gas in system three times, adds catalyst Pd (dppf) Cl20.3g continues with the gas three in reaction system with nitrogen
Secondary to be heated to 90 DEG C and reacted, LCMS monitors raw material fully reacting after reacting 3h, is cooled to room temperature, and ethyl acetate is added
200mL extracts reaction solution three times, merges organic phase, and it is primary to wash organic phase with saturated sodium chloride solution 200mL, then with anhydrous sulphur
Sour magnesium is dry, obtains compound through column chromatography (V methanol: V methylene chloride=2:1) separating-purifying after concentration
16g, yield 80%；1H NMR(CDCl3, 400MHz) and δ 8.91 (d, J=8.0Hz, 1H), 8.37 (d, J=8.0Hz, 1H),
7.77-7.75(m,2H),7.62-7.61(m,1H),7.46(s,1H),6.34-6.33(m,1H)。
Embodiment 2
Under nitrogen protection, compound15g (0.1mol) is added to 1,4- dioxane 150mL
In, deionized water 30g, 2- thienyl boric acid 15g (0.12mol) and potassium carbonate 20.7g (0.15mol) are added, is replaced with nitrogen
Gas in reaction system three times, adds catalyst Pd (dppf) Cl20.3g continues in reaction system with nitrogen
Gas is heated to 90 DEG C afterwards three times and is reacted, and LCMS monitors raw material fully reacting after reacting 3h, is cooled to room temperature, and acetic acid is added
Ethyl ester 200mL extracts reaction solution three times, merges organic phase, it is primary to wash organic phase with saturated sodium chloride solution 200mL, then use nothing
Water magnesium sulfate is dry, obtains compound through column chromatography (V methanol: V methylene chloride=2:1) separating-purifying after concentration15g, yield 75%；1H NMR(CDCl3, 400MHz) and δ 8.91 (d, J=8.0Hz, 1H), 8.37
(d, J=8.0Hz, 1H), 7.77-7.75 (m, 2H), 7.62-7.61 (m, 1H), 7.46 (s, 1H), 6.34-6.33 (m, 1H).
Embodiment 3
Under nitrogen protection, compound15g (0.1mol) is added to 1,4- dioxane 150mL
In, deionized water 30g, 2- thienyl boric acid 15g (0.12mol) and saleratus 15g (0.15mol) are added, is replaced with nitrogen
Gas in reaction system three times, adds catalyst Pd (dppf) Cl20.3g continues in reaction system with nitrogen
Gas is heated to 90 DEG C afterwards three times and is reacted, and LCMS monitors raw material fully reacting after reacting 3h, is cooled to room temperature, and acetic acid is added
Ethyl ester 200mL extracts reaction solution three times, merges organic phase, it is primary to wash organic phase with saturated sodium chloride solution 200mL, then use nothing
Water magnesium sulfate is dry, obtains compound through column chromatography (V methanol: V methylene chloride=2:1) separating-purifying after concentration9g, yield 45%；1H NMR(CDCl3, 400MHz) and δ 8.91 (d, J=8.0Hz, 1H), 8.37 (d, J
=8.0Hz, 1H), 7.77-7.75 (m, 2H), 7.62-7.61 (m, 1H), 7.46 (s, 1H), 6.34-6.33 (m, 1H).
Embodiment 4
Under nitrogen protection, compound20g (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 9.0g (total 27g,
0.15mol), restore that ethyl acetate 1000mL is added after to 15 DEG C of reaction 12h, LCMS monitoring raw material fully reactings after adding, stir
Use saturated sodium chloride solution washing reaction liquid into organic phase without n,N-Dimethylformamide after mixing 10min, organic phase is through nothing
Water magnesium sulfate 30g is dry, addition n-hexane 100mL after concentration, stirring to pulp under the conditions of 0 DEG C, is dried to obtain chemical combination after suction filtration
Object21g, yield 75%, HPLC purity are 98.7%；1H NMR(CDCl3,400MHz) δ8.98-
8.97(m,1H),8.16-8.15(m,1H),7.85-7.83(m,2H),7.70-7.69(m,1H),6.95-6.94(m, 1H)。
Embodiment 5
Under nitrogen protection, compound20g (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 9.0g (total 27g,
0.15mol), restore that ethyl acetate 1000mL is added after to 25 DEG C of reaction 12h, LCMS monitoring raw material fully reactings after adding, stir
Use saturated sodium chloride solution washing reaction liquid into organic phase without n,N-Dimethylformamide after mixing 10min, organic phase is through nothing
Water magnesium sulfate 30g is dry, addition n-hexane 100mL after concentration, stirring to pulp under the conditions of 0 DEG C, is dried to obtain chemical combination after suction filtration
Object23g, yield 82%, HPLC purity are 96.9%；1H NMR(CDCl3,400MHz) δ8.98-
8.97(m,1H),8.16-8.15(m,1H),7.85-7.83(m,2H),7.70-7.69(m,1H),6.95-6.94(m, 1H)。
Embodiment 6
Under nitrogen protection, compound20g (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 9.0g (total 27g,
0.15mol), restore that ethyl acetate 1000mL is added after to 35 DEG C of reaction 12h, LCMS monitoring raw material fully reactings after adding, stir
Use saturated sodium chloride solution washing reaction liquid into organic phase without n,N-Dimethylformamide after mixing 10min, organic phase is through nothing
Water magnesium sulfate 30g is dry, addition n-hexane 100mL after concentration, stirring to pulp under the conditions of 0 DEG C, is dried to obtain chemical combination after suction filtration
Object25g, yield 89.2%, HPLC purity are 94.7%；1H NMR(CDCl3,400 MHz)δ8.98-
8.97(m,1H),8.16-8.15(m,1H),7.85-7.83(m,2H),7.70-7.69(m,1H),6.95-6.94 (m,1H)。
Embodiment 7
Under nitrogen protection, compound28g (0.1mol) and dimethyl sulfoxide 250mL are added to
In reaction flask, connection boric acid pinacol ester 25g (0.1mol) and potassium acetate 30g (0.3mol) are added, is passed through hydrogen displacement reaction
Catalyst Pd (dppf) Cl is added in system gas afterwards three times20.5g adds afterwards three times again by hydrogen displacement reaction system gas
Heat is reacted to 100 DEG C, is reacted and is monitored raw material fully reacting by LCMS after 2h, reaction system is cooled to room temperature, addition second
Acetoacetic ester 150mL is used saturated sodium chloride solution 50mL washing reaction liquid four times after stirring 30min, then dry with anhydrous magnesium sulfate
Organic phase chromatographs (V through column after concentrationPE:VEA=5:1) separating-purifying obtains compound26g is received
Rate 78.8%；1H NMR(CDCl3, 400MHz) and δ 9.06 (d, J=8.0Hz, 1H), (m, 1H), 8.75 (s, 1H), 8.22-8.21
(m, 1H), 7.73 (d, J=4.0Hz, 1H), 7.14 (d, J=4.0Hz, 1H), 1.25-1.23 (m, 12H),13C NMR
(CDCl3,400MHz)δ169.2,158.3,156.6,141.7,133.2,132.6, 127.1,116.6,103.4,81.8,
69.3,26.1。
Embodiment 8
Under nitrogen protection, the chloro- 4- methyl formate yl pyridines 20g (0.1mol) of 2,6- bis- and N-Methyl pyrrolidone
100g, 3- methoxyl group azetidine hydrochloride 12g (0.1mol) are added in reaction flask, react 10h at room temperature,
LCMS monitors raw material fully reacting, and ethyl acetate 1000mL is added, and uses saturated sodium chloride solution washing reaction after stirring 10min
Liquid separates organic phase until not containing N-Methyl pyrrolidone in organic phase, with addition methyl- tert fourth after anhydrous sodium sulfate drying
Base ether 100mL is stirred mashing under the conditions of being placed in 10 DEG C, filter drying and obtain chloro- 4- methyl formate base -6- (the 3- methoxy of 2-
Base azetidinyl) pyridine15g, yield 26%；- HRMS ((+)-ESI): m/z=
257.6957(calcd.257.6955 for C11H14ClN2O3,[M+H]+)。
Embodiment 9
Under nitrogen protection, the chloro- 4- methyl formate yl pyridines 20g (0.1mol) of 2,6- bis- and N-Methyl pyrrolidone
200g, 3- methoxyl group azetidine hydrochloride 12g (0.1mol) are added in reaction flask, react 10h at room temperature,
LCMS monitors raw material fully reacting, and ethyl acetate 1000mL is added, and uses saturated sodium chloride solution washing reaction after stirring 10min
Liquid separates organic phase until not containing N-Methyl pyrrolidone in organic phase, with addition methyl- tert fourth after anhydrous sodium sulfate drying
Base ether 100mL is stirred mashing under the conditions of being placed in 10 DEG C, filter drying and obtain chloro- 4- methyl formate base -6- (the 3- methoxy of 2-
Base azetidinyl) pyridine21g, yield 84%；- HRMS ((+)-ESI): m/z=
257.6957(calcd.257.6955 for C11H14ClN2O3,[M+H]+)。
Embodiment 10
Under nitrogen protection, the chloro- 4- methyl formate yl pyridines 20g (0.1mol) of 2,6- bis- and N-Methyl pyrrolidone
300g, 3- methoxyl group azetidine hydrochloride 12g (0.1mol) are added in reaction flask, react 10h at room temperature,
LCMS monitors raw material fully reacting, and ethyl acetate 1000mL is added, and uses saturated sodium chloride solution washing reaction after stirring 10min
Liquid separates organic phase until not containing N-Methyl pyrrolidone in organic phase, with addition methyl- tert fourth after anhydrous sodium sulfate drying
Base ether 100mL is stirred mashing under the conditions of being placed in 10 DEG C, filter drying and obtain chloro- 4- methyl formate base -6- (the 3- methoxy of 2-
Base azetidinyl) pyridine 18g, yield 69%；- HRMS ((+)-ESI): m/z=257.6957 (calcd.257.6955
for C11H14ClN2O3,[M+H]+)。
Embodiment 11
Under nitrogen protection, the chloro- 4- methyl formate base -6- of 2- (3- methoxyl group azetidinyl) pyridine 25g
(0.1mol) is added in the mixed liquor of tetrahydrofuran 400mL, methanol 400mL and deionized water 200mL, adds lithium hydroxide
5g (0.2mol) is to slowly warm up to 20 DEG C, and LCMS monitors raw material fully reacting after reacting 2h, reaction solution is cooled to room temperature, mistake
It is concentrated in vacuo after filter reaction solution, adds dichloroethanes 400mL, stirring to pulp under the conditions of 0 DEG C, it is chloro- that suction filtration drying obtains 2-
4- carboxyl -6- (3- methoxyl group azetidinyl) pyridine22g, yield 92%；1H NMR
(DMSO-d6,400MHz)δ11.32(s,2H),7.79(s,1H),6.74-6.73(m,1H),3.89-3.87(m,2H),
3.52-3.50 (m, 1H), 3.29 (s, 3H) ,-HRMS ((+)-ESI): m/z=241.6681 (calcd.241.6673 for
C10H10ClN2O3,[M-H]-)。
Embodiment 12
Under nitrogen protection, the chloro- 4- methyl formate base -6- of 2- (3- methoxyl group azetidinyl) pyridine (0.1mol)
It is added in the mixed liquor of tetrahydrofuran 400mL, methanol 400mL and deionized water 200mL, adds lithium hydroxide 5g
(0.2mol) is to slowly warm up to 30 DEG C, and LCMS monitors raw material fully reacting after reacting 2h, and reaction solution is cooled to room temperature, and filters
It is concentrated in vacuo after reaction solution, adds dichloroethanes 400mL, stirring to pulp under the conditions of 0 DEG C filters drying and obtains the chloro- 4- of 2-
Carboxyl -6- (3- methoxyl group azetidinyl) pyridine17g, yield 71%；1H NMR
(DMSO-d6,400MHz)δ11.32(s,2H),7.79(s,1H),6.74-6.73(m,1H),3.89-3.87(m,2H),
3.52-3.50 (m, 1H), 3.29 (s, 3H) ,-HRMS ((+)-ESI): m/z=241.6681 (calcd.241.6673 for
C10H10ClN2O3,[M-H]-)。
Embodiment 13
Under nitrogen protection, the chloro- 4- methyl formate base -6- of 2- (3- methoxyl group azetidinyl) pyridine (0.1mol)
It is added in the mixed liquor of tetrahydrofuran 400mL, methanol 400mL and deionized water 200mL, adds lithium hydroxide 5g
(0.2mol) is to slowly warm up to 50 DEG C, and LCMS monitors raw material fully reacting after reacting 2h, and reaction solution is cooled to room temperature, and filters
It is concentrated in vacuo after reaction solution, adds dichloroethanes 400mL, stirring to pulp under the conditions of 0 DEG C filters drying and obtains the chloro- 4- of 2-
Carboxyl -6- (3- methoxyl group azetidinyl) pyridine14g, yield 58%；1H NMR
(DMSO-d6,400MHz)δ11.32(s,2H),7.79(s,1H),6.74-6.73(m,1H),3.89-3.87(m,2H),
3.52-3.50 (m, 1H), 3.29 (s, 3H) ,-HRMS ((+)-ESI): m/z=241.6681 (calcd.241.6673 for
C10H10ClN2O3,[M-H]-)。
Embodiment 14
In reaction flask, compound24g (0.1mol) and diisopropylethylamine 20g
(0.15mol) is added in toluene 300mL, is heated to 80 DEG C, opens vacuum after being stirred to react 1h, is obtained after toluene 100mL is evaporated off
To solution A；Benzylalcohol 32g (0.3mol) is added in toluene 1000mL, is heated to 130 DEG C, toluene 200mL is evaporated off, is mixed
Close liquid B；Solution A as under the conditions of 10 DEG C, the toluene solution 1000mL dissolved with diphenyl phosphate azide 27g (0.1mol) is delayed
Slowly it is added drop-wise in solution A, is slowly increased to room temperature after dripping, continue to be stirred to react 3h, after TLC monitors raw material fully reacting, use
Saturated sodium bicarbonate solution 500mL washs solution A reaction solution three times, is filtered to remove the solid of washing process generation, retains filtrate
A；Solution B is heated to 85 DEG C, under nitrogen protection, filtrate A is slowly added dropwise, toluene 100mL is added after dripping, the reaction was continued
Saturation sodium hydroxide solution 1000mL is added in phase reaction liquid, is cooled to 10 DEG C, has a large amount of solids to be precipitated in whipping process by 5h,
Filter cake drying after water 1000mL and methanol 300mL washing obtains compound after suction filtration20g is received
Rate is 57% ,-HRMS ((+)-ESI): m/z=348.8033 (calcd.348.8029 for C17H19ClN3O3,[M+H]+)。
Embodiment 15
In reaction flask, compound24g (0.1mol) and ethylenediamine 8g (0.15mol)
It is added in toluene 300mL, is heated to 40 DEG C, open vacuum after being stirred to react 1h, obtain solution A after toluene 100mL is evaporated off；?
Benzylalcohol 32g (0.3mol) is added in toluene 1000mL, is heated to 130 DEG C, and toluene 200mL is evaporated off, obtains mixed liquid B；Molten
Liquid A is slowly dropped to the toluene solution 1000mL dissolved with diphenyl phosphate azide 27g (0.1mol) molten as under the conditions of 10 DEG C
In liquid A, it is slowly increased to room temperature after dripping, continues to be stirred to react 3h, after TLC monitors raw material fully reacting, with unsaturated carbonate hydrogen
Sodium solution 500mL washs solution A reaction solution three times, is filtered to remove the solid of washing process generation, retains filtrate A；Solution B plus
Heat is to 85 DEG C, under nitrogen protection, filtrate A is slowly added dropwise, toluene 100mL is added after dripping, the reaction was continued 5h, phase reaction liquid
Middle addition is saturated sodium hydroxide solution 1000mL, is cooled to 10 DEG C, has a large amount of solids to be precipitated in whipping process, filter cake after suction filtration
Drying obtains compound after water 1000mL and methanol 300mL washing31g, yield 85% ,-
HRMS ((+)-ESI): m/z=348.8033 (348.8029 for C of calcd.17H19ClN3O3,[M+H]+)。
Embodiment 16
In reaction flask, compound24g (0.1mol) and triethylamine 15g (0.15mol)
It is added in toluene 300mL, is heated to 60 DEG C, opens vacuum after being stirred to react 1h, obtain solution A after toluene 100mL is evaporated off；Benzyl
Alcohol 32g (0.3mol) is added in toluene 1000mL, is heated to 130 DEG C, and toluene 200mL is evaporated off, obtains mixed liquid B；Solution A
Under the conditions of 10 DEG C, the toluene solution 1000mL dissolved with diphenyl phosphate azide 27g (0.1mol) is slowly dropped to solution A
In, it is slowly increased to room temperature after dripping, continues to be stirred to react 3h, it is molten with saturated sodium bicarbonate after TLC monitors raw material fully reacting
Liquid 500mL washs solution A reaction solution three times, is filtered to remove the solid of washing process generation, retains filtrate A；Solution B is heated to
85 DEG C, under nitrogen protection, filtrate A is slowly added dropwise, toluene 100mL is added after dripping, the reaction was continued 5h, in phase reaction liquid plus
Enter to be saturated sodium hydroxide solution 1000mL, be cooled to 10 DEG C, there are a large amount of solids to be precipitated in whipping process, filter cake is through water after suction filtration
Drying obtains compound after 1000mL and methanol 300mL washing29g, yield 82.8% ,-
HRMS ((+)-ESI): m/z=348.8033 (calcd.348.8029 for C17H19ClN3O3,[M+H]+)。
Embodiment 17
In a high pressure reaction kettle,35g (0.1mol) is added in methanol 500mL, adds
It is saturated sodium hydroxide solution 1000mL, adds the palladium carbon 2g that content is 5%, three times with gas in nitrogen displacement reaction flask, then
Twice with hydrogen displacement, being passed through hydrogen makes pressure in kettle reach 0.1MPa, reacts 2h at room temperature, it is anti-that TLC monitors raw material
Should completely, filtering reacting liquid, then active carbon 10g is added into filtrate, it is filtered after stirring 20min, concentration filtrate obtains17g, yield 81%；1H NMR(CDCl3,400MHz)δ6.55(s,2H),6.17(s, 1H),
5.86 (d, J=8.0,1H), 3.79-3.78 (m, 1H), 3.64-3.61 (m, 4H), 3.22 (s, 3H).
Embodiment 18
In reaction flask, compound21g (0.1mol) and 3,3- dimethoxy methyl propionate
18g (0.12mol) is added in tetrahydrofuran 80mL, and sodium hydride 6g (0.15mol) is added under the conditions of 0 DEG C after mixing
THF solution 50mL in, react 30min after dripping, be warming up to 25 DEG C the reaction was continued 5h, be then cooled to 5 DEG C, quality is added
The sodium citrate aqueous solution 60mL that percentage composition is 20% separates organic phase after stirring 30min, methylene chloride is added after concentration
100mL is washed twice with water 50mL, then is concentrated to get compound after being dried with anhydrous sodium sulfate29g, yield 87.8% ,-HRMS ((+)-ESI): m/z=330.7862 (calcd.
330.7855 for C14H21ClN3O4,[M+H]+)。
Embodiment 19
In reaction flask, under the conditions of 0~5 DEG C, dissolved with compound33g
The dichloromethane solution 700mL of (0.1mol), is slowly dropped in concentrated sulfuric acid 1000g, 60 DEG C is warming up to after dripping, stirring
It is concentrated in vacuo reaction solution after 2h, is cooled to 0 DEG C, ice 2000g and water 500g is added, there are a large amount of solids to be precipitated after stirring 1h, filters
Reaction solution, filter cake washed once with water 1000mL and tert-butyl alcohol 1000mL respectively, and drying filter cake obtains compound22g, yield 83%；1H NMR(CDCl3,400MHz)δ8.46(s,1H),6.49(s,
1H), 5.93 (d, J=8.0,1H), 3.80 (s, 1H), 3.56-3.53 (m, 4H), 3.53 (s, 3H)；Anal.Calcd for
C12H12ClN3O2:C,54.25；H,4.55；N,15.82.Found:C,54.41；H,4.67；N,15.68.
Embodiment 20
In reaction flask, under the conditions of 0~5 DEG C, dissolved with compound33g
The dichloromethane solution 700mL of (0.1mol), is slowly dropped in concentrated sulfuric acid 660g, and 60 DEG C are warming up to after dripping, and stirs 2h
After be concentrated in vacuo reaction solution, be cooled to 0 DEG C, ice 2000g and water 500g be added, there are a large amount of solids to be precipitated after stirring 1h, filter anti-
Liquid is answered, filter cake washed once with water 1000mL and tert-butyl alcohol 1000mL respectively, and drying filter cake obtains compound14g, yield 52%；1H NMR(CDCl3,400MHz)δ8.46(s,1H),6.49(s,
1H), 5.93 (d, J=8.0,1H), 3.80 (s, 1H), 3.56-3.53 (m, 4H), 3.53 (s, 3H)；Anal.Calcd for
C12H12ClN3O2:C,54.25；H,4.55；N,15.82.Found:C,54.41；H,4.67；N,15.68.
Embodiment 21
In reaction flask, under the conditions of 0~5 DEG C, dissolved with compound33g
The dichloromethane solution 700mL of (0.1mol), is slowly dropped in concentrated sulfuric acid 1320g, 60 DEG C is warming up to after dripping, stirring
It is concentrated in vacuo reaction solution after 2h, is cooled to 0 DEG C, ice 2000g and water 500g is added, there are a large amount of solids to be precipitated after stirring 1h, filters
Reaction solution, filter cake washed once with water 2000mL and tert-butyl alcohol 1500mL respectively, and drying filter cake obtains compound20g, yield 74%；1H NMR(CDCl3,400MHz)δ8.46(s,1H),6.49(s,
1H), 5.93 (d, J=8.0,1H), 3.80 (s, 1H), 3.56-3.53 (m, 4H), 3.53 (s, 3H)；Anal.Calcd for
C12H12ClN3O2:C,54.25；H,4.55；N,15.82.Found:C,54.41；H,4.67；N,15.68.
Embodiment 22
In reaction flask, under the conditions of 0~5 DEG C, dissolved with compound33g
The dichloromethane solution 700mL of (0.1mol), being slowly dropped to the mixed acid of the concentrated sulfuric acid and concentrated phosphoric acid, (m (concentrated sulfuric acid): m is (dense
Phosphoric acid)=1:2) in 660g, 60 DEG C are warming up to after dripping, it is concentrated in vacuo reaction solution after stirring 2h, is cooled to 0 DEG C, ice is added
2000g and water 500g has a large amount of solids to be precipitated, filters reaction solution after stirring 1h, and filter cake uses water 500mL and the tert-butyl alcohol respectively
1000mL washed once, and drying filter cake obtains compound23g, yield 85%；1H NMR
(CDCl3, 400MHz) and δ 8.46 (s, 1H), 6.49 (s, 1H), 5.93 (d, J=8.0,1H), 3.80 (s, 1H), 3.56-3.53
(m,4H), 3.53(s,3H)；Anal.Calcd for C12H12ClN3O2:C,54.25；H,4.55；N,15.82.Found:C,
54.41；H, 4.67；N,15.68.
Embodiment 23
In reaction flask, under the conditions of 0~5 DEG C, dissolved with compound33g
The dichloromethane solution 700mL of (0.1mol), being slowly dropped to the mixed acid of the concentrated sulfuric acid and concentrated phosphoric acid, (m (concentrated sulfuric acid): m is (dense
Phosphoric acid)=1:2) in 1000g, 60 DEG C are warming up to after dripping, it is concentrated in vacuo reaction solution after stirring 2h, is cooled to 0 DEG C, is added
Ice 2000g and water 500g has a large amount of solids to be precipitated, filters reaction solution after stirring 1h, and filter cake uses water 800mL and the tert-butyl alcohol respectively
1200mL washed once, and drying filter cake obtains compound25g, yield 93%；1H NMR
(CDCl3, 400MHz) and δ 8.46 (s, 1H), 6.49 (s, 1H), 5.93 (d, J=8.0,1H), 3.80 (s, 1H), 3.56-3.53
(m,4H), 3.53(s,3H)；Anal.Calcd for C12H12ClN3O2:C,54.25；H,4.55；N,15.82.Found:C,
54.41；H, 4.67；N,15.68.
Embodiment 24
Under nitrogen protection, compound33g (0.1mol) is added to 1,4- dioxane
In 1000mL and deionized water 500mL, compound is added32g (0.12mol) and potassium phosphate
Catalyst Pd (dppf) Cl is added by reaction system with nitrogen gas in 42g (0.2mol) afterwards three times21.6g, again by
Reaction system with nitrogen gas is heated to 90 DEG C afterwards three times and is reacted, and has been reacted after reacting 3h by LCMS monitoring raw material
Entirely, ethyl acetate 1000mL is added after reaction temperature is cooled to room temperature to extract reaction solution 3 times, uses saturation chlorination after merging organic phase
Sodium solution washed once, then with being concentrated after anhydrous sodium sulfate drying, chromatograph (V through columnPE:VEA=5:1) separating-purifying obtains chemical combination
Object34g, yield 79%；1H NMR (DMSO-d6,400MHz) δ 9.24 (d, J=
12.0,1H),9.13-9.12(m,1H),8.97(s,1H),8.62-8.60(m,2H),7.16-7.15(m,1H), 6.82(s,
1H), 5.82 (s, 1H), 3.98-3.95 (m, 4H), 3.80 (s, 1H), 3.74 (d, J=8.0,2H), 3.53 (s, 3H)；MS m/z
=431.5023 (431.5036 for C of Calcd22H18N6O2S+H).Anal.Calcd for C22H18N6O2S:C,61.38；
H,4.21；N,19.52.Found:C,61.45；H,4.27；N,19.66.
Embodiment 25
The present embodiment selects staphylococcus epidermis and Staphylococcus aureus as antibacterial activity test object.It prepares first
Peptone 1g, yeast extract 0.5g, sodium chloride 1g, distilled water 100mL (are placed in 250mL conical flask, are placed on electricity by fluid nutrient medium
Heated while stirring on furnace, it is to be mixed clarification it is uniform when, stop heating, bottleneck gauze and brown paper are successively sealed for use)
(peptone 1g, yeast extract 0.5g, sodium chloride 1g, agar 2g, distilled water 100mL are placed in 250mL conical flask with 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, epidermis grape
After coccus and 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
It is uniformly mixed in distilled water.It sterilizes finally by ultraviolet lamp to plate, then culture medium is quickly poured into plate while hot,
Thickness 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 nothing
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 26
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, and compound is added5g sequentially adds monoglyceride 4g, IPP 12g, white
Vaseline 4g, Nepal gold propyl ester 0.5g, nepal Gold methyl ester 1.5g, MAP emulsifier 3g and essence 3g, are maintained at 10 DEG C of items
2h is stirred under part to get drug ointment is arrived.
Embodiment 27
The drug ointment prepared using embodiment 26, to 30 diabetics because skin ulcer caused by pressure sore protects
Reason treatment.Skin ulcer multidigit is before shin, shank lower part, dorsal portion and toes portion.Ulcer area maximum 4.0cm × 5.0cm, most
Small is 1.0cm × 1.5cm, and depth is 0.2~1.0cm, and part ulcer basal part has different degrees of suppuration or septic secretion
Object and a small amount of necrotic tissue.
Conventional iodophor disinfection is carried out first, and such as trauma surface infestation is pressed again after first cleaning its concentrated secretion with 3wt% hydrogen peroxide
Program debridement, the excessive surface of a wound of necrotic tissue preferably use a small amount of multiple debridement method.Medical staff applies ointment in treatment group
In the surface of a wound, the covering of external use sterile gauze, fixed, primary every dressing on the two, the daily dressing of severe infection person is primary, until healing.
Blank control group uses petrolatum oil gauze, is covered in the surface of a wound after soaking 1wt% gentamicin, daily dressing is primary.
From the point of view of therapeutic effect is by ulcer surface healing rate, the 7th day average healing rate for the treatment of group is (0.39 ± 0.15)
cm2/ day, hence it is evident that be faster than (0.33 ± 0.15) cm of blank control group2/ day.
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 (9)
1. a kind of pyrazolo [1,5-a] pyridines drug molecule for skin ulcer nursing, it is characterised in that the pyrazolo [1,
5-a] pyridines drug molecule have following molecular structure:
2. a kind of preparation of pyrazolo [1,5-a] pyridines drug molecule described in claim 1 for skin ulcer nursing
Method, it is characterised in that specific steps are as follows:
(1) under inert gas protection, compoundIt is added in Isosorbide-5-Nitrae-dioxane, adds deionization
Water, 2- thienyl boric acid and alkali compounds, the alkali compounds are potassium phosphate, potassium carbonate or saleratus, are replaced with nitrogen anti-
Gas in system is answered to add catalyst Pd (dppf) Cl three times2, continue to be added with after the air in reaction system with nitrogen
Heat is reacted to 90 DEG C, and reaction to raw material fully reacting is cooled to room temperature, and it is multiple to be added ethyl acetate extraction reaction solution, is closed
And organic phase, organic phase is washed with saturated sodium chloride solution, then dry with anhydrous magnesium sulfate, is purified after concentration through column chromatography for separation
Obtain compound
(2) under inert gas protection, compoundIt is added in n,N-Dimethylformamide, at 10 DEG C
Under the conditions of N-bromosuccinimide is added portionwise, be warming up to after adding 15~35 DEG C reaction until raw material fully reacting after be added
Ethyl acetate is free of n,N-Dimethylformamide with saturated sodium chloride solution washing reaction liquid into organic phase after mixing evenly,
Organic phase is dry through anhydrous magnesium sulfate, n-hexane is added after concentration, in the cooling condition stirring to pulp, being dried to obtain after suction filtration
Close object
(3) under inert gas protection, compoundIt is added in reaction flask with dimethyl sulfoxide, then plus
Enter connection boric acid pinacol ester and potassium acetate, is passed through hydrogen displacement reaction system gas and catalyst Pd (dppf) Cl is repeatedly added afterwards2,
Be passed through again hydrogen displacement reaction system gas it is multiple after be heated to 100 DEG C and 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 mixing evenly, then with anhydrous
Magnesium sulfate dries organic phase, purifies to obtain compound through column chromatography for separation after concentration
(4) under nitrogen protection, the chloro- 4- methyl formate yl pyridines of 2,6- bis-, solvent N-methyl pyrilidone and 3- methoxyl group
Azetidine hydrochloride is added in reaction flask, is reacted at room temperature to raw material fully reacting, ethyl acetate is added, stirs
With saturated sodium chloride solution washing reaction liquid until being separated organic without containing N-Methyl pyrrolidone in organic phase after mixing uniformly
Phase is placed under cooling condition with methyl tertiary butyl ether(MTBE) is added after anhydrous sodium sulfate drying and is stirred mashing, filtered drying and obtained
The chloro- 4- methyl formate base -6- of 2- (3- methoxyl group azetidinyl) pyridine；
(5) under nitrogen protection, the chloro- 4- methyl formate base -6- of 2- (3- methoxyl group azetidinyl) pyridine is added to four
In the mixed solution of hydrogen furans, methanol and deionized water, lithium hydroxide is added, 20~50 DEG C is warming up to and carries out reaction until former
Expect fully reacting, reaction solution is cooled to room temperature, is concentrated in vacuo after filtering reacting liquid, dichloroethanes is added, under the conditions of 0 DEG C
Stirring to pulp filters drying and obtains the chloro- 4- carboxyl -6- of 2- (3- methoxyl group azetidinyl) pyridine；
(6) the chloro- 4- carboxyl -6- of 2- (3- methoxyl group azetidinyl) pyridine and aminated compounds are added in toluene, it should
Aminated compounds be triethylamine, ethylenediamine or diisopropylethylamine, be heated to 40~80 DEG C be stirred to react after open vacuum, be evaporated off
Solution A is obtained after the one third of toluene additional amount；Benzylalcohol is added in toluene, normal pressure be evaporated off toluene additional amount five/
One obtains solution B；Under the conditions of solution A is placed in 10 DEG C, the toluene solution dissolved with diphenyl phosphate azide is added drop-wise to solution A
In, it is warming up to room temperature after dripping, continues to be stirred to react to raw material fully reacting, washs solution A with saturated sodium bicarbonate solution
Reaction solution is filtered to remove the solid of washing process generation, retains filtrate A；Solution B is heated to 85 DEG C, under nitrogen protection, drop
Add filtrate A, add toluene after dripping, the reaction was continued, and saturation sodium hydroxide solution is then added into reaction solution, is cooled to 10
DEG C, there are a large amount of solids to be precipitated in whipping process, filter cake drying after water and methanol washing obtains compound after suction filtration
(7) in a high pressure reaction kettle, compoundIt is added in methanol, adds saturation hydrogen-oxygen
Change the palladium carbon that sodium solution and mass percentage are 5%, it is multiple with gas in nitrogen displacement reaction flask, then replaced and reacted with hydrogen
Gas is multiple in bottle, and being passed through hydrogen makes pressure in reaction kettle reach 0.1MPa, carries out reaction at room temperature until raw material is anti-
Should completely, filtering reacting liquid, then active carbon is added into filtrate, it is filtered after stirring, concentration filtrate obtains compound
(8) compoundIt is added in tetrahydrofuran with 3,3- dimethoxy methyl propionate, mixing is equal
After even under the conditions of 0 DEG C be added sodium hydride THF it is molten in, reacted after dripping, then heating to 25 DEG C, the reaction was continued, then cools down
The sodium citrate aqueous solution that mass percentage is 20% is added to 5 DEG C, separates organic phase after mixing evenly, is added two after concentration
Chloromethanes is washed with water, then is concentrated to get compound after being dried with anhydrous sodium sulfate
(9) under 0~5 DEG C of reaction condition, dissolved with compoundDichloromethane solution
It is added drop-wise in acid solution, which is the mixed acid of the concentrated sulfuric acid or the concentrated sulfuric acid and concentrated phosphoric acid, is warming up to 60 after dripping
It is concentrated in vacuo reaction solution after DEG C being reacted, is then cooled to 0 DEG C, ice and water is added, there are a large amount of solids to be precipitated after stirring, is filtered
Reaction solution, filter cake are washed with water and the tert-butyl alcohol respectively, and drying filter cake obtains compound
(10) under nitrogen protection, compoundIt is added in Isosorbide-5-Nitrae-dioxane and deionized water,
Add compoundAnd potassium phosphate, being passed through reaction system with nitrogen gas, addition is urged 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
Expect fully reacting, reaction temperature be cooled to room temperature after be added ethyl acetate extraction reaction solution, merge organic phase after through be saturated chlorination
Sodium solution washing with being concentrated after anhydrous sodium sulfate drying, purifies to obtain target product through column chromatography for separation again
3. the preparation of pyrazolo [1,5-a] pyridines drug molecule according to claim 1 for skin ulcer nursing
Method, it is characterised in that: compound described in step (1)Molar ratio with alkali compounds is 1:
1.5。
4. the preparation of pyrazolo [1,5-a] pyridines drug molecule according to claim 1 for skin ulcer nursing
Method, it is characterised in that: compound described in step (3)The throwing of connection boric acid pinacol ester and potassium acetate
Material molar ratio is 1:1:3.
5. the preparation of pyrazolo [1,5-a] pyridines drug molecule according to claim 1 for skin ulcer nursing
Method, it is characterised in that: the chloro- 4- methyl formate yl pyridines of 2,6- bis- described in step (4) and solvent N-methyl pyrilidone
The mass ratio that feeds intake is 1:5~15.
6. the preparation of pyrazolo [1,5-a] pyridines drug molecule according to claim 1 for skin ulcer nursing
Method, it is characterised in that: the chloro- 4- carboxyl -6- of 2- described in step (6) (3- methoxyl group azetidinyl) pyridine and amine
The molar ratio for closing object is 1:1.5；The chloro- 4- carboxyl -6- of 2- (the 3- methoxyl group azetidinyl) pyridine and mazidox
The molar ratio of diphenyl phthalate is 1:1.
7. the preparation of pyrazolo [1,5-a] pyridines drug molecule according to claim 1 for skin ulcer nursing
Method, it is characterised in that: the concentrated sulfuric acid and the mass ratio of concentrated phosphoric acid are in the concentrated sulfuric acid described in step (9) and the mixed acid of concentrated phosphoric acid
1:2；The compoundThe mass ratio that feeds intake with acid solution is 1:20~40.
8. a kind of pharmaceutical composition for skin ulcer nursing, it is characterised in that it is 5:4 that the pharmaceutical composition, which is by mass ratio:
12:4:0.5:20:1.5:5:3:3:2:40 compoundMonoglyceride, IPP, Bai Fanshi
What woods, Nepal's gold propyl ester, propylene glycol, nepal Gold methyl ester, glycerine, MAP emulsifier, essence, peppermint oil and water were configured to
Drug ointment.
9. the pharmaceutical composition according to claim 8 for skin ulcer nursing, it is characterised in that: the skin ulcer
It is as caused by staphylococcus epidermis or/and Staphylococcus aureus.
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| CN108912147A (en) * | 2018-02-09 | 2018-11-30 | 河南科技大学第附属医院 | A kind of sulphur azatropylidene medicinal compound and preparation method thereof for human burn skin nursing |
| CN113754541A (en) * | 2020-06-02 | 2021-12-07 | 深圳湾实验室 | Micromolecule inhibitor targeting EB virus nuclear antigen protein, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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2018
- 2018-02-09 CN CN201810131601.4A patent/CN108329334A/en active Pending
- 2018-08-03 CN CN201810880271.9A patent/CN108997381A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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Application publication date: 20181214 |