CN104447735A - Preparation method and use of tetrahydropalmatine derivative with antibacterial activity - Google Patents
Preparation method and use of tetrahydropalmatine derivative with antibacterial activity Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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Abstract
The invention discloses a preparation method of a tetrahydropalmatine derivative with antibacterial activity. The chemical name is N-ethoxy-tetrahydropalmatine ammonium bromide, and the formula structure is shown in the specification. The preparation method comprises the following steps: 1) by taking chloridized palmatine as a raw material, preparing tetrahydropalmatine (2) after NaBH4 reduction; 2) carrying out nucleophilic substitution reaction on obtained tetrahydropalmatine and alpha-bromoethyl acetate to prepare N-ethyl acetate substituted tetrahydropalmatine ammonium bromide (3); and 3) after crystallizing the reduced product 3 by absolute ethyl alcohol, separating out white massive crystals and identifying the product by hydrogen spectra and X-single crystal diffraction as N-ethoxy-tetrahydropalmatine ammonium bromide (4). The antibacterial experiment in vitro shows that the N-ethoxy-tetrahydropalmatine ammonium bromide provided by the invention has relatively strong antibacterial activity.
Description
Technical field
The present invention relates to medical art, particularly antibacterials technical field, specifically a kind of preparation method and purposes with the tetrahydropalmatine derivative of anti-microbial activity.
Background technology
Along with microbiotic widespread use, bacterial drug resistance is made to increase year by year clinically, some microbiotic curative effects are caused to reduce, even invalid, as methicillin-resistant staphylococcus aureus (MRSA), penicillin-fast streptococcus pneumoniae (PRSP), vancomycin-resistant enterococcus (VRE) and many patience tubercule bacillus etc.In addition, find again that more than 30 plant new pathogenic agent in recent years, there is trend popular again in some communicable diseases that the past has controlled such as tuberculosis etc., this all needs constantly to provide new antibiotic and novel antibacterials, to meet the needs of.
Fibrauretin is also chlorination prothionamide, be be separated from the root menispermaceous plants herba fibraureae recisae Fibrurea recisa Pieme and stem obtain one in quaternary ammonium type alkaloid, immunity of organisms can be improved, there is the effects such as clearing heat and detoxicating, anti-inflammatory is antibacterial, have broad-spectrum antibacterial action to the pathogenic bacterias such as intestinal bacteria, streptococcus aureus, Bacillus subtilus, Candida albicans and resistant organism.Current Fibrauretin has been widely used in all kinds infection and gynaecopathia etc. clinically, all has good curative effect.But still have the report of some untoward reactions clinically, as symptoms such as anaphylactic shock, epidermolysis's necrosis, stomachache stool.Therefore, cause pay close attention to widely with the transformation research that chlorination prothionamide carries out series compound for lead compound, but due to chlorination prothionamide source comparatively difficulty, less to the research of its derivative, its exploitation are also restricted.Therefore the present invention first with chlorination prothionamide for raw material, structural modification is carried out to it, expects to find the prothionamide class antibacterials that a kind of activity is better, side effect is less.
Summary of the invention
The object of this invention is to provide a kind of preparation method and the purposes with anti-microbial activity tetrahydropalmatine and derivative.
The technical scheme that the present invention solves the problems of the technologies described above is as follows:
There is a tetrahydropalmatine derivative for anti-microbial activity, it is characterized in that:
1) chemical name of this compound is N-hydroxyethyl substituted-tetrahydro prothionamide quaternary ammonium salt;
2) structural formula:
Molecular formula: C
23h
31brNO
5
Relative molecular weight: 481.40
3) physico-chemical property: be pale yellow powder, m.p.170 ~ 171 DEG C, FAB-MS m/z:482 [M+H]
+;
1h-NMR (d
6-DMSO, 400MHz) δ: 7.16 (s, 1H ,-ArH), 7.10 (d, 1H, J=8.4 ,-ArH), 6.99 (d, 1H, J=8.4 ,-ArH), 6.91 (s, 2H ,-ArH), 5.42 (q, 1H ,-CH), 4.81-4.86 (m, 2H ,-CH
2), 3.77 ~ 3.82 (12H, m, 4 ×-OCH
3), 3.82-3.84 (m, 2H ,-CH
2), 3.11-3.18 (m, 2H ,-CH
2), 2.50-2.51 (m, 4H ,-CH
2).
The above-mentioned tetrahydropalmatine derivative with anti-microbial activity, its synthetic method comprises the steps:
A) with chlorination prothionamide for raw material, under potassium alkaline catalyzer, slowly add borane reducing agent Sodium Borohydride powder in batches, at 100 DEG C, react 1h, yellow powder is separated out, suction filtration, solids with methanol recrystallization after cooling, obtain pale yellow powder, namely there is structural formula (II) compound;
B) described step a) is prepared in structural formula (II) compound and added toluene, rising temperature for dissolving, dissolve completely and add ethyl bromoacetate, be warming up to 100 DEG C of backflows 2 hours, be cooled to room temperature, separate out white powder, suction filtration, obtains structural formula (III) compound;
C) by described step b) structural formula (III) compound prepared dissolves in methyl alcohol, the ethanolic soln of sodium borohydride is added while stirring under room temperature, stirring is continued 2 hours under room temperature, white powder yellowing powder, suction filtration, filter residue ethanol in proper amount recrystallization, suction filtration, obtains pale yellow powder and gets product.3, the preparation method of tetrahydropalmatine derivative as described in right 2, is characterized in that: at described step c) after carry out the preparation of product monocrystalline, concrete steps are:
By described step c) finished product prepared take dehydrated alcohol as solvent, with preservative film sealing, then frustrates several apertures with Herba Damnacanthi, at room temperature the standing a few days slowly solvent flashing obtain faint yellow bulk-shaped monocrystal.
Preferably, described step a) in, the ratio of weight and number of described potassium alkaline catalyzer and described chlorination prothionamide is 1: 2-2.2, and the ratio of weight and number of described sodium borohydride and described chlorination prothionamide is 1: 4-5.
Preferably, described step b) in, the ratio of weight and number of described structural formula (II) compound and described ethyl bromoacetate is 1.8-2.2: 1.
Preferably, described step c) in, the ratio of weight and number of described methanol solution and described sodium borohydride is 70-100: 1.
The invention has the beneficial effects as follows: the present invention is raw material in order to natural antibacterial medicine chlorination prothionamide, through three-step reaction synthesis target products such as reduction, replacements, reaction conditions is gentle, and select the solvent of the solvent of some low toxicities, stable in properties as reaction and the solvent of recrystallization, reaction process is simple, productive rate is higher, is convenient to suitability for industrialized production, has larger implementary value.
Accompanying drawing explanation
Fig. 1 is schema of the present invention.Fig. 2 is X-single crystal diffraction figure of the present invention
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, can implement according to this with reference to specification sheets word to make those skilled in the art.
Embodiment 1
The preparation of N-hydroxyethyl tetrahydropalmatine brometo de amonio, its concrete steps are as follows:
A) preparation of tetrahydropalmatine (II)
Being dropped into by 6g chlorination prothionamide has in the 100mL three-necked bottle of magnetic agitation, add 3g salt of wormwood and 50mL methyl alcohol 100 DEG C backflow dissolving, slowly add 1.5g sodium borohydride 100 DEG C reaction 1h after dissolving completely, let cool, after cooling, separate out yellow powder, suction filtration, filter residue proper amount of methanol recrystallization ,-10 DEG C of ice baths separate out yellow powder, and suction filtration obtains 4.08g pale yellow powder 2, productive rate 54%, m.p.188 ~ 189 DEG C.
B) preparation of N-tetrahydropalmatine ethyl acetate (III)
4g compound 2 is dropped into and has in the 100mL three-necked bottle of magnetic agitation, add 30mL toluene, rising temperature for dissolving, dissolve completely and add 2.2mL ethyl bromoacetate, be warming up to 100 DEG C of backflows 2 hours, after cooling, white powder is separated out again, suction filtration, obtain white powder 3, productive rate 63%, m.p.201 ~ 203 DEG C.
C) preparation of N-hydroxyethyl tetrahydropalmatine brometo de amonio (IV)
The compound 3 obtained by suction filtration drops into the 50mL round-bottomed flask having magnetic agitation, add 20mL methyl alcohol, the ethanolic soln of 0.25g sodium borohydride is added while stirring, stirred at ambient temperature 2 hours, white powder yellowing powder under room temperature, suction filtration, filter residue ethanol in proper amount recrystallization, suction filtration, obtains pale yellow powder IV, productive rate 42%, m.p.170 ~ 171 DEG C.FAB-MS m/z：482[M+H]
+；
1H-NMR(d
6-DMSO，400MHz)δ：7.16(s，1H，-ArH)，7.10(d，1H，J＝8.4，-ArH)，6.99(d，1H，J＝8.4，-ArH)，6.91(s，2H，-ArH)，5.42(q，1H，-CH)，4.81-4.86(m，2H，-CH
2)，3.77～3.82(12H，m，4×-OCH
3)，3.82-3.84(m，2H，-CH
2)，3.11-3.18(m，2H，-CH
2)，2.50-2.51(m，4H，-CH
2)。
D) preparation of target product monocrystalline and x-ray crystal structure measure; Be solvent with dehydrated alcohol by compound 4, with preservative film sealing, then frustrate several apertures with Herba Damnacanthi, at room temperature the standing a few days slowly solvent flashing obtain faint yellow bulk-shaped monocrystal.Choose monocrystalline that size is about 0.30mm*0.15mm*0.08mm to be placed on Brucker SMART 1000CCD X-ray single crystal diffractometer and to carry out diffraction, with through graphite monochromator monochromatization Mo K alpha-ray (
) be incident radiation, in the scope of 6.04 ° to 52.74 °, collect diffraction data 10173 with ω/2 scan mode, wherein 5112 is independent point (R (int)=0.0378).All data all corrects through Lp Summing Factor empirical absorption.Adopt SHELXS-97 program to be solved by direct method, obtain its structure iron as shown in Figure 1, its structure is consistent with target product.
Antibacterial activity in vitro is tested
Adopt doubling dilution, carry out Antimicrobial test, measure naked eyes visible colonies and grow the lowest concentration of drug (MIC) be totally constrained.N-hydroxyethyl substituted-tetrahydro prothionamide quaternary ammonium salt embodiment 1 obtained and Candida albicans hatch 24 hours, and its MIC result is as shown in table 1.
Table 1N-hydroxyethyl replaces the MIC of N-hydroxyethyl tetrahydropalmatine brometo de amonio and Candida albicans
From the results shown in Table 1, N-hydroxyethyl tetrahydropalmatine brometo de amonio of the present invention shows through Antimicrobial test, and this compound has strong anti-microbial activity, is eager to excel than parent chlorination prothionamide.
Embodiment 2
The preparation of N-hydroxyethyl tetrahydropalmatine brometo de amonio, its concrete steps are as follows:
A) preparation of tetrahydropalmatine (II)
Being dropped into by 6.6g chlorination prothionamide has in the 100mL three-necked bottle of magnetic agitation, add 3g salt of wormwood and 50mL methyl alcohol 100 DEG C backflow dissolving, slowly add 1.5g sodium borohydride 100 DEG C reaction 1h after dissolving completely, let cool, after cooling, separate out yellow powder, suction filtration, filter residue proper amount of methanol recrystallization ,-10 DEG C of ice baths separate out yellow powder, and suction filtration obtains 4.1g pale yellow powder 2, productive rate 57%, m.p.188 ~ 189 DEG C.
B) preparation of N-tetrahydropalmatine ethyl acetate (III)
4.8g compound 2 is dropped into and has in the 100mL three-necked bottle of magnetic agitation, add 30mL toluene, rising temperature for dissolving, dissolve completely and add 2.2mL ethyl bromoacetate, be warming up to 100 DEG C of backflows 2 hours, after cooling, white powder is separated out again, suction filtration, obtain white powder 3, productive rate 65%, m.p.201 ~ 203 DEG C.
C) preparation of N-hydroxyethyl tetrahydropalmatine brometo de amonio (IV)
The compound 3 obtained by suction filtration drops into the 50mL round-bottomed flask having magnetic agitation, add 20mL methyl alcohol, the ethanolic soln of 0.2g sodium borohydride is added while stirring, stirred at ambient temperature 2 hours, white powder yellowing powder under room temperature, suction filtration, filter residue ethanol in proper amount recrystallization, suction filtration, obtains pale yellow powder 4, productive rate 42%, m.p.170 ~ 171 DEG C.FAB-MS m/z：482[M+H]
+；
1H-NMR(d
6-DMSO，400MHz)δ：7.16(s，1H，-ArH)，7.10(d，1H，J＝8.4，-ArH)，6.99(d，1H，J＝8.4，-ArH)，6.91(s，2H，-ArH)，5.42(q，1H，-CH)，4.81-4.86(m，2H，-CH
2)，3.77～3.82(12H，m，4×-OCH
3)，3.82-3.84(m，2H，-CH
2)，3.11-3.18(m，2H，-CH
2)，2.50-2.51(m，4H，-CH
2)。
D) preparation of target product monocrystalline and x-ray crystal structure measure; Be solvent with dehydrated alcohol by compound 4, with preservative film sealing, then frustrate several apertures with Herba Damnacanthi, at room temperature the standing a few days slowly solvent flashing obtain faint yellow bulk-shaped monocrystal.Choose monocrystalline that size is about 0.30mm*0.15mm*0.08mm to be placed on Brucker SMART 1000CCD X-ray single crystal diffractometer and to carry out diffraction, with through graphite monochromator monochromatization Mo K alpha-ray (
) be incident radiation, in the scope of 6.04 ° to 52.74 °, collect diffraction data 10173 with ω/2 scan mode, wherein 5112 is independent point (R (int)=0.0378).All data all corrects through Lp Summing Factor empirical absorption.Adopt SHELXS-97 program to be solved by direct method, obtain its structure iron as shown in Figure 1, its structure is consistent with target product.
Antibacterial activity in vitro is tested
Adopt doubling dilution, carry out Antimicrobial test, measure naked eyes visible colonies and grow the lowest concentration of drug (MIC) be totally constrained.N-hydroxyethyl substituted-tetrahydro prothionamide quaternary ammonium salt embodiment 1 obtained and Candida albicans hatch 24 hours, and its MIC result is as shown in table 2.
Table 2N-hydroxyethyl replaces the MIC of N-hydroxyethyl tetrahydropalmatine brometo de amonio and Candida albicans
From the results shown in Table 2, N-hydroxyethyl tetrahydropalmatine brometo de amonio of the present invention shows through Antimicrobial test, and this compound has strong anti-microbial activity, is eager to excel than parent chlorination prothionamide.
Embodiment 3
The preparation of N-hydroxyethyl tetrahydropalmatine brometo de amonio, its concrete steps are as follows:
A) preparation of tetrahydropalmatine (II)
Being dropped into by 6.2g chlorination prothionamide has in the 100mL three-necked bottle of magnetic agitation, add 3g salt of wormwood and 50mL methyl alcohol 100 DEG C backflow dissolving, slowly add 1.5g sodium borohydride 100 DEG C reaction 1h after dissolving completely, let cool, after cooling, separate out yellow powder, suction filtration, filter residue proper amount of methanol recrystallization ,-10 DEG C of ice baths separate out yellow powder, and suction filtration obtains 4.07g pale yellow powder 2, productive rate 54%, m.p.188 ~ 189 DEG C.
B) preparation of N-tetrahydropalmatine ethyl acetate (III)
4.1g compound 2 is dropped into and has in the 100mL three-necked bottle of magnetic agitation, add 30mL toluene, rising temperature for dissolving, dissolve completely and add 2.2mL ethyl bromoacetate, be warming up to 100 DEG C of backflows 2 hours, after cooling, white powder is separated out again, suction filtration, obtain white powder 3, productive rate 62%, m.p.201 ~ 203 DEG C.
C) preparation of N-hydroxyethyl tetrahydropalmatine brometo de amonio (IV)
The compound 3 obtained by suction filtration drops into the 50mL round-bottomed flask having magnetic agitation, add 20mL methyl alcohol, the ethanolic soln of 0.26g sodium borohydride is added while stirring, stirred at ambient temperature 2 hours, white powder yellowing powder under room temperature, suction filtration, filter residue ethanol in proper amount recrystallization, suction filtration, obtains pale yellow powder 4, productive rate 42%, m.p.170 ~ 171 DEG C.FAB-MS m/z：482[M+H]
+；
1H-NMR(d
6-DMSO，400MHz)δ：7.16(s，1H，-ArH)，7.10(d，1H，J＝8.4，-ArH)，6.99(d，1H，J＝8.4，-ArH)，6.91(s，2H，-ArH)，5.42(q，1H，-CH)，4.81-4.86(m，2H，-CH
2)，3.77～3.82(12H，m，4×-OCH
3)，3.82-3.84(m，2H，-CH
2)，3.11-3.18(m，2H，-CH
2)，2.50-2.51(m，4H，-CH
2)。
D) preparation of target product monocrystalline and x-ray crystal structure measure; Be solvent with dehydrated alcohol by compound 4, with preservative film sealing, then frustrate several apertures with Herba Damnacanthi, at room temperature the standing a few days slowly solvent flashing obtain faint yellow bulk-shaped monocrystal.Choose monocrystalline that size is about 0.30mm*0.15mm*0.08mm to be placed on Brucker SMART 1000CCD X-ray single crystal diffractometer and to carry out diffraction, with through graphite monochromator monochromatization Mo K alpha-ray (
) be incident radiation, in the scope of 6.04 ° to 52.74 °, collect diffraction data 10173 with ω/2 scan mode, wherein 5112 is independent point (R (int)=0.0378).All data all corrects through Lp Summing Factor empirical absorption.Adopt SHELXS-97 program to be solved by direct method, obtain its structure iron as shown in Figure 1, its structure is consistent with target product.
Antibacterial activity in vitro is tested
Adopt doubling dilution, carry out Antimicrobial test, measure naked eyes visible colonies and grow the lowest concentration of drug (MIC) be totally constrained.N-hydroxyethyl substituted-tetrahydro prothionamide quaternary ammonium salt embodiment 1 obtained and Candida albicans hatch 24 hours, and its MIC result is as shown in table 3.
Table 3N-hydroxyethyl replaces the MIC of N-hydroxyethyl tetrahydropalmatine brometo de amonio and Candida albicans
From the results shown in Table 3, N-hydroxyethyl tetrahydropalmatine brometo de amonio of the present invention shows through Antimicrobial test, and this compound has strong anti-microbial activity, is eager to excel than parent chlorination prothionamide.
Although embodiment of the present invention are open as above, but it is not restricted to listed in specification sheets and embodiment utilization, it can be applied to various applicable the field of the invention completely, for those skilled in the art, can easily realize other amendment, therefore do not deviating under the universal that claim and equivalency range limit, the present invention is not limited to specific details and illustrates here and the legend described.
Claims (7)
1. a tetrahydropalmatine derivative, is characterized in that:
Its structural formula is (I):
Its molecular formula is: C
23h
31brNO
5
Its relative molecular weight is: 481.40.
2. a preparation method for the tetrahydropalmatine derivative as described in right 1, is characterized in that, comprise the steps:
A) with chlorination prothionamide for raw material, under potassium alkaline catalyzer, slowly add borane reducing agent Sodium Borohydride powder in batches, at 100 DEG C, react 1h, yellow powder is separated out, suction filtration, solids with methanol recrystallization after cooling, obtain pale yellow powder, namely there is structural formula (II) compound;
B) described step a) is prepared in structural formula (II) compound and added toluene, rising temperature for dissolving, dissolve completely and add ethyl bromoacetate, be warming up to 100 DEG C of backflows 2 hours, be cooled to room temperature, separate out white powder, suction filtration, obtains structural formula (III) compound;
C) by described step b) structural formula (III) compound prepared dissolves in methyl alcohol, the ethanolic soln of sodium borohydride is added while stirring under room temperature, stirring is continued 2 hours under room temperature, white powder yellowing powder, suction filtration, filter residue ethanol in proper amount recrystallization, suction filtration, obtains pale yellow powder and gets product.
3. the preparation method of tetrahydropalmatine derivative as described in right 2, is characterized in that: at described step c) after carry out the preparation of product monocrystalline, concrete steps are:
By described step c) finished product prepared take dehydrated alcohol as solvent, with preservative film sealing, then frustrates several apertures with Herba Damnacanthi, at room temperature the standing a few days slowly solvent flashing obtain faint yellow bulk-shaped monocrystal.
4. the preparation method of tetrahydropalmatine derivative as described in right 2, it is characterized in that: described step a) in, the ratio of weight and number of described potassium alkaline catalyzer and described chlorination prothionamide is 1: 2-2.2, and the ratio of weight and number of described sodium borohydride and described chlorination prothionamide is 1: 4-5.
5. the preparation method of tetrahydropalmatine derivative as described in right 2, is characterized in that: described step b) in, the ratio of weight and number of described structural formula (II) compound and described ethyl bromoacetate is 1.8-2.2: 1.
6. the preparation method of tetrahydropalmatine derivative as described in right 2, is characterized in that: described step c) in, the ratio of weight and number of described methanol solution and described sodium borohydride is 70-100: 1.
7. gather the purposes of the tetrahydropalmatine derivative as described in right 1, it is characterized in that, for the preparation of antibacterials, can be made into injection, tablet, pill, capsule, suspension agent or emulsion.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1071666A (en) * | 1991-10-21 | 1993-05-05 | 中国药科大学 | Tetrahydroberberine type quaternary ammonium componnd and preparation method thereof |
| CN1958584A (en) * | 2005-11-04 | 2007-05-09 | 吴晓枫 | Derivative of fibrauretine, and preparation method |
| CN101830897A (en) * | 2010-05-10 | 2010-09-15 | 中国科学院化学研究所 | Novel isoquinoline alkaloid derivatives and preparation method and application thereof |
-
2014
- 2014-09-30 CN CN201410522536.XA patent/CN104447735A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1071666A (en) * | 1991-10-21 | 1993-05-05 | 中国药科大学 | Tetrahydroberberine type quaternary ammonium componnd and preparation method thereof |
| CN1958584A (en) * | 2005-11-04 | 2007-05-09 | 吴晓枫 | Derivative of fibrauretine, and preparation method |
| CN101830897A (en) * | 2010-05-10 | 2010-09-15 | 中国科学院化学研究所 | Novel isoquinoline alkaloid derivatives and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 黄枕亚 等: ""四氢原小檗碱型季铵化合物的合成及其某些参数的测定"", 《中国药科大学学报》 * |
| 黄枕亚 等: ""四氢原小檗碱型季铵化合物的合成及其某些参数的测定"", 《中国药科大学学报》, vol. 19, no. 4, 31 December 1988 (1988-12-31), pages 249 - 252 * |
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Application publication date: 20150325 |