CN101230023A - Method for preparing azo onium diol sodium salt - Google Patents
Method for preparing azo onium diol sodium salt Download PDFInfo
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- CN101230023A CN101230023A CNA2008100202046A CN200810020204A CN101230023A CN 101230023 A CN101230023 A CN 101230023A CN A2008100202046 A CNA2008100202046 A CN A2008100202046A CN 200810020204 A CN200810020204 A CN 200810020204A CN 101230023 A CN101230023 A CN 101230023A
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Abstract
The invention relates to the field of the medicinal chemistry and in particular relates to a method for preparing azo onium diol sodium salt. The invention is characterized in that: the primary amine or secondary amine reacts with nitric oxide and sodium methoxide/methanol solution under catalysis of NO gas adsorbent. The preparation method of the invention does not need autoclave and the corresponding equipment. The invention shows simple operation and lower cost with good safety, and is suitable for industrialized production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a kind of method for preparing the azo diol sodium salt.
Technical background
The azo diol sodium salt (state as follows, and wherein the O that links to each other with the nitrogen ion is O by structure
1, the O that links to each other with nitrogen-atoms is O
2) be the extremely important nitrogen protoxide of a class (NO) donor, it discharges NO in selectivity, and the targeting aspect is particularly outstanding.The anionic form of known azo diol sodium salt (NONOate) is (7.4,37 ℃ of pH) instability under physiological condition, very easily discharges NO, and the transformation period is that several minutes arrives several hours and do not wait; In case but O
2Protected, just formed stable prodrug, the transformation period can extend to tens hours.This prodrug can optionally discharge NO if under the effect of certain enzyme, thus the performance targeting.For example, with the O of azo diol sodium salt
2With-CH
2OAc connects, resultant is the energy stable existence in neutral aqueous solution, but just can discharge NO quantitatively through the effect of pig liver esterase, and its proliferative effect that suppresses the leukemia cell is than big two [the J Med Chem more than the order of magnitude of original azo diol sodium salt, 2000,43 (2): 261-269]; Similarly, with azo diol sodium salt and-CH=CH
2Link to each other, resultant has liver target, can selectivity suppress hepatocellular apoptosis, brings into play liver-protective effect [J MedChem, 1997,40 (13): 1947-1954]; The azo diol sodium salt is linked to each other by ester bond with polypeptide with a series of amino acid with prostate specific antigen (PSA) substrate feature, and resultant can be discharged NO[Tetrabedron Lett, 2001,42:2625-2639 by PSA activation back]; The azo diol sodium salt is connected with some monose, and its product can be activated the back specifically by Glycosylase and discharge NO[Tetrabedron Lett, 2001,42:3779-3782]; With azo diol sodium salt and 2, the 4-dinitrofluorobenzene links to each other, and obtains the NO donator type prodrug of a kind of JS-K by name, optionally discharges NO in acute marrow leukemia (AML) HL-60 cell, kills cancer cells, and does not injure normal cell.Again find that to HL-60 cell and prostate cancer cell PPC-1 that immunodeficiency type mouse body is implanted into, JS-K all can suppress its growth, and do not cause side effect such as mouse blood pressure drops thereafter.Further with 60 kinds of different carcinoma clones JS-K is studied, the result shows that JS-K has antitumour activity [Mol Cancer Ther, 2003,2 (4): 409-17] widely.
In view of the azo diol sodium salt discharges NO in selectivity, the characteristics of targeting aspect are so its preparation just seems extremely important.At present the azo diol sodium salt generally by primary amine or secondary amine and NO gas in the presence of sodium methylate/methyl alcohol, make [J.Org.Chem.1993,58,1472-1476 through reaction under high pressure; Nitric Oxide, 2002,6,135-141].Because NO gas has than the deep-etching effect, need stainless steel autoclave and relevant auxiliary facilities, therefore to equipment requirements than higher, and operation goes up inconveniently, is unfavorable for large-scale production.
Summary of the invention
The invention discloses a kind of method for preparing the azo diol sodium salt, this method need not autoclave and relevant device, and is easy and simple to handle, and cost reduces, and security is good, is fit to scale operation.
The present invention reacts primary amine or secondary amine and NO and sodium methylate/methanol solution, adopts the catalysis of NO adsorbent, can obtain the azo diol sodium salt of high yield at normal temperatures and pressures.
The preferred Al of described NO adsorbent
2O
3, TiO
2, SiO
2, activated carbon or zeolite.Preferred sorbent material is TiO
2
Above-mentioned reaction can be carried out in common solvent, and preferred solvent is an ether.
The mol ratio of primary amine or secondary amine and sodium methylate is preferably 1: 1 to 1: 1.5 in the reaction.More preferably 1: 1.2.
The mole dosage of NO gas is preferably 6: 1 to 2: 1 with the molar weight ratio of primary amine or secondary amine.More preferably 3: 1.
Described sodium methylate/methanol solution is that sodium methylate is dissolved in the solution that obtains in the methyl alcohol, and its percentage concentration is 5% to 30%, and preferred percent is 25%, is weight percentage.
Gordian technique of the present invention is to adopt the NO sorbent material as catalyzer, and it is preferably 1: 10 to 10: 1 with the amount ratio of solvent (preferably ether), and preferred amount ratio is 1: 1, and unit is g/L.
Primary amine or secondary amine be preferably 1: 1 to 1: 10 with volume ratio solvent ether, preferred volume ratio is 1: 5, and unit is mol/L.
The time of reaction is preferably 4-96 hour, more preferably 48 hours.
Preparation method of the present invention can represent with following reaction formula:
Primary amine R-NH wherein
2Be the big amine of steric hindrance, R represents C
1～18Alkyl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle also can connect following substituting group on these groups: hydroxyl, carboxyl, sulfonic group, C
1～8Hydroxyalkyl, nitro, itrile group, C
1～8Alkoxyl group, protected amino, sulfydryl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle; Described heterocycle is five yuan or the six-ring that contains N, O or S.
Secondary amine R
1-NH-R
2Can be symmetrical amine, i.e. R
1And R
2Represent identical group; Secondary amine R
1-NH-R
2Also can be asymmetric amine, i.e. R
1And R
2Represent group inequality.R
1Or R
2Represent C independently of one another
1～18Alkyl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle also can connect following substituting group on these groups: hydroxyl, carboxyl, sulfonic group, C
1～8Hydroxyalkyl, nitro, itrile group, C
1～8Alkoxyl group, protected amino, sulfydryl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle; Described heterocycle is five yuan or the six-ring that contains N, O or S.
Secondary amine can also be cyclammonium, and described cyclammonium is four～octatomic ring, also can connect following substituting group on the ring: hydroxyl, carboxyl, sulfonic group, C
1～8Hydroxyalkyl, nitro, itrile group, C
1～8Alkoxyl group, protected amino, sulfydryl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle; Described heterocycle is five yuan or the six-ring that contains N, O or S.
Protecting group preferred tertiary butoxy carbonyl, ethanoyl or the benzyl of above-mentioned amino.
The azo diol sodium salt that above-mentioned preparation method obtains can be made with extra care, and process for purification comprises: reaction product is dissolved in methyl alcohol, and through organic membrane filtration of 0.22 μ m, the solution of clear is removed methyl alcohol under low temperature or the normal temperature, promptly gets the azo diol sodium salt.
More specifically synthetic method is undertaken by following description step:
Get a suitable volumetrical glass three-necked bottle, on one side neck connect NO gas cylinder and N respectively by the glass threeway
2Gas cylinder, middle neck connects by the gentle capsule of glass valve, and the other side neck connects vacuum pump by threeway.A certain amount of amine, amount of methanol sodium/methanol solution, NO adsorbent and an amount of ether are added in the above-mentioned three-necked bottle (note: do not allow ventpipe immersed in liquid level), the confined reaction system, with the air in the nitrogen replacement reaction flask, use the nitrogen in the NO gas displacement reaction flask then, supply diethyl ether solution by Y-tube at last, stir and slowly feed NO gas down.After reaction for some time, there are a large amount of white precipitates to produce.In case reaction is finished, and can take out unnecessary NO gas by water pump, filter, filter cake repeatedly washs the final vacuum drying through ether, gets the off-white color crude product.Crude product is dissolved in methyl alcohol, owing to contain catalyzer, so can only obtain having slight opalescent solution.This solution obtains the solution of clear through organic membrane filtration of 0.22 μ m.Remove the methyl alcohol in the solution under the low temperature, get final product purified azo diol sodium salt product.
The azo diol sodium salt structure that the present invention obtains is passed through
1H-NMR, ultimate analysis, HPLC, X crystalline diffraction and NO release and transformation period mensuration thereof etc. are verified.The result shows that the product that azo diol sodium salt that this method obtains and bibliographical information obtain through high pressure method is on all four.
Specific implementation method:
Following embodiment will further specify the preparation method of The compounds of this invention, and these embodiment also do not mean that limitation of the present invention.The azo diol sodium salt product that embodiment 1,2,3,5,8 and 9 relates to is for existing bibliographical information, so list the productive rate of bibliographical information in embodiment.The azo diol sodium salt product that embodiment 4,6,7 and 10 relates to is not seen bibliographical information.
Embodiment 1
The preparation of diethylamine azo diol sodium salt
In the three-necked bottle device of 100mL, add diethylamine (0.01mol), anhydrous diethyl ether 50mL, zeolite 50mg, 25% methanol solution of sodium methylate 3.2mL uses N
2Air is 3 times in the replacement(metathesis)reaction bottle, uses the N in the NO gas displacement reaction flask again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, remaining NO gas is taken out in decompression, filters, filter cake washs with the 50mL ether, and vacuum-drying gets crude product, and it is dissolved in the 10mL anhydrous methanol, with organic membrane filtration of 0.22 μ m 3 times, methyl alcohol is removed in the room temperature decompression, and vacuum-drying gets the white solid powder, m.p.196-199 ℃, productive rate 34%[bibliographical information yield 26%, Bioorg.Med.Chem, 2007,15:6796-6801].
1H?NMR(300MHz，D
2O)δ：1.12(t，J＝7.3Hz，6H?N(CH
2CH
3)
2)，2.93(q，J＝7.3Hz，4H，N(CH
2CH
3)
2)。
Embodiment 2
The preparation of tetramethyleneimine azo diol sodium salt
In the three-necked bottle device of 250mL, add tetramethyleneimine (0.02mol), anhydrous diethyl ether 100mL, TiO
2100mg, the methanol solution 6.4mL of 25% sodium methylate.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out remaining NO gas, filter, filter cake washs with the 100mL ether, vacuum-drying.Be dissolved in again in the 20mL anhydrous methanol, organic membrane filtration of 0.22 μ m 3 times, methyl alcohol is removed in decompression, vacuum-drying gets the white solid powder, and m.p.168-171 ℃, productive rate 89.5%[bibliographical information yield 54%, J.Med.Chem.1997,40 (13): 1947-1954].
1H?NMR(D
2O，300MHz)δ：2.99(m，4H)，1.68(m，4H)。
Embodiment 3
The preparation of piperidines azo diol sodium salt
In the three-necked bottle device of 250mL, add piperidines (0.03mol), anhydrous diethyl ether 150mL, TiO
2150mg, the methanol solution 9.6mL of 25% sodium methylate.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out the intact NO gas of unreacted, filter, filter cake washs with the 150mL ether, vacuum-drying.Be dissolved in again in the 30mL anhydrous methanol, organic membrane filtration of 0.22 μ m 3 times, methyl alcohol is removed in decompression, and vacuum-drying gets the white solid powder, and m.p.277 ℃, productive rate 89.4%[yield 70%, J.Am.Chem.Soc.1961,83:1819-1822].
1H?NMR(D
2O，300MHz)δ：3.10(m，4H)，1.53-1.59(m，6H)。，
Embodiment 4
The preparation of 4-hydroxy piperidine azo diol sodium salt
In the three-necked bottle device of 500mL, add 4-hydroxy piperidine (0.04mol), anhydrous diethyl ether 200mL, TiO
2200mg, 25% methanol solution of sodium methylate 12.8mL.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out the intact NO gas of unreacted, filter, filter cake washs with the 200mL ether, vacuum-drying.Be dissolved in again in the 40mL anhydrous methanol, organic membrane filtration of 0.22 μ m 3 times, methyl alcohol is removed in decompression, and vacuum-drying gets the white solid powder, m.p.＞280 ℃, productive rate 74.3%.
1H?NMR(300MHz，D
2O)δ：3.13(m，2H)，2.98(m，2H)，1.97(m，2H)，1.67(m，2H)。
Embodiment 5
The preparation of N-hydroxyethyl piperazine azo diol sodium salt
In the three-necked bottle device of 500mL, add N-hydroxyethyl piperazine (0.05mol), anhydrous diethyl ether 250mL, TiO
2250mg, the methanol solution 16mL of 25% sodium methylate.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out the intact NO gas of unreacted, filter, filter cake washs with the 250mL ether, vacuum-drying.Be dissolved in again in the 50mL anhydrous methanol, organic membrane filtration of 0.22 μ m 3 times, methyl alcohol is removed in decompression, and vacuum-drying gets the white solid powder, and m.p.120-124 ℃, productive rate 90%[91%, Bioorganic ﹠amp; Medicinal Chemistry, 2004,12:3831-3840].
1H?NMR(300MHz，D
2O)δ：2.50(t，2H，OCH
2 CH 2N)，2.653(m，4H)，3.050(m，4H)，3.615(t，2H，O
CH 2CH
2N)，3.218(s，1H，OH)
Embodiment 6
The preparation of N methyl piperazine azo diol sodium salt
In the three-necked bottle device of 500mL, add N methyl piperazine (0.06mol), anhydrous diethyl ether 30mL, TiO
2300mg, the methanol solution 19.2mL of 25% sodium methylate.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out the intact NO gas of unreacted, filter, filter cake washs with the 300mL ether, vacuum-drying.Be dissolved in again in the 60mL anhydrous methanol, organic membrane filtration of 0.22 μ m, methyl alcohol is removed in decompression, and vacuum-drying gets the white solid powder, m.p.＞280 ℃, productive rate 95.7%.
1H?NMR(300MHz，D
2O)δ：2.21(s，3H，CH
3)，3.091(m，4H)，2.619(m，4H)。
Embodiment 7
The preparation of N-sec.-propyl piperazine azo diol sodium salt
In the three-necked bottle device of 500mL, add N-sec.-propyl piperazine (0.07mol), anhydrous diethyl ether 350mL, TiO
2350mg, 25% methanol solution of sodium methylate 22.4mL.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out the intact NO gas of unreacted, filter, filter cake washs with the 350mL ether, vacuum-drying.Be dissolved in again in the 70mL anhydrous methanol, organic membrane filtration of 0.22 μ m, methyl alcohol is removed in decompression, and vacuum-drying gets the white solid powder, and m.p.215-218 ℃, productive rate 88.9%.
1H?NMR(300MHz，D
2O)δ：0.95(d，6H，2CH
3)，2.59(m，1H，CH)，2.615(m，4H)，3.052(m，4H)。
Embodiment 8
The preparation of N-tert-butoxycarbonyl-piperazine azo diol sodium salt
In the three-necked bottle device of 1000mL, add N-tert-butoxycarbonyl-piperazine (0.08mol), anhydrous diethyl ether 400mL, TiO
2400mg, 25% methanol solution of sodium methylate 25.6mL.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out the intact NO gas of unreacted, filter, filter cake washs with the 400mL ether, vacuum-drying.Be dissolved in again in the 80mL anhydrous methanol, organic membrane filtration of 0.22 μ m 3 times, methyl alcohol is removed in decompression, vacuum-drying gets the white solid powder, m.p.＞280 ℃, productive rate 92.4%[42%, J.Org.Chem.1999,64:5124-5131].
1HNMR(300MHz，D
2O)δ：1.37(s，9H，(CH
3)
3)，3.01(m，4H)，3.55(m，4H)。
Embodiment 9
The preparation of N-phenylpiperazine azo diol sodium salt
In the three-necked bottle device of 1000mL, add N-phenylpiperazine (0.09mol), anhydrous diethyl ether 450mL, TiO
2450mg, 25% methanol solution of sodium methylate 28.8mL.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out the intact NO gas of unreacted, filter, filter cake washs with the 450mL ether, vacuum-drying.Be dissolved in again in the 90mL anhydrous methanol, organic membrane filtration of 0.22 μ m, methyl alcohol is removed in decompression, and vacuum-drying gets the white solid powder, and m.p.208-211 ℃, productive rate 93.8%[33%, J.Org.Chem.1999,64:5124-5131].
1H?NMR(300MHz，D
2O)δ：3.22(m，4H)，3.27(m，4H)，6.97(t，1H)，7.06(d，2H)，7.29(t，2H)。
Embodiment 10
The preparation of N-benzyl diethylenediamine azo diol sodium salt
In the three-necked bottle device of 1000mL, add N-benzyl diethylenediamine (0.1mol), anhydrous diethyl ether 500mL, TiO
2500mg, 25% methanol solution of sodium methylate 32mL.Use N
2Air in the replacement(metathesis)reaction device 3 times is used the N in the NO gas displacement reaction unit again
23 times.Stir and slowly feed NO gas, room temperature reaction 48h down.Close the NO gas cylinder valve, take out the intact NO gas of unreacted, filter, filter cake washs with the 500mL ether, vacuum-drying.Be dissolved in again in the 100mL anhydrous methanol, organic membrane filtration of 0.22 μ m, methyl alcohol is removed in decompression, and vacuum-drying gets the white solid powder, and m.p.204-208 ℃, productive rate 83.0%.
1H?NMR(300MHz，D
2O)δ：2.62(m，4H)，3.03(m，4H)，3.50(s，2H)，7.29(m，5H)。
Claims (10)
1. a method for preparing the azo diol sodium salt comprises primary amine or secondary amine and nitrogen protoxide and sodium methylate/methanol solution reaction, it is characterized in that: with NO adsorbent catalyzed reaction.
2. the process of claim 1 wherein that the NO adsorbent is Al
2O
3, TiO
2, SiO
2, activated carbon or zeolite.
3. the method for claim 2, wherein the NO adsorbent is TiO
2
4. the process of claim 1 wherein that reaction solvent is an ether.
5. the process of claim 1 wherein that the mol ratio of primary amine or secondary amine and sodium methylate is 1: 1 to 1: 1.5; The mole dosage of NO gas is 6: 1 to 2: 1 with the molar weight ratio of primary amine or secondary amine.
6. the process of claim 1 wherein that weight percent is 5% to 30% in sodium methylate/methanol solution.
7. the method for claim 4, wherein the volume ratio of the mole number of primary amine or secondary amine and ether is 1: 1 to 1: 10, unit is mol/L; NO sorbent material and ether weightmeasurement ratio are 1: 10 to 10: 1, and unit is g/L.。
8. the process of claim 1 wherein that primary amine is R-NH
2, wherein R is C
1～18Alkyl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle also connect following substituting group: hydrogen, hydroxyl, carboxyl, sulfonic group, C on these groups
1～8Hydroxyalkyl, nitro, itrile group, C
1～8Alkoxyl group, protected amino, sulfydryl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle; Described heterocycle is five yuan or the six-ring that contains N, O or S.
9. the process of claim 1 wherein that secondary amine is expressed as R
1-NH-R
2, R wherein
1Or R
2Represent C independently of one another
1～18Alkyl, phenyl, benzheterocycle, fear base, naphthyl or heterocycle, also connect following substituting group on these groups: hydrogen, hydroxyl, carboxyl, sulfonic group, C
1～8Hydroxyalkyl, nitro, itrile group, C
1～8Alkoxyl group, protected amino, sulfydryl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle; Described heterocycle is five yuan or the six-ring that contains N, O or S;
Secondary amine also is expressed as cyclammonium, and described cyclammonium is four～octatomic ring, also connects following substituting group on the ring: hydrogen, hydroxyl, carboxyl, sulfonic group, C
1～8Hydroxyalkyl, nitro, itrile group, C
1～8Alkoxyl group, protected amino, sulfydryl, phenyl, benzheterocycle, anthryl, naphthyl or heterocycle; Described heterocycle is five yuan or the six-ring that contains N, O or S.
10. the preparation method of claim 1 also comprises: reaction product is dissolved in methyl alcohol, through organic membrane filtration of 0.22 μ m, gets the solution of clear, remove methyl alcohol, promptly get the azo diol sodium salt.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109608371A (en) * | 2019-01-16 | 2019-04-12 | 泰州学院 | O2Two alkoxide derivative of -4- (3- (4- sulfamic phenyl) urea) phenylazo, Preparation method and use |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109608371A (en) * | 2019-01-16 | 2019-04-12 | 泰州学院 | O2Two alkoxide derivative of -4- (3- (4- sulfamic phenyl) urea) phenylazo, Preparation method and use |
| CN109608371B (en) * | 2019-01-16 | 2020-12-29 | 泰州学院 | O2-4- (3- (4-sulfamoylphenyl) urea) phenylazoium dialkoxide derivative, preparation method and application |
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