5 Must-Have Features in a 4-amino-1,3-dimethyluracil for synthesis

R-BU-CsSB and R-BU-Cs hydrogels ( ) were obtained at the final stage of a reaction consisted of four consecutive steps. In the first step, the primary amine groups in Cs were protected by condensing them with the C=O groups of the benzaldehyde, producing CsSB. Hence, in the second step, the reaction with epichlorohydrin was confined on the primary hydroxyl groups at C6, creating ECsSB. Afterwards, epoxy rings of ECsSB, in the third step, were facilely opened using nitrogen-rich R-BU derivatives via their lone pair of electrons, yielding R-BU-CsSB hydrogels. At the end, in the fourth step, the amino groups of Cs were recovered by the removal of the protection in an acidic medium, producing R-BU-Cs hydrogels. Thus, the combination of a nitrogen-rich R-BU, as linkages between the CsSB chains (R-BU-CsSB hydrogels) and between Cs chains (R-BU-Cs hydrogels), hydroxyl groups, and the regained amino groups at Cs, will greatly enhance the cationic sites that possess a high capacity to inhibit the microbial growth. Further, some ZnO nanocomposites based on 2Nph-BU-Cs and 2Mph-BU-CS were made using three different concentrations of ZnONPs of 1, 3, and 5% (based on the weight of the hydrogel), producing 2Nph-BU-Cs/ZnONPs-1%, 2Nph-BU-Cs/ZnONPs-3%, 2Nph-BU-Cs/ZnONPs-5%, 2Mph-BU-Cs/ZnONPs-1%, 2Mph-BU-Cs/ZnONPs-3%, and 2Mph-BU-Cs/ZnONPs-5%.

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The elements in the 2Nph-BU-Cs/ZnONPs-5% composite were identified using EDS. The EDS spectrum ( ) showed the presence of zinc (4.72%), oxygen (27.03%), carbon (46.43%), and nitrogen (21.83%) elements in synthesized nano bio-composite. The detection of these elements indicated the successful formation of the 2Nph-BU-Cs/ZnONPs-5% composite. depicted the distribution of different components in the synthesized nano bio-composite after it was imaged.

The SEM images of the topographical features of the surfaces of Cs, CsSB, ECsSB, as well as 2Nph-BU-CsSB, 2Nph-BU-Cs, 2Mph-BU-CsSB, and 2Mph-BU-Cs hydrogels are shown in . It was observed that the Cs surface was very smooth, while its hydrogels had much more rough surfaces that were composed of lumps of various sizes due to the size differences of the inserted modifier moieties. It can be also noted that the distribution of these lumps in each derivative was homogenous, referring to the fact that the modification of Cs in each step was successfully accomplished.

In order to confirm the loading of ZnONPs into the matrices of 2Nph-BU-Cs, XRD measurement was performed for the prepared 2Nph-BU-Cs/ZnONPs-5% composite ( ). Its XRD pattern showed six new peaks, in addition to the amorphous peaks of 2Nph-BU-Cs near 2θ = 20°, at 2θ = 32.2°, 34.76°, 36.37°, 41.8°, 66.14°, and 69.1° that were indexed to crystal planes of (100), (002), (101), (102), (200), and (202), respectively. These peaks and their corresponding crystal planes are in good agreement with those for the pure ZnO as previously reported (JCPDS card no. 36-145) [ 28 , 29 , 38 , 39 , 40 , 41 ]. This evidences the successful formation of the 2Nph-BU-Cs/ZnONPs composite.

XRD was utilized to inspect the changes in the internal structure of chitosan before and after its modification. The XRD patterns of the virgin Cs and representative examples of its hydrogels were illustrated in . In Cs, two distinguished peaks close to 2θ = 20° and 10° that were indexed to crystal planes of (110) and (020), respectively [ 37 ], were observed attributable to its crystalline nature [ 35 ]. This can be attributed to the creation of a lot of hydrogen bonds throughout its chains as a result of the abundance of its hydroxyl and amino groups. In comparison to Cs, the CsSB and ECsSB are less crystalline. This was illustrated not only by lowering the intensity of both these peaks but also by increasing their broadening. Moreover, the near disappearance of the peak at 2θ = 10°, together with a further broadening and reduction in the intensity of the peak at 2θ = 20°, were observed in all patterns of 2Nph-BU-CsSB, 2Nph-BU-Cs, 2Mph-BU-CsSB, and 2Mph-BU-Cs, suggesting their much less crystallinity ( ). The incorporation of the R-BU linkages between the repeating units of CsSB as well as Cs greatly decreased the possibility of the formation of the hydrogen bonds between their chains. This is ascribed not only by the exhausting of their polar groups (-NH 2 and/or -OH) during modification process but also by separating the Cs chains away from each other.

showed the FTIR spectra of 2Nph-BU-Cs/ZnONPs-1%, 2Nph-BU-Cs/ZnONPs-3%, 2Nph-BU-Cs/ZnONPs-5%, 2Mph-BU-Cs/ZnONPs-1%, 2Mph-BU-Cs/ZnONPs-3%, 2Mph-BU-Cs/ZnONPs-5% composites. The doublet peak at and cm &#;1 corresponded to NH 2 bonds in 2Nph-BU-Cs, and 2Mph-BU-Cs appreciably shifted to a lower frequency of and cm &#;1 , respectively, together with an observable decrease in their intensity in all the ZnONPs bio-composites. Further, the intensity of the peak at cm &#;1 related to C=O in both 2Nph-BU-Cs and 2Mph-BU-Cs considerably decreased after the incorporation of ZnONPs into their matrices. The spectra also showed a new peak at 546 cm &#;1 , attributed to the O-ZnO bond [ 36 ]. All these changes prove that ZnONPs interacted with the functional groups of both 2Nph-BU-Cs and 2Mph-BU-Cs.

In , the spectra of 2Nph-BU-CsSB and 2Mph-BU-CsSB revealed the evanescence of the peak at cm &#;1 that related to the epoxy nuclei. This was accompanied with the apparition of new absorption peaks: at around , &#;, and cm &#;1 (C=C, aromatic ring) of R-BU moiety for both, at , , and 854 cm &#;1 (-NO 2 group) for 2Nph-BU-CsSB, and at , , and cm &#;1 (-OCH 3 group) for 2Mph-BU-CsSB. The peak appeared around cm &#;1 , corresponding to C=O of BU moiety, overlapping with that of the amide I in chitosan at cm &#;1 . This affirms the completeness of the reaction of ECsSB with 2Nph-BU and 2Mph-BU, respectively. The restoring of the doublet peak of the -NH 2 groups of chitosan moieties at and cm &#;1 , in addition to the demise of the of mono-substituted benzene rings absorption bands at 755 and 690 cm &#;1 , confirm the elimination of benzaldehyde nuclei to obtain 2Nph-BU-Cs and 2Mph-BU-Cs hydrogels.

In the CsSB spectrum, the doublet peak corresponding to NH 2 groups of chitosan disappeared and was replaced by a single one at cm &#;1 , which can be attributed to -OH groups. In addition, some new peaks were observed: at and cm &#;1 (C-H, aromatic), at cm &#;1 (C=N groups), at , , , and cm &#;1 (C=C, aromatic), and at 755 and 690 cm &#;1 (mono-substituted benzene ring) [ 24 ], indicating that all the -NH 2 groups were consumed during protection with benzaldehyde and confirming the successful formation of CsSB.

shows the FTIR spectra of Cs before and after modification. In virgin Cs, between and cm &#;1 , a very broad absorption peak was observed, corresponding to the stretching vibration of the hydroxyl groups overlapping with that of -NH 2 groups and their hydrogen bonds. In this wavenumber range, there is a doublet peak at and cm &#;1 related to the -NH 2 groups. The symmetric stretching vibration peaks of the -CH and -CH 2 groups in the moieties of pyranose appeared at and cm &#;1 , respectively. Further, two weak peaks appeared at and cm &#;1 attributable to amide I and amide II, respectively, confirming the high Cs degree of deacetylation. The four absorption peaks that appeared at , , , and 892 cm &#;1 confirmed the saccharide moieties of Cs [ 35 ].

The elemental analysis values of all R-BU-CsSB and R-BU-Cs hydrogels were recorded in . In regard to %C and %N, it could be noted that the %C value of CsSB (62.80) increased at the expense of its %N value (5.70) in comparison to those of the virgin Cs (%C, 44.90 and %N, 8.61). This confirms the successful amalgamation of the carbon- rich benzaldehyde moieties into the repeating units of Cs. On contrast, the %N values of the 2Nph-BU-CsSB, 2Clph-BU-CsSB, 4Clph-BU-CsSB, ph-BU-CsSB, H-BU-CsSB, and 2Mph-BU-CsSB were 13.14, 11.73, 11.84, 12.10, 13.35, and 11.68, respectively, which were higher than those obtained for both CsSB (5.70) and ECsSB (4.48). This is due to various nitrogen-rich R-BU moieties that were incorporated into the repeating units of ECsSB. This was additionally proved by the presence of chlorine element in the elemental analysis of 2Clph-BU-CsSB (3.42%) and 4Clph-BU-CsSB (3.81%). Moreover, a decrease in the %C values accompanied with further increases in the %N values of the 2Nph-BU-Cs (C, 50.56 and N, 14.47), 2Clph-BU-Cs (C, 51.14 and N, 13.00), 4Clph-BU-Cs (C, 51.09 and N, 12.98), ph-BU-Cs (C, 53.45, and N, 13.46) H-BU-Cs (C, 49.09 and N, 14.85), and 2Mph-BU-Cs (C, 53.11 and N, 12.92) in comparison to 2Nph-BU-CsSB (C, 54.61 and N, 13.14), 2Clph-BU-CsSB (C, 55.17 and N, 11.73), 4Clph-BU-CsSB (C, 55.12 and N, 11.84), ph-BU-CsSB (C, 57.50 and N, 12.10), H-BU-CsSB (C, 53.89 and N, 13.35), and 2Mph-BU-CsSB (C, 56.97 and N, 11.68) were observed. This emphasizes the removing of the benzaldehyde moieties from chitosan part and retrieving its 1 ry amino groups.

3.3. Antibacterial Activity

By employing the micro-dilution method, the antibacterial activity of the Cs, CsSB, ECsSB, the prepared hydrogels, and the ZnONPs bio-composites was assessed against some Gram-positive bacteria, namely Staphylococcus aureus (S. aureus ATCC ), Streptococcus pyogenes (S. pyogenes ATCC ), Bacillus subtilis (B. subtilis ATCC ), and Staphylococcus epidermidis (S. epidermidis ATCC ), as well as against some Gram-negative bacteria, namely Escherichia coli (E. coli ATCC ), Proteus mirabilis (P. mirabilis ATCC ), Klebsiella pneumonia (K. pneumonia ATCC ), and Pseudomonas aeruginosa (P. aeruginosa ATCC ) using XTT examination. Vancomycin, as an example of a classical antibacterial medication, was employed for a comparison.

The findings demonstrated that the prepared R-BU-CsSB and R-BU-Cs hydrogels had much more antibacterial activity compared to virgin Cs ( a and a).

There have already been proposed three action methods for explaining how chitosan inhibits bacterial growth. The most logical one is that polyanionic bacterial cell membranes and polycationic chitosan chains interact together electrostatically. Thus, the internal electrolytes and protein-rich components of the bacterial cells are lost as a result of changing the permeability of their membranes [35,42]. According to this hypothesis, the materials&#; antibacterial effectiveness will be enhanced as the number of cationized sites on them grows. Compared to the chitosan&#;s structure, R-BU-CsSB hydrogels include -C=O, -N=CH, -NH, -NCH3, -CO-N-CH, and -OH as more sites, whereas R-BU-Cs hydrogels comprise -C=O, -NH, -NCH3, -CO-N-CH, and -OH in addition to the regained -NH2 groups. Due to the ease with which the aforementioned polar groups may be protonated, the R-BU-CsSB and R-BU-Cs hydrogels have a significantly higher number of cationic sites. As a consequence, the net result of their positive charge intensifies, their electrostatic contact with the membranes of bacterial cells that have negative charge sites grows, and as a result, the activity against bacteria is enhanced [32].

According to the second hypothesized mechanism, chitosan combines with microbe&#;s DNA and prevents the production of protein and mRNA [43]. The separation between the chains in R-BU-CsSB and R-BU-Cs hydrogels predominates. This is explained by the incorporation of both the benzaldehyde pendant moieties and R-BU linkages in R-BU-CsSB hydrogels and the inclusion of R-BU linkages in R-BU-Cs hydrogels. As a result, the attraction forces between chains greatly decreased, which aided their entry into the microorganisms&#; cells, leading to a better antibacterial effect by preventing DNA from being turned into RNA, which inhibits the microbes from growing.

The third mechanism was hypothesized in reliance on the distinctive binding ability of chitosan with metal salts, significant nutritive ingredients, and spore elements [44]. Compounds with imine groups and R-BU linkages have long been recognized as acting as efficient ligands for chelating metals [32,45]. As a result, the insertion of these linkages into R-BU-CsSB and R-BU-Cs hydrogels improves their chelating sites for key nutrients, metal salts, and spore components. This explains why the investigated hydrogels are more effective than their parent Cs in killing germs.

R-BU-Cs hydrogels perform better in inhibiting all the tested bacteria compared to R-BU-CsSB hydrogels. The MIC values of R-BU-Cs hydrogels varied from 7.5 to 62.5 μg/mL, whereas the MIC values of R-BU-CsSB hydrogels ranged from 15 to 137.5 μg/mL. This is ascribed to the R-BU linkages beside the restored primary -NH2 groups which can be facilely converted to their protonated states. The latter can easily bind with anionized sites on the membranes of the bacterial cells by electrostatic interactions. This affirms the most agreeable assumption for the chitosan capacity as an antibacterial agent. R-BU-Cs hydrogels are characterized by their higher inhibition potency than R-BU-CsSB hydrogels, referring to the greater inhibitory capacity of the primary -NH2 groups against the bacterial activity relative to that of the imino groups. This is ascribed to the fact that the protonation of the primary -NH2 groups is proceeded easier and to a higher extent than that of the imine groups, enhancing their electrostatic interaction performance with the negative charged sites on the membranes of the bacterial cells and boosting their activities against bacteria relative to that of R-BU-CsSB hydrogels.

Moreover, the inhibition effectiveness of the R-BU-Cs and R-BU-CsSB hydrogels against the tested Gram-negative bacteria might be varied in the following ways: K. pneumonia > P. mirabilis > P. aeruginosa > E. coli ( a). While, their effectiveness in reducing Gram-positive bacteria activity may be summarized as follows: B. subtilis > S. epidermidis > S. aureus > S. pyogenes ( a).

Further, both R-BU-Cs and R-BU-CsSB hydrogels do better in inhibiting Gram-positive bacteria than Gram-negative ones. The MIC values of R-BU-Cs hydrogels varied from 7.5 to 23.75 μg/mL and from 12.5 to 62.5 μg/mL, whereas the MIC values of R-BU-CsSB hydrogels ranged from 15 to 87.5 μg/mL and from 20 to 137.5 μg/mL against the Gram-positive bacteria ( a) and Gram-negative ones, respectively ( a). The structure of the walls of the Gram-positive bacterial cells differs from the Gram-negative ones; whereas the first is distinguished by a porous nature which facilitates the penetration of the external substances within their cells, the Gram-negative bacteria is comprised of a complex two-layer walls (a thick outer layer and a thin inner layer). The exterior layer behaves as a barrier for obstructing the external substances to be penetrated into the cells [46]. Consequently, the variance in the structures of these two kinds of bacteria is accountable for the difference in the inhibition potency of the R-BU-Cs and R-BU-CsSB hydrogels.

The inhibitory action of the prepared hydrogels is considerably influenced by the type of the substituent group in the aryl moiety of the BU derivatives, as shown in a and a. The results indicate that BU derivatives can be assorted in accordance with their inhibition efficiencies into two major classes, between which lies the unsubstituted derivative. To the first class, distinguished by a higher inhibition potency comparative to that of the unsubstituted derivative, belongs the BU derivative of an electron-poor substituent (-NO2, -Cl) which reduces the electrons&#; density on its derivative. On the other hand, the derivatives having lower inhibitory action comparative to that of the unsubstituted derivative possess an electron-rich substituent (-OMe) that can increase the electrons&#; density on its derivative. Experimental evidence boosting these conclusions has been affirmed by the higher inhibition potency of the nitro- and chloro- hydrogels compared to that of the methoxy hydrogel. This is in accordance with the higher electron-withdrawing capacity of the nitro- and chloro- groups relative to methoxy group. Moreover, there is another evidence shown from the greater potency of the chloro- group in position two compared to its inhibitory effect when it is in position four in the aryl moiety of the BU. Because in the first case, electron withdrawing is much faster and consequently easier.

Although 2Nph-BU-Cs is the most effective hydrogel in inhibiting the activity of the tested bacteria in comparison to the other hydrogels, its level of inhibition is less effective than that of the medication Vancomycin. Thus, 2Nph-BU-Cs and 2Mph-BU-Cs, having the highest and the lowest inhibition performance against the tested bacterial activity, respectively, have been chosen to create some ZnONPs composites to reinforce their antibacterial action.

As would be predicted, the MIC values of the 2Nph-BU-Cs/ZnONPs-1%, 2Nph-BU-Cs/ZnONPs-3%, and 2Nph-BU-Cs/ZnONPs-5% against all the tested Gram-negative bacteria which ranged from 0.38 to 6.25 μg/mL ( b) and Gram-positive bacteria which ranged from 0.75 to 1.13 μg/mL ( b) were substantially lower than the MIC values of 2Nph-BU-Cs free from ZnONPs (ranged from 12.5 to 16.25 μg/mL and from 7.5 to 10 μg/mL, respectively), Similarly, MIC values of 2Mph-BU-Cs/ZnONPs-1%, 2Mph-BU-Cs/ZnONPs-3%, and 2Mph-BU-Cs/ZnONPs-5% ranged from 0.5 to 7.5 μg/mL and from 0.88 to 5 μg/mL against Gram-negative and Gram-positive bacteria, respectively, which were significantly lesser than that of their parent 2Mph-BU-Cs (ranging from 25 to 62.5 μg/mL and from 17.5 to 20 μg/mL, respectively), as shown in b and b, respectively.

Moreover, for both the 2Nph-BU-Cs/ZnONPs and 2Mph-BU-Cs/ZnONPs composites, the increment of the inserted ZnONPs from 1% to 5% resulted in improvement in the inhibitory efficacy of the ZnONPs bio-composites against all the kind of examined Gram-negative and Gram-positive bacteria as illustrated in b and b, respectively. In comparison to the typical medicine Vancomycin, both 2Nph-BU-Cs/ZnONPs and 2Mph-BU-Cs/ZnONPs composites have shown much stronger activity against most of the tested Gram-negative bacteria ( b) and all tested Gram-positive bacteria ( b).

It was established that ZnONPs can directly contact with the bacterial cell wall, release the antibacterial Zn+2 ions and the reactive oxygen species which destroy the bacterial walls [26,47], and increase of the permeability of the cell membrane, letting the penetration of the nanoparticles into the bacterial cytoplasm [47]. Therefore, the synthesized ZnONPs bio-composites might be a promising option to antibiotics, particularly against bacterial strains resistant to standard medications.

A kind of synthetic method of theophylline

Technical field

The present invention relates to theophylline synthesis technical field, particularly relate to a kind of synthetic method of theophylline.

Background technology

Theophylline is 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-diketone, and can be described as again dioxy dimethylpurine, 1,3-dimethyl xanthine, 1,3-dimethyl xanthine etc., outward appearance is white crystals or crystalline powder, odorless, bitter, and its molecular formula is C 7h 8n 4o 2, molecular weight is 180.16, No. CAS is 58-55-9, and density is 1.62g/cm 3, fusing point is 270-274 DEG C, dissolved in water (1:120), ethanol (1:18), chloroform (1:86), hydroxide alkali lye, ammoniacal liquor, dilute hydrochloric acid and dust technology, is slightly soluble in ether.It is methyl purine class medicine, has cardiac stimulant, diuresis, coronary artery dilator, excited maincenter through effects such as systems, can be used for treating bronchial asthma, pulmonary emphysema, bronchitis, cardiac dyspnea.Its structural formula is:

Current theophylline preparation method mainly contains biological extraction method and chemical synthesis two kinds.Wherein biological extraction method take mainly tealeaves as raw material, wait until theophylline, but the purity of theophylline is not high by steps such as extraction, resin absorption, purifying.And chemical synthesis major part is by following two kinds of approach preparation: one is employing 1,3-dimethyl-4-amino-5-formamido-uracil and sodium hydroxide solution react at 90-95 DEG C, obtained theophylline crude product, obtain finished product, but the yield of theophylline is low through hot water recrystallization, activated carbon decolorizing; Two be with ethyl cyanoacetate and dimethyl urea for raw material, obtain crude product through condensation, nitrosification, reduction, formylation, ring-closure reaction, then recrystallization and obtaining, but cumbersome, and the yield of each step reaction is low.

Summary of the invention

The technical problem that basic background technology exists, the present invention proposes a kind of synthetic method of theophylline, and the theophylline purity adopting chemical synthesis to obtain is higher, and raw material is cheaply easy to get, and preparation cost is low, and preparation technology is simple, and comprehensive yield is high.

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, amino-1, the 3-FU dimethyl of preparation 6-: methyl-sulfate, 6-Urea,amino-pyrimidine, sodium hydroxide solution and water are added in the first reaction vessel, after 4-5h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl;

S2, preparation 5-nitroso-group-6-amino-1,3-FU dimethyl: by S1 gained 6-amino-1, after 3-FU dimethyl, acetic acid and water add and mix in the second reaction vessel, be warming up to 78-82 DEG C, then drip sodium nitrite in aqueous solution, insulation 28-32min, do not stop in insulating process to stir, then be cooled to after 10-14h is stirred in 0-2 DEG C of continuation and filter, the cleaning of filter cake cold water, drying are obtained amino-1, the 3-FU dimethyl of 5-nitroso-group-6-;

S3, prepare theophylline: in hydrogen autoclave, add S2 gained 5-nitroso-group-6-amino-1,3-FU dimethyl, palladium-carbon catalyst and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 2.5-3.5MPa, after maintaining pressure 3-4h, diatomite filtration is utilized to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 33-37 DEG C, again brown oil is dissolved in acton, after being heated to 97-100 DEG C, insulation 3.5-4.5h, obtains theophylline through underpressure distillation.

Wherein, the cold water in S2 refers to that temperature is the distilled water of 1-2 DEG C, and the acton in S3 can be called triethyl orthoformate again.

Preferably, in S1, concentration of sodium hydroxide solution is 30-35wt%, and the volume ratio of sodium hydroxide solution and water is 5-8:24-28.

Preferably, in S1, the mol ratio of methyl-sulfate and 6-Urea,amino-pyrimidine is the mass volume ratio (g/ml) of 2:1,6-Urea,amino-pyrimidine and sodium hydroxide solution is 3-6:5-8.

Preferably, in S1, be that the sodium hydroxide solution of 31-33wt% and water add in the first reaction vessel by 2 parts of methyl-sulfates, 1 part of 6-Urea,amino-pyrimidine, concentration by molar part, after 4.3-4.7h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl, wherein the mass volume ratio (g/ml) of 6-Urea,amino-pyrimidine and sodium hydroxide solution is 4-5:6-7, and the volume ratio of sodium hydroxide solution and water is 6-7:25-27.

Methyl-sulfate in above-mentioned S1 and 6-Urea,amino-pyrimidine mol ratio theoretical value in methyl reaction is 2:1, namely should be 2:1 according to the mol ratio of reaction mechanism release methyl-sulfate and 6-Urea,amino-pyrimidine; But in actual production process, often add into methyl-sulfate, make mol ratio be greater than 2:1, thus make 6-Urea,amino-pyrimidine react complete as far as possible, improve yield, as described in Example 7.

Preferably, in S2, the mass volume ratio (g/ml) of amino-1, the 3-FU dimethyl of 6-and acetic acid is 0.8-1.2:8-12, and the volume ratio of acetic acid and water is 0.8-1.2:0.8-1.2.

Preferably, in S2, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 1.5-2.5:4-6, and the concentration of sodium nitrite in aqueous solution is 2-4mol/L, and the rate of addition of sodium nitrite in aqueous solution is 18-22ml/h.

Preferably, in S2, by S1 gained 6-amino-1, 3-FU dimethyl, after acetic acid and water add and mix in the second reaction vessel, be warming up to 79-81 DEG C, then drip with the rate of addition of 19-21ml/h the sodium nitrite in aqueous solution that concentration is 2.5-3.5mol/L, insulation 29-31min, do not stop in insulating process to stir, then be cooled to after 11-13h is stirred in 0-1 DEG C of continuation and filter, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 0.9-1.1:9-11, the volume ratio of acetic acid and water is 0.9-1.1:0.9-1.1, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 1.8-2.2:4.5-5.5.

Preferably, in S3,5-nitroso-group-6-amino-1, the mass ratio of 3-FU dimethyl and palladium-carbon catalyst is -:97-103, palladium content in palladium carbon catalyzer is 9.8-10.2wt%, the mass volume ratio (g/ml) of amino-1, the 3-FU dimethyl of 5-nitroso-group-6-and methyl alcohol is 2-3:28-32.

Preferably, in S3, the volume ratio of methyl alcohol and acton is 2-4:4.5-5.5.

Preferably, in S3, - part S2 gained 5-nitroso-group-6-amino-1 is added by weight in hydrogen autoclave, 3-FU dimethyl, 99-101 part palladium-carbon catalyst and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 2.8-3.2MPa, after maintaining pressure 3.3-3.7h, diatomite filtration is utilized to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 34-36 DEG C, again brown oil is dissolved in acton, after being heated to 99-100 DEG C, insulation 3.7-4.3h, theophylline is obtained through underpressure distillation, wherein palladium content in palladium carbon catalyzer is 10wt%, 5-nitroso-group-6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and methyl alcohol is 2.4-2.6:29-31, the volume ratio of methyl alcohol and acton is 2.5-3.5:4.8-5.2.

In the present invention, theophylline synthetic route is as follows:

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The present invention is relative to prior art, adopt chemical synthesis can obtain the higher theophylline of purity, and adopt methyl-sulfate, 6-Urea,amino-pyrimidine as starting raw material, simple and easy to get, and palladium-carbon catalyst can promote quick and high efficient reaction to carry out, make energy-conserving and environment-protective of the present invention, also greatly reduce by the preparation cost invented, adopt method such as cryosel bath stirring, hydrogen high pressure, rotary evaporation etc. combined simultaneously, not only make synthesis technique of the present invention simple, and comprehensive yield is higher than the yield of other synthesis techniques, be suitable for industrial production.

Embodiment

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, amino-1, the 3-FU dimethyl of preparation 6-: methyl-sulfate, 6-Urea,amino-pyrimidine, sodium hydroxide solution and water are added in the first reaction vessel, after 4-5h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl;

S2, preparation 5-nitroso-group-6-amino-1,3-FU dimethyl: by S1 gained 6-amino-1, after 3-FU dimethyl, acetic acid and water add and mix in the second reaction vessel, be warming up to 78-82 DEG C, then drip sodium nitrite in aqueous solution, insulation 28-32min, do not stop in insulating process to stir, then be cooled to after 10-14h is stirred in 0-2 DEG C of continuation and filter, the cleaning of filter cake cold water, drying are obtained amino-1, the 3-FU dimethyl of 5-nitroso-group-6-;

S3, prepare theophylline: in hydrogen autoclave, add S2 gained 5-nitroso-group-6-amino-1,3-FU dimethyl, palladium-carbon catalyst and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 2.5-3.5MPa, after maintaining pressure 3-4h, diatomite filtration is utilized to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 33-37 DEG C, again brown oil is dissolved in acton, after being heated to 97-100 DEG C, insulation 3.5-4.5h, obtains theophylline through underpressure distillation.

Below, by specific embodiment, technical scheme of the present invention is described in detail.

Embodiment 1

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, amino-1, the 3-FU dimethyl of preparation 6-: methyl-sulfate, 6-Urea,amino-pyrimidine, sodium hydroxide solution and water are added in the first reaction vessel, after 4h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl;

S2, preparation 5-nitroso-group-6-amino-1,3-FU dimethyl: by S1 gained 6-amino-1, after 3-FU dimethyl, acetic acid and water add and mix in the second reaction vessel, be warming up to 82 DEG C, then drip sodium nitrite in aqueous solution, insulation 28min, do not stop in insulating process to stir, then be cooled to after 10h is stirred in 2 DEG C of continuation and filter, the cleaning of filter cake cold water, drying are obtained amino-1, the 3-FU dimethyl of 5-nitroso-group-6-;

S3, prepare theophylline: in hydrogen autoclave, add S2 gained 5-nitroso-group-6-amino-1,3-FU dimethyl, palladium-carbon catalyst and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 3.5MPa, after maintaining pressure 3h, utilizes diatomite filtration to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 37 DEG C, then brown oil is dissolved in acton, after being heated to 97 DEG C, insulation 4.5h, obtains theophylline through underpressure distillation.

Embodiment 2

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, amino-1, the 3-FU dimethyl of preparation 6-: methyl-sulfate, 6-Urea,amino-pyrimidine, sodium hydroxide solution and water are added in the first reaction vessel, after 5h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl;

S2, preparation 5-nitroso-group-6-amino-1,3-FU dimethyl: by S1 gained 6-amino-1, after 3-FU dimethyl, acetic acid and water add and mix in the second reaction vessel, be warming up to 78 DEG C, then drip sodium nitrite in aqueous solution, insulation 32min, do not stop in insulating process to stir, then be cooled to after 14h is stirred in 0 DEG C of continuation and filter, the cleaning of filter cake cold water, drying are obtained amino-1, the 3-FU dimethyl of 5-nitroso-group-6-;

S3, prepare theophylline: in hydrogen autoclave, add S2 gained 5-nitroso-group-6-amino-1,3-FU dimethyl, palladium-carbon catalyst and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 2.5MPa, after maintaining pressure 4h, utilizes diatomite filtration to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 33 DEG C, then brown oil is dissolved in acton, after being heated to 100 DEG C, insulation 3.5h, obtains theophylline through underpressure distillation.

Embodiment 3

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, preparation 6-amino-1,3-FU dimethyl: be that the sodium hydroxide solution of 31wt% and water add in the first reaction vessel by 2 parts of methyl-sulfates, 1 part of 6-Urea,amino-pyrimidine, concentration by molar part, after 4.7h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl, wherein the mass volume ratio (g/ml) of 6-Urea,amino-pyrimidine and sodium hydroxide solution is 4:7, and the volume ratio of sodium hydroxide solution and water is 6:27;

S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl: by S1 gained 6-amino-1, 3-FU dimethyl, after acetic acid and water add and mix in the second reaction vessel, be warming up to 79 DEG C, then drip with the rate of addition of 21ml/h the sodium nitrite in aqueous solution that concentration is 2.5mol/L, insulation 31min, do not stop in insulating process to stir, then be cooled to after 13h is stirred in 0 DEG C of continuation and filter, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 0.9:11, the volume ratio of acetic acid and water is 0.9:1.1, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 1.8:5.5,

S3, prepare theophylline: in hydrogen autoclave, add parts of S2 gained 5-nitroso-group-6-amino-1 by weight, 3-FU dimethyl, 101 parts of palladium-carbon catalysts and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 2.8MPa, after maintaining pressure 3.7h, diatomite filtration is utilized to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 34 DEG C, again brown oil is dissolved in acton, after being heated to 100 DEG C, insulation 3.7h, theophylline is obtained through underpressure distillation, wherein palladium content in palladium carbon catalyzer is 10wt%, 5-nitroso-group-6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and methyl alcohol is 2.6:29, the volume ratio of methyl alcohol and acton is 3.5:4.8.

Embodiment 4

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, preparation 6-amino-1,3-FU dimethyl: be that the sodium hydroxide solution of 33wt% and water add in the first reaction vessel by 2 parts of methyl-sulfates, 1 part of 6-Urea,amino-pyrimidine, concentration by molar part, after 4.3h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl, wherein the mass volume ratio (g/ml) of 6-Urea,amino-pyrimidine and sodium hydroxide solution is 5:6, and the volume ratio of sodium hydroxide solution and water is 7:25;

S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl: by S1 gained 6-amino-1, 3-FU dimethyl, after acetic acid and water add and mix in the second reaction vessel, be warming up to 81 DEG C, then drip with the rate of addition of 19ml/h the sodium nitrite in aqueous solution that concentration is 3.5mol/L, insulation 29min, do not stop in insulating process to stir, then be cooled to after 11h is stirred in 1 DEG C of continuation and filter, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 1.1:9, the volume ratio of acetic acid and water is 1.1:0.9, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.2:4.5,

S3, prepare theophylline: in hydrogen autoclave, add parts of S2 gained 5-nitroso-group-6-amino-1 by weight, 3-FU dimethyl, 99 parts of palladium-carbon catalysts and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 3.2MPa, after maintaining pressure 3.3h, diatomite filtration is utilized to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 36 DEG C, again brown oil is dissolved in acton, after being heated to 99 DEG C, insulation 4.3h, theophylline is obtained through underpressure distillation, wherein palladium content in palladium carbon catalyzer is 10wt%, 5-nitroso-group-6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and methyl alcohol is 2.4:31, the volume ratio of methyl alcohol and acton is 2.5:5.2.

Embodiment 5

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, preparation 6-amino-1,3-FU dimethyl: be that the sodium hydroxide solution of 30wt% and water add in the first reaction vessel by 2 parts of methyl-sulfates, 1 part of 6-Urea,amino-pyrimidine, concentration by molar part, after 4.5h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl, wherein the mass volume ratio (g/ml) of 6-Urea,amino-pyrimidine and sodium hydroxide solution is 6:5, and the volume ratio of sodium hydroxide solution and water is 1:3;

S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl: by S1 gained 6-amino-1, 3-FU dimethyl, after acetic acid and water add and mix in the second reaction vessel, be warming up to 80 DEG C, then drip with the rate of addition of 22ml/h the sodium nitrite in aqueous solution that concentration is 2mol/L, insulation 30min, do not stop in insulating process to stir, then be cooled to after 12h is stirred in 0 DEG C of continuation and filter, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 0.3:2, the volume ratio of acetic acid and water is 3:2, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.5:4,

S3, prepare theophylline: in hydrogen autoclave, add parts of S2 gained 5-nitroso-group-6-amino-1 by weight, 3-FU dimethyl, 97 parts of palladium-carbon catalysts and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 3MPa, after maintaining pressure 3.5h, diatomite filtration is utilized to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 35 DEG C, again brown oil is dissolved in acton, after being heated to 100 DEG C, insulation 4h, theophylline is obtained through underpressure distillation, wherein palladium content in palladium carbon catalyzer is 10.2wt%, 5-nitroso-group-6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and methyl alcohol is 1:16, the volume ratio of methyl alcohol and acton is 2:5.5.

Embodiment 6

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, preparation 6-amino-1,3-FU dimethyl: be that the sodium hydroxide solution of 35wt% and water add in the first reaction vessel by 2 parts of methyl-sulfates, 1 part of 6-Urea,amino-pyrimidine, concentration by molar part, after 4.5h is stirred in cryosel bath, filtration, washing, drying obtain 6-amino-1,3-FU dimethyl, wherein the mass volume ratio (g/ml) of 6-Urea,amino-pyrimidine and sodium hydroxide solution is 3:8, and the volume ratio of sodium hydroxide solution and water is 5:28;

S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl: by S1 gained 6-amino-1, 3-FU dimethyl, after acetic acid and water add and mix in the second reaction vessel, be warming up to 80 DEG C, then drip with the rate of addition of 18ml/h the sodium nitrite in aqueous solution that concentration is 4mol/L, insulation 30min, do not stop in insulating process to stir, then be cooled to after 12h is stirred in 0 DEG C of continuation and filter, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 0.2:3, the volume ratio of acetic acid and water is 2:3, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 1:4,

S3, prepare theophylline: in hydrogen autoclave, add parts of S2 gained 5-nitroso-group-6-amino-1 by weight, 3-FU dimethyl, 103 parts of palladium-carbon catalysts and methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 3MPa, after maintaining pressure 3.5h, diatomite filtration is utilized to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 35 DEG C, again brown oil is dissolved in acton, after being heated to 100 DEG C, insulation 4h, theophylline is obtained through underpressure distillation, wherein palladium content in palladium carbon catalyzer is 9.8wt%, 5-nitroso-group-6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and methyl alcohol is 3:28, the volume ratio of methyl alcohol and acton is 4:4.5.

Embodiment 7

The synthetic method of a kind of theophylline that the present invention proposes, comprises the steps:

S1, preparation 6-amino-1,3-FU dimethyl: be that sodium hydroxide solution and the 52ml water of 32wt% adds in the first reaction vessel by 158.6mmol methyl-sulfate (20g), 67.2mmol6-Urea,amino-pyrimidine (8.6g), 12.6ml concentration, after 4.5h is stirred in cryosel bath, filtration, washing, drying obtain amino-1, the 3-FU dimethyl of 7.14g 6-;

S2, preparation 5-nitroso-group-6-amino-1,3-FU dimethyl: by 5g S1 gained 6-amino-1, after 3-FU dimethyl, 50ml acetic acid and 50ml water add and mix in the second reaction vessel, be warming up to 80 DEG C, then drip with the rate of addition of 20ml/h the sodium nitrite in aqueous solution that 20ml concentration is 3.1mol/L, insulation 30min, do not stop in insulating process to stir, then be cooled to after 12h is stirred in 0 DEG C of continuation and filter, the cleaning of filter cake cold water, drying are obtained amino-1, the 3-FU dimethyl of 4.19g 5-nitroso-group-6-;

S3, prepare theophylline: in hydrogen autoclave, add 2.55g S2 gained 5-nitroso-group-6-amino-1, 3-FU dimethyl, 100mg palladium-carbon catalyst and 30ml methyl alcohol, passing into hydrogen makes the pressure in hydrogen autoclave be 3MPa, after maintaining pressure 3.5h, diatomite filtration is utilized to obtain filtrate, filtrate rotary evaporation is obtained brown oil, the temperature of rotary evaporation is 35 DEG C, again brown oil is dissolved in 50ml acton, after being heated to 100 DEG C, insulation 4h, 1.42g theophylline is obtained through underpressure distillation, wherein palladium content in palladium carbon catalyzer is 10wt%.

Embodiment 1 and embodiment 2 do not provide proportioning raw materials situation, and namely raw material can react by arbitrary proportion, because ratio change does not affect the carrying out of reaction usually, just can have influence on the height of yield.

Amino-1, the 3-FU dimethyl of obtained 7.14g 6-in the S1 of embodiment 7, yield is 68.6%; Amino-1, the 3-FU dimethyl of obtained 4.19g 5-nitroso-group-6-in S2, yield is 71.3%; Obtained 1.42g theophylline in S3, yield is 78.2%.

The above; be only the present invention's preferably embodiment; but protection scope of the present invention is not limited thereto; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses; be equal to according to technical scheme of the present invention and inventive concept thereof and replace or change, all should be encompassed within protection scope of the present invention.

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