CN104744469A - Preparation method for theophylline - Google Patents
Preparation method for theophylline Download PDFInfo
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- CN104744469A CN104744469A CN201410610151.9A CN201410610151A CN104744469A CN 104744469 A CN104744469 A CN 104744469A CN 201410610151 A CN201410610151 A CN 201410610151A CN 104744469 A CN104744469 A CN 104744469A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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Abstract
The invention discloses a preparation method for theophylline. The preparation method comprises the following steps: preparing 6-amino-1,3-dimethyl uracil by taking 6-amino uracil, a dimethyl sulfoxide solution, sodium hydride and methyl iodide as raw materials through methylation reaction; obtaining 5-nitroso-6-amino-1,3- dimethyl uracil by adding acetic acid and a sodium nitrite aqueous solution to perform nitrosation reaction; generating 5,6-diamido-1,3- dimethyl uracil DADMU by reducing Na2S2O4 and ammonia water; and finally, adding s-triazine to directly form a ring to generate the theophylline. The preparation method is simple in process, low in reaction condition requirement and high in yield; and the obtained theophylline is high in purity which is as high as 95%.
Description
Technical field
The present invention relates to theophylline preparing technical field, particularly relate to a kind of preparation method of theophylline.
Background technology
Theophylline is 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-diketone, and outward appearance is white crystals or crystalline powder, odorless, bitter, and its molecular formula is C
7h
8n
4o
2molecular weight is 180.16, boiling point is 390.1 DEG C (760mmHg), vapour pressure is 2.72E-06mmHg (25 DEG C), dissolved in water (1:120), ethanol (1:18), chloroform (1:86), hydroxide alkali lye, ammoniacal liquor, dilute hydrochloric acid and dust technology, be 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 often 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 preparation method of theophylline, simple process, and reaction conditions requires low, and yield is high, and the purity of gained theophylline is high, can reach 95%.
The preparation method of a kind of theophylline that the present invention proposes, comprises the steps:
S1, preparation 6-amino-1, 3-FU dimethyl: by molar part 51-54 part 6-Urea,amino-pyrimidine added and be equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 8-10h, then be stirred to after adding 207-210 part sodium hydride after bubble-free produces and continue to stir 1.8-2.2h, then in the first reaction vessel, 250-280 part methyl iodide is dripped with the speed of 25-28mol/min, continue to stir 38-41min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 1-2, then 20-23min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 51-54:280-310, the volume ratio of dimethyl sulphoxide solution and water is 2-4:1,
S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU: 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 80-83 DEG C, then drip with the rate of addition of 20-23ml/h the sodium nitrite in aqueous solution that concentration is 3-4mol/L, insulation 31-34min, do not stop in insulating process to stir, then 8-10h is stirred after being cooled to 0-1 DEG C, after filtration, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 1-1.3:11-14, the volume ratio of acetic acid and water is 1-1.5:1.2-1.4, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.1-2.4:5-6,
S3, preparation 5,6-diaminostilbene, 3-FU dimethyl DADMU: by molar part by 5-8 part 5-nitroso-group-6-amino-1,3-FU dimethyl ANDMU adds the ammoniacal liquor that concentration is 13-15wt%, then be warming up to 68-71 DEG C, insulation 29-31min, do not stop to stir in insulating process, then be cooled to 47-50 DEG C, add 17-20 part Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.4-0.7h, be cooled to 2-5 DEG C after vacuum desolventizes, insulation 0.8-1.1h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 5-8:18-21;
S4, prepare theophylline: by weight by S3 gained 51-54 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 9-12 part s-triazine and toluene are placed in the 3rd reaction vessel, temperature is increased to 80-83 DEG C, after being stirred well to bubble-free generation, temperature is increased to 111-114 DEG C, insulation 1.5-1.8h, then add cold water washing, then obtain theophylline through underpressure distillation.
Wherein, in S1, do not limit the usage quantity of methylene dichloride, because methylene dichloride is as extraction agent, do not participate in reaction, and can vacuum remove in subsequent disposal, the usage quantity of methylene dichloride need not be limited.
Wherein, the cold water in S2 refers to that temperature is the distilled water of 1-2 DEG C.
Wherein, the usage quantity of toluene is not limited in S4, because toluene is as reaction media, namely toluene is as 5,6-diaminostilbene, the solvent of 3-FU dimethyl DADMU and s-triazine, toluene can by 5,6-diaminostilbene, 3-FU dimethyl DADMU and s-triazine dissolve, and need not limit the usage quantity of toluene.
Wherein, saturated sodium bicarbonate solution is in water, add enough sodium bicarbonate solids until cannot dissolve again, and gained solution is saturated sodium bicarbonate solution, and 25 DEG C time, the concentration of saturated sodium bicarbonate solution is 9.38wt%.
In the present invention, the synthetic route of theophylline is as follows:
Preferably, in S1, the mol ratio of 6-Urea,amino-pyrimidine, sodium hydride and methyl iodide is 52-53:208-209:260-270.
Preferably, in S1, being added by 52-53 part 6-Urea,amino-pyrimidine by molar part is equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 8.5-9.5h, then be stirred to after adding 208-209 part sodium hydride after bubble-free produces and continue to stir 1.9-2h, then in the first reaction vessel, 260-270 part methyl iodide is dripped with the speed of 26-27mmol/min, continue to stir 39-40min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 1-2, then 21-22min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 52-53:290-300, the volume ratio of dimethyl sulphoxide solution and water is 2.5-3.1:1.
Preferably, in S3, by molar part by 6-7 part 5-nitroso-group-6-amino-1,3-FU dimethyl ANDMU adds the ammoniacal liquor that concentration is 13.2-14.5wt%, then be warming up to 69-70 DEG C, insulation 29.5-30.2min, do not stop to stir in insulating process, then be cooled to 48-49 DEG C, add 18-19 part Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.5-0.6h, be cooled to 3-4 DEG C after vacuum desolventizes, insulation 0.9-1h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 6-7:19-20.
Preferably, in S4,5,6-diaminostilbene, the weight ratio of 3-FU dimethyl DADMU and s-triazine is 52-53:10-11.
Preferably, in S4, by weight by S3 gained 52-53 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 10-11 part s-triazine and toluene are placed in the 3rd reaction vessel, temperature is increased to 81-82 DEG C, after being stirred well to bubble-free generation, temperature is increased to 112-113 DEG C, insulation 1.6-1.7h, then add cold water washing, then obtain theophylline through underpressure distillation.
The present invention adopts 6-Urea,amino-pyrimidine, dimethyl sulfoxide (DMSO), sodium hydride, methyl iodide to generate amino-1, the 3-FU dimethyl of 6-as raw material, improves yield of the present invention; By adopting Na
2s
2o
4as strong reductant, amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-is made to be reduced generation 5,6-diaminostilbene, 3-FU dimethyl DADMU, easier relative to prior art mesohigh hydrogen reduction method, without the need to building hyperbaric environment, and adopting ammoniacal liquor as solvent, preventing Na
2s
2o
4be decomposed; Also adopt 5,6-diaminostilbene, 3-FU dimethyl DADMU and s-triazine synthesize theophylline in toluene, and operating procedure is easy, and raw material is easy to get, and yield significantly improves relative to prior art, can reach 76%; And theophylline purity prepared by the present invention is greatly enhanced relative to prior art, can reach 95%.
Embodiment
The preparation method of a kind of theophylline that the present invention proposes, comprises the steps:
S1, preparation 6-amino-1, 3-FU dimethyl: by molar part 51-54 part 6-Urea,amino-pyrimidine added and be equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 8-10h, then be stirred to after adding 207-210 part sodium hydride after bubble-free produces and continue to stir 1.8-2.2h, then in the first reaction vessel, 250-280 part methyl iodide is dripped with the speed of 25-28mol/min, continue to stir 38-41min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 1-2, then 20-23min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 51-54:280-310, the volume ratio of dimethyl sulphoxide solution and water is 2-4:1,
S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU: 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 80-83 DEG C, then drip with the rate of addition of 20-23ml/h the sodium nitrite in aqueous solution that concentration is 3-4mol/L, insulation 31-34min, do not stop in insulating process to stir, then 8-10h is stirred after being cooled to 0-1 DEG C, after filtration, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 1-1.3:11-14, the volume ratio of acetic acid and water is 1-1.5:1.2-1.4, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.1-2.4:5-6,
S3, preparation 5,6-diaminostilbene, 3-FU dimethyl DADMU: by molar part by 5-8 part 5-nitroso-group-6-amino-1,3-FU dimethyl ANDMU adds the ammoniacal liquor that concentration is 13-15wt%, then be warming up to 68-71 DEG C, insulation 29-31min, do not stop to stir in insulating process, then be cooled to 47-50 DEG C, add 17-20 part Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.4-0.7h, be cooled to 2-5 DEG C after vacuum desolventizes, insulation 0.8-1.1h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 5-8:18-21;
S4, prepare theophylline: by weight by S3 gained 51-54 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 9-12 part s-triazine and toluene are placed in the 3rd reaction vessel, temperature is increased to 80-83 DEG C, after being stirred well to bubble-free generation, temperature is increased to 111-114 DEG C, insulation 1.5-1.8h, then add cold water washing, then obtain theophylline through underpressure distillation.
Below, by specific embodiment, technical scheme of the present invention is described in detail.
Embodiment 1
The preparation method of a kind of theophylline that the present invention proposes, comprises the steps:
S1, preparation 6-amino-1, 3-FU dimethyl: by molar part 51 parts of 6-Urea,amino-pyrimidines are added and be equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 10h, then be stirred to after adding 207 parts of sodium hydrides after bubble-free produces and continue to stir 2.2h, then in the first reaction vessel, 280 parts of methyl iodide are dripped with the speed of 25mol/min, continue to stir 38min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 2, then 20min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 54:280, the volume ratio of dimethyl sulphoxide solution and water is 4:1,
S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU: 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 22ml/h the sodium nitrite in aqueous solution that concentration is 3.4mol/L, insulation 33min, do not stop in insulating process to stir, then 9h is stirred after being cooled to 0.5 DEG C, after filtration, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 1.1:13, the volume ratio of acetic acid and water is 1.2:1.3, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.3:5.4,
S3, preparation 5,6-diaminostilbene, 3-FU dimethyl DADMU: by molar part by 5 parts of 5-nitroso-group-6-amino-1,3-FU dimethyl ANDMU adds the ammoniacal liquor that concentration is 13wt%, then be warming up to 71 DEG C, insulation 29min, do not stop to stir in insulating process, then be cooled to 50 DEG C, add 17 parts of Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.7h, be cooled to 2 DEG C after vacuum desolventizes, insulation 1.1h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 5-8:18;
S4, prepare theophylline: by weight by S3 gained 53 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 10 parts of s-triazine and toluene are placed in the 3rd reaction vessel, temperature is increased to 82 DEG C, after being stirred well to bubble-free generation, temperature is increased to 112 DEG C, insulation 1.7h, then add cold water washing, then obtain theophylline through underpressure distillation.
Embodiment 2
The preparation method of a kind of theophylline that the present invention proposes, comprises the steps:
S1, preparation 6-amino-1, 3-FU dimethyl: by molar part 52 parts of 6-Urea,amino-pyrimidines are added and be equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 9.5h, then be stirred to after adding 208 parts of sodium hydrides after bubble-free produces and continue to stir 2h, then in the first reaction vessel, 270 parts of methyl iodide are dripped with the speed of 26mmol/min, continue to stir 39min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 2, then 21min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 53:290, the volume ratio of dimethyl sulphoxide solution and water is 3.1:1,
S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU: 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 23ml/h the sodium nitrite in aqueous solution that concentration is 3mol/L, insulation 34min, do not stop in insulating process to stir, then 10h is stirred after being cooled to 0 DEG C, after filtration, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 1:14, the volume ratio of acetic acid and water is 1:1.4, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.1:6,
S3, preparation 5,6-diaminostilbene, 3-FU dimethyl DADMU: by molar part by 8 parts of 5-nitroso-group-6-amino-1,3-FU dimethyl ANDMU adds the ammoniacal liquor that concentration is 15wt%, then be warming up to 68 DEG C, insulation 31min, do not stop to stir in insulating process, then be cooled to 47 DEG C, add 20 parts of Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.4h, be cooled to 5 DEG C after vacuum desolventizes, insulation 0.8h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 5-8:21;
S4, prepare theophylline: by weight by S3 gained 51 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 12 parts of s-triazine and toluene are placed in the 3rd reaction vessel, temperature is increased to 80 DEG C, after being stirred well to bubble-free generation, temperature is increased to 114 DEG C, insulation 1.5h, then add cold water washing, then obtain theophylline through underpressure distillation.
Embodiment 3
The preparation method of a kind of theophylline that the present invention proposes, comprises the steps:
S1, preparation 6-amino-1, 3-FU dimethyl: by molar part 54 parts of 6-Urea,amino-pyrimidines are added and be equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 8h, then be stirred to after adding 210 parts of sodium hydrides after bubble-free produces and continue to stir 1.8h, then in the first reaction vessel, 250 parts of methyl iodide are dripped with the speed of 28mol/min, continue to stir 41min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 1, then 23min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 51:310, the volume ratio of dimethyl sulphoxide solution and water is 2:1,
S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU: 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 82 DEG C, then drip with the rate of addition of 21ml/h the sodium nitrite in aqueous solution that concentration is 3.8mol/L, insulation 32min, do not stop in insulating process to stir, then 8.3h is stirred after being cooled to 0.7 DEG C, after filtration, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 1:10, the volume ratio of acetic acid and water is 1.4:1.3, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.2:5.6,
S3, preparation 5,6-diaminostilbene, 3-FU dimethyl DADMU: by molar part by 6 parts of 5-nitroso-group-6-amino-1,3-FU dimethyl ANDMU adds the ammoniacal liquor that concentration is 14.5wt%, then be warming up to 69 DEG C, insulation 30.2min, do not stop to stir in insulating process, then be cooled to 48 DEG C, add 19 parts of Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.5h, be cooled to 4 DEG C after vacuum desolventizes, insulation 0.9h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 6-7:20;
S4, prepare theophylline: by weight by S3 gained 54 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 9 parts of s-triazine and toluene are placed in the 3rd reaction vessel, temperature is increased to 83 DEG C, after being stirred well to bubble-free generation, temperature is increased to 111 DEG C, insulation 1.8h, then add cold water washing, then obtain theophylline through underpressure distillation.
Embodiment 4
The preparation method of a kind of theophylline that the present invention proposes, comprises the steps:
S1, preparation 6-amino-1, 3-FU dimethyl: by molar part 53 parts of 6-Urea,amino-pyrimidines are added and be equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 8.5h, then be stirred to after adding 209 parts of sodium hydrides after bubble-free produces and continue to stir 1.9h, then in the first reaction vessel, 260 parts of methyl iodide are dripped with the speed of 27mmol/min, continue to stir 40min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 1, then 22min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 52:300, the volume ratio of dimethyl sulphoxide solution and water is 2.5:1,
S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU: 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 83 DEG C, then drip with the rate of addition of 20ml/h the sodium nitrite in aqueous solution that concentration is 4mol/L, insulation 31min, do not stop in insulating process to stir, then 8h is stirred after being cooled to 1 DEG C, after filtration, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 1.3:11, the volume ratio of acetic acid and water is 1.5:1.2, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.4:5,
S3, preparation 5,6-diaminostilbene, 3-FU dimethyl DADMU: by molar part by 7 parts of 5-nitroso-group-6-amino-1,3-FU dimethyl ANDMU adds the ammoniacal liquor that concentration is 13.2wt%, then be warming up to 70 DEG C, insulation 29.5min, do not stop to stir in insulating process, then be cooled to 49 DEG C, add 18 parts of Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.6h, be cooled to 3 DEG C after vacuum desolventizes, insulation 1h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 6-7:19;
S4, prepare theophylline: by weight by S3 gained 52 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 11 parts of s-triazine and toluene are placed in the 3rd reaction vessel, temperature is increased to 81 DEG C, after being stirred well to bubble-free generation, temperature is increased to 113 DEG C, insulation 1.6h, then add cold water washing, then obtain theophylline through underpressure distillation.
Carry out yield and purity test to embodiment 1-4, result is as follows:
| Test event | Embodiment 1-4 | Prior art |
| Purity | 95％ | 85％ |
| Yield | 76％ | 49％ |
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.
Claims (6)
1. a preparation method for theophylline, is characterized in that, comprises the steps:
S1, preparation 6-amino-1, 3-FU dimethyl: by molar part 51-54 part 6-Urea,amino-pyrimidine added and be equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 8-10h, then be stirred to after adding 207-210 part sodium hydride after bubble-free produces and continue to stir 1.8-2.2h, then in the first reaction vessel, 250-280 part methyl iodide is dripped with the speed of 25-28mol/min, continue to stir 38-41min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 1-2, then 20-23min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 51-54:280-310, the volume ratio of dimethyl sulphoxide solution and water is 2-4:1,
S2, preparation 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU: 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 80-83 DEG C, then drip with the rate of addition of 20-23ml/h the sodium nitrite in aqueous solution that concentration is 3-4mol/L, insulation 31-34min, do not stop in insulating process to stir, then 8-10h is stirred after being cooled to 0-1 DEG C, after filtration, filter cake cold water is cleaned, drying obtains 5-nitroso-group-6-amino-1, 3-FU dimethyl ANDMU, wherein 6-amino-1, the mass volume ratio (g/ml) of 3-FU dimethyl and acetic acid is 1-1.3:11-14, the volume ratio of acetic acid and water is 1-1.5:1.2-1.4, the volume ratio of sodium nitrite in aqueous solution and acetic acid is 2.1-2.4:5-6,
S3, preparation 5,6-diaminostilbene, 3-FU dimethyl DADMU: by molar part by 5-8 part 5-nitroso-group-6-amino-1,3-FU dimethyl ANDMU adds the ammoniacal liquor that concentration is 13-15wt%, then be warming up to 68-71 DEG C, insulation 29-31min, do not stop to stir in insulating process, then be cooled to 47-50 DEG C, add 17-20 part Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.4-0.7h, be cooled to 2-5 DEG C after vacuum desolventizes, insulation 0.8-1.1h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 5-8:18-21;
S4, prepare theophylline: by weight by S3 gained 51-54 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 9-12 part s-triazine and toluene are placed in the 3rd reaction vessel, temperature is increased to 80-83 DEG C, after being stirred well to bubble-free generation, temperature is increased to 111-114 DEG C, insulation 1.5-1.8h, then add cold water washing, then obtain theophylline through underpressure distillation.
2. the preparation method of theophylline according to claim 1, it is characterized in that, in S1, the mol ratio of 6-Urea,amino-pyrimidine, sodium hydride and methyl iodide is 52-53:208-209:260-270.
3. the preparation method of theophylline according to claim 1 or 2, it is characterized in that, in S1, being added by 52-53 part 6-Urea,amino-pyrimidine by molar part is equipped with in the first reaction vessel of dimethyl sulphoxide solution, stir 8.5-9.5h, then be stirred to after adding 208-209 part sodium hydride after bubble-free produces and continue to stir 1.9-2h, then in the first reaction vessel, 260-270 part methyl iodide is dripped with the speed of 26-27mmol/min, continue to stir 39-40min, in the first reaction vessel, adding water and drip concentrated hydrochloric acid to pH is again 1-2, then 21-22min is stirred after adding methylene dichloride, stratification, wash to solution in neutral with saturated sodium bicarbonate solution after lower floor's liquid is taken out, 6-amino-1 is obtained after vacuum desolventizes, 3-FU dimethyl, wherein the molecular volume ratio (mmol/ml) of 6-Urea,amino-pyrimidine and dimethyl sulphoxide solution is 52-53:290-300, the volume ratio of dimethyl sulphoxide solution and water is 2.5-3.1:1.
4. the preparation method of theophylline according to any one of claim 1-3, it is characterized in that, in S3, by molar part, amino for 6-7 part 5-nitroso-group-6--1,3-FU dimethyl ANDMU is added the ammoniacal liquor that concentration is 13.2-14.5wt%, be then warming up to 69-70 DEG C, insulation 29.5-30.2min, do not stop to stir in insulating process, be then cooled to 48-49 DEG C, add 18-19 part Na
2s
2o
4after continue to be stirred to solution in yellow, then room temperature is cooled the temperature to, continue to stir 0.5-0.6h, be cooled to 3-4 DEG C after vacuum desolventizes, insulation 0.9-1h, filtration, drying obtain 5,6-diaminostilbene, 3-FU dimethyl DADMU, wherein the molecular volume (mmol/ml) of amino-1, the 3-FU dimethyl ANDMU of 5-nitroso-group-6-and ammoniacal liquor is than being 6-7:19-20.
5. the preparation method of theophylline according to any one of claim 1-4, it is characterized in that, in S4,5,6-diaminostilbene, the weight ratio of 3-FU dimethyl DADMU and s-triazine is 52-53:10-11.
6. the preparation method of theophylline according to any one of claim 1-5, it is characterized in that, in S4, by weight by S3 gained 52-53 part 5,6-diaminostilbene, 3-FU dimethyl DADMU, 10-11 part s-triazine and toluene are placed in the 3rd reaction vessel, and temperature is increased to 81-82 DEG C, after being stirred well to bubble-free generation, temperature is increased to 112-113 DEG C, insulation 1.6-1.7h, then adds cold water washing, then obtains theophylline through underpressure distillation.
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