CN104003941A - Preparation method of caffeine intermediate N,N-1,3-dimethyl-4,5-diamido urazine - Google Patents
Preparation method of caffeine intermediate N,N-1,3-dimethyl-4,5-diamido urazine Download PDFInfo
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- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960001948 caffeine Drugs 0.000 title claims abstract description 22
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000007259 addition reaction Methods 0.000 claims abstract description 12
- 229910001507 metal halide Inorganic materials 0.000 claims abstract description 12
- 150000005309 metal halides Chemical class 0.000 claims abstract description 12
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 239000012429 reaction media Substances 0.000 claims abstract description 9
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 230000009467 reduction Effects 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- QHTPSODXPLCXJB-UHFFFAOYSA-N piperazine;urea Chemical compound NC(N)=O.C1CNCCN1 QHTPSODXPLCXJB-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 5
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- -1 alkaline matter Inorganic materials 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims 1
- IYPZRUYMFDWKSS-UHFFFAOYSA-N piperazin-1-amine Chemical compound NN1CCNCC1 IYPZRUYMFDWKSS-UHFFFAOYSA-N 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 9
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000007868 Raney catalyst Substances 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 230000022244 formylation Effects 0.000 description 7
- 238000006170 formylation reaction Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000003637 basic solution Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229960000278 theophylline Drugs 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- LNDZXOWGUAIUBG-UHFFFAOYSA-N 6-aminouracil Chemical compound NC1=CC(=O)NC(=O)N1 LNDZXOWGUAIUBG-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a preparation method of the caffeine intermediate N,N-1,3-dimethyl-4,5-diamido urazine and belongs to the technical field of synthesis and preparation of organic compounds. According to the preparation method, a hydrogen addition reaction is carried out under heated and pressurized conditions with N,N-1,3-dimethyl-4-imido-5-isonitroso urazine as the starting material and raney nickel as the catalyst, an aqueous solution containing metal halide and alkaline substances is used as the reaction medium, the preparation method has the advantages of being smooth and controllable in reaction, high in catalytic activity and stable in quality of dimethyl-DAU, and the yield and the quality of the dimethyl-DAU are improved.
Description
Technical field
The present invention relates to a kind of preparation method of caffeine intermediate, relate in particular to caffeine intermediate N, N-1,3-dimethyl-4, the preparation method of 5-diaminourea piperazine, belongs to the synthetic preparing technical field of organic compound.
Background technology
Xanthine drug caffeine has excited heart and cerebral nerve and diuretic properties, extensively for clinical.N, N-1,3-dimethyl-4,5-diaminourea piperazine (dimethyl-DAU) is an important intermediate of synthetic caffeine, and at present, it is by N, N-1,3-dimethyl-4-imino--5-isonitroso urea piperazine (dimethyl-NAU) makes through reduction reaction.Wherein, the method for reduction reaction mainly contains iron powder and adds three kinds of chlorination sodium reduction, catalytic hydrogenating reduction and electrochemical reductions.Iron powder reducing reaction can produce a large amount of iron mud, and environment is made a very bad impression; Electrochemical reduction as a kind of novel method of reducing at present also under study for action; Catalytic hydrogenating reduction method can not generate other by product, is the green method of reducing that caffeine manufacturer extensively adopts both at home and abroad at present.Catalyzer adopts Raney's nickel mostly, and under the condition of pressurization of heating, logical hydrogen makes diformazan NAU change diformazan DAU into.
British patent document GB2001310 discloses a kind of method of being prepared diformazan DAU by diformazan NAU, it adopts Raney's nickel is catalyzer, at 2～100ats, hydro-reduction at 20～60 DEG C, this patent documentation points out that the katalysis of Raney's nickel in basic solution is better, but this patent documentation also points out that diformazan DAU is unstable under alkaline condition simultaneously, so it has increased the step that diformazan DAU is prepared into vitriol.
Chinese patent literature CN1017241B also discloses a kind of method of preparing dimethyl-NAU, and itself and the disclosed technology difference of above-mentioned british patent document GB2001310 are: (1) reaction medium is warm water; (2) dimethyl-NAU is used to formic acid formylation immediately.Based on above-mentioned difference technical characterictic, the technical problem that this Chinese patent literature CN1017241B solves is to overcome the unsettled problem of diformazan DAU that uses basic solution to cause in british patent document GB2001310, but, in this Chinese patent literature CN1017241B, record and adopt neutral water to make reaction medium, reaction is finished immediately by diformazan DAU formic acid formylation, about increase by diformazan DAU formic acid formylated step, to obtain stable form because diformazan DAU is still unstable with formic acid formylation, still be exactly only to prepare target product, this Chinese patent literature does not show, also not corresponding record in embodiment, but from the statement of " reaction is finished immediately by diformazan DAU formic acid formylation ", embody the urgency of time, also shown that in Chinese patent literature CN1017241B reaction system, the unsettled problem of diformazan DAU still exists, in addition, diformazan NAU solvability in water is poor, be unfavorable for reacting and carry out, and the catalytic selectivity of Raney's nickel in water is bad, provocative reaction is too fast, make reaction generate some by product, cause gained diformazan DAU yield low, make thick theophylline, the final product qualities such as thick caffeine are poor, need to carry out secondary refining and just can reach salable product specification of quality.
As can be seen here, for the technology of being prepared diformazan DAU by diformazan NAU, not only to consider the katalysis of catalyzer, also will consider the problems such as the stability of diformazan DAU in reaction system.
Summary of the invention
Technical problem to be solved by this invention is the defect that overcomes prior art, a kind of caffeine intermediate N is provided, N-1,3-dimethyl-4, the preparation method of 5-diaminourea piperazine, this preparation method has advantages of that reacting balance is controlled, catalytic activity is high, diformazan DAU steady quality, yield and quality improve.
Technical problem of the present invention is realized by following technical scheme.
A kind of caffeine intermediate N, N-1,3-dimethyl-4, the preparation method of 5-diaminourea piperazine, this preparation method is with N, N-1,3-dimethyl-4-imino--5-isonitroso urea piperazine is starting raw material, taking Raney's nickel as catalyzer, under the pressurized conditions of heating, there is addition reaction of hydrogen, this preparation method is taking the aqueous solution that contains metal halide and alkaline matter as reaction medium.
Above-mentioned preparation method, described metal halide be selected from KI, NaCl or NaBr, preferably NaCl; Described alkaline matter is selected from the NaOH aqueous solution of mass concentration 30%, ammoniacal liquor, the solid Na that mass concentration is 20%
2cO
3or solid NaHCO
3, preferably solid Na
2cO
3.
Above-mentioned preparation method, in this preparation method's reaction system, described N, N-1,3-dimethyl-4-imino--5-isonitroso urea piperazine is 1:0.05～0.2:0.02～0.5:3～15 with the ratio of the weight of described Raney's nickel, alkaline matter, water, preferably 1:0.12:0.03:12; Described Raney's nickel is 1:0.05～0.2 with the ratio of the weight of metal halide, preferably: 1:0.08.
Above-mentioned preparation method, the pressure of described addition reaction of hydrogen is 0.25～0.60MPa, preferably 0.40MPa.
Above-mentioned preparation method, the temperature of reaction of described addition reaction of hydrogen is 15～60 DEG C, preferably 55 DEG C.
Above-mentioned preparation method, the time of described addition reaction of hydrogen is 40～150min, preferably 50min.
Above-mentioned preparation method, comprises the steps:
Take N, N-1,3-dimethyl-4-imino--5-isonitroso urea piperazine dry product 200g, water 2400ml, Raney's nickel 24g, solid Na
2cO
36g, NaCl1.92g, adds in hydrogenating reduction still, replaces, and to reactor heating, starts reaction, H in the time of 55 DEG C
2pressure 0.40MPa, reaction times 50min, diformazan DAU yield 94.5%, purity 95.3%.
The applicant is devoted for years in the study on the synthesis of caffeine intermediate, surprised discovery in research process, the aqueous solution that employing contains metal halide and alkaline matter is reaction medium, can overcome the problem of diformazan DAU at alkaline condition or neutral water conditional instability, can overcome again diformazan NAU solvability in water poor, be unfavorable for reacting and carry out, and the catalytic selectivity of Raney's nickel in water is bad, provocative reaction is too fast, make reaction generate some by product, cause gained diformazan DAU yield low, make thick theophylline, the poor problems of final product quality such as thick caffeine.The aqueous solution that contains metal halide and alkaline matter of the present invention is reaction medium, in reaction system, halogenide makes the part passivation of catalyzer Raney's nickel surface, make reaction more steadily controlled, adding alkaline matter to regulate reaction system is weakly alkaline, both be more conducive to the dissolving of diformazan NAU, reaction is better carried out, the reaction system that formed thus, can keep raney ni catalysis effect, improve its catalytic selectivity, improve yield and the quality of diformazan DAU, caffeine intermediate N of the present invention, N-1, 3-dimethyl-4, the preparation method of 5-diaminourea piperazine, the yield of diformazan DAU is up to 94.5%, purity is up to 95.3%.In addition, in reaction system of the present invention, diformazan DAU stable in properties can directly obtain, do not need to carry out again any processing to obtain its stable form or need to carry out immediately next step reaction for next target product, reduce the step of reaction, reduce the kind that organic solvent uses, improved production efficiency, reduced enterprise cost.Because british patent document GB2001310 has pointed out that the katalysis of Raney's nickel in basic solution is better, but diformazan DAU is unstable under alkaline condition, and the aqueous solution that the present invention contains metal halide and alkaline matter by use is reaction medium, can keep the performance of the katalysis of Raney's nickel, can make again diformazan DAU stable in reaction system, so the present invention has overcome the existing technical problem of british patent document GB2001310.In addition; be reaction medium because Chinese patent literature CN1017241B instruction is used warm water; and dimethyl-NAU is used to formic acid formylation immediately; but because diformazan DAU unsettled problem in Chinese patent literature CN1017241B reaction system still exists; in addition; diformazan NAU solvability in water is poor; be unfavorable for reacting and carry out; and the catalytic selectivity of Raney's nickel in water is bad; provocative reaction is too fast etc., so also solved the problem that Chinese patent literature CN1017241B exists in reaction system of the present invention.In sum, the present invention is compared with the disclosed technical scheme of british patent document GB2001310, Chinese patent literature CN1017241B, diformazan DAU stable in properties in reaction system, and its yield, purity are all very high, have outstanding substantive distinguishing features and significant progressive.
Brief description of the drawings
The high-efficient liquid phase chromatogram of diformazan DAU purity in embodiment 1 reaction system in Fig. 1 GB2001310
The high-efficient liquid phase chromatogram of diformazan DAU purity in embodiment 2 reaction systems in Fig. 2 CN1017241B
The high-efficient liquid phase chromatogram of diformazan DAU purity in Fig. 3 embodiment of the present invention 1 reaction system
Embodiment
Below by embodiment, the present invention is described in further detail, but these embodiments do not form any restriction to the present invention.
Embodiment 1 caffeine intermediate of the present invention N, N-1,3-dimethyl-4, the preparation of 5-diaminourea piperazine
Take diformazan NAU dry product 200g, water 2400ml, Raney's nickel 24g, solid Na
2cO
36g, NaCl1.92g, adds in hydrogenating reduction still, replaces, and to reactor heating, starts reaction, H in the time of 55 DEG C
2pressure 0.40MPa, reaction times 50min, diformazan DAU yield 94.5%, purity 95.3%.
Embodiment 2 caffeine intermediate of the present invention N, N-1,3-dimethyl-4, the preparation of 5-diaminourea piperazine
Take diformazan NAU dry product 200g, water 2400ml, Raney's nickel 25g, solid Na
2cO
310g, NaBr2g, adds in hydrogenating reduction still, replaces, and to reactor heating, starts reaction, H in the time of 55 DEG C
2pressure 0.35MPa, reaction times 40min, diformazan DAU yield 93.2%, purity 93.4%.
Embodiment 3 caffeine intermediate of the present invention N, N-1,3-dimethyl-4, the preparation of 5-diaminourea piperazine
Take diformazan NAU dry product 200g, water 3000ml, Raney's nickel 15g, solid NaHCO
335g, KI0.8g, adds in hydrogenating reduction still, replaces, and to reactor heating, starts reaction, H in the time of 30 DEG C
2pressure 0.60MPa, reaction times 100min, diformazan DAU yield 90.9%, purity 92.5%.
Embodiment 4 caffeine intermediate of the present invention N, N-1,3-dimethyl-4, the preparation of 5-diaminourea piperazine
Take diformazan NAU dry product 200g, water 600ml, the NaOH aqueous solution 4g of Raney's nickel 10g, mass concentration 30%, NaCl0.5g, adds in hydrogenating reduction still, replaces, and to reactor heating, starts reaction, H in the time of 60 DEG C
2pressure 0.25MPa, reaction times 150min, diformazan DAU yield 91.2%, purity 93.4%.
Embodiment 5 caffeine intermediate of the present invention N, N-1,3-dimethyl-4, the preparation of 5-diaminourea piperazine
Take diformazan NAU dry product 200g, water 3000ml, the ammoniacal liquor 100g of Raney's nickel 40g, mass concentration 20%, NaBr8g, adds in hydrogenating reduction still, replaces, and to reactor heating, starts reaction, H in the time of 40 DEG C
2pressure 0.50MPa, reaction times 80min, diformazan DAU yield 93.5%, purity 89.3%.
Embodiment 6 caffeine intermediate of the present invention N, N-1,3-dimethyl-4, the preparation of 5-diaminourea piperazine
Take diformazan NAU dry product 200g, water 1800ml, Raney's nickel 25g, solid NaHCO
350g, NaBr3g, adds in hydrogenating reduction still, replaces, and to reactor heating, starts reaction, H in the time of 20 DEG C
2pressure 0.60MPa, reaction times 60min, diformazan DAU yield 92.5%, purity 92.4%.
Comparative example 1
(1) embodiment 1 in british patent document GB2001310, the 6-amino uracil of 131.0g (1mol) 97% is dissolved in to 1.2L water, under room temperature, add the aqueous sodium hydroxide solution of 180g25%, then add the sub-sodium of 80g, be cooled to 5 DEG C, add about 450ml concentrated hydrochloric acid/water (volume ratio 1:1) mixing liquid, regulating pH value is 2, separates out red-purple crystal.Reaction mixture is continued to stir 15min, and by adding about 3ml hydrazine hydrate that unnecessary nitrite is reacted away, reaction mixture reduces gradually.
Nitrosification mixture is poured in an autoclave of 2 liters of being furnished with paddle stirrer, added the aqueous sodium hydroxide solution of 540ml25%, 20g Raney's nickel, at pressure 0.80MPa, 40 DEG C, carries out hydrogenation reaction under the condition of turn/min of stir speed (S.S.) 1000.Until hydrogen pressure does not decline.This reaction needed 2.5h.After reacting, solution diformazan DAU filters, and gets filtrate and carries out high-efficient liquid phase analysis, measures diformazan DAU purity 82.6% (Fig. 1, peak area 82.6%) in solution, yield 76.4%.Illustrate that diformazan DAU is unstable in independent alkaline matter.
(2) embodiment 2 in Chinese patent literature CN1017241B, N, N-1,3-dimethyl-4-imino--5-isonitroso uridylic 10kg, skeleton nickel 2kg, distilled water 200kg, add in self-priming hydro-reduction tank, after conventional displacement, logical electrolytic sodium chloride by-product hydrogen, gas-chromatography record in hydrogen oxygen level qualified after, start reaction, tank pressure 0.098～0.49MPa, 20～60 DEG C of temperature, the time is 1～3h approximately, and hydrogen flowmeter instruction reaches after terminal, logical nitrogen press filtration, obtains diformazan DAU.Diformazan DAU purity 85.9% (Fig. 2, peak area 85.9%), yield 78.4%.Prove that diformazan DAU is unstable in independent warm water.
(3) get embodiment 1 and prepare the reaction system solution after complete diformazan DAU filtration, high performance liquid phase is measured the purity 95.3% (Fig. 3, peak area 95.3%) of diformazan DAU in solution.
By above contrast, we also can find out, in the disclosed technology of british patent document GB2001310, diformazan DAU is unsettled under alkaline condition, and the step that diformazan DAU need to be prepared into vitriol could obtain higher yield; In Chinese patent literature CN1017241B reaction system, diformazan DAU is also unstable, still needs the formylation of diformazan DAU formic acid could obtain higher yield; And method described in the embodiment of the present invention 1, diformazan DAU stable in properties in reaction system, and very high yield and purity are obtained, further prove that technical solution of the present invention can overcome the problem of diformazan DAU at alkaline condition or neutral water conditional instability, can overcome again diformazan NAU solvability in water poor, be unfavorable for reacting and carry out, and the catalytic selectivity of Raney's nickel in water is bad, provocative reaction is too fast, make reaction generate some by product, cause gained diformazan DAU yield low, make the poor problem of final product quality such as thick theophylline, thick caffeine.Technical solutions according to the invention are compared with british patent document GB2001310, Chinese patent literature CN1017241B; under alkaline condition, can make diformazan DAU stable existence; and do not need to be prepared into vitriol or formylation immediately; reduce the use of operation steps and organic solvent; improve production efficiency; reduce cost, avoided the generation of environmental hazard, there is environmental protection.
The explanation of above embodiment is just for helping to understand the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any amendment of doing, is equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (8)
1. a caffeine intermediate N, N-1,3-dimethyl-4, the preparation method of 5-Urea,amino-piperazine, this preparation method is with N, N-1,3-dimethyl-4-imino--5-isonitroso urea piperazine is starting raw material, taking Raney's nickel as catalyzer, under the pressurized conditions of heating, addition reaction of hydrogen occurs, it is characterized in that, this preparation method is taking the aqueous solution that contains metal halide and alkaline matter as reaction medium.
2. preparation method according to claim 1, is characterized in that, described metal halide is selected from KI, NaCl or NaBr; It is 30% the NaOH aqueous solution, ammoniacal liquor, the solid Na that mass concentration is 20% that described alkaline matter is selected from mass concentration
2cO
3or solid NaHCO
3.
3. preparation method according to claim 1 and 2, is characterized in that, described metal halide is NaCl; Described alkaline matter is solid Na
2cO
3.
4. preparation method according to claim 1 and 2, it is characterized in that, in this preparation method's reaction system, described N, N-1,3-dimethyl-4-imino--5-isonitroso urea piperazine is 1:0.05～0.2:0.02～0.5:3～15 with the ratio of the weight of described Raney's nickel, alkaline matter, water; Described Raney's nickel is 1:0.05～0.2 with the ratio of the weight of metal halide.
5. preparation method according to claim 4, is characterized in that, in this preparation method's reaction system, and described N, N-1,3-dimethyl-4-imino--5-isonitroso urea piperazine is 1:0.12:0.03:12 with the ratio of the weight of described Raney's nickel, alkaline matter, water; Described Raney's nickel is 1:0.08 with the ratio of the weight of metal halide.
6. preparation method according to claim 1 and 2, is characterized in that, the pressure of described addition reaction of hydrogen is 0.25～0.60MPa; The temperature of reaction of described addition reaction of hydrogen is 15～60 DEG C; The time of described addition reaction of hydrogen is 40～150min.
7. preparation method according to claim 6, is characterized in that, the pressure of described addition reaction of hydrogen is 0.40MPa; The temperature of reaction of described addition reaction of hydrogen is 55 DEG C; The time of described addition reaction of hydrogen is 50min.
8. preparation method according to claim 1, is characterized in that, comprises the steps:
Take N, N-1,3-dimethyl-4-imino--5-isonitroso urea piperazine dry product 200g, water 2400ml, Raney's nickel 24g, solid Na
2cO
36g, NaCl1.92g, adds in hydrogenating reduction still, replaces, and to reactor heating, starts reaction, H in the time of 55 DEG C
2pressure 0.40MPa, reaction times 50min, N, N-1,3-dimethyl-4, the yield 94.5% of 5-diaminourea piperazine, purity 95.3%.
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