CN108069972A - A kind of production method of Dipyridamole bulk pharmaceutical chemicals - Google Patents
A kind of production method of Dipyridamole bulk pharmaceutical chemicals Download PDFInfo
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- CN108069972A CN108069972A CN201611006751.XA CN201611006751A CN108069972A CN 108069972 A CN108069972 A CN 108069972A CN 201611006751 A CN201611006751 A CN 201611006751A CN 108069972 A CN108069972 A CN 108069972A
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- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960002768 dipyridamole Drugs 0.000 title claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- 239000000126 substance Substances 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000004202 carbamide Substances 0.000 claims abstract description 14
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229940043237 diethanolamine Drugs 0.000 claims abstract description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000460 chlorine Substances 0.000 claims abstract description 9
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 9
- 150000003053 piperidines Chemical class 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- PGNYNCTUBKSHHL-UHFFFAOYSA-N 2,3-diaminobutanedioic acid Chemical compound OC(=O)C(N)C(N)C(O)=O PGNYNCTUBKSHHL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 239000003054 catalyst Substances 0.000 claims description 19
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- 230000035484 reaction time Effects 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- 238000005660 chlorination reaction Methods 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 5
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 229940092714 benzenesulfonic acid Drugs 0.000 claims 1
- 239000007809 chemical reaction catalyst Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004321 preservation Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000005862 Whey Substances 0.000 description 3
- 102000007544 Whey Proteins Human genes 0.000 description 3
- 108010046377 Whey Proteins Proteins 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- ZFDIRQKJPRINOQ-HWKANZROSA-N Ethyl crotonate Chemical compound CCOC(=O)\C=C\C ZFDIRQKJPRINOQ-HWKANZROSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000003257 anti-anginal effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000002473 artificial blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- -1 nitroorotic acid sodium Chemical compound 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- WOZOCNSIPFNZFR-UHFFFAOYSA-N pyrimidine;sodium Chemical compound [Na].C1=CN=CN=C1 WOZOCNSIPFNZFR-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 231100001028 renal lesion Toxicity 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention provides a kind of production methods of the bulk pharmaceutical chemicals of Dipyridamole, are related to medicinal chemicals synthesis field, including step：With 2 after the carbonyl-protection of urea; 3 diamino succinic acid are condensed; condensation reaction products hydroxyl is through superchlorination; then substitution chlorine is removed with piperidines; obtained product hydrolyzes to obtain containing there are two the compounds of carbonyl; product is separated, separation product occurs condensation reaction with diethanol amine and obtains Dipyridamole, is refining to obtain finished product.The method of the present invention simplifies the synthesis step of synthesis Dipyridamole, can significantly improve the conversion ratio of raw material, reduces production cost.
Description
Technical field
The invention discloses a kind of production methods of the bulk pharmaceutical chemicals of Dipyridamole, are related to medicinal chemicals synthesis field.
Background technology
The chemistry of Dipyridamole is entitled：2,2', 2 ", 2'''- [4,8- dipiperidino pyrimido [5,4-d] pyrimidines -2,6- bis-
Base] double nitrilo-s]-tetraethoxide, molecular formula：C24H40N8O4, molecular weight 504.63, chemical structural formula is as follows：
The main pharmacological action of Dipyridamole is expansion blood vessel, inhibits platelet aggregation and adherency, has anti-thrombosis function,
It can inhibit hematoblastic first phase aggregation with second mutually to assemble, high concentration can inhibit hematoblastic release reaction, be a kind of hat
Arteries and veins expands medicine, can enhance coronary blood flow, has Antianginal effect.In addition, available for heart valve prosthesis or artificial blood
2 grades of preventions, peripheral angiopathy, ischemic cerebrovascular disease, renal lesionses after pipe post-transplantation antithrombotic, myocardial infarction
Deng, microcirculation can be improved and strengthen heparin and the blood coagulation resisting function of oral anticoagulant, it is intravascular to thrombosis and diffusivity
Blood coagulation has certain effect.
The method for being used to prepare Dipyridamole is disclosed in patent US3031450, this method includes 2,6-, bis- chloro- 4,8- bis-
Piperidyl-pyrimido（5,4-d）The reaction of pyrimidine and diethanol amine, the patent also report 2,6-, bis- chloro- 4,8- dipiperidinos-
Pyrimido（5,4-d）The preparation method of pyrimidine.
For Dipyridamole production line using urea and ethyl acetoacetate as raw material, synthetic route is longer at present, mainly have with
Lower step, urea are condensed into β-urine base ethyl crotonate with ethyl acetoacetate in ethyl alcohol and hydrochloric acid solution, then cyclization 6- first
Base uracil adds in sodium hydroxide, air oxidation in dry reaction pot, then generates nitroorotic acid sodium through nitric acid nitrating, so
Afterwards reduction, cyclization, chlorination and be condensed respectively with piperidines, diethanol amine to crude Dipyridamole, last Dipyridamole and second
Acetoacetic ester be mixed, it is filtered, dry, obtain refine finished product.
Specifically synthetic route is：
This method is by compound（8）Synthesize compound（9）Reaction in, substantial amounts of by-product, the by-product of generation can be generated
Object has：
From compound（9）Synthesize compound（11）During, 2,6- bis- chloro- 4,8- dipiperidinos-pyrimidos（5,4-d）Pyrimidine
Molar ratio with diethanol amine theory is 1:2, but the molar ratio in actual production process is 1:8, the consumption of diethanol amine is non-
The characteristics of Chang Yanchong, step is more because current synthetic method has, and by-product is more, and production cost is high.
The content of the invention
The deficiency for aiming to overcome that existing production method of the method for the present invention, it is few to provide a kind of step, and raw material utilizes
Rate is high, the production method of the low Dipyridamole of production cost.
The invention discloses a kind of production methods of Dipyridamole, comprise the following steps：
（1）The carbonyl-protection of urea：Ethylene glycol and urea are fed intake according to a certain percentage, generate compound 3；
（2）Condensation reaction：2,3- diamino succinic acid generate compound 5 with 3 cyclic condensation of compound；
（3）Chlorination reaction：In the case where phosphorus oxychloride, phosphorus trichloride exist and lead to chlorine, compound 5 carries out chlorination reaction life
Into compound 6；
（4）Piperidines substitution reaction：Chlorine on piperidines substituted compound 6 obtains compound 8；
（5）Hydrolysis：The hydrolysis of compound 8 obtains compound 9；
（6）Ketoamine is condensed：Certain H2Under pressure, compound 9 and diethanol amine condensation generation crude product Dipyridamole；
（7）Dipyridamole refines；
Specifically synthetic route is：
Step（1）In, the carbonyl of starting material urea is protected, ethylene glycol is 1 with urea mol ratio:1~3, reaction
100~200 DEG C of temperature, catalyst is p-methyl benzenesulfonic acid.
Step（2）In, the catalyst of reaction is the copper-based or nickel-base catalyst of support type, reaction temperature 160~260
DEG C, 3~5h of reaction time.
Step（3）In, chlorination reaction temperature is 100~130 DEG C, and the reaction time is 24~36h.
Step（6）In, the catalyst of ketoamine condensation reaction is the copper-based or nickel-base catalyst of support type, compound 9 with
The molar ratio of diethanol amine is 1:2~8, it has been filled with hydrogen in reaction process, Hydrogen Vapor Pressure is 1~2MPa, reaction temperature 180~
260 DEG C, the reaction time is 3~5h.
Step（7）In, the process for purification of Dipyridamole：
Dipyridamole crude product is dissolved in suitable ethyl acetate, is stirred, is warming up to 74~76 DEG C of reflux 2h, cool to 40~
50 DEG C plus activated carbon, continue temperature rising reflux 2h, and filtering cools to 0~10 DEG C of filtering, is dried to obtain Dipyridamole finished product.
Advantages of the present invention has the following：
1. the synthetic route of the present invention is more brief than current synthetic route, it is possible to reduce the energy consumption of production process reduces life
Produce cost.
It 2.,, can compared to a current method is played when piperidyl substitutes chlorine in the reaction of synthesis compound 8
The generation of by-product is reduced, is controlled by reaction condition, the selectivity of reaction product is more than 95%.
3. synthesize Dipyridamole（11）Final step, the substitution that current synthetic method is substituted with ketoamine condensation reaction is anti-
It answers, improves the utilization rate of diethanol amine.
Specific embodiment
Embodiment 1
Weigh urea 120g（2mol）, ethylene glycol 62g（1mol）120 DEG C are heated in a kettle, in Catalyzed by p-Toluenesulfonic Acid
Effect is lower to carry out step（1）Reaction, generate compound 3；Then 2,3- diamino succinic acid 37g is weighed（0.25mol）With step
The compound 3 generated in rapid 1 carries out the reaction generation compound 5 of step 2,220 DEG C, reaction time 3h of reaction temperature, catalyst
For the nickel-base catalyst of support type, catalyst is filtered out after the completion of reaction；Exist in phosphorus oxychloride, phosphorus trichloride and lead to chlorine
In the case of, compound 5 carries out chlorination reaction generation compound 6,110 DEG C of reaction temperature, reaction time 30h；Weigh piperidines 85g
（1mol）Step is carried out with compound（4）Reaction, after reaction liquid hydrolysis, cooling filtering, be dried to obtain compound 9；Claim
Take 105g（1mol）Diethanol amine and compound 9 carry out step（6）Reaction, 220 DEG C of reaction temperature, reaction time 3h fills
1.5 MPa of Hydrogen Vapor Pressure, catalyst are the crude product of the nickel-base catalyst, after reaction cold filtration of support type, and crude product passes through
It is refining to obtain Dipyridamole finished product, quality 62.10g, purity 99.21%, product yield 48.74%（Yield is with 2,3- diamino fourths
Diacid is calculating benchmark）.
Embodiment 2
Weigh urea 120g（2mol）, ethylene glycol 62g（1mol）120 DEG C are heated in a kettle, in Catalyzed by p-Toluenesulfonic Acid
Effect is lower to carry out step（1）Reaction, generate compound 3；Then 2,3- diamino succinic acid 30g is weighed（0.2mol）With step
The compound 3 generated in rapid 1 carries out the reaction generation compound 5 of step 2,220 DEG C, reaction time 3h of reaction temperature, catalyst
For the nickel-base catalyst of support type, catalyst is filtered out after the completion of reaction；Exist in phosphorus oxychloride, phosphorus trichloride and lead to chlorine
In the case of, compound 5 carries out chlorination reaction generation compound 6,110 DEG C of reaction temperature, reaction time 30h；Weigh piperidines 85g
（1mol）Step is carried out with compound（4）Reaction, after reaction liquid hydrolysis, cooling filtering, be dried to obtain compound 9；Claim
Take 105g（1mol）Diethanol amine and compound 9 carry out step（6）Reaction, 220 DEG C of reaction temperature, reaction time 3h fills
1.5 MPa of Hydrogen Vapor Pressure, catalyst are the crude product of the nickel-base catalyst, after reaction cold filtration of support type, and crude product passes through
It is refining to obtain Dipyridamole finished product, quality 50.34g, purity 99.3%, product yield 49.53%（Yield is with 2,3- diamino fourth two
Acid is calculating benchmark）.
Embodiment 3
Other steps are the same as embodiment 2, step（6）In reaction temperature for 240 DEG C, product yield 50.31%.Comparative example 1
Weigh urea 36g（0.6mol）, ethyl acetoacetate 26g（0.2mol）, add in ethanol-hydrogen chloride liquid（30% hydrochloric acid：95% second
Alcohol=1:4）Then 200ml, drying and dehydrating after stirring add in sodium hydroxide solution and are warming up to 95 DEG C, then cool to 75 DEG C, add
Hydrochloric acid adjusts PH=1, cold filtration, the 6- methyluracils of washing filtering；Nitric acid is added in reaction pot, is cooled to less than 10 DEG C,
Stirring adds in 6- methyluracils, be warming up to 30 DEG C of heat preservations 1 it is small when the nitro whey liquid that filters；Take a policy powder in water, stirring
After dissolving plus nitro whey liquid, temperature control keep the temperature 30min at 35 DEG C, add the static 3h of hydrochloric acid, stir 2h, filtration drying obtains amino breast
Clear liquid；Again weigh urea 36g and add in reaction kettle with amino whey liquid, stirring is warming up to 100 DEG C of heat preservation 20min, cools to 90
DEG C add in 2mol/L sodium hydroxide solution, be warming up to 100 DEG C heat preservation dissolving 1h.Cool to 40 DEG C, filter tetrahydroxy pyrimidine-
[4,5d] and pyrimidine sodium salt, adds water, 60 DEG C of heat preservation 30min add hydrochloric acid to adjust PH=4, is cooled to 15 DEG C of filterings, washing, dries
2,4,6,8- tetrahydroxys pyrimidine-[4,5d] and pyrimidine；Tetrahydroxy object, phosphorus oxychloride, phosphorus trichloride are added in reaction kettle, is stirred,
10 DEG C of similarly hereinafter chlorine are warming up to 110 DEG C of reflux for 24 hours, be cooled to 15 DEG C of filterings, washing, dry 2,4,6,8- tetrachloro-pyrimidines-
[4,5d] and pyrimidine；Acetone, tetrachloride are sequentially added, piperidines-acetone mixture, 30 DEG C of heat preservations are added dropwise in 20 DEG C of heat preservation 30min
1h, adds water to stir 1h, and filtration drying obtains 2,6- bis- chloro- 4,8 ,-two piperidines-pyrimidine（Dichloride）；Weigh diethanol amine 63g with
Dichloride is mixed, and is warming up to 200 DEG C of heat preservation 15min, is cooled to less than 25 DEG C plus acetone and stirs 30min, then 30 DEG C
4h is kept the temperature, filtration drying obtains Dipyridamole crude product, then carries out refined Dipyridamole finished product 13.53, purity 98.5%, yield
13.21%（Using ethyl acetoacetate as calculating standard）.
It is found by being compared with comparative example：The method of the production Dipyridamole of the present invention is short with synthetic route, into
The characteristics of product high income, production cost is low.
Claims (5)
1. a kind of production method of Dipyridamole bulk pharmaceutical chemicals, which is characterized in that comprise the following steps：
（1）The carbonyl-protection of urea：Ethylene glycol and urea are fed intake according to a certain percentage, generate compound 3；
（2）Condensation reaction：2,3- diamino succinic acid generate compound 5 with 3 cyclic condensation of compound；
（3）Chlorination reaction：In the case where phosphorus oxychloride, phosphorus trichloride exist and lead to chlorine, compound 5 carries out chlorination reaction life
Into compound 6；
（4）Piperidines substitution reaction：Chlorine on piperidines substituted compound 6 obtains compound 8；
（5）Hydrolysis：The hydrolysis of compound 8 obtains compound 9；
（6）Ketoamine is condensed：Certain H2Under pressure, compound 9 and diethanol amine condensation generation crude product Dipyridamole；
（7）Dipyridamole refines；
Specifically synthetic route is：
。
2. the step of production method of Dipyridamole according to claim 1（1）, which is characterized in that starting material is urinated
The carbonyl of element is protected, and ethylene glycol is 1 with urea mol ratio:1~3,100~200 DEG C of reaction temperature, catalyst is to first
Benzene sulfonic acid.
3. the step of production method of Dipyridamole according to claim 1（2）, which is characterized in that the catalyst of reaction
For the copper-based or nickel-base catalyst of support type, 160~260 DEG C of reaction temperature, 3~5h of reaction time.
4. the step of production method of Dipyridamole according to claim 1（3）, which is characterized in that chlorination reaction temperature
For 100~130 DEG C, the reaction time is 24~36h.
5. the step of production method of Dipyridamole according to claim 1（6）, which is characterized in that ketoamine condensation reaction
Catalyst be support type copper-based or nickel-base catalyst, the molar ratio of compound 9 and diethanol amine is 1:2~8, it reacted
Hydrogen is filled in journey, Hydrogen Vapor Pressure is 1~2MPa, and 180~260 DEG C of reaction temperature, the reaction time is 3~5h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111454269A (en) * | 2020-04-13 | 2020-07-28 | 南通森萱药业有限公司 | High-efficiency dipyridamole synthesis method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007080463A1 (en) * | 2006-01-12 | 2007-07-19 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of dipyridamole |
| CN103108874A (en) * | 2010-05-31 | 2013-05-15 | 基因里克斯(英国)有限公司 | Processes for the preparation of dipyridamole |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007080463A1 (en) * | 2006-01-12 | 2007-07-19 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of dipyridamole |
| CN103108874A (en) * | 2010-05-31 | 2013-05-15 | 基因里克斯(英国)有限公司 | Processes for the preparation of dipyridamole |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111454269A (en) * | 2020-04-13 | 2020-07-28 | 南通森萱药业有限公司 | High-efficiency dipyridamole synthesis method |
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