CN108383844B - Synthesis method of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine - Google Patents
Synthesis method of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine Download PDFInfo
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- PCVJQTVUJJJSRQ-UHFFFAOYSA-N 2,6-dichloro-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine Chemical compound C=12N=C(Cl)N=C(N3CCCCC3)C2=NC(Cl)=NC=1N1CCCCC1 PCVJQTVUJJJSRQ-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- ZEKJTVBUDUYZOU-UHFFFAOYSA-N 1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8-tetrone Chemical compound O=C1NC(=O)NC2=C1NC(=O)NC2=O ZEKJTVBUDUYZOU-UHFFFAOYSA-N 0.000 claims abstract description 15
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
- 229940126214 compound 3 Drugs 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 238000007086 side reaction Methods 0.000 abstract description 5
- 238000010189 synthetic method Methods 0.000 abstract description 4
- 238000005660 chlorination reaction Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 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 description 6
- 229960002768 dipyridamole Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000916 dilatatory effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- QNKFHUMDHRWWES-UHFFFAOYSA-N 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine Chemical compound N1=C(Cl)N=C(Cl)C2=NC(Cl)=NC(Cl)=C21 QNKFHUMDHRWWES-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010069729 Collateral circulation Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine. The method comprises the steps of taking 2,4,6, 8-tetrahydroxy pyrimido [5,4-D ] pyrimidine as a starting material, adding 4-tosyl chloride, reacting with piperidine after hydroxyl is selectively protected, carrying out chlorination reaction on a compound obtained by the reaction under the microwave condition, and finally washing and recrystallizing to obtain the 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine. The method reduces the selectivity of piperidine to hydroxyl in the reaction process, thereby avoiding the defects of more side reactions and the like in the reaction of the traditional process, improving the purity and yield of the target product, and having simple operation, mild reaction conditions and convenient realization of industrialization.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine.
Background
Dipyridamole, alias dipyridamole, dipyridamole piproline, which is a non-nitrate coronary artery dilating agent, has effects of dilating coronary blood vessels, promoting collateral circulation formation and slightly anticoagulating, and has antiviral effect. 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine is a key intermediate in the manufacture of dipyridamole. At present, the synthesis process of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine is extensive, has a lot of side reactions and poor quality of synthesized products, and limits the subsequent application range of the products.
Chinese patent (CN201510735750.8) discloses a refining method of a dipyridamole intermediate 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine, and the related synthetic route is as follows:
reaction formula 1: traditional synthesis method of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine
From the synthetic route, the problems of extensive process, more side reactions, poor quality of the synthesized product and the like of the 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine synthetic process cannot be fundamentally solved because the piperidine has poor selectivity to the 2,4,6, 8-tetrachloropyrimido [5,4-D ] pyrimidine and a large number of byproducts are easily generated.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: aiming at the problems of extensive synthesis process, more side reactions and high impurity content in a synthetic product of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine, the synthesis method of the key intermediate 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine of dipyridamole is provided.
In order to solve the technical problems, the invention adopts the technical scheme that:
the synthetic route of the invention is as follows:
reaction formula 2: synthesis of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine
The invention relates to a synthetic method of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine, which comprises the following specific synthetic steps:
(1) adding 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine and ethanol into a three-neck flask with a stirrer and a thermometer, putting the three-neck flask into an ice-water bath, adding 4-tosyl chloride, stirring for reaction for 0.5-1 h, and evaporating the ethanol under reduced pressure after the reaction is finished. Adding piperidine, stirring and reacting for 3-5 h, stopping the reaction when the 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine is completely reacted, and distilling off redundant piperidine under reduced pressure for repeated use to obtain a compound 3;
(2) mixing the compound 3 with thionyl chloride and triethylamine, putting the mixture into a microwave reactor for reaction, pouring the mixture into cold water at 0-5 ℃ while the mixture is hot after the reaction, naturally heating the mixture to room temperature, performing suction filtration, and collecting filter residues;
(3) washing the filter residue with 85% sodium chloride aqueous solution by mass fraction, filtering, and recrystallizing the filter residue with 75% ethanol by mass fraction to obtain 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine.
The molar ratio of the 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine, 4-tosyl chloride and piperidine in the step (1) is 1: 2-2.5: 7-10;
the power of the microwave reactor in the step (2) is 400-500W, and the microwave time is 5-8 min.
The molar ratio of the compound 3 in the step (2) to thionyl chloride and triethylamine is 1: 2-2.5: 3.
The reagents and raw materials used in the synthesis steps of the present invention are commercially available.
The invention has the beneficial effects that:
(1) the invention firstly adds 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine into 4-tosyl chloride, can protect hydroxyl at a designated position due to steric hindrance effect, and can selectively protect the hydroxyl at the 2, 6-site and 6-site on the 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine, so as to ensure that the hydroxyl at the 4, 8-site reacts with piperidine, greatly reduce the selectivity of piperidine, avoid side reaction and achieve the aim of improving yield and purity;
(2) the addition amount of the piperidine is excessive, and on one hand, the excessive amount can ensure that the compound 2 can be completely reacted; secondly, the piperidine is alkaline and can be used as an acid-binding agent to neutralize HCl generated in the reaction, thereby being beneficial to the full reaction; thirdly, excessive piperidine can be used as a solvent, so that the conditions of cost increase, secondary pollution and the like caused by the use of other solvents in a reaction system are avoided;
(3) according to the invention, 4-tosyl chloride is used for hydroxyl protection, and the tosyl group formed after protection can be directly subjected to chlorination reaction without dehydroxylation protection and then chlorination, so that the synthesis steps are greatly simplified, and the production cost is reduced;
(4) the synthetic method has the advantages of easily available raw materials, convenient operation and mild reaction conditions, and the prepared 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine has high purity and yield which can reach more than 92 percent and purity which can reach more than 99 percent, and is suitable for large-scale production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine.
Detailed Description
Example 1
The method comprises the following steps: adding 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine 19.6g and ethanol 100mL into a three-neck flask with a stirrer and a thermometer, putting the three-neck flask into an ice-water bath, adding 4 g of tosyl chloride 38g, stirring for reaction for 0.5-1 h, and evaporating ethanol under reduced pressure after the reaction is finished. Adding 59.5g of piperidine, stirring for reacting for 3 hours at the temperature of 0 ℃, stopping the reaction, and distilling the redundant piperidine under reduced pressure for repeated use to obtain a compound 3; the molar ratio of the 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine to the 4-tosyl chloride to the piperidine is 1:2: 7;
step two: mixing a compound 3 with thionyl chloride and triethylamine, putting the mixture into a microwave reactor for reaction, wherein the power of the microwave reactor is 400W, the microwave reaction time is 5min, pouring the mixture into cold water at 0 ℃ while the mixture is hot after the reaction, naturally heating the mixture to room temperature, carrying out suction filtration, and collecting filter residues, wherein the molar ratio of the compound 3 to the thionyl chloride to the triethylamine is 1:2: 3;
step three: washing the filter residue with 85% sodium chloride aqueous solution by mass fraction, filtering, recrystallizing the filter residue with 75% ethanol by mass fraction to obtain 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine, wherein the yield is 89.1% and the purity is 98.8%. Example 2
The method comprises the following steps: adding 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine 19.6g and ethanol 100mL into a three-neck flask with a stirrer and a thermometer, putting the three-neck flask into an ice-water bath, adding 4-tosyl chloride 43.7g, stirring for reaction for 0.5-1 h, and evaporating ethanol under reduced pressure after the reaction is finished. Adding 68g of piperidine, reacting for 4 hours under stirring at 0 ℃, stopping the reaction, and distilling off the redundant piperidine under reduced pressure for repeated use to obtain a compound 3; the molar ratio of the 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine to the 4-tosyl chloride to the piperidine is 1:2.3: 8;
step two: mixing a compound 3 with thionyl chloride and triethylamine, putting the mixture into a microwave reactor for reaction, wherein the power of the microwave reactor is 450W, the microwave reaction time is 6min, pouring the mixture into cold water at the temperature of 3 ℃ while the mixture is hot after the reaction, naturally heating the mixture to room temperature, carrying out suction filtration, and collecting filter residues, wherein the molar ratio of the compound 3 to the thionyl chloride to the triethylamine is 1:2.3: 3;
step three: washing the filter residue with 85% sodium chloride aqueous solution by mass fraction, filtering, recrystallizing the filter residue with 75% ethanol by mass fraction to obtain 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine, wherein the yield is 92.3% and the purity is 99.0%. Example 3
The method comprises the following steps: adding 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine 19.6g and ethanol 100mL into a three-neck flask with a stirrer and a thermometer, putting the three-neck flask into an ice-water bath, adding 4-tosyl chloride 47.5g, stirring for reaction for 0.5-1 h, and evaporating ethanol under reduced pressure after the reaction is finished. Adding 85.1g of piperidine, stirring and reacting for 5 hours at the temperature of 0 ℃, stopping the reaction, and distilling off redundant piperidine under reduced pressure for repeated use to obtain a compound 3; the molar ratio of the 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine to the 4-tosyl chloride to the piperidine is 1:2.5: 10;
step two: mixing a compound 3 with thionyl chloride and triethylamine, putting the mixture into a microwave reactor for reaction, wherein the power of the microwave reactor is 500W, the microwave reaction time is 8min, pouring the mixture into cold water at 5 ℃ while the mixture is hot after the reaction, naturally heating the mixture to room temperature, carrying out suction filtration, and collecting filter residues, wherein the molar ratio of the compound 3 to the thionyl chloride to the triethylamine is 1:2.5: 3;
step three: washing the filter residue with 85% sodium chloride aqueous solution by mass fraction, filtering, recrystallizing the filter residue with 75% ethanol by mass fraction to obtain 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine with the yield of 93.5% and the purity of 99.01%.
Claims (4)
- The synthesis method of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine is characterized by comprising the following specific synthesis steps:(1) adding 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine and ethanol into a three-neck flask with a stirrer and a thermometer, putting the three-neck flask into an ice water bath, adding 4-tosyl chloride, stirring for reaction for 0.5-1 h, evaporating the ethanol under reduced pressure after the reaction is finished, adding piperidine, stirring for reaction for 3-5 h, stopping the reaction after the 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine is completely reacted, distilling the redundant piperidine under reduced pressure, and repeatedly using the piperidine to obtain a compound 3;(2) mixing the compound 3 with thionyl chloride and triethylamine, putting the mixture into a microwave reactor for reaction, pouring the mixture into cold water at 0-5 ℃ while the mixture is hot after the reaction, naturally heating the mixture to room temperature, performing suction filtration, and collecting filter residues;(3) washing the filter residue with 85% sodium chloride aqueous solution by mass fraction, filtering, and recrystallizing the filter residue with 75% ethanol by mass fraction to obtain 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine.
- 2. The method of synthesizing 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine according to claim 1, wherein: the molar ratio of the 2,4,6, 8-tetrahydroxy pyrimido [5,4-d ] pyrimidine, 4-tosyl chloride and piperidine in the step (1) is 1: 2-2.5: 7 to 10.
- 3. The method of synthesizing 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine according to claim 1, wherein: the power of the microwave reactor in the step (2) is 400-500W, and the microwave reaction time is 5-8 min.
- 4. The method of synthesizing 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine according to claim 1, wherein: the mol ratio of the compound 3 in the step (2) to thionyl chloride and triethylamine is 1: 2-2.5: 3.
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Application publication date: 20180810 Assignee: Jiangsu Dao'an Chemical Co.,Ltd. Assignor: CHANGZHOU University Contract record no.: X2023980052015 Denomination of invention: Synthesis method of 2,6-dichloro-4,8-dipiperidine pyrimidino [5,4-D] pyrimidine Granted publication date: 20200320 License type: Common License Record date: 20231213 |
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