- Production method of dipyridamole bulk drug
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The invention provides a production method of a bulk drug of dipyridamole, which relates to the field of the synthesis of chemical bulk drugs. The production method comprises the following steps: protecting carbonyl of urea, performing condensation reaction with 2,3-diaminosuccinic acid, performing chlorination for hydroxyl of a condensation reactant, replacing chlorine with piperidine, hydrolyzing an obtained product, obtaining a compound containing two carbonyls, separating the product, enabling the separated product to have condensation reaction with diethanol amine, obtaining dipyridamole,and refining to obtain a finished product. By adopting the production method, the synthetic procedure of the dipyridamole is simplified, the conversion rate of raw materials can be greatly increased,and the production cost is decreased.
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Paragraph 0005; 0017
(2018/06/04)
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- 2. 6 - Dichloro - 4, 8 - II piperidino pyrimido [5, 4 - D] pyrimidine synthesis method (by machine translation)
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The invention belongs to the field of chemical synthesis, in particular relates to 2, 6 - dichloro - 4, 8 - II piperidino pyrimido [5, 4 - D] pyrimidine synthesis method. The invention relates to 2, 4, 6, 8 - tetrahydroxy pyrimido [5, 4 - d] pyrimidine as the starting material, adding 4 - toluene sulfonyl chloride, hydroxy selective protection after and piperidine reaction, reaction of a compound of the microwave under the condition of a chlorination reaction, the final washing, recrystallization, to obtain 2, 6 - dichloro - 4, 8 - II piperidino pyrimido [5, 4 - D] pyrimidine. The invention in the reaction process is reduced in the piperidine to hydroxy group selectivity, thereby avoiding the side reaction are many traditional process in the reaction and the like, target product purity and yield are improved, and the operation is simple, mild reaction conditions, is easy to realize industrialization. (by machine translation)
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Paragraph 0029; 0030; 0032; 0033; 0035; 0036
(2018/09/08)
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- Novel technology with introduced catalyst to optimize synthesis of dipyridamole
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The invention discloses a novel technology with an introduced catalyst to optimize the synthesis of dipyridamole, and belongs to the technical field of medical intermediates. According to the technology, in the step of oxidizing a methyl group of 6-methyl uracil into formic acid, a Co(OAc)2/HOAc/AIBN/O2 catalytic system is introduced, and the reaction yield is increased to 90 to 95%. In the step of reducing a nitro group of nitro-orotic acid into an amino group, activated copper powder is taken as the catalyst, the yield is more than 85%; and moreover, the environmental pollution and danger caused by sodium hydrosulfite are avoided. In the step of converting substituted hydroxyl group into substituted chlorine, SOCl12 and N,N-dimethyl formamide are introduced into the reaction system so as to reduce the environment pollution and the difficulty of post treatment. In the reactions of preparing 2,6-dichloro-4,8-bis(piperidine-1-yl)pyrimido[5,4-d]pyrimidine from perchloro pyrimido[5,4-d]pyrimidine, a CuI/PhNO2 catalytic system is introduced into the reaction system, the reaction yield reaches 95%, moreover, the operation is easy, and the treatment is simple. The provided technology increases the yield, reduces the cost, guarantees the safety, saves the energy, and meets the requirements of green reactions and modern chemical production.
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Paragraph 0035; 0036; 0037
(2017/08/31)
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- Synthesis, flow cytometric evaluation, and identification of highly potent dipyridamole analogues as equilibrative nucleoside transporter 1 inhibitors
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Dipyridamole (Persantine) is a clinically used vasodilator with equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2) inhibitory activity albeit less potent than the prototype ENT1 inhibitor nitrobenzylmercaptopurine riboside (NBMPR). Dipyridamole is a good candidate for further exploration because it is a non-nucleoside and has a proven record of safe use in humans. A series of dipyridamole analogues were synthesized with systematic modification and evaluated as ENT1 inhibitors by flow cytometry. Compounds with much higher potency were identified, the best being 2,6-bis(diethanolamino)-4,8-diheptamethyleneiminopyrimido[5,4-d]pyrimidine (13) with a Ki of 0.49 nM compared to a Ki of 308 nM for dipyridamole. Compound 13 is similar in potency to the prototype potent ENT1 inhibitor NBMPR (0.43 nM). For the first time, a dipyridamole analogue has been identified that is equipotent with NBMPR. The SAR indicated that diethanolamine substituted analogues were more active than monoethanolamine compounds. Also, free hydroxyl groups are not essential for activity.
- Lin, Wenwei,Buolamwini, John K.
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p. 3906 - 3920
(2008/02/11)
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- Resistance-modifying agents. 11. Pyrimido[5,4-d]pyrimidine modulators of antitumor drug activity. Synthesis and structure-activity relationships for nucleoside transport inhibition and binding to α1-acid glycoprotein
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The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, α1-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of 3H-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4?-methoxybenzylamino, 3?,4?-dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.
- Curtin, Nicola J.,Barlow, Hannah C.,Bowman, Karen J.,Calvert, A. Hilary,Davison, Richard,Golding, Bernard T.,Huang, Bing,Loughlin, Peter J.,Newell, David R.,Smith, Peter G.,Griffin, Roger J.
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p. 4905 - 4922
(2007/10/03)
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- Structure-activity relationships of pyrimido-pyrimidine series of 5-lipoxygenase inhibitors
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A series of pyrimido-pyrimidine compounds were synthesized and a SAR study was conducted for 5-LO inhibition using a broken cell preparation from RBL-1 cells. In this series compound 21 was found to be a potent 5-LO inhibitor in vitro.
- Basha, Anwer,Ratajczyk, James D.,Dyer, Richard D.,Young, Patrick,Carter, George W.,Brooks, Clint D.W.
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