- 2,6-bis(diethanolamine)-4,8-dipiperidine-pyrimidine-[5,4-d]pyrimidine synthetic method
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The invention discloses a 2,6-bis(diethanolamine)-4,8-dipiperidine-pyrimidine-[5,4-d]pyrimidine synthetic method. According to the invention, orotic acid is taken as an initial raw material, which iscompletely different with the raw material in the prior art, usage of diethanolamine is omitted, so that an end product as a uniform target product is obtained, the target product is shown as a formula I, and at the same time, the end product yield is increased so that the end product is economic and practical on industrial production.
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Paragraph 0030; 0043-0048
(2018/11/22)
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- 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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- Synthesis method of dipyridamole intermediate
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The invention relates to the technical field of medicine and material intermediates, in particular to a synthesis method of a dipyridamole intermediate. The method is characterized in that pyrimido-[5,4-D]pyrimidine crude products are added into a solvent A; then, a bromination reagent is added; temperature rise is performed till the backflow; reaction is performed for 24 to 48h; after HPLC (HighPerformance Liquid Chromatography) detection display raw materials disappear, reaction stops; aftertreatment and drying are performed to obtain tetrabromo pyrimido-[5,4-D]pyrimidine crude products; (2) the tetrabromo pyrimido-[5,4-D]pyrimidine crude products obtained in the step (1) are added into concentrated hydrochloric acid; heating is performed till the backflow; backflow reaction is maintained for 24 to 36h; the reaction is completed; the temperature is lowered to the room temperature after the reaction stops; aftertreatment and drying are performed to obtain a crude product; after the crude product is recrystallized, drying is performed to obtain the product. The synthesis method has the beneficial effects that the experiment steps are reduced; nitratlon reaction with higher risk and the use of phosphorus pentachloride/phosphorus oxychloride with high toxicity are avoided; the product purity is greater than 98 percent; the total yield is higher than 50 percent; the operation issimple and convenient; the number of three wastes is greatly reduced; the use of strong corrosion and risk reagents is avoided; the safety coefficient is high; the synthesis method is applicable to industrial production.
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Paragraph 0027; 0035-0037; 0043-0045; 0050-0052
(2018/06/04)
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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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- NOVEL BREATHING CONTROL MODULATING COMPOUNDS, AND METHODS OF USING SAME
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The present invention includes pyrimido[5,4-d]pyrimidines that are useful in the prevention and/or treatment of breathing control diseases or disorders in a subject in need thereof. The present invention also includes a method of preventing and/or treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. The present invention further includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention.
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Page/Page column 107; 108
(2014/10/04)
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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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- Controlled stepwise conversion of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine into 2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines
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For the rational synthesis of 2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines, required as purine mimetics, sequential nucleophilic substitutions of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine have been investigated. Reaction conditions have been devised leading to 2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines with patterns of substitution denoted as abab (reaction with nucleophile 1 at C-4 and C-8, followed by nucleophile 2 at C-2 and C-6) or abac (reaction with nucleophile 1 at C-4 and C-8, nucleophile 2 at C-2 and nucleophile 3 at C-6) or abcd (reaction with nucleophile 1 at C-4, nucleophile 2 at C-8, nucleophile 3 at C-2 and nucleophile 4 at C-6). The use of low temperature, relatively dilute solution and careful addition of the amine nucleophile can control the critical first step. The third step in the production of the abcd pattern leads to two regioisomers, which have been structurally characterised by 1H NMR and a crystal structure analysis. Selected 2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines were tested as inhibitors of the cyclin-dependent kinase 1 complex (cyclin B/CDK1), but none of the compounds showed significant activity.
- Northen, Julian S.,Boyle, F. Thomas,Clegg, William,Curtin, Nicola J.,Edwards, Andrew J.,Griffin, Roger J.,Golding, Bernard T.
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p. 108 - 115
(2007/10/03)
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