A kind of preparation method of iodo-1H-pyrazolo [3,4-D] pyrimidine-4-amine of Ibrutinib intermediate 3-Technical field
The present invention relates to a kind of cancer therapy drug field, the preparation method especially relating to a kind of iodo-1H-pyrazolo [3,4-D] pyrimidine-4-amine of Ibrutinib intermediate 3-.
Background technology
Iodo-1H-pyrazolo [3, the 4-D] pyrimidine-4-amine of 3-, CASNO151266-23-8, it is a kind of new anti-cancer drug thing Ibrutinib key intermediate, and its chemical structural formula is as follows:
Lymphoma mantle cell (MCL) is common in person in middle and old age, is a kind of rare but is in progress rapid non-Hodgkin′s B cell lymphoma (NHL).In the U.S., its patient numbers occupies the 6% of all non-Hodgkin lymphoma cases.List the end of the year in 2013 for Buddhist nun (Imbruvica) according to Shandong, be get permission the third medicine for treating lymphoma mantle cell (MCL).Breakthrough medicine qualification is authorized in February, 2014 by U.S. FDA for Buddhist nun (Ibrutinib) according to Shandong.Imbruvica is that FDA releases second medicine enjoying this treatment got permission since breakthrough new drug new policies.FDA have approved the Gazyva (obinutuzumab) of Roche (Roche) in JIUYUE, 2014, is used for treating chronic lymphocytic leukemia (CLL), is that the first FDA that obtains breaks through therapy identification granted medicine.Previously having analyst it is predicted that the year of all indications of Ibrutinib sells peak value will reach about 5,000,000,000 dollars, its maximum sales quota may be from chronic lymphocytic leukemia indication (CLL).
And iodo-1H-pyrazolo [3, the 4-D] pyrimidine-4-amine of 3-is the key intermediate of synthesis Ibrutinib, according to existing synthetic route, it is in DMF, carry out iodination reaction by substrate and N-N-iodosuccinimide to prepare.This step react maximum cost pressure be that N-N-iodosuccinimide is much more expensive, per kilogram price 3000-4000 unit, account for the whole whole Material Cost of this product more than half, thus greatly adding the production cost of Ibrutinib crude drug.
Summary of the invention
It is an object of the invention to the defect overcoming prior art to there is cost intensive, it is provided that the preparation method of a kind of iodo-1H-pyrazolo [3,4-D] pyrimidine-4-amine of Ibrutinib intermediate 3-.Adopt one pot reaction, utilize DMF as the feature of aprotic polar solvent, N-N-iodosuccinimide is generated in the reaction of reaction system situ with cheap N-chlorosuccinimide and sodium iodide, then pass through reaction in-situ and substrate reactions, obtain the novel synthesis of target product, whole preparation method cost is low, simple to operate, is suitable for industrialized production.
The technical solution adopted for the present invention to solve the technical problems is: in aprotic polar solvent DMF system, N-chlorosuccinimide and sodium iodide reaction, N-N-iodosuccinimide is generated by reaction in-situ, then with 4-amino-pyrazol also [3,4-d] pyrimidine (A) reaction in-situ, generating 3-iodo-1H-pyrazolo [3,4-D] pyrimidine-4-amine (B), its chemical equation is as follows:
A kind of preparation method of iodo-1H-pyrazolo [3, the 4-D] pyrimidine-4-amine of Ibrutinib intermediate 3-, concrete steps include:
(1) in aprotic polar solvent DMF, add N-chlorosuccinimide, with hot bath or ice-water bath temperature control, then be dividedly in some parts sodium iodide, stirring, then it is dividedly in some parts 4-amino-pyrazol also [3,4-d] pyrimidine, temperature reaction；
(2) after reaction terminates, adding water, temperature is back to 0-5 DEG C of stirring, sucking filtration, can obtain iodo-1H-pyrazolo [3, the 4-D] pyrimidine-4-amine of 3-.
Additionally, the present invention also proposes following attached technical scheme:
In described step (1), the molar ratio of sodium iodide and N-chlorosuccinimide is 1:1.
In described step (1), the molar ratio of sodium iodide and 4-amino-pyrazol also [3,4-d] pyrimidine is 1.2:1-2.0:1.
In described step (1), the molar ratio of N-chlorosuccinimide and 4-amino-pyrazol also [3,4-d] pyrimidine is 1.2:1-2.0:1.
In described step (1), DMF is added in reaction bulb, add N-chlorosuccinimide, with hot bath or ice-water bath temperature control, temperature controls at 15-30 DEG C, then is dividedly in some parts sodium iodide, stir 6.0-7.0 hour, it is dividedly in some parts 4-amino-pyrazol also [3,4-d] pyrimidine again, is warmed up to 80-100 DEG C of reaction.
Adopt the beneficial effect that technical scheme reaches:
The present invention adopts one pot reaction, by utilizing DMF as the feature of aprotic polar solvent, generate N-N-iodosuccinimide with cheap N-chlorosuccinimide and sodium iodide at reaction system situ, then pass through reaction in-situ and substrate reactions, obtain purpose product.Reduce Ibrutinib key intermediate 3-iodo-1H-pyrazolo [3,4-D] pyrimidine-4-amine production cost, thus greatly reducing the production cost of Ibrutinib crude drug.
Detailed description of the invention
Below in conjunction with specific embodiment, technical scheme is further described:
Embodiment 1:
In four-hole boiling flask, add DMF (800ml), add N-chlorosuccinimide (118.57g, 0.888mol), with hot bath or ice-water bath temperature control, temperature controls, at 15 DEG C, to add NaI (133.11g, 0.888mol), 6.0h is stirred after adding, it is dividedly in some parts 4-amino-pyrazol also [3,4-d] pyrimidine (100g, 0.74mol) again, add, be warmed up to 100 DEG C.Controlling in HPLC, reaction terminates.Post processing, reactant liquor adds water, cools to 0-5 DEG C, sucking filtration, dries, obtains product.Yield: 84%, purity: 99.0% (HPLC).
Embodiment 2:
In four-hole boiling flask, add DMF (800ml), add N-chlorosuccinimide (197.62g, 1.48mol), with hot bath or ice-water bath temperature control, temperature controls, at 30 DEG C, to add NaI (221.84g, 1.48mol), 7.0h is stirred after adding, it is dividedly in some parts 4-amino-pyrazol also [3,4-d] pyrimidine (100g, 0.74mol) again, add, be warmed up to 80 DEG C.Controlling in HPLC, reaction terminates.Post processing, reactant liquor adds water, cools to 0-5 DEG C, sucking filtration, dries, obtains product.Yield: 89%, purity: 99.3% (HPLC).
Embodiment 3:
In four-hole boiling flask, add DMF (800ml), add N-chlorosuccinimide (148.22g, 1.11mol), with hot bath or ice-water bath temperature control, temperature controls, at 25 DEG C, to add NaI (166.38g, 1.11mol), 6.5h is stirred after adding, it is dividedly in some parts 4-amino-pyrazol also [3,4-d] pyrimidine (100g, 0.74mol) again, add, be warmed up to 85 DEG C.Controlling in HPLC, reaction terminates.Post processing, reactant liquor adds water, cools to 0-5 DEG C, sucking filtration, dries, obtains product.Yield: 86%, purity: 98.5% (HPLC).
Compared to prior art, it is an advantage of the current invention that: adopt one pot reaction, by utilizing DMF as the feature of aprotic polar solvent, N-N-iodosuccinimide is generated at reaction system situ with cheap N-chlorosuccinimide and sodium iodide, then original position and substrate reactions, obtains purpose product.Reduce Ibrutinib key intermediate 3-iodo-1H-pyrazolo [3,4-D] pyrimidine-4-amine production cost, thus greatly reducing the production cost of Ibrutinib crude drug.
Should be appreciated that specific embodiment described above is only for explaining the present invention, is not intended to limit the present invention.The apparent change extended out by the spirit of the present invention or variation are still among protection scope of the present invention.