A kind of synthetic method of sirolimus 40-ether derivative

Abstract

The invention discloses a synthesis method of sirolimus 40-ether derivatives. Among the existing various synthesis methods, the key intermediates are too active in nature, are easily degraded in the post-processing operation process and the subsequent reaction, the reaction steps are relatively many, and the reaction yield is low. The technical scheme adopted in the present invention is as follows: sirolimus or a 28-position protected sirolimus derivative reacts with a halogen compound and silver trifluoromethanesulfonate under the action of an acid binding agent, and after post-treatment, the sirolimus is obtained Division 40-ether derivatives. The invention adopts a new synthetic route, omits the reaction of synthesizing and separating key intermediates, greatly simplifies the reaction steps and improves the yield.

Description

technical field [0001] The invention relates to a synthesis method of sirolimus 40-ether derivatives. Background technique [0002] Sirolimus 40-ether derivatives are a class of sirolimus derivatives, belonging to a new generation of macrolide immunosuppressants and antineoplastic drugs. This type of compound was discovered by the Swiss company Sandoz and is mainly suitable for immunosuppressive and anticancer effects in organ transplant recipients. Sirolimus 40-ether derivatives include everolimus, which was approved by the FDA by Novartis in March 2009 for the treatment of patients treated with conventional anticancer drugs such as sunitinib and sorafenib. Ineffective advanced renal cell carcinoma, in addition to renal cell carcinoma, everolimus is also being studied in neuroendocrine tumors, lymphomas, other cancers, and tuberous sclerosis as a single agent or in combination with existing cancer treatments The combination of methods has a very broad prospect of clinical...

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Problems solved by technology

[0007] The synthesis method in this patent has several defects: 1. Triflate must be synthesized and separated separately; 2. The property of triflate is extremely unstable. When it is used to react with sirolimus, Trifluoromethanesulfonate must remove water, otherwise the reaction cannot proceed, so it is very important for the water removal post-treatment of triflate, but because it takes a certain amount of time, but the trifluoromethanesulfonate is unstable in nature, It will degrade completely within 5-7 days at room temperature; 3. Triflate should be used immediately, even if it is stored at low temperature, it will degrade; 4. When triflate reacts with sirolimus, Because triflate is degraded with time, so will constantly add triflate and acid binding agent; 5, because triflate can degrade, cause reaction yield low, sirolimus reaction is not good completely, to recycle

[0015] The defect that said method exists is: 1, this route is analyzed from synthetic mechanism, mainly is that sirolimus and trifluoromethanesulfonic anhydride react and generate sirolimus trifluoromethanesulfonate this step reaction is SN2 reaction, will Chirality inversion of sirolimus 42, so separation of isomers is required

2. The reaction also produces active intermediates, which have the same problems as the above two patents, that is, the properties of the active intermediates are unstable, and water needs to be removed during the reaction, so they cannot be stored.

[0016] Among the above methods, active intermediates such as triflate must be synthesized separately. Due to the active nature of triflate, post-treatment operations are sensitive to moisture, temperature, oxygen, etc., and are easily degraded. It is not conducive to post-treatment operations such as dewatering and desalination; when reacting with sirolimus or its derivatives, because sirolimus is unstable in nature and not resistant to high temperatures, the reaction temperature cannot be too high, resulting in a long reaction time. And trifluoromethanesulfonate is easily degraded again, causes reaction yield to be low

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