4-(tert-butyldimethylsilyl)oxo-1-butanol is a colorless to light yellow oily substance with a CAS number of 87184-99-4. The compound is obtained by single-protecting 1,4-butanediol with TBS, and TBS is used as a hydroxyl protecting group and is stable under alkaline conditions. With this characteristic, 4-(tert-butyldimethylsilyl)oxo-1-butanol can modify the other terminal hydroxyl group under alkaline conditions. The dehydrogenation of the hydroxyl group of 4-(tert-butyldimethylsilyl)-1-butanol to form aldehyde can be used as an intermediate in the synthesis of anticoagulant beraprost sodium tablets, and the oxidation to acid can be used in the synthesis The Napabucasin derivatives can also be directly used in the synthesis of ROCK kinase inhibitors and indoleamine 2,3-dioxygenase (IDO) enzyme activity regulators.
Synthesis of Beraprost Sodium
Beraprost sodium can be made from 4-(tert-butyldimethylsilyl)oxo-1-butanol as raw material. Beraprost (see Figure 1 for its synthetic route) is a derivative of prostacyclin, and a benzene ring is connected in parallel to the secondary five-membered ring of prostacyclin to increase the stability of the molecule. Beraprost sodium is the sodium salt form of the anticoagulant drug beraprost, which is suitable for symptoms such as intermittent claudication, pain and cold sensation caused by pulmonary hypertension and chronic arterial occlusive disease.
Figure 1 Synthesis of Beraprost
Oxidize the unprotected hydroxyl group of 4-(tert-butyldimethylsilyl) oxo-1-butanol into acid, which can be used to synthesize derivatives of cancer cell stemness inhibitor Napabucasin (see Figure 2 for its synthetic route ), Napabucasin is an oral naphthoquinone small molecule that targets the signal transducer and transcriptional activator STAT3 pathway, prevents the activity of cancer stem cells, can be used to treat cancer stem cells, and has the ability to inhibit cancer cell metastasis and prevent cancer in various cancer types potential for relapse. However, the poor solubility of Napabucasin limits its application. Napabucasin derivatives improve the solubility problem to a certain extent, so that Napabucasin can be better used in the treatment of cancer stem cells.
Figure 2 The synthetic route of Napabucasin derivatives
(S)-4-(3-Amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl(4-(nitrooxy (yl)butyl)carbonate is a nitroxide derivative of a ROCK kinase inhibitor. ROCK kinase inhibitors can be used to treat glaucoma and retinal diseases, and NO plays an important physiological role in regulating the intraocular pressure. It can effectively reduce intraocular pressure and treat retinal diseases. Its synthetic route (see Figure 3) is as follows:
Figure 3. A synthetic route of a nitroxide derivative of a ROCK kinase inhibitor
Indoleamine 2,3-dioxygenase IDO plays an important role in immune regulation, through the regulation of IDO, immune function can be regulated, resulting in therapeutic effects on many diseases, disorders and conditions. There is a pathophysiological link between IDO and tumors, and the disruption of immune homeostasis is closely related to tumor growth and progression. IDO production in the tumor microenvironment appears to contribute to tumor growth and metastasis. Currently small molecule inhibitors of IDO have been developed for the treatment or prevention of IDO-related diseases, such as (S)-((4-(phospho)butyl)carbonyl)oxy)methyl 3-(4-(diisobutyl) Amino)-3-(3-(tert-butyl)ureido)phenyl)pentanoate starting from 4-(tert-butyldimethylsilyl)oxo-1-butanol. Its synthetic route (see Figure 4) is as follows:
Figure 4 Synthesis of an IDO indoleamine 2,3-dioxygenase
4-(tert-butyldimethylsilyl)oxo-1-butanol can also be prepared into compounds such as ethers and ketones, which can be used in the synthesis of various finished pharmaceuticals and pharmaceutical intermediates, and has a good application market, and its synthesis has certain difficulties. During the synthesis process, a double-protected by-product of the TBS protecting group will be generated. The boiling point of the two is close, so it is difficult to purify by distillation. At the same time, the two have good solubility in common solvents and are difficult to separate. Haofan Biology has mastered the synthesis and separation and purification of 4-(tert-butyldimethylsilyl)oxo-1-butanol, and can further realize the 4-(tert-butyldimethylsilyl)oxo-1-butanol The mass production of 1-butanol provides the market with better intermediates for drug synthesis.