3-Hydroxyazetidine hydrochloride is an building block used in a recent synthesis of a fluoroquinolone antibiotic and a useful intermediate in the synthesis of polypeptides.Here we'll introduce two synthetic routes of 3-Hydroxyazetidine hydrochloride.

Synthesis from N-(trityl)-3-hydroxyazetidine

3-Hydroxyazetidine hydrochloride is an important intermediate for the synthesis of barricktinib, which is finally obtained by multi-step reactions. Barricktinib has been approved by the European Union as a single agent or combined with methotrexate for the treatment of moderate to severely active rheumatoid arthritis with insufficient or intolerance to one or more anti-rheumatic drugs (DMARDs) Treatment of adult patients. This is also the first JAK inhibitor approved by the European Union for the treatment of rheumatoid arthritis.For the preparation of 3-hydroxyazetidine hydrochloride, it is reported in the literature that tert-butylamine and epichlorohydrin are used as raw materials, followed by cyclization, acetylation, and deacetylation reactions to obtain 3-hydroxyazetidine hydrochloride. Butane hydrochloride. However, the acetylation reaction has high reaction temperature, low yield, difficult purification, long production cycle, and is not suitable for industrialized scale-up production. 3-Preparation of hydroxyazetidine hydrochloride. The literature reports that benzylamine or benzhydrylamine and epichlorohydrin are used as raw materials, followed by cyclization and hydrogenation to prepare 3-hydroxyazetidine salt. Acid salt.[1]

3-Preparation of hydroxyazetidine hydrochloride. The literature reported that this method provides a method of using chloroformate-1-chloroethyl to replace the benzyl or benzyl group of the aryl group, and remove the formate under heating. Furthermore, a method for obtaining 3-hydroxyazetidine hydrochloride in one step, which uses highly toxic, strongly irritating, and lacrimal chloroformate-1-chloroethyl ester, which is not suitable for industrial scale-up production. This application provides a new method for synthesizing 3-hydroxyazetidine hydrochloride to solve at least one of the above technical problems. In the solution formed by N-(trityl)-3-hydroxyazetidine and the first organic solvent, hydrogen chloride gas is passed into the solution to remove triphenylchloromethane, and the solid-liquid separation is carried out to obtain 3- Hydroxyazetidine hydrochloride. In the above-mentioned process, the triphenylchloromethane of N-(trityl)-3-hydroxyazetidine is effectively removed by hydrogen chloride to obtain 3-hydroxyazetidine hydrochloride, which is not only the preparation cycle It is short, avoids the use of toxic or expensive reagents, has good safety, and has a high reaction yield. It can obtain 3-hydroxyazetidine hydrochloride with high purity, simple operation and suitable for large-scale industrial production. In the above-mentioned realization process, the preparation method of N-(trityl)-3-hydroxyazetidine is simple in operation and the reaction time is short, and N-(trityl)-3-hydroxyazetidine is synthesized The efficiency of alkane is high. At the same time, it is possible to produce 3-hydroxyazetidine hydrochloride with tritylamine as a raw material, among which tritylamine is easy to obtain and cheap, which can reduce the production of 3-hydroxyazetidine hydrochloride cost.

The method for synthesizing 3-hydroxyazetidine hydrochloride of the present application will be further described in detail below in conjunction with examples. Add the N-(trityl)-3-hydroxyazetidine (formula IV) (200g, 0.634mol) and chloroform (1600ml) provided in Example 2 to the L three-necked flask, control the temperature at 0-5°C, Pass 80g of hydrogen chloride gas, react for 7h, filter and dry to obtain 66g of white solid. The synthesized white solid was analyzed by proton nuclear magnetic resonance spectroscopy. The characterization data of the proton nuclear magnetic resonance spectrum are as follows: 1HNMR (400MHz, DMSO-D6) δ: 3.73 (2H, br), 3.93-4.03 (2H, m), 4.47-4.55 (1H, m), 6.21 (1H, d, J=6.3 Hz), 9.12 (2H, br). After analysis, the synthesized white solid is 3-hydroxyazetidine hydrochloride represented by formula V. Among them, the purity of the synthesized 3-hydroxyazetidine hydrochloride was 99.8% (HPLC), and the yield was 95%.

Synthesis from N-benzyl-3-hydroxyazetidine

As a pharmaceutical intermediate, azetidinoid compounds have been gradually paid attention to and used in large quantities in recent years because of their good pharmaceutical activity. For example, 3-aminoazetidine and 3-hydroxyazetidine and their derivatives are important intermediates in the synthesis of antidepressants and antibiotics. Among them, 3-hydroxyazetidine hydrochloride is an important intermediate for the synthesis of terbinate, which is finally subjected to a multi-step reaction to obtain terbinate. Taibipenem is used in pediatric pneumonia, otitis media, sinusitis, and has strong effects on pneumococcal bacteria, including macrolide-resistant Streptococcus pneumoniae and penicillin-resistant pneumococcal bacteria, and it belongs to oral carbapenem Ethyl antibiotics, which are convenient for administration, are one of the excellent drugs for upgrading children's antibiotics. Preparation of 3-hydroxyazetidine hydrochloride, reported in the literature as 1-benzyl-3-hydroxyazetidine or 1-diphenylmethyl-3-hydroxyazetidine It is obtained by a hydrogenation reaction.[2]

The object of the present invention is to provide a benzyl or diphenylmethyl group substituted with an aryl group by using 1-chloroethyl chloroformate, followed by heating to remove the formate and further obtaining 3-hydroxyazetidine hydrochloride in one step. The new salt method can overcome the shortcomings of the existing hydrogenation technology, has the advantages of low equipment requirements, short time, high production efficiency, low cost, and good quality of the produced 3-hydroxyazetidine hydrochloride. Add 100 g (0.42 mol) of N-benzyl-3-hydroxyazetidine and 1000 ml of toluene to the L reaction flask, stir and dissolve, and cool to -5 ° C. 108 g of 1-chloroethyl chloroformate (0.76 mol) Soluble in 80ml of toluene, slowly add dropwise to the above solution, control the temperature does not exceed 0 ° C during the addition process, continue to maintain the temperature reaction for 10 minutes after the completion of the addition, then slowly warm to 70 ° C, continue at this temperature The reaction was carried out for 2 hours, and the reaction was monitored by HPLC. The mixture was cooled, and concentrated to dryness under reduced pressure at 45 ° C to give 72.4 g of product. The purity of HPLC was 98.0% and the yield was 96.5%.

Technical Solution of the Invention: An N-arylheterocyclobutane dearylation method, comprising the steps of: Step 1: Dissolving 1-benzyl-3-hydroxyazetidine or 1-diphenylmethyl-3-hydroxyazetidine in an organic solvent, and cooling to -10 to 0 ° C;Step 2: slowly adding 1.1 to 2.1 equivalents of 1-chloroethyl chloroformate to the solution obtained in the first step;Step 3: The solution obtained in the second step is heated to 50-80 ° C, the reaction is 1-3 hours, and the solvent is distilled off under reduced pressure to obtain a first-step product;Step 4: Dissolve the first step product in 5 times the amount of methanol, stir to dissolve at room temperature, heat to 60-65 ° C, reflux reaction for 1-2 hours;Step 5: The solution obtained in the second step is distilled off under reduced pressure, acetone is added, stirred for 1 h, and filtered;Step 6: The filtrate obtained in the third step is concentrated under reduced pressure, stirred with petroleum ether, and cooled to give a white solid, that is, 3-hydroxyazetidine hydrochloride. The above product was put into 370 ml of methanol, stirred and dissolved at room temperature, gradually heated to 65 ° C, and refluxed for 1 hour. The reaction was monitored by HPLC, the methanol was evaporated under reduced pressure, the mixture was cooled to room temperature, and then 200 ml of acetone was added, stirred for 1 hour, and filtered. The filtrate was concentrated under reduced pressure to 1/3 of the original volume, and was cooled to room temperature. 100 ml of petroleum ether was added, and the crystals were cooled to give 41.5 g of white solid, 3-hydroxyazetidine hydrochloride. The purity of HPLC was 98.3%, yield 92.6. %. This embodiment uses epichlorohydrin as a raw material, and reacts with benzylamine or diphenylmethylamine to form 1-benzyl-3-hydroxyazetidine or 1-diphenylmethyl-3-hydroxy nitrogen heterocycle. Butane, 1-benzyl-3-hydroxyazetidine or 1-diphenylmethyl-3-hydroxyazetidine is substituted with 1-chloroethyl chloroformate, and the intermediate product can be separated. Or directly heated in an organic solvent to give the final product 3-hydroxyazetidine hydrochloride.

References

[1]SICHUAN TONGSHENG BIOPHARMACEUTICAL - CN111825592, 2020, A

[2]TIANJIN DADI KANGHE MEDICAL TECHNOLOGY - CN104292142, 2019, B