A method for synthesizing 2-(3-azetidinyl)thiazole salt

Abstract

The invention discloses a kind of synthetic method of 2 (3 azetidinyl) thiazole salt, belong to the field of organic medicine.Specific steps are:S1. 3 hydroxyl 1 tert-butyloxycarbonyl azetidine is reacted with iodine under the catalysis of imidazole and triphenylphosphine to generate 3 iodine 1 tert-butyloxycarbonyl azetidine;S2. 3 iodine 1 tert-butyloxycarbonyl azetidine and 2 bromothiazole are then coupled to synthesize intermediate 2 (1 N Boc 3 azetidinyl) thiazole compound under zinc reagent and catalyst catalysis;S3. finally 2 (1 N Boc 3 azetidinyl) thiazole compound and acid reaction can obtain 2 (3 azetidinyl) thiazole salt.The raw material used in the present invention is simple, with low cost, easily obtained, and reaction conditions are simple, the product chemical purity obtained is high.

Description

Technical Field

[0001] The invention belongs to the field of organic medicines, and particularly relates to a method for synthesizing 2-(3-azetidinyl)thiazole salts. Background Art

[0002] 2-(3-Azetidinyl)thiazole salt is an important pharmaceutical intermediate. It is mainly used in the synthesis and production of drugs for the prevention or treatment of obesity and non-insulin-dependent diabetes mellitus.

[0003] Azetidinyl compounds have made up a significant portion of the marketed drugs in recent years. Currently, the primary synthetic strategy involves directly closing the nitrogen or thiazole ring within the molecule. Low yields in the ring-closure step can lead to high costs for the entire synthetic route. Chemists are gradually realizing that using azetidinyl compounds as individual building blocks and directly docking them with key intermediates to synthesize drugs can effectively avoid the high costs associated with low ring-closure yields. However, there are currently few reports on the synthesis of 2-(3-azetidinyl)thiazole. The only known method is the synthesis method reported in PCT Int. Appl., WO2009-EP65883. This method uses 3-(thioamido)-1-tert-butyloxycarbonylazetidine as the starting material and reacts it with chloroacetone. This method has significant limitations, as it introduces a methyl group onto the thiazole ring. Furthermore, the preparation of 3-(thioamido)-1-tert-butyloxycarbonylazetidine requires the use of Lawesson's reagent, which has a strong odor. Summary of the Invention

[0004] In view of the above shortcomings of the prior art, the present invention provides a method for synthesizing 2-(3-azetidinyl)thiazole salts, which has a short synthesis route, can effectively control costs, and improve economic benefits. Specifically, it is achieved through the following techniques.

[0005] A method for synthesizing a 2-(3-azetidinyl)thiazole salt comprises the following steps:

[0006] S1. Add 3-hydroxy-1-tert-butoxycarbonylazetidine, imidazole, triphenylphosphine and iodine to the first solvent, react at 80-120° C. for 1-1.5 h, and separate and purify to obtain 3-iodo-1-tert-butoxycarbonylazetidine;

[0007] S2. 2-bromothiazole, isopropylmagnesium chloride and zinc chloride were added to the second solvent and stirred evenly, and then 3-iodo-1-tert-butyloxycarbonylazetidine and the catalyst obtained in step S1 were added, and the reaction was carried out at 20-30° C. for 1.5-2.5 h. After separation and purification, the intermediate 2-(1-N-Boc-3-azetidinyl)thiazole compound was obtained;

[0008] S3. Add an ethyl acetate solution of an acid to the intermediate 2-(1-N-Boc-3-azetidinyl)thiazole compound obtained in step S2, and stir at 0-5°C for 2-3 hours to obtain a 2-(3-azetidinyl)thiazole salt.

[0009] Preferably, step S2 is specifically as follows: dissolving 2-bromothiazole in THF, adding isopropylmagnesium chloride solution, stirring for 10 minutes, then adding zinc chloride solution, and stirring at room temperature for 1 hour; then slowly dripping 3-iodo-N-tert-butyloxycarbonyl-azetidine in tetrahydrofuran and catalyst PdCl2(PPh3)2 into the above solution, stirring for 2 hours at a temperature not exceeding 30°C, then quenching with water, and extracting with MTBE; after combining the organic phases, washing once with saturated brine, drying over anhydrous sodium sulfate, and filtering to obtain an MTBE solution of the intermediate 2-(1-N-Boc-3-azetidine)thiazole compound.

[0010] Preferably, step S3 is specifically as follows: adding HCl / EtOAc solution to the filtrate obtained in step S2, stirring continuously until a large amount of white solid precipitates; then cooling to 0°C, filtering under nitrogen protection; the filtrate is vacuum concentrated, and the obtained oil is purified by flash column to obtain a colorless oil.

[0011] Preferably, the first solvent is toluene; the second solvent is tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether or acetonitrile.

[0012] Preferably, the molar ratio of imidazole, triphenylphosphine, iodine and 3-hydroxy-1-tert-butoxycarbonylazetidine in step S1 is (2.8-3.2):(1.7-2.4):(1.2-1.6):1; the volume weight ratio of the first solvent to 3-hydroxy-1-tert-butoxycarbonylazetidine is (50-60) mL:1 g.

[0013] Further preferably, the molar ratio of imidazole, triphenylphosphine, iodine and 3-hydroxy-1-tert-butyloxycarbonylazetidine in step S1 is 3:2:1.5:1.

[0014] Preferably, the catalyst in step S2 is PdCl2(PPh3)2, Pd2(dba)3 or Pd(PPh3)4.

[0015] Further preferably, the catalyst in step S2 is PdCl2(PPh3)2.

[0016] Preferably, in step S2, the volume-to-weight ratio of the second solvent to 3-iodo-1-tert-butyloxycarbonylazetidine is (10-20) mL:1 g.

[0017] Preferably, the molar ratio of zinc chloride, 2-bromothiazole and 3-iodo-1-tert-butyloxycarbonylazetidine in step S2 is (0.9-2.5):(0.9-1.5):1.

[0018] Preferably, the acid in step S3 may be hydrochloric acid or sulfuric acid, and the obtained product is 2-(3-azetidinyl)thiazole hydrochloride or 2-(3-azetidinyl)thiazole sulfate.

[0019] Compared with the prior art, the present invention is beneficial in that:

[0020] (1) The raw materials used in the synthesis method of the present invention are relatively low in price and easy to obtain, the entire synthesis method is low in cost and the product yield is high;

[0021] (2) The synthesis method of the present invention does not require special production equipment, does not require (extremely) low temperature operation, and the product purity is high (not less than 97%). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The synthetic route of 2-(3-azetidinyl)thiazole salt is shown in FIG. DETAILED DESCRIPTION

[0023] The technical solutions of the present invention are described clearly and completely below. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0024] The raw materials used in the present invention can be purchased or synthesized using methods well known in the art.

[0025] Example 1

[0026] like Figure 1 As shown, the synthesis method of 2-(3-azetidinyl)thiazole salt specifically comprises the following steps:

[0027] S1. Add 35g of 3-hydroxy-1-tert-butyloxycarbonylazetidine to a 3L three-necked flask with mechanical stirring, add 2.1L of toluene to dissolve and clarify, then add 3 equivalents of imidazole (40.8g) and 2 equivalents of triphenylphosphine (104.8g) to obtain a clear and transparent solution; then add 1.5 equivalents of iodine (76g), disperse evenly, heat to 100°C, stir for 1 hour, and the reaction is completed by GC control. After the reaction is completed, stop heating and cool to obtain a light yellow system; pour the system into 300mL of saturated sodium bicarbonate solution, separate the liquid, and add the organic phase to sodium sulfite (5%) solution and stir until there is no yellow color; after separation, use 200mL of saturated brine to wash the organic phase, dry it with anhydrous Na2SO4, concentrate it, crystallize it at room temperature with 10v n-heptane, cool it to -20°C, filter it with suction, and dry it to obtain 48.2g of product with a yield of 85.8%.

[0028] S2. 2-bromothiazole (25 g, 1.0 eq) was added to a three-necked flask, replaced with nitrogen three times, and then 125 mL of tetrahydrofuran was added and stirred to dissolve. The solution was then cooled to 0-5°C and isopropylmagnesium chloride solution (1.3 mol / L, 1.2 eq) was added within 10 minutes. The mixture was stirred at 0-5°C for 10 minutes. The reaction was controlled to be complete by HPLC (sampling, quenching with water, and the 2-bromothiazole content was less than 1.0 A%). After the reaction was completed, a solution of ZnCl2 in methyltetrahydrofuran (1.9 mol / L, 1.2 eq) was added. The mixture was then heated to 20-25°C and reacted for 1 hour. The reaction was controlled to be complete by HPLC (sampling, quenching with iodine, and the bromine compound was less than 8 A%). Finally, 3-iodo-1-tert-butyloxycarbonylazetidine (43.1 g, 1.0 eq) and catalyst PdCl2(PPh3)2 (0.02 eq) were added, and the atmosphere was replaced with nitrogen three times and reacted at room temperature for 1 hour. After completion of the reaction, 50 mL of water was added to quench the reaction, and the mixture was extracted three times with 125 mL of MTBE. The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate for 2 hours.

[0029] S3. At room temperature, HCl / EtOAc (2 mol / L, 125 mL) was added to the organic phase and stirred for 2 hours until a large amount of white solid precipitated. The temperature was then slowly lowered to 0°C and stirring was continued for 3 hours. After the reaction was completed, the mixture was filtered under nitrogen protection and the solid was rinsed once with MTBE. After drying, 21.3 g of a white solid product was obtained with a yield of 79% and a purity of 97%.

Claims

1. A method for synthesizing a 2-(3-azetidinyl)thiazole salt, characterized in that: The following steps are involved: S1. 3-hydroxy-1-tert-butoxycarbonylazetidine, imidazole, triphenylphosphine, and iodine are added to a first solvent, reacted at 80-120° C. for 1-1.5 hours, and separated and purified to obtain 3-iodo-1-tert-butoxycarbonylazetidine; the molar ratio of imidazole, triphenylphosphine, iodine, and 3-hydroxy-1-tert-butoxycarbonylazetidine is (2.8-3.2):(1.7-2.4):(1.2-1.6):1; the volume-to-weight ratio of the first solvent to 3-hydroxy-1-tert-butoxycarbonylazetidine is (50-60) mL:1 g; S2. 2-bromothiazole, isopropylmagnesium chloride, and zinc chloride are added to tetrahydrofuran and stirred evenly. Then, 3-iodo-1-tert-butoxycarbonylazetidine and PdCl2(PPh3)2 obtained in step S1 are added, and the mixture is reacted at 20-30°C for 1.5-2.5 hours. After separation and purification, an intermediate 2-(1-N-Boc-3-azetidinyl)thiazole compound is obtained. The molar ratio of the zinc chloride, 2-bromothiazole, and 3-iodo-1-tert-butoxycarbonylazetidine is (0.9-2.5):(0.9-1.5):

1. S3. Add an acid in ethyl acetate to the intermediate 2-(1-N-Boc-3-azetidinyl)thiazole compound obtained in step S2, and stir at 0-5°C for 2-3 hours to obtain a 2-(3-azetidinyl)thiazole salt.

2. The method for synthesizing 2-(3-azetidinyl)thiazole salt according to claim 1, wherein The first solvent is toluene.

3. The method for synthesizing 2-(3-azetidinyl)thiazole salt according to claim 1, wherein The molar ratio of imidazole, triphenylphosphine, iodine and 3-hydroxy-1-tert-butyloxycarbonylazetidine in step S1 is 3:2:1.5:

1.

4. The method for synthesizing 2-(3-azetidinyl)thiazole salt according to claim 1, wherein The volume-to-weight ratio of tetrahydrofuran to 3-iodo-1-tert-butyloxycarbonylazetidine in step S2 is (10-20) mL:1 g.

5. The method for synthesizing 2-(3-azetidinyl)thiazole salt according to claim 1, wherein The acid in step S3 is hydrochloric acid or sulfuric acid.

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