Synthesis method of (S)-2-(N-t-butyloxycarbonyl)-3-(4-bromo-2-thiazolyl) methyl propionate

Abstract

The invention discloses a synthetic method of (S)-2-(N-t-butyloxycarboryl)-3-(4-bromine-2-thiazolyl) methyl propionate, which is characterized in that (R)-N-t-butyloxycarbonyl-3-iodo-alanine methyl ester and 2, 4-dibromothiazole are used as reactants, a reducing agent, a catalyst and a cocatalyst are added into a reaction solvent, and the (S)-2-(N-t-butyloxycarboryl)-3-(4-bromine-2-thiazolyl) methyl propionate is synthesized through one-step reaction. According to the invention, cheap reagents are adopted, the reaction can be completed in one step, the defects of use of an expensive noble metal catalyst, harsh reaction conditions and complex operation in the existing synthesis method are overcome, the yield is higher, and the method can be suitable for industrial production and has good economic value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to a method for synthesizing methyl (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate. Background Technology

[0002] Thrombosis poses a serious threat to human life and health, easily leading to death and disability. Thrombin, an extracellular trypsin-like serine protease, plays a crucial role in thrombus formation, regulating fibrin aggregation while inducing platelet activation and aggregation. Thrombin can serve as a potential target for anticoagulant and antithrombotic drugs; currently available anticoagulants include direct and indirect thrombin inhibitors. Methyl (S)-2-(N-tert-butoxycarbo)-3-(4-bromo-2-thiazolyl)propionate has been shown to be an important intermediate fragment for the preparation of thrombin inhibitors containing thiazolyl groups; these compounds can inhibit thrombin synthesis during blood coagulation.

[0003] Currently, there are few reports on the synthetic methods for this compound. The existing reported method, patent US2021 / 130303,2021,A1, obtains the product through the Negishi reaction. This method involves preparing compound (I) ((R)-N-tert-butoxycarbonyl-3-iodoalanine methyl ester) as a zinc reagent, and then reacting it with compound (II) 2,4-dibromothiazole under bis(triphenylphosphine)palladium dichloride catalysis to yield compound (III) (see appendix). Figure 2 ).

[0004] However, this synthetic method has several drawbacks: First, as mentioned above, it requires two steps to complete; second, while there are many commercially available methods for preparing organozinc reagents, most require strict operating conditions and complex catalytic reactions. Furthermore, organozinc reagents are easily oxidized and decompose upon contact with protic solvents, thus requiring immediate preparation and use to avoid separation, purification, or long-term storage. Third, the reaction requires a palladium catalyst, which is expensive and economically unfeasible. Fourth, the yield is low, only 27%. Therefore, the existing synthetic method urgently needs improvement. Summary of the Invention

[0005] In view of the above-mentioned deficiencies in the prior art, the present invention discloses a method for synthesizing methyl (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate, which is simple to operate and can effectively solve the above-mentioned technical problems. The specific technical solution is attached. Figure 1 .

[0006] A method for synthesizing (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate methyl ester, using compounds 1 and 2 as reactants, involves adding a reducing agent, a catalyst, and a co-catalyst to a reaction solvent, followed by a one-step reaction. The synthetic reaction route is as follows:

[0007] Furthermore, in some specific embodiments, the reducing agent is selected from one or more of zinc powder and manganese powder.

[0008] Furthermore, in some specific embodiments, the catalyst is selected from one or more of NiCl2(dme) and NiI2.

[0009] Furthermore, in some specific embodiments, the co-catalyst is 2-amidinylpyridine hydrochloride.

[0010] Furthermore, in some specific embodiments, the solvent includes one or more of toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and tetrahydrofuran.

[0011] Furthermore, in some specific implementation schemes, the reaction temperature is 0~30℃.

[0012] Furthermore, in some specific implementation schemes, the reaction time is 0.5 to 15 hours.

[0013] This invention uses inexpensive reducing agents, catalysts, and co-catalysts, and can complete the reaction in one step, overcoming the disadvantages of existing synthesis methods that use expensive precious metal catalysts, have harsh reaction conditions, and are complex to operate.

[0014] In summary, compared with the prior art, the present invention has the following advantages: (1) The reaction can be completed in only one step, which is simple and convenient to operate and conducive to large-scale production; (2) The reducing agent and catalyst used are inexpensive, avoiding the use of precious metal catalysts, reducing costs and resource consumption; (3) The reaction temperature is low, the reaction time is short, the reaction conditions are mild, and the reaction safety is effectively improved; (4) The synthesis yield is high, which is significantly higher than the synthesis yield of the prior art. Attached Figure Description

[0015] Figure 1 This is a schematic diagram of the synthesis reaction of the technology of this invention. Figure 2 This is a schematic diagram of the synthesis reaction using existing technology. Detailed Implementation

[0017] To better understand the purpose, technical means, inventive features and effects of the present invention, the present invention will be described below with reference to the accompanying drawings and through embodiments, but the present invention is not limited to the following embodiments.

[0018] It should be noted that the accompanying drawings in this specification are only used to complement the content disclosed in the specification, so as to enable those skilled in the art to understand and read them, and are not intended to limit the conditions under which the present invention can be implemented. Therefore, they have no substantial technical significance. Any modifications to the structure, changes or adjustments to the proportions, without affecting the effects and objectives that the present invention can produce, should still fall within the scope of the technical content disclosed in the present invention.

[0019] Example 1

[0020] Compound (I) (R)-N-tert-Butoxycarbonyl-3-iodoalanine methyl ester (10 g, 30.3 mol) was dissolved in DMA (100 mL). Compound (II) 2,4-dibromothiazole (7.4 g, 30.3 mol) was added, and the temperature was controlled at 0 °C. Manganese powder (3.3 g, 60.7 mol), compound (IV) 2-amidinepyridine hydrochloride (940 mg, 600 mmol), and nickel(II) ethylene glycol dimethyl ether complex (657 mg, 3 mmol) were slowly added. The temperature was raised to 30 °C, and the reaction was stirred for 2 hours. LCMS analysis showed that the target product was formed. The reaction solution was quenched with water (1000 mL), extracted with ethyl acetate (300 mL), filtered directly with diatomaceous earth, extracted twice with ethyl acetate (300 mL), washed three times with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was obtained by column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 1). The crude product was then pulped (petroleum ether / ethyl acetate = 10 / 1) and isopropanol. The filtrate was concentrated to obtain the target product, methyl (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate (5 g, 13.7 mmol), as a yellow solid with a yield of 45%.

[0021] The compound characterization data are as follows: 1 H NMR (400 MHz, DMSO-D6) δ 7.70 (s, 1H), 7.45 (d,J = 8.5 Hz, 1H), 4.35 (dt, J = 13.5, 4.8 Hz, 1H), 3.62 (s, 3H), 3.45-3.37 (m,1H), 3.30-3.22 (m, 1H), 1.31 (d, J = 20.6 Hz, 9H).

[0022] LCMS [M-55]+=308.9 / 310.9

[0023] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A method for synthesizing methyl (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate, using compound 1 and compound 2 as reactants, characterized in that, A reducing agent, catalyst, and co-catalyst are added to the reaction solvent, and the synthesis is carried out in one step. The synthetic reaction route is as follows:

2. The method for synthesizing (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate methyl ester according to claim 1, characterized in that, The reducing agent is selected from one or more of zinc powder and manganese powder.

3. The method for synthesizing (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate methyl ester according to claim 1, characterized in that, The catalyst is selected from one or more of NiCl2(dme) and NiI2.

4. The method for synthesizing (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate methyl ester according to claim 1, characterized in that, It also includes the addition of a co-catalyst, which is 2-amidinylpyridine hydrochloride.

5. The method for synthesizing (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate methyl ester according to claim 1, characterized in that, It also includes the addition of a solvent, said solvent including one or more of toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and tetrahydrofuran.

6. The method for synthesizing (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate methyl ester according to claim 1, characterized in that, The reaction temperature is 0~30℃.

7. The method for synthesizing (S)-2-(N-tert-butoxycarbonyl)-3-(4-bromo-2-thiazolyl)propionate methyl ester according to claim 1, characterized in that, The reaction time is 0.5~15h.

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