A new method for synthesizing 5-methylene substituted thiazole-2-amine derivatives

Abstract

The invention provides a novel method for synthesizing a 5-methylene-substituted thiazole-2-amine derivative. The 5-methylene-substituted thiazole-2-amine derivative is synthesized through a two-step reaction of lithiation reaction and simultaneous dehydroxylation and protection group reaction. The synthesis method of the invention has short steps in the entire synthesis route, few side reactions, high conversion rate and yield, cheap and easy raw materials, a wide range of applicable substrates, mild operating conditions, high safety, and is conducive to scale-up production and industrial promotion and application.

Description

Technical Field

[0001] The present invention relates to the technical field of organic compound synthesis, and more particularly to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives. Background Art

[0002] The 5-methylene-substituted thiazole-2-amine derivative has a structure containing the active structure of 2-aminothiazole and a freely rotatable methylene structure, and can introduce different designed fragment molecules such as alkyl, cycloalkyl, aryl, and heteroaryl groups. It is an important intermediate compound for synthesizing a variety of thiazole heterocyclic pharmaceutical new drug compounds. The structure of the 5-methylene-substituted thiazole-2-amine derivative is shown in the following formula:

[0003]

[0004] According to literature and technical retrieval, the existing disclosed method for synthesizing 5-methylene substituted thiazole-2-amine derivatives is to use α-halogenated aldehydes or ketones and thiourea for ring closure. The defects are that the starting raw material aldehyde or ketone substrate is difficult to synthesize, the α-halogenation reaction is difficult to control and the product is difficult to purify, and the subsequent ring closure reaction by-products are difficult to separate and purify, resulting in low yield, and is not suitable for industrial scale-up production and industrial application.

[0005] Therefore, those skilled in the art are committed to developing a new method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives, aiming to solve the defects of the above-mentioned synthesis methods of such compounds in the prior art. Summary of the invention

[0006] The technical problem to be solved by the present invention is that in the prior art, the method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives has poor reaction selectivity, low yield, difficulty in separation and purification, poor safety, and difficulty in obtaining starting materials, poor universality, and is not suitable for industrial scale-up production and industrial practical application.

[0007] To achieve the above object, the present invention provides a novel method for synthesizing a 5-methylene-substituted thiazole-2-amine derivative, wherein the structure of the 5-methylene-substituted thiazole-2-amine derivative is shown in the following formula A:

[0008]

[0009] The novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives is shown in Scheme I:

[0010] Route I:

[0011]

[0012] wherein R is independently selected from hydrogen, C1-C10 alkyl and cycloalkyl, C1-C10 aryl and heteroaryl;

[0013] The specific steps are:

[0014] Step 1, compound A-1 is dissolved in tetrahydrofuran, n-butyl lithium is added dropwise at -40°C for lithiation reaction, and then a tetrahydrofuran solution of A-2 is added dropwise at -40°C for reaction, and post-treatment is performed to obtain compound A-3;

[0015] Step 2: dissolve compound A-3 in dichloromethane, add triethylsilane and trifluoroacetic acid in sequence to react at room temperature, and post-treat to obtain the target compound 5-methylene-substituted thiazol-2-ylamine derivative (Formula A).

[0016] Further, the alkyl group is straight chain or branched or contains 5 to 8 membered rings;

[0017] Furthermore, the aromatic group is a C5-C14 aliphatic aromatic group or a heterocyclic aromatic group containing 1 to 10 carbon atoms;

[0018] Furthermore, the 5- to 8-membered ring is an alicyclic ring containing 1 to 10 carbon atoms or a heterocyclic ring containing 1 to 10 carbon atoms;

[0019] Further, the alkyl, aryl, 5- to 8-membered ring is unsubstituted or substituted by one or more substituents selected from the following: halogen, cyano, ester, aliphatic, aryl, heteroaryl;

[0020] Further, each of the R groups is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrazole, furan, tetrahydropyrrole, and piperidine are unsubstituted or substituted with one or more substituents selected from the following: halogen, cyano, ester, aliphatic, aryl, and heterocyclic aromatic.

[0021] Further, each of the R's is independently selected from pyridine, furan, and cyclohexyl;

[0022] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the lithiation reagent is n-BuLi, s-BuLi, t-BuLi, LDA, LHMDS; preferably n-BuLi;

[0023] According to the synthesis method of 4-bromo-1-methyl-1H-imidazole-5-carboxamide derivatives of the present invention, in step 1, the organic solvent is Et2O, TBME, DCM, THF; preferably THF;

[0024] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the molar ratio of compound A-1 to the lithiation reagent is 1:2 to 1:3;

[0025] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the weight-to-volume ratio (g / ml) of compound A-1 to the organic solvent is 1:10 to 1:15;

[0026] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the molar ratio of compound A-1 to compound A-2 is 1:2 to 1:3;

[0027] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in the step 1, the reaction temperature is controlled at -40°C, and after the reaction materials are added dropwise, the temperature is kept at -40°C and stirred for about 30 minutes, and then the temperature is slowly raised to room temperature and stirred for 2 to 3 hours;

[0028] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the acid reagent is trifluoroacetic acid;

[0029] According to a novel method for synthesizing 5-methylene-substituted thiazol-2-amine derivatives of the present invention, in step 2, the dehydroxylation agent is triethylsilane;

[0030] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the organic solvent is Et2O, DCM, THF, AcOEt; preferably DCM;

[0031] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the reaction process temperature is controlled at room temperature, and after the reaction materials are added dropwise, the room temperature is maintained and the stirring reaction is continued until the reaction of A-3 is complete;

[0032] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the weight volume ratio (g / ml) of compound A-3 to solvent is 1:20 to 1:25;

[0033] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the molar ratio of compound A-3 to the acid reagent is 1:8 to 1:10;

[0034] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the molar ratio of compound A-3 to the dehydroxylation agent is 1:3 to 1:5.

[0035] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, the specific operation of step 1 is:

[0036] Under nitrogen protection, the THF solution of compound A-1 was cooled to -40°C, and n-butyl lithium was slowly added dropwise for lithiation for 30 minutes, and then the tetrahydrofuran solution of A-2 was added dropwise to the reaction solution while maintaining low temperature. After stirring at low temperature for 30 minutes, the mixture was slowly heated to room temperature and continued to stir for 2 hours. A saturated ammonium chloride solution was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate and dried. The mixture was concentrated by column chromatography to obtain compound A-3;

[0037] According to a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, the specific operation of step 2 is:

[0038] Compound A-3 was dissolved in dichloromethane, triethylsilane and trifluoroacetic acid were added dropwise in turn, and the mixture was stirred at room temperature for reaction. After the reaction was complete, the solvent was removed by concentration, and water was added. The pH was adjusted to 7 with sodium bicarbonate, and the mixture was extracted with dichloromethane. The mixture was dried, concentrated, and purified by column chromatography to obtain a 5-methylene-substituted thiazole-2-ylamine derivative (Formula A).

[0039] According to a preferred embodiment of a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the lithiation reagent used is a 2.5 mol / L n-BuLi THF solution;

[0040] According to a preferred embodiment of a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the low temperature reaction temperature is -40°C;

[0041] According to a preferred embodiment of a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the molar ratio of compound A-1 to the lithiating agent is 1:2.5;

[0042] According to a preferred embodiment of a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the molar ratio of compound A-1 to compound A-2 is 1:2;

[0043] According to a preferred embodiment of a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 1, the weight-to-volume ratio (g / ml) of compound A-1 to the organic solvent is 1:15;

[0044] According to a preferred embodiment of a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the weight-to-volume ratio (g / ml) of compound A-3 to dichloromethane solvent is 1:20;

[0045] According to a preferred embodiment of a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the molar ratio of compound A-3 to the acid reagent trifluoroacetic acid is 1:10;

[0046] According to a preferred embodiment of a novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention, in step 2, the molar ratio of compound A-3 to dehydroxylation agent triethylsilane is 1:3;

[0047] The technical parameter features in the above preparation method of the present invention can be combined arbitrarily.

[0048] In the above-described operations, post-treatment includes but is not limited to quenching with a quenching agent, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, freeze-drying and the like, or one or a combination of the operations of quenching with water, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, freeze-drying and the like.

[0049] In a preferred embodiment of the present invention, the quenching refers to the process of adding a quenching agent to the reaction solution to stop the reaction from proceeding to the right;

[0050] The quenching agent is water, ice water, or a saturated aqueous solution of ammonium chloride;

[0051] In a preferred embodiment of the present invention, the extraction solvent is ethyl acetate or dichloromethane;

[0052] In a preferred embodiment of the present invention, the drying comprises drying the filtrate with anhydrous sodium sulfate or vacuum drying;

[0053] In a preferred embodiment of the present invention, the concentration refers to the process of removing the liquid solvent, including reduced pressure concentration, normal pressure concentration, low temperature spin drying, etc.;

[0054] The steps, solvents, reagents, drying, concentration, extraction, separation, etc. in the novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives of the present invention can be arbitrarily combined / separated to achieve the purpose of the present invention.

[0055] The room temperature described in this application is 15-30°C.

[0056] The invention discloses a novel method for synthesizing a 5-methylene-substituted thiazole-2-amine derivative. The method uses N-Boc-2-aminothiazole as a raw material, adopts a route method of lithiation, dehydroxylation and protective agent two-step reaction to obtain the target product compound 5-methylene-substituted thiazole-2-amine derivative (Formula A). The reaction products of lithiation reaction and subsequent dehydroxylation and protective group are single, high in conversion rate and easy to purify, and the yield of the whole synthetic route is improved. The whole synthetic method does not use highly toxic and explosive chemical hazardous substances, the reaction conditions are mild and the operation safety is high. The route steps have good repeatability, high conversion rate and high yield, can be applied to the synthesis of 5-methylene-substituted thiazole-2-amine derivatives with various substituent structures, have good versatility, are suitable for scale-up workshop operation, and have broad application prospects. DETAILED DESCRIPTION

[0057] The following describes the preferred embodiments of the present invention to make its technical content clearer and easier to understand. The present invention can be embodied in many different forms of embodiments, which are exemplary descriptions, and the protection scope of the present invention is not limited to the embodiments mentioned in the text.

[0058] If there are experimental methods without specific conditions, they are usually implemented according to conventional conditions, such as those in the relevant instructions or manuals.

[0059] Embodiment 1,

[0060]

[0061] Step 1, N-Boc-2-aminothiazole (2g) (Compound A-1) was dissolved in tetrahydrofuran (20mL) solution and cooled to -40°C, n-butyllithium solution (10mL, 2.5N THF solution) was added dropwise under argon protection and reacted at this temperature for 30 minutes, 3-pyridinecarboxaldehyde (2.14g) (Compound A-2a) was dissolved in tetrahydrofuran (10mL) and added dropwise to the above reaction solution, the temperature was maintained and the reaction was continued for 30 minutes, and the temperature was slowly raised to room temperature; after the reaction was completed, saturated ammonium chloride solution was added to the reaction solution for quenching, extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and the residue was separated and purified by column chromatography to obtain an off-white solid target product Compound A-3a (2.9g, yield 95%)

[0062] Step 2, compound A-3a (1.84 g) was dissolved in dichloromethane (36 mL) solvent, triethylsilane (2.09 g) and trifluoroacetic acid (6.83 g) were added dropwise in sequence under stirring at room temperature, and the reaction was continued under stirring at room temperature for 2 hours; after the reaction was completed, the solvent was concentrated and removed, water was added and the pH was adjusted to 7 with a saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The residue was separated and purified by column chromatography to obtain an off-white solid target product compound Aa (0.97 g, yield 85%);

[0063] The compound Aa obtained above was subjected to structural NMR detection, and the detection results are as follows:

[0064] 1 H NMR (400MHz, DMSO-d6): δppm 8.47-8.41(m,2H),7.46(dt,J=7.5,1.6Hz,1H),7.25(s,2H),6.84(d,J=7.1Hz,1H), 6.77(m,1H),4.12(s,2H);

[0065] The test results show that the structure of the synthesized compound Aa is correct.

[0066] Embodiment 2,

[0067]

[0068] Step 1, N-Boc-2-aminothiazole (2g) (Compound A-1) was dissolved in tetrahydrofuran (20mL) solution and cooled to -40°C, n-butyl lithium solution (10mL, 2.5N THF solution) was added dropwise under argon protection and reacted at this temperature for 30 minutes, 3-furancarboxaldehyde (1.92g) (Compound A-2b) was dissolved in tetrahydrofuran (10mL) and added dropwise to the above reaction solution, the temperature was maintained and the reaction was continued for 30 minutes, and the temperature was slowly raised to room temperature; after the reaction was completed, saturated ammonium chloride solution was added to the reaction solution for quenching, extracted with ethyl acetate, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and the residue was separated and purified by column chromatography to obtain an off-white solid target product Compound A-3b (2.84g, yield 96%)

[0069] Step 2, compound A-3b (1.66 g) was dissolved in dichloromethane (35 mL) solvent, triethylsilane (1.95 g) and trifluoroacetic acid (6.39 g) were added dropwise in sequence under stirring at room temperature, and the reaction was continued under stirring at room temperature for 2 hours; after the reaction was completed, the solvent was concentrated and removed, water was added and the pH was adjusted to 7 with a saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The residue was separated and purified by column chromatography to obtain an off-white solid target product compound Ab (0.88 g, yield 87%);

[0070] The compound Ab obtained above was subjected to structural NMR detection, and the detection results are as follows:

[0071] 1 H NMR (400MHz, DMSO-d6): δppm 7.41(dd,J=7.5Hz,1.5Hz,1H),7.17(s,2H),6.83(d,J=7.1Hz,1H),6.66(d,J=7.5Hz,1H),6.17(dd,J=7.5Hz,1.5Hz,1H),4.05(s,2H);

[0072] Embodiment 3,

[0073]

[0074] Step 1, N-Boc-2-aminothiazole (2g) (Compound A-1) was dissolved in tetrahydrofuran (20mL) solution and cooled to -40°C, n-butyl lithium solution (10mL, 2.5N THF solution) was added dropwise under argon protection and reacted at this temperature for 30 minutes, cyclohexanecarboxaldehyde (2.24g) (Compound A-2c) was dissolved in tetrahydrofuran (10mL) and added dropwise to the above reaction solution, the temperature was maintained and the reaction was continued for 30 minutes, and the temperature was slowly raised to room temperature; after the reaction was completed, saturated ammonium chloride solution was added to the reaction solution for quenching, extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and the residue was separated and purified by column chromatography to obtain an off-white solid target product Compound A-3c (2.87g, yield 90%)

[0075] Step 2, compound A-3c (1.56 g) was dissolved in dichloromethane (30 mL) solvent, triethylsilane (1.74 g) and trifluoroacetic acid (5.7 g) were added dropwise in sequence under stirring at room temperature, and the reaction was continued under stirring at room temperature for about 2 hours; after the reaction was completed, the solvent was concentrated and removed, water was added and the pH was adjusted to 7 with a saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The residue was separated and purified by column chromatography to obtain an off-white solid target product compound Ac (0.89 g, yield 90%);

[0076] The compound Ac obtained above was subjected to structural NMR detection, and the detection results are as follows:

[0077] 1 H NMR (400MHz, DMSO-d6): δppm 6.83 (s, 2H), 6.76 (s, 1H), 2.59 (d, J = 7.0Hz, 2H), 2.07-1.97 (m, 1H), 1.64-1.39 (m, 10H)

[0078] The present invention is not limited to the above-mentioned specific embodiments, but extends to any new features or any new combination disclosed in this specification, as well as any new method or process steps or any new combination disclosed.

Claims

1. A novel method for synthesizing 5-methylene-substituted thiazole-2-amine derivatives, characterized in that: The structure of the 5-benzylthiazol-2-ylamine derivative is shown in the following formula A: The synthesis method of the 5-methylene substituted thiazole-2-amine derivative is shown in the following route I: Route I: wherein R is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridine, and furan; wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridine, and furan are unsubstituted or substituted with one or more halogens; The specific operation steps are: Step 1, compound A-1 is dissolved in tetrahydrofuran, n-butyl lithium is added dropwise at -40°C for lithiation reaction, and then a tetrahydrofuran solution of A-2 is added dropwise at -40°C for reaction, and post-treatment is performed to obtain compound A-3; Step 2: dissolve compound A-3 in dichloromethane, add triethylsilane and trifluoroacetic acid in sequence to react at room temperature, and post-treat to obtain the target compound of formula A, a 5-methylene-substituted thiazol-2-ylamine derivative.

2. The method according to claim 1, characterized in that: In the step 1, After the reaction material is added dropwise, the mixture is stirred at -40°C for about 30 minutes, then slowly heated to room temperature and stirred for 2 to 3 hours; The molar ratio of the compound A-1 to n-butyl lithium is 1:2 to 1:3; The weight-to-volume ratio of the compound A-1 to tetrahydrofuran is 1:10 to 1:15 g / ml; The molar ratio of compound A-1 to compound A-2 is 1:2 to 1:3; In the step 2, After the reaction materials are added dropwise, continue stirring until A-3 reacts completely; The weight volume ratio of the compound A-3 to dichloromethane is 1:20 to 1:25 g / ml; The molar ratio of the compound A-3 to trifluoroacetic acid is 1:8 to 1:10; The molar ratio of the compound A-3 to triethylsilane is 1:3 to 1:5.

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