Synthesis method of 4-(4-chlorothiophene-2-yl)-5-(4-cyclohexyl piperazine-1-yl) thiazole-2-amine

Abstract

The invention discloses a synthesis method of 4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazine-1-yl) thiazole-2-amine, and belongs to the technical field of organic chemical synthesis. Thiophene-2-formic acid is used as an initial raw material, and is subjected to esterification with methanol, chlorination and synthesis of alpha, beta-dione, and the alpha, beta-dione is used as a catalyst. The target product is obtained by cyclization of the alpha, alpha-dichloro carbonyl product and thiourea and substitution with 1-cyclohexylpiperazine, so that the polybromination side reaction caused by alpha-position bromination of the carbonyl compound in the prior art is avoided, the dichloro carbonyl compound is generated in one step, the number of process steps is reduced, the purification difficulty is reduced, and the yield is increased. The method has the advantages of mild reaction conditions, simple production operation, low cost and high safety, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and in particular to a method for synthesizing an avatrombopag intermediate, 4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazine-1-yl)thiazole-2-amine. Background Art

[0002] Avatrombopag is a thrombopoietin receptor agonist (TPO-RA) used for thrombocytopenia. It can greatly improve the quality of life of patients with thrombocytopenia and has the characteristics of long-lasting efficacy, safety and convenience.

[0003] 4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazine-1-yl)thiazole-2-amine is an important intermediate for the synthesis of avatrombopag. There are relatively few existing synthesis methods, mainly the following methods:

[0004] The synthesis route of patent document 1 (WO2003062233) is as follows:

[0005]

[0006] In the above-mentioned synthesis steps, the bromination reaction will produce polybrominated by-products, which are difficult to purify and separate in post-treatment, affecting product quality; the starting raw materials are expensive and the industrial production cost is high.

[0007] The synthetic route of patent document 2 (CN 117551093 A) is as follows:

[0008]

[0009] The synthesis process is complex, and there is also the problem of difficulty in single-step purification, and the cost of industrial production is high.

[0010] Based on the above problems, it is necessary to develop a synthesis route and production process with simple process operation, low cost, safety and environmental protection.

[0011] The above contents are only used to assist in understanding the technical solution of the present invention and do not constitute an admission that the above contents are prior art. Summary of the invention

[0012] The main purpose of the present invention is to provide a synthesis route and production process with simple process operation, low cost, safety and environmental protection, so as to solve the problems of long process route, high production cost and many by-products that are difficult to purify in the existing synthesis method.

[0013] To achieve the above object, the present invention provides a method for synthesizing 4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazine-1-yl)thiazole-2-amine, comprising the following steps:

[0014] (a) dissolving thiophene-2-carboxylic acid in methanol, adding concentrated sulfuric acid, and heating under reflux to obtain intermediate Ia;

[0015] (b) dissolving the intermediate Ia in an organic solvent A, and adding a catalyst and a chlorination agent in batches to react to obtain an intermediate Ib;

[0016] (c) dissolving the intermediate Ib and the dichloro compound in tetrahydrofuran, adding a strong base to obtain the intermediate Ic;

[0017] (d) dissolving the intermediate Ic in an organic solvent B, adding thiourea to react, and obtaining the intermediate Id;

[0018] (e) The intermediate Id and 1-cyclohexylpiperazine are dissolved in an organic solvent C, and a base is added to react to obtain the target product Ie.

[0019] in:

[0020] In step (b), the catalyst is selected from one of aluminum chloride, zinc chloride, ferric chloride, tetraisopropoxytitanium, boron trifluoride etherate, concentrated sulfuric acid, and p-toluenesulfonic acid;

[0021] In step (b), the chlorination reagent is selected from one of N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid and sulfonyl chloride;

[0022] The organic solvent A is selected from one or more of N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, dichloromethane, and 1,2-dichloroethane;

[0023] In step (c), the dichloro compound is selected from one of dichloroacetic acid, methyl dichloroacetate and ethyl dichloroacetate;

[0024] In step (c), the strong base is selected from one of lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and lithium diisopropylamide;

[0025] The organic solvent B is selected from one or more of methanol, ethanol, acetonitrile and polyethylene glycol 400;

[0026] The organic solvent C is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile and dimethyl sulfoxide;

[0027] In step (e), the base is selected from one of potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, sodium tert-butoxide and potassium tert-butoxide;

[0028] The reflux temperature in step (a) is 90° C. and the reflux time is 6 h.

[0029] In step (b), the catalyst was added in batches and stirred for reaction for 1 h, and the chlorination reagent was added in batches for a reaction time of 6 h;

[0030] In step (c), a strong base is added at -40°C to 0°C under a nitrogen environment and the reaction is carried out for 10 minutes;

[0031] Step (d) reaction temperature 60 ° C, reaction time 6h ~ 12h;

[0032] The reaction temperature of step (e) is 80° C. and the reaction time is 4 h to 5 h.

[0033] In step (b), the catalyst is added in batches in an ice bath, and the chlorination reagent is added in batches in an ice bath, and the reaction is carried out at room temperature for 6 hours;

[0034] Step (e) further comprises removing the solvent under vacuum, washing the crude product with n-hexane, and recrystallizing the crude product with a mixed solvent of ethyl acetate / n-hexane.

[0035] The synthesis method of 4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazine-1-yl)thiazole-2-amine provided by the present invention has the following advantages: the present invention uses thiophene-2-carboxylic acid as a starting material, and obtains the final product through some conventional simple reactions, esterification, chlorination, carbonyl dichlorination, cyclization and substitution. The present invention has mild reaction conditions, simple production operation, few side reactions, low cost, high safety, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 It is the hydrogen spectrum nuclear magnetic resonance image of the target product Ie involved in the embodiment of the present invention.

[0037] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical solution and advantages of the embodiments of the present disclosure clearer, the technical solution of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, rather than all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present disclosure.

[0039] The present invention provides a method for synthesizing 4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazine-1-yl)thiazole-2-amine, which specifically comprises the following steps:

[0040] (a) dissolving thiophene-2-carboxylic acid in methanol, adding concentrated sulfuric acid, and heating under reflux to obtain intermediate Ia;

[0041] Wherein: the heating reflux temperature is 90°C, and the heating reflux time is 6h.

[0042]

[0043] (b) dissolving the intermediate Ia in an organic solvent A, and adding a catalyst and a chlorination agent in batches to obtain an intermediate Ib;

[0044] Wherein: organic solvent A is selected from one or more of N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, dichloromethane, and 1,2-dichloroethane;

[0045] The catalyst is selected from one of aluminum chloride, zinc chloride, ferric chloride, tetraisopropoxytitanium, boron trifluoride etherate, concentrated sulfuric acid, and p-toluenesulfonic acid;

[0046] The chlorination agent is selected from one of N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid, and sulfonyl chloride;

[0047] After adding the catalyst in batches, stirring and reacting for 1 hour, adding the chlorination agent in batches, the reaction time is 6 hours; preferably, adding the catalyst in batches in an ice bath, adding the chlorination agent in batches in an ice bath, and reacting at room temperature for 6 hours.

[0048]

[0049] (c) dissolving the intermediate Ib and the dichloro compound in tetrahydrofuran, adding a strong base to obtain the intermediate Ic;

[0050] Wherein: the dichloro compound is selected from one of dichloroacetic acid, methyl dichloroacetate, and ethyl dichloroacetate;

[0051] The strong base is selected from one of lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and lithium diisopropylamide;

[0052] Add strong base at -40℃~0℃ and nitrogen environment and react for 10 minutes.

[0053]

[0054] (d) dissolving the intermediate Ic in an organic solvent B, adding thiourea to react, and obtaining the intermediate Id;

[0055] Wherein: the organic solvent B is selected from one or more of methanol, ethanol, acetonitrile, and polyethylene glycol 400;

[0056] The reaction temperature is 60°C and the reaction time is 6h to 12h.

[0057]

[0058] (e) dissolving the intermediate Id and 1-cyclohexylpiperazine in an organic solvent C, adding a base to react, and obtaining the target product Ie;

[0059] Wherein: the organic solvent C is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile and dimethyl sulfoxide;

[0060] The base is selected from one of potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, sodium tert-butoxide, and potassium tert-butoxide;

[0061] Reaction temperature 80°C, reaction time 4h~5h;

[0062] The solvent was removed under vacuum, and the crude product was washed with n-hexane and recrystallized from a mixed solvent of ethyl acetate / n-hexane.

[0063]

[0064] Example 1

[0065] (a) Preparation of Intermediate Ia

[0066] 200.0 g of thiophene-2-carboxylic acid was weighed and dissolved in 2 L of methanol. 40 mL of concentrated sulfuric acid was slowly added dropwise. After the addition was completed, the mixture was refluxed at 90 ° C for 6 h. The reaction solution was cooled to room temperature and poured into 2 L of ice-water mixture. The mixture was extracted twice with dichloromethane (1 L × 2). The organic layers were combined, washed with water, saturated sodium bicarbonate, and saturated brine, and dried. The solvent was removed under vacuum and distilled under reduced pressure to obtain 220.8 g of intermediate Ia as a colorless oily liquid.

[0067] (b) Preparation of Intermediate Ib

[0068] 220.8 g of the intermediate Ia obtained in step (a) was dissolved in 2 L of dichloromethane, and placed in an ice bath. 591.4 g of aluminum chloride was added in batches (5 times), and the reaction was stirred for 1 h. 127.1 g of trichloroisocyanuric acid was added in batches (5 times), and the temperature was raised to room temperature. The reaction was reacted for 6 h. The reaction solution was poured into 2 L of sodium bicarbonate ice water solution, extracted twice with ethyl acetate (1 L×2), the organic layers were combined, washed with water, saturated sodium bicarbonate, and saturated brine, and dried. The solvent was removed under vacuum and distilled under reduced pressure to obtain 214.1 g of intermediate Ib as a colorless oily liquid. The total yield of step (a) and step (b) was 77.7%.

[0069] (c) Preparation of Intermediate Ic

[0070] 214.1 g of intermediate Ib obtained in step (b) and 234.5 g of dichloroacetic acid were dissolved in 2 L of tetrahydrofuran, and 3.7 L of 1 mol / L tetrahydrofuran solution of lithium hexamethyldisilazide was added under a nitrogen atmosphere at -40 ° C. The reaction mixture was reacted for 10 min. The reaction mixture was poured into 4 M hydrochloric acid on ice and stirred for 30 min. The mixture was extracted twice with ethyl acetate (2 L × 2). The organic layers were combined, washed with water, saturated sodium bicarbonate, and saturated brine, dried, and spin-dried to obtain 387.1 g of intermediate Ic as a brown oil.

[0071] (d) Preparation of intermediate Id

[0072] 387.1 g of intermediate Ic obtained in step (c) was dissolved in 1 L of polyethylene glycol 400, 128.3 g of thiourea was added, and the mixture was reacted at 60° C. for 12 h. The reaction solution was poured into 2 L of ice water, extracted twice with ethyl acetate (1 L×2), the organic layers were combined, washed with water, saturated sodium bicarbonate, and saturated brine, and dried. The solvent was removed under vacuum until the solution volume was 500 mL, and n-hexane was added to the solution until a large amount of light yellow solid precipitated. The solution was filtered and washed with n-hexane to obtain 215.3 g of intermediate Id.

[0073] (e) Preparation of target product Ie

[0074] 215.3 g of the intermediate Id obtained in step (d) was dissolved in 1 L of N,N-dimethylformamide, and 158.7 g of 1-cyclohexylpiperazine and 237.0 g of potassium carbonate were added. The reaction was carried out at 80° C. for 5 h. The reaction solution was diluted and extracted twice with ethyl acetate (1 L×2). The organic layers were combined, washed with water, saturated sodium bicarbonate, and saturated brine, and dried. The solvent was removed under vacuum, and the crude product was washed with n-hexane and recrystallized with an ethyl acetate / n-hexane mixture to obtain 305.3 g of the target product Ie as a yellow solid with a liquid phase purity of 99.1% and a total yield of 51.1%.

[0075] like Figure 1 As shown, where: H NMR spectrum

[0076] 1 HNMR(400MHz, CDCl3)(ppm): δ7.43(s,1H),6.96(s,1H),5.01(s,2H),2.88–2.90(m,4H),2.75–2.77(m,4H),2.29– 2.35(m,1H),1.90–1.93(m,2H),1.80–1.83(m,2H),1.65(d,J=12.0Hz,1H),1.22–1.31(m,4H),1.10–1.15(m,1H).

[0077] Example 2

[0078] The difference between this embodiment and embodiment 1 is that:

[0079] (a) 10.0 g of thiophene-2-carboxylic acid was dissolved in 100 mL of methanol, and 2 mL of concentrated sulfuric acid was slowly added dropwise. After the addition was completed, the mixture was refluxed at 90°C for 6 h while keeping other conditions unchanged to obtain 11.8 g of intermediate Ia.

[0080] (b) 11.8 g of the intermediate Ia obtained in step (a) was dissolved in 100 mL of dichloromethane, and ice-bathed. 33.2 g of aluminum chloride was added in batches (3 times) and stirred for reaction for 1 h; 13.3 g of N-chlorosuccinimide was added in batches (3 times) and reacted at room temperature for 6 h. The other conditions remained unchanged to obtain 9.5 g of intermediate Ib. The total yield of step (a) and step (b) was 68.8%.

[0081] (c) 9.5 g of intermediate Ib obtained in step (b) and 10.4 g of dichloroacetic acid were dissolved in 100 mL of tetrahydrofuran, 12.9 g of lithium tert-butoxide was added under an ice bath and nitrogen atmosphere, and the reaction was continued overnight (12 h), and the other conditions were kept unchanged to obtain 15.3 g of intermediate Ic.

[0082] (d) 15.3 g of the intermediate Ic obtained in step (c) was dissolved in 100 mL of acetonitrile, 5.1 g of thiourea was added, and the mixture was reacted at 60° C. for 6 h while keeping the other conditions unchanged to obtain 9.3 g of the intermediate Id.

[0083] (e) 9.3 g of the intermediate Id obtained in step (d) was dissolved in 50 mL of N,N-dimethylformamide, 6.8 g of 1-cyclohexylpiperazine and 7.9 g of sodium carbonate were added, and the reaction was carried out at 80° C. for 5 h. The other conditions remained unchanged to obtain 12.7 g of the target product Ie with a liquid phase purity of 98.5% and a total yield of 42.5%.

[0084] Example 3

[0085] The difference between this embodiment and embodiment 2 is that:

[0086] (b) 33.7 g of aluminum chloride was added in batches (3 times) and the reaction was stirred for 1 hour; 13.7 g of sulfuryl chloride was added in batches (3 times) and the reaction was carried out at room temperature for 6 hours. The other conditions remained unchanged to obtain 9.8 g of intermediate Ib. The total yield of step (a) and step (b) was 71.0%.

[0087] (c) 83 mL of a 2 mol / mL tetrahydrofuran / n-heptane solution of lithium diisopropylamide was added under an ice bath and nitrogen atmosphere, and the reaction was carried out for 10 min. Other conditions remained unchanged to obtain 17.4 g of intermediate Ic.

[0088] (d) 17.4 g of the intermediate Ic obtained in step (c) was dissolved in 100 mL of ethanol, 5.9 g of thiourea was added, and the mixture was reacted at 60° C. for 10 h while keeping the other conditions unchanged to obtain 9.4 g of the intermediate Id.

[0089] (e) 9.4 g of the intermediate Id obtained in step (d) was dissolved in 50 mL of N,N-dimethylformamide, 6.9 g of 1-cyclohexylpiperazine and 10.4 g of potassium carbonate were added, and the reaction was carried out at 80° C. for 4 h. The other conditions remained unchanged to obtain 13.3 g of the target product Ie with a liquid phase purity of 98.8% and a total yield of 44.5%.

Claims

1. A method for synthesizing 4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazine-1-yl)thiazol-2-amine, characterized in that: The following steps are involved: (a) Dissolve thiophene-2-carboxylic acid in methanol, add concentrated sulfuric acid, and heat under reflux to obtain intermediate Ia (b) Dissolve the intermediate Ia in an organic solvent A, and add a catalyst and a chlorination agent in batches to react to obtain an intermediate Ib (c) Dissolve the intermediate Ib and the dichloro compound in tetrahydrofuran and add a strong base to obtain the intermediate Ic (d) Dissolve the intermediate Ic in an organic solvent B, add thiourea to react, and obtain the intermediate Id (e) Dissolve the intermediate Id and 1-cyclohexylpiperazine in an organic solvent C, add a base to react, and obtain the target product Ie 2. The method according to claim 1, characterized in that In step (b), the catalyst is selected from one of aluminum chloride, zinc chloride, ferric chloride, tetraisopropoxytitanium, boron trifluoride etherate, concentrated sulfuric acid, and p-toluenesulfonic acid; In step (b), the chlorination reagent is selected from one of N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid and sulfonyl chloride; The organic solvent A is selected from one or more of N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, dichloromethane and 1,2-dichloroethane.

3. The method according to claim 2, characterized in that In step (c), the dichloro compound is selected from one of dichloroacetic acid, methyl dichloroacetate and ethyl dichloroacetate; In step (c), the strong base is selected from one of lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and lithium diisopropylamide.

4. The method according to claim 3, characterized in that The organic solvent B is selected from one or more of methanol, ethanol, acetonitrile and polyethylene glycol 400; The organic solvent C is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile and dimethyl sulfoxide.

5. The method according to claim 4, characterized in that In step (e), the base is selected from one of potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, sodium tert-butoxide and potassium tert-butoxide.

6. The method according to claim 5, characterized in that The reflux temperature in step (a) is 90° C. and the reflux time is 6 h. In step (b), the catalyst was added in batches and stirred for reaction for 1 h, and the chlorination reagent was added in batches for a reaction time of 6 h; In step (c), a strong base is added at -40°C to 0°C under a nitrogen environment and the reaction is carried out for 10 minutes; Step (d) reaction temperature 60 ° C, reaction time 6h ~ 12h; The reaction temperature of step (e) is 80° C. and the reaction time is 4 h to 5 h.

7. The method according to claim 6, characterized in that In step (b), the catalyst is added in batches in an ice bath, and the chlorination reagent is added in batches in an ice bath, and the reaction is carried out at room temperature for 6 hours.

8. The method according to claim 7, characterized in that Step (e) further comprises removing the solvent under vacuum, washing the crude product with n-hexane, and recrystallizing the crude product with a mixed solvent of ethyl acetate / n-hexane.

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