A method for preparing 2-acylaminothiazole compounds

Abstract

The application relates to a preparation method of 2-acylaminothiazole compounds, in particular to a preparation method of an intermediate of alvocidib, in the preparation method, a mixed solution of tetrahydrofuran and DMSO is used as a solvent to form a homogeneous system, so that the preparation method has the advantages of simple post-treatment, high yield and high product purity, and the method is especially suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of a 2-acylaminothiazole compound, in particular to a preparation method of an intermediate of a drug, ethyl 1-(3-chloro-5-((4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylate in the synthesis of Avatrombopag. BACKGROUND

[0002] Avatrombopag is an orally bioavailable small molecule thrombopoietin receptor agonist that stimulates the proliferation and differentiation of megakaryocytes in the bone marrow, resulting in increased production of platelets. The product has been approved by FDA in May 2018.

[0003] At present, the synthesis of Avatrombopag has been reported in related literatures. The synthesis route reported in the compound patent CN1639157A involves an intermediate: ethyl 1-(3-chloro-5-((4-(4-chlorothiophene-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylate (compound of formula III), and the structure of the compound is as follows:

[0004]

[0005] The inventors found that the product is not easy to precipitate and the yield is low when using the single solvent tetrahydrofuran reported in CN1639157A, and the post-treatment method reported in CN1639157A is complex, which needs extraction, drying, concentration and column chromatography, and is not suitable for large-scale industrial production. In addition, when the inventors tried to use DMF or DMSO as a single solvent, a heterogeneous system was formed, and the reaction could not reach the end point. SUMMARY

[0006] In order to solve the above technical problems, the present application provides an improved synthesis method of the compound of formula III.

[0007] In one aspect, the present application provides a synthesis method of the compound of formula III, wherein the compound of formula I, the compound of formula II and the basic reagent are reacted in a solvent to prepare the compound of formula III,

[0008]

[0009] The solvent is a mixed solution of THF and other organic solvents, and the organic solvent is selected from aprotic polar solvents other than THF.

[0010] In some embodiments of the present application, the aprotic polar solvent is selected from the group consisting of DMF, DMSO and acetonitrile, preferably DMSO.

[0011] In some embodiments of the present application, the solvent is preferably a mixed solution of THF and DMSO.

[0012] In some embodiments of the present application, the volume ratio of THF and DMSO in the solvent is 3:3-3:7, preferably 3:5-3:7, and further preferably 3:7.

[0013] In some embodiments of the present application, the basic reagent is 1,8-diazabicycloundec-7-ene, pyridine, triethylamine and N,N-diisopropylethylamine; preferably triethylamine.

[0014] In some embodiments of the present application, the molar ratio of the compound of formula I to the compound of formula II is 1:1-1:2, preferably 1:1.5-1:2, and further preferably 1:2.

[0015] In some embodiments of the present application, the molar ratio of the compound of formula I to the base is 1:1-1:3, preferably 1:2-1:3, and further preferably 1:2-1:2.5, and more further preferably 1:2.

[0016] In some embodiments of the present application, the compound of formula I, the compound of formula II and the base are reacted at 50-80°C, preferably 60-80°C, and further preferably 70°C-80°C.

[0017] In another aspect, the present application further provides a post-treatment method, which comprises the following steps: cooling, adding solvent I, stirring to precipitate the solid.

[0018] In some embodiments, the post-treatment method further comprises cooling, adding solvent I to the untreated reaction solution, and stirring to precipitate the solid.

[0019] In some typical embodiments, the untreated includes extraction, drying, concentration and the like.

[0020] In some embodiments, the solvent I is anhydrous ethanol.

[0021] In some preferred embodiments, the post-treatment method comprises the following steps:

[0022] (1) cooling the reaction solution, controlling the temperature, and adding solvent I;

[0023] (2) cooling, controlling the temperature, stirring, and precipitating the solid;

[0024] (3) filtering, rinsing with solvent I, filtering again, and drying;

[0025] In some embodiments, the cooling in step (1) refers to natural cooling;

[0026] In some embodiments, the time for stirring to precipitate the solid in step (2) is 1-2h, preferably 1h;

[0027] In some preferred embodiments, the post-treatment method comprises the following steps:

[0028] (1a) cooling the reaction solution to below 60°C, controlling the temperature to be 30-60°C, and adding anhydrous ethanol;

[0029] (2a) cooling to 0-10°C, and controlling the temperature to be 0-10°C, stirring, and precipitating the solid;

[0030] (3a) filtering, eluting with solvent I, filtering again, and drying;

[0031] In the present application, the following terms have the following meanings unless otherwise specified:

[0032] In the present application, "h" refers to hour, and "min" refers to minute;

[0033] In the present application, "DMF" refers to dimethylformamide;

[0034] In the present application, "THF" refers to tetrahydrofuran;

[0035] In the present application, "DMSO" refers to dimethyl sulfoxide;

[0036] In the present application, "reaction end point" refers to monitoring the disappearance of the raw material point by thin layer chromatography (TLC) or monitoring the reaction end point by high performance liquid chromatography (HPLC) until the content of starting material I is less than or equal to 1.0%.

[0037] In the present application, "aprotic polar solvent" refers to a class of solvents with large dipole moment and high dielectric constant but without dissociative hydrogen atoms. Exemplary solvents include but are not limited to N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), 1, 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide (DMSO), THF, ethylene glycol dimethyl ether, t-butyl methyl ether, ethers such as 1, 4-dioxane, halogenated hydrocarbons such as chlorobenzene, esters such as ethyl acetate, butyl acetate, and nitriles such as acetonitrile.

[0038] The preparation method provided by the present application has the characteristics of simple post-treatment, high yield and high product purity; and the method is particularly suitable for industrial production. DETAILED DESCRIPTION

[0039] In order to better understand the content of the application, the application will be further described below in conjunction with specific examples.

[0040] The reagents and raw materials used in the present application are commercially available products.

[0041] The method for measuring the purity (%) in the embodiments of the present application is as follows:

[0042] Solution preparation: an appropriate amount of the compound of formula III obtained in the following examples was accurately weighed, dissolved in about 30% of the volume of a tetrahydrofuran measuring flask by ultrasonic, and diluted with acetonitrile to prepare a solution containing about 0.5 mg per 1 ml.

[0043] Chromatographic conditions: octadecyl-bonded silica gel (Agilent ZORBAX Eclipse Plus C18, 4.6 mm x 100 mm, 3.5 μm or a chromatographic column with equivalent performance) was used as the filler; 0.01 mol / L ammonium formate solution (ammonium formate 1.26 g was dissolved in 2000 ml of water, and the pH was adjusted to 3.0 with formic acid) was used as the mobile phase A, and acetonitrile was used as the mobile phase B; gradient elution was performed according to the following table; the flow rate was 1.0 ml / min; the column temperature was 35°C; the detection wavelength was 250 nm; and the injection volume was 10 μl.

[0044]

[0045]

[0046] Example 1

[0047] The compound of formula I (1.3 g), the compound of formula II (0.73 g) and triethylamine (0.47 g) were added to THF (10 ml), and the temperature was controlled at 60-70°C, and the reaction was stirred for 3-4 h. The temperature was lowered to below 60°C, and anhydrous ethanol (21 ml) was added while controlling the temperature at 30-60°C. After the addition was completed, the temperature was again lowered to 0-5°C, and the product was crystallized by stirring for 3-5 h; the product was filtered, the filter cake was washed with anhydrous ethanol (6 ml), and filtered, and the wet product was dried at 55-65°C under vacuum to obtain the compound of formula III, with a yield of 71.3%.

[0048] Example 2

[0049] The compound of formula I (3.0 g), the compound of formula II (1.7 g) and triethylamine (1.1 g) were added to a mixed solvent of solvent S (30 ml) while stirring, and the temperature was controlled at 70-80°C, and the reaction was stirred for 3-4 h. The temperature was lowered to below 60°C, and anhydrous ethanol (60 ml) was added while controlling the temperature at 30-60°C. After the addition was completed, the temperature was again lowered to 0-10°C, and the product was crystallized by stirring for 1 h; the product was filtered, the filter cake was washed with anhydrous ethanol (12 ml), and filtered, and the wet product was dried at 55-65°C under vacuum to obtain the compound of formula III.

[0050]

[0051] The inventors tried different solvents using the above preparation method, and the results are shown in Table 1:

[0052] Table 1: Effect of solvent on reaction

[0053] Solvent S Yield % System state DMSO 86.8 Heterogeneous DMF 84.5 Heterogeneous

[0054] As can be seen from Table 1, using a single solvent in the table forms a heterogeneous system, which is not conducive to subsequent production and quality control.

[0055] Therefore, the inventors tried a mixed solution of DMSO and THF as the solvent, and found that a homogeneous system was formed, and thus continued to study the effect of different volume ratios of THF and DMSO on the reaction yield and product purity. The results are shown in Table 2.

[0056] Table 2: Effect of different volume ratios of THF and DMSO on reaction yield and product purity

[0057]

[0058]

[0059] As can be seen from the results in Table 2, when using a mixed solution of DMSO and THF as the solvent, the yield and purity of the reaction are both good. Moreover, compared with THF, the crystallization time is also shortened, indicating that it is more difficult to crystallize using THF as the solvent.

[0060] In addition, the inventors also explored the effect of the molar ratio of the raw materials on the reaction yield and purity. Example 3 shows the effect of the molar ratio of the compound of formula I and the compound of formula II on the reaction yield and purity, and Example 4 shows the effect of the molar ratio of the compound of formula I and triethylamine on the reaction yield and purity.

[0061] Example 3

[0062] The compound of formula I (3.0 g), the compound of formula II (N g), and triethylamine (1.1 g) were added to the mixed solvent of DMSO (30 ml) under stirring, and the temperature was controlled at 70-80°C, and the reaction was stirred for 3-4 h. The temperature was lowered to below 60°C, and anhydrous ethanol (60 ml) was added while controlling the temperature at 30-60°C. After the addition was completed, the temperature was lowered to 0-10°C, and the wet product was crystallized for 1 h while stirring; it was filtered, the filter cake was washed with anhydrous ethanol (12 ml) and filtered, and the wet product was dried at 55-65°C under vacuum to obtain the compound of formula III.

[0063] The inventors adjusted the amount of the compound of formula II, and the results are shown in Table 3:

[0064] Table 3: Effect of molar ratio of compound of formula I and compound of formula II on reaction yield and purity

[0065]

[0066] Example 4

[0067] The compound of formula I (3.0 g), the compound of formula II (1.7 g) and triethylamine (1.1 g) were added into a mixed solvent of DMSO (30 ml) under stirring, and the temperature was controlled at 70-80 °C, and the reaction was stirred for 2.5 h. The temperature was lowered to below 60 °C, and anhydrous ethanol (60 ml) was added under temperature control at 30-60 °C. After the addition was completed, the temperature was lowered to 0-10 °C, and the product was crystallized by stirring for 1 h. The product was filtered, the filter cake was washed with anhydrous ethanol (12 ml), and the wet product was dried at 55-65 °C under vacuum to obtain the compound of formula III.

[0068] The inventors adjusted the amount of triethylamine, and the results are shown in Table 4.

[0069] Table 4 Effect of the molar ratio of the compound of formula I and triethylamine on the yield and purity of the reaction

[0070]

[0071]

[0072] Examples 5-7 were based on the foregoing examples, and process scale-up was performed.

[0073] Example 5

[0074] The compound of formula I (30.0 g), the compound of formula II (17.1 g) and triethylamine (10.8 g) were added into a mixed solvent of DMSO / THF (210 ml / 90 ml), and the temperature was controlled at 70-80 °C, and the reaction was stirred for 3-4 h. The temperature was lowered to below 60 °C, and anhydrous ethanol (600 ml) was added under temperature control at 30-60 °C. After the addition was completed, the temperature was lowered to 0-10 °C, and the product was crystallized by stirring for 1 h. The product was filtered, the filter cake was washed with anhydrous ethanol (90 ml), and the wet product was dried at 55-65 °C under vacuum to obtain the compound of formula III, with a yield of 96.1 % and a purity of 99.75 %.

[0075] Example 6

[0076] Compound I (500 g), compound II (214 g), and triethylamine (135 g) were added to a mixed solvent of DMSO / THF (3.5 L / 1.5 L). The mixture was stirred at 70–80 °C for 3–4 h. The temperature was then lowered to below 60 °C, and anhydrous ethanol (10 L) was added while maintaining the temperature at 30–60 °C. After the addition was complete, the temperature was lowered to 0–10 °C, and the mixture was stirred at this temperature to allow crystallization to occur for 1 h. The mixture was then filtered, and the filter cake was washed with anhydrous ethanol (1 L), filtered again, and dried under vacuum at 55–65 °C to obtain compound III, with a yield of 93.7% and a purity of 99.63%.

[0077] Example 7

[0078] Compound I (5.38 kg), compound II (3.06 kg), and triethylamine (1.94 kg) were added to a mixed solvent of DMSO / THF (38 L / 16 L). The mixture was stirred at 70–80 °C for 3–4 h. The temperature was then lowered to below 60 °C, and anhydrous ethanol (108 L) was added while maintaining the temperature at 30–60 °C. After the addition was complete, the temperature was lowered to 0–10 °C, and the mixture was stirred to allow crystallization for 1 h. The crystals were filtered, and the filter cake was washed with anhydrous ethanol (16 L), filtered again, and dried under vacuum at 55–65 °C to obtain compound III, with a yield of 95.0% and a purity of 99.80%.

Claims

1. A method for synthesizing a compound of formula III, wherein, Compounds of formula I and II, along with a basic reagent, are reacted in a solvent to prepare compound III. The solvent is a mixed solution of THF and DMSO, and the volume ratio of THF to DMSO is 3:3 to 3:

7. The alkaline reagent is triethylamine.

2. The method according to claim 1, wherein the volume ratio of THF to DMSO in the solvent is 3:5 to 3:

7.

3. The method of claim 1, wherein the volume ratio of THF to DMSO in the solvent is 3:

7.

4. The method according to claim 1, wherein the molar ratio of the compound of formula I to the compound of formula II is 1:1.5 to 1:

2.

5. The method according to claim 1, wherein the molar ratio of the compound of formula I to the compound of formula II is 1:

2.

6. The method according to claim 1, wherein the molar ratio of the compound of formula I to the base is 1:2 to 1:

3.

7. The method according to claim 1, wherein the molar ratio of the compound of formula I to the base is 1:2 to 1:2.

5.

8. The method according to claim 1, wherein the molar ratio of the compound of formula I to the base is 1:

2.

9. The method according to claim 1, wherein the compound of formula I and the compound of formula II react with a base at 60–80°C.

10. The method of claim 1, wherein the compound of formula I and the compound of formula II react with a base at 70°C to 80°C.

11. The method of claim 1, wherein the post-processing method comprises the following steps: cooling, adding solvent I, and stirring to precipitate a solid, wherein solvent I is anhydrous ethanol.

12. The method of claim 11, wherein the post-processing method further includes cooling, adding solvent I to the untreated reaction solution, and stirring to precipitate solids; wherein the untreated solution includes extraction, drying, and concentration steps.

13. The method of claim 1, wherein the post-processing method comprises the following steps: (1) Cool the reaction solution, control the temperature, and add solvent I; (2) Cool down, control the temperature, stir, and precipitate solid; (3) Filter, rinse with solvent I, filter again, and dry; Solvent I is anhydrous ethanol; The cooling in step (1) refers to natural cooling; The stirring time for solid precipitation in step (2) is 1-2 hours.

14. The method as described in claim 13, wherein the stirring time for solid precipitation in step (2) is 1 hour.

15. The method of claim 1, wherein the post-processing method comprises the following steps: (1a) Cool the reaction solution to below 60°C, control the temperature at 30-60°C, and add anhydrous ethanol; (2a) Cool down to 0-10℃ and control the temperature at 0-10℃, stir, and precipitate solid; (3a) Filter, rinse with anhydrous ethanol, filter again, and dry to obtain compound III.

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