A method for synthesizing a dasatinib intermediate

Abstract

The application discloses a kind of synthesis method of dasatinib intermediate in the field of organic synthesis, with 2-aminothiazole-4-carboxylic acid as raw material, first and tert-pivaloyl chloride in situ generates mixed anhydride, further and 2-chloro-6-methylaniline condensation reaction occurs after, the compound 2 obtained is not separated directly hydrolyzed to obtain high-purity 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-formamide.Due to the mixed anhydride formed by tert-pivaloyl chloride has greater steric hindrance, and the further reaction of corresponding amine is conducive to the regioselectivity, and by-product tert-pivalic acid can be easily removed by post-treatment, so as to solve the disadvantages existing in the prior art, the unit operation involved in the whole preparation process is simpler, and the product purity and yield are higher, with good application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a synthesis method of a dasatinib intermediate. BACKGROUND

[0002] The dasatinib intermediate is 2-amino-N-(2-methyl-6-chlorophenyl)thiazole-5-carboxamide, English name: 2-amino-N-(2-methyl-6-chlorophenyl)thiazole-5-carboxamide, CAS Registry Number(s): 302964-24-5, melting point: 258-262℃, and chemical structural formula is as follows:

[0003]

[0004] 2-amino-N-(2-methyl-6-chlorophenyl)thiazole-5-carboxamide is a key intermediate for synthesizing dasatinib. Dasatinib (Sprycel) is an oral tyrosine kinase inhibitor developed by BMS. The drug was approved for marketing by FDA in June 2006 and is used for treating chronic myeloid leukemia and can also be used for treating Philadelphia chromosome-positive acute lymphoblastic leukemia. BMS disclosed in an annual document that due to the settlement agreement reached with Apotex and some undisclosed companies, the generic drug may be launched in September 2024 or earlier. As of now, the generic drugs of Biocon, Lupin, Dr. Reddy's Laboratories, Alebmic and Teva have been approved by FDA.

[0005] The synthesis of 2-amino-N-(2-methyl-6-chlorophenyl)thiazole-5-carboxamide in the prior art is as follows:

[0006] 1. Patent US200737978 is treated with 2,3-dichloropropenoic acid and thionyl chloride to form an acyl chloride, then 2-chloro-6-methylaniline is connected, then dimethyl acetal is generated by treating with methanol-sodium methoxide, and finally the target compound is obtained by deprotection under acidic conditions and in situ and thiourea ring closure.

[0007] Reaction formula:

[0008]

[0009] In the reaction process, the synthesis of 2,3-dichloropropenoyl chloride is involved, which is easy to polymerize and needs to be distilled under reduced pressure, and the energy consumption and requirements for equipment are high, and volatile chlorinated reagents such as thionyl chloride are used, which pollutes the environment.

[0010] 2, WO2017 / 2131, 2017, A1 and WO2005077945A2 reacted with 3-ethoxyacryloyl chloride and 2-chloro-6-methylaniline to obtain N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide, and then reacted with NBS and thiourea to obtain the target compound.

[0011] Reaction formula:

[0012]

[0013] The compound 3-ethoxyacryloyl chloride is easy to polymerize, resulting in low yield, impure intermediate product, and the need for purification by reduced pressure distillation, which requires high energy consumption for the equipment; in addition, the large amount of NBS must be used at low temperature, which greatly increases the cost, and the harsh conditions also increase the workload of post-treatment.

[0014] 3, [Synthetic Communications, 2017, vol. 47, #17, p. 1610-1621] and patent US2004 / 54186 both use oxalyl chloride to first prepare acyl chloride, and then react with 2-chloro-6-methylaniline in the presence of diisopropylethylamine, and the highest separation yield is 51%; Chinese patent CN106279061, 2017, A uses 2-tert-butoxycarbonyl amino thiazole-5-carboxylic acid and sulfur chloride to react, and then reacts with 2-chloro-6-methylaniline in the presence of pyridine, and finally removes the protecting group to obtain the target compound.

[0015] Reaction formula:

[0016]

[0017] First, the carboxylic acid is converted into acyl chloride, and then the amide is prepared by reacting the acyl chloride with the amine. The yield of the amide synthesized by this method should be relatively high in theory, but the reported preparation yield of the intermediate is relatively low. Therefore, it is necessary to further study the preparation method of the intermediate to improve the yield and reduce the cost.

[0018] In summary, it is necessary to find a method for synthesizing 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-formamide with "low raw material cost, high product purity and yield, and less waste", which is a technical problem to be solved in the field. SUMMARY

[0019] Therefore, the present application provides a synthesis method of a dasatinib intermediate, which aims to improve the product purity and yield, reduce the raw material cost of dasatinib, and obtain better economic and social benefits.

[0020] The technical scheme of the present application is implemented as follows: the present application provides a preparation method of a dasatinib intermediate, i.e. 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide, which comprises the following steps:

[0021] Step one, preparing the compound 1 shown in formula I by reacting 2-aminothiazole-4-carboxylic acid and pivaloyl chloride;

[0022] Step two, preparing the compound 2 shown in formula II by reacting the compound 1 shown in formula I with 2-chloro-6-methylphenylamine;

[0023] Step three, preparing 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide by hydrolyzing the compound 2 shown in formula II;

[0024] The compound 1 is formula I:

[0025] The compound 2 is formula II:

[0026] The specific reaction route of the above reaction is as follows:

[0027]

[0028] In step one, the acylation reaction of 2-aminothiazole-4-carboxylic acid and pivaloyl chloride prepares the compound 1, and then the reaction of the compound 1 with 2-chloro-6-methylphenylamine, because the mixed acid anhydride formed by pivaloyl chloride has high reactivity and large steric hindrance, and the further condensation reaction with the corresponding amine is beneficial to the regioselectivity, thereby the purity of the target product is improved, and the by-product pivalic acid is easy to remove, which is beneficial to simplify the operation.

[0029] In some embodiments, the molar ratio of 2-aminothiazole-4-carboxylic acid to pivaloyl chloride is 1:(2-4), and the molar ratio of 2-aminothiazole-4-carboxylic acid to 2-chloro-6-methylphenylamine is 1:(1-2), preferably 1:1.

[0030] In some embodiments, step one specifically comprises: adding 2-aminothiazole-4-carboxylic acid into tetrahydrofuran under a nitrogen atmosphere, stirring and cooling to 0-10℃, adding an acid-binding agent, adding pivaloyl chloride dropwise under insulation, and obtaining a reaction solution containing the compound 1 shown in formula I after the completion of the dropwise addition and stirring reaction.

[0031] In some embodiments, the acid-binding agent comprises any one of triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine.

[0032] In some embodiments, in step one, the method for determining the completion of the reaction comprises: sampling and detecting, and when the content of 2-aminothiazole-4-carboxylic acid / (2-aminothiazole-4-carboxylic acid + compound 1) is less than or equal to 1% by weight, the reaction is complete.

[0033] In some embodiments, step two further comprises adding 2-chloro-6-methylaniline to the reaction solution containing compound 1 represented by formula I, controlling the reaction temperature to be 0-10°C, and stirring until the reaction is complete to obtain a reaction solution containing compound 2 represented by formula II.

[0034] In some embodiments, in step two, the method for determining the completion of the reaction comprises: sampling and detecting, and when the content of compound 1 / (compound 1 + compound 2) is less than or equal to 1% by weight, the reaction is complete.

[0035] In some embodiments, step three further comprises adding sodium hydroxide aqueous solution dropwise to the reaction solution containing compound 2 represented by formula II, heating to 10-100°C, stirring until the reaction is complete, adjusting the pH to 5-7 using hydrochloric acid, cooling to 20-30°C, collecting the filter cake by filtration, and obtaining 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide.

[0036] In some embodiments, in step three, the heating temperature is preferably 50-60°C.

[0037] In some embodiments, in step three, the method for determining the completion of the reaction comprises: sampling and detecting, and when the content of compound 2 / (compound 2 + 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide) is less than or equal to 1% by weight, the reaction is complete.

[0038] In some embodiments, step four is further included, wherein 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide obtained in step three is mixed with a crystallization solvent, heated to 70-80°C, stirred until the solution is clear, then cooled to 0-5°C, and the solid is collected by filtration to obtain refined 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide.

[0039] In some embodiments, in step four, the crystallization solvent comprises one of ethanol, tetrahydrofuran, isopropanol, ethyl acetate, and isopropyl acetate.

[0040] The present application has the following beneficial effects over the prior art:

[0041] The present application generates mixed anhydride in-situ from 2-aminothiazole-4-carboxylic acid and pivaloyl chloride, and then the obtained compound is directly hydrolyzed in the form of reaction solution to obtain the target product with high purity. The process is simple and has high yield. The mixed anhydride formed by pivaloyl chloride has large steric hindrance, and the further reaction with the corresponding amine is beneficial to the regioselectivity, and the by-product pivalic acid can be easily removed by post-treatment, thereby forming a preparation process which solves the defects of the prior art process and leads the industry. BRIEF DESCRIPTION OF DRAWINGS

[0042] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or the prior art description. Obviously, the drawings described below are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative effort on the basis of these drawings.

[0043] Figure 1 HPLC spectrum of the product prepared in Example 1. DETAILED DESCRIPTION

[0044] The technical solutions in the embodiments of the present application will be described clearly and completely in combination with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative effort belong to the scope of protection of the present application.

[0045] In the following examples, the methods used are conventional methods unless otherwise specified. The materials, reagents and instruments used are conventional materials, reagents and instruments in the art unless otherwise specified, and can be obtained by commercial channels by those skilled in the art.

[0046] When an equivalent, concentration or other value or parameter is expressed in a range, a preferred range or a range defined by a series of upper preferred values and lower preferred values, it should be understood that all ranges formed by any pair of upper or lower preferred values of any range are specifically disclosed, regardless of whether the range is disclosed separately. For example, when the range "1 to 5" is disclosed, the described range should be interpreted as including the ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described herein, unless otherwise stated, the range is intended to include its end values and all integers and fractions within the range. In the specification and claims of the present application, the range definitions can be combined and / or interchanged if not otherwise stated, and these ranges include all sub-ranges contained therein.

[0047] Currently, the prior art mainly includes: BSM company in US2004 / 54186 uses oxalyl chloride to first prepare acyl chloride, then reacts with 2-chloro-6-methylaniline in the presence of diisopropylethylamine for 24 hours, and the separation yield is 48%; Shanghai Kesheng in CN106279061, 2017, A uses 2-tert-butoxycarbonyl amino thiazole-5-carboxylic acid and sulfur chloride to react, then reacts with 2-chloro-6-methylaniline in the presence of pyridine, and finally removes the protective group to obtain the target product 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide.

[0048] Using 2-tert-butoxycarbonyl amino thiazole-5-carboxylic acid as a raw material, the protective group Boc is partially removed during the reaction process to obtain impurity 1, and impurity 1 and 2-chloro-6-methylaniline continue to further react to obtain impurity 2, so that the product is difficult to purify, and it is difficult to obtain a product with high purity. This is a technical problem to be solved in the prior art.

[0049] The reaction equation of the side reaction is as follows:

[0050]

[0051] The present application directly hydrolyzes the compound obtained by in-situ generation of mixed anhydride of 2-aminothiazole-4-carboxylic acid and pivaloyl chloride and condensation reaction of 2-chloro-6-methylaniline in the form of reaction liquid to obtain the target product with high purity. The mixed anhydride formed by pivaloyl chloride has large steric hindrance, and the further reaction with the corresponding amine is beneficial to the regioselectivity, and the by-product pivalic acid can be easily removed by post-treatment, thereby solving the process defects existing in the prior art.

[0052] Example 1

[0053] S1-1: In the reaction device, 2-aminothiazole-4-carboxylic acid (14.5 g, 0.1 mol) was added to 50 ml of tetrahydrofuran under nitrogen protection, stirred and cooled to 5℃, and N-methylmorpholine (25.2 g, 0.25 mol) was added; pivaloyl chloride (26.5 g, 0.22 mol) was added dropwise at 0-10℃, after the dropwise addition was completed, the mixture was stirred and kept in the range of 0-10℃, and the sample was tested by weight content. When the test results showed that 2-aminothiazole-4-carboxylic acid / (2-aminothiazole-4-carboxylic acid+compound 1)≤1%, the reaction was complete; 2-chloro-6-methylaniline (14.2 g, 0.1 mol) was added, the temperature was controlled at 0-10℃, and the reaction was kept, and the sample was tested by weight content. When the test results showed that compound 1 / (compound 1+compound 2)≤1.0%, the reaction was completed;

[0054] S1-2: To the reaction solution, 20% sodium hydroxide aqueous solution (50 g, 0.25 mol) was added dropwise, and the temperature was raised to 55°C, and the reaction was kept at this temperature. When the assay results showed that the weight content of compound 2 / (compound 2 + 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide) was ≤1.0%, the reaction was stopped. The pH was adjusted to 6.2 using hydrochloric acid, and the temperature was lowered to 25°C. The solid was collected by filtration and washed with water to obtain a crude product;

[0055] S1-3: Under nitrogen protection, the crude product prepared in step S1-2 and 100 ml of isopropyl acetate were added to the reaction device, and the temperature was raised to 75°C. After the solution was clear, the temperature was lowered to 2°C, and the solid was collected by filtration. The obtained wet solid was dried under reduced pressure to obtain 25.8 g of product. The HPLC results are shown in Table 1, wherein the purity of the target product 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide is 99.9%, and the molar yield is 96.0%. Figure 1

[0056] Examples 2-4 are based on Example 1, only the type of acid binding agent is changed, and other conditions remain unchanged.

[0057] The data of different acid binding agents, product yield and purity in Examples 1-5 are as follows:

[0058] Group Reaction base Yield (%) Purity (%) Example 1 N-methylmorpholine 96.0 99.9 Example 2 Triethylamine 92.6 99.7 Example 3 Diisopropylethylamine 92.5 99.6 Example 4 Pyridine 91.3 99.8 Example 5 N,N-dimethylaniline 93.2 99.5

[0059] Examples 6-12 differ from Example 1 only in that the reaction temperature in step S1-2 is different, and other conditions remain unchanged. The specific reaction conditions and product yield and purity data are as follows:

[0060] Group Step S1-2 reaction temperature Yield (%) Purity (%) Example 6 5 -(unreacted) - Example 7 10 85.6 97.2 Example 8 30 88.3 98.2 Example 9 50 93.6 99.6 Example 10 60 95.3 99.5 Example 11 80 89.0 99.1 Example 12 100 76.0 98.2 Example 1 55 96.0 99.9

[0061] From the above data, it can be seen that the optional reaction temperature is 10-100°C, and preferably 50-60°C.

[0062] Examples 13-16 differ from Example 1 only in that the selection of the crystallization solvent in step S1-3 is different, and other conditions remain unchanged. The specific selection of the crystallization solvent and the product yield and purity data are as follows:

[0063] Group Step S1-3 crystallization solvent Yield (%) Purity (%) Example 13 Ethanol 89.1 99.7 Example 14 Tetrahydrofuran 86.6 99.8 Example 15 Isopropanol 91.9 99.6 Example 16 Ethyl acetate 92.5 99.6 Example 1 Isopropyl acetate 96.0 99.9

[0064] From the above data, it can be seen that the crystallization solvent in step S1-3 can be selected from one of ethanol, tetrahydrofuran, isopropyl alcohol, ethyl acetate and isopropyl acetate, and isopropyl acetate is preferred.

[0065] ​Examples 17-19 differ from Example 1 only in that the molar ratio of 2-aminothiazole-4-carboxylic acid to pivaloyl chloride is different.

[0066]

[0067] The above data show that the molar ratio of 2-aminothiazole-4-carboxylic acid to pivaloyl chloride in 1:(2-4) all have good yield and purity, but 1:2.2 is the best.

[0068] Examples 20-21 differ from Example 1 only in that the molar ratio of 2-aminothiazole-4-carboxylic acid to 2-chloro-6-methylaniline is different.

[0069]

[0070] The above data show that the molar ratio of 2-aminothiazole-4-carboxylic acid to 2-chloro-6-methylaniline in 1:(1-2) all have good yield and purity, but 1:1 is the best, and the cost of raw materials is the lowest.

[0071] Comparative Example 1

[0072] This comparative example is to repeat the technical solutions of CN106279061, 2017, A and Synthetic Communications, 2017, vol. 47, #17, p. 1610-1621:

[0073]

[0074] S1-S2: according to the preparation method of CN106279061, 2017, A

[0075] S1: In reaction bottle 1, 2-tert-butoxycarbonylaminothiazole-5-carboxylic acid (50 g, 0.20 mol), dichloromethane (1 L), N,N-dimethylformamide (1.5 g, 0.02 mol) and sulfurous chloride (48 g, 0.4 mol) were added in sequence, heated to 40°C for 1 hour, until 2-tert-butoxycarbonylaminothiazole-5-carboxylic acid was less than 1%, and the dichloromethane was removed under reduced pressure, and then chlorobenzene (800 ml) was added to dissolve, ready for use.

[0076] S2-1: In reaction bottle 2, pyridine (81 g, 1.0 mol), 2-chloro-6-methylaniline (24 g, 0.17 mol) and chlorobenzene (150 ml) were added, heated to 90-100°C, and the solution in reaction bottle 1 was added dropwise, about 35 minutes to drop, then reacted at 90-100°C until 2-chloro-6-methylaniline was less than 0.5%.

[0077] S2-2: After the reaction, the system was cooled to 0-10°C, and stirred at this temperature for 2 hours. Filtration gave the crude product as a light yellow solid. The solid was slurried with 150 ml of 2% sodium hydroxide aqueous solution and 250 ml of methanol for 3 hours. Filtration and drying of the solid at 50°C gave a white solid 52 g, yield 80%, HPLC purity 98.12%.

[0078] S3: Preparation according to [Synthetic Communications, 2017, vol. 47, #17, p. 1610-1621]:

[0079] Reaction flask 3 was charged with trifluoroacetic acid (250.0 ml), (5-(((2-chloro-6- methylphenyl)carbamoyl)thiazol-2-yl)carbamic acid tert-butyl ester (25.0 g, 0.07 mol) was added with stirring and stirred at 25-30°C for 2 hours. Completion of the reaction was confirmed by HPLC, trifluoroacetic acid was distilled off and the residue was diluted with ethyl acetate (250.0 ml). The ethyl acetate layer was washed with saturated NaHC03solution (2 X 25.0 ml) and then with saturated NaCl solution (125.0 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated, crystallized with methyl tert-butyl ether (250.0 ml) to give compound 1 (16.2 g, 89%). On testing, the HPLC purity was 97.56%.

[0080] The results of the comparative experiments show that, according to the preparation methods of Chinese patent CN106279061A and [Synthetic Communications, 2017, vol. 47, #17, p. 1610-1621], the intermediate 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide of dasatinib is obtained. The total yield of the three-step reaction is only 71.2% and the purity is 97.5%, which is far lower than the process of the mixed anhydride formed by pivaloyl chloride used in the present application, further illustrating that the technical effect of the present application has a major improvement and innovation compared with the prior art.

[0081] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the synthesis of a dasatinib intermediate, said dasatinib intermediate being 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide, characterized in that, The method comprises the following steps: Step one, preparing compound 1 shown in formula I by reacting 2-aminothiazole-4-carboxylic acid and pivaloyl chloride; Step two, preparing compound 2 shown in formula II by reacting compound 1 shown in formula I with 2-chloro-6-methylaniline; Step three, preparing 2-amino-N-(2-chloro-6-methylaniline)thiazole-5-formamide by hydrolyzing compound 2 shown in formula II; I： II:

2. The method of synthesis of dasatinib intermediate as claimed in claim 1 wherein, In step one, 2-aminothiazole-4-carboxylic acid is added into tetrahydrofuran under nitrogen atmosphere, stirred and cooled to 0-10 DEG C, acid-binding agent is added, pivaloyl chloride is added dropwise under insulation, and the reaction is completed after the dropwise addition is completed, so that a reaction solution containing compound 1 shown in formula I is obtained.

3. The method for synthesizing the dasatinib intermediate as described in claim 2, characterized in that, The acid-binding agent comprises any one of triethylamine, diisopropyl ethylamine, pyridine and N-methyl morpholine.

4. The method for synthesizing the dasatinib intermediate as described in claim 2, characterized in that, In step one, the reaction completion is determined by sampling and detecting, and when 2-aminothiazole-4-carboxylic acid / (2-aminothiazole-4-carboxylic acid+compound 1)≤1% is calculated by weight content, the reaction is completed.

5. The method for synthesizing the dasatinib intermediate as described in claim 2, characterized in that, In step two, the reaction completion is determined by sampling and detecting, and when compound 1 / (compound 1+compound 2)≤1% is calculated by weight content, the reaction is completed.

6. The method of synthesis of dasatinib intermediate as claimed in claim 5 wherein, In step three, the reaction completion is determined by sampling and detecting, and when compound 2 / (compound 2+2-amino-N-(2-chloro-6-methylaniline)thiazole-5-formamide)≤1% is calculated by weight content, the reaction is completed.

7. The method for synthesizing the dasatinib intermediate as described in claim 5, characterized in that, In step three, the reaction completion is determined by sampling and detecting, and when compound 2 / (compound 2+2-amino-N-(2-chloro-6-methylaniline)thiazole-5-formamide)≤1% is calculated by weight content, the reaction is completed.

8. The method for synthesizing the dasatinib intermediate as described in claim 7, characterized in that, Step four, the 2-amino-N-(2-chloro-6-methylaniline)thiazole-5-formamide obtained in step three is mixed with a crystallization solvent, heated to 70-80 DEG C, stirred until the solution is clear, then cooled to 0-5 DEG C, and the solid is collected by filtration to obtain refined 2-amino-N-(2-chloro-6-methylaniline)thiazole-5-formamide.

9. The process for synthesis of dasatinib intermediate as claimed in claim 1, wherein, The crystallization solvent comprises one of ethanol, tetrahydrofuran, isopropyl alcohol, ethyl acetate and isopropyl acetate.

10. The method for synthesizing the dasatinib intermediate as described in claim 9, characterized in that, ​

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