CN111303142A - Preparation method of dasatinib monohydrate - Google Patents
Preparation method of dasatinib monohydrate Download PDFInfo
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- CN111303142A CN111303142A CN202010251116.8A CN202010251116A CN111303142A CN 111303142 A CN111303142 A CN 111303142A CN 202010251116 A CN202010251116 A CN 202010251116A CN 111303142 A CN111303142 A CN 111303142A
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Abstract
The invention provides a preparation method of dasatinib monohydrate, which is used for obtaining dasatinib monohydrate by reacting dasatinib in an ethanol water solution. The technical scheme provided by the invention can obtain the high-quality dasatinib monohydrate, avoids complicated separation and purification steps, is simple to operate, avoids the waste of raw materials, reduces the production cost, and is more suitable for industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of dasatinib monohydrate.
Background
Dasatinib monohydrate has the chemical name of N- (2-chloro-6-methylphenyl) -2- [ [6- [4- (2-hydroxyethyl) -1-piperazinyl ] -2-methyl-4-pyrimidinyl ] amino ] -5-thiazolecarboxamide (monohydrate) and the structural formula as follows:
dasatinib (Dasatinib) is a potent tyrosine kinase multi-target inhibitor, another drug used in imatinib-resistant and intolerant chronic phase of CML following nilotinib. Compared with imatinib and nilotinib which aim at a single target of Bcr-Abl fusion protein, dasatinib belongs to a multi-target drug and has an effect on 5 key oncogenic tyrosine protein kinases. The product was first developed by the company Mitsui Mei Shi Guibao, approved for the market in the United states in 2006-6, and marketed in the European Union in 11 months. The existing synthetic route of dasatinib is as follows.
One is document J. Med. Chem. 2004, 47, 6658-; the route provided in J. Med. Chem. 2006, 49, 6819-6832 is as follows
The process has the disadvantages that the reaction conditions are harsh, the yield is high, sodium hydride is required in the process, the reaction conditions are harsh, the process is only suitable for laboratory scale production, and the process is not suitable for industrial production in commercial scale production (kilogram level), so that people are still continuously exploring a new synthesis route.
Another way disclosed for patent CN200580011916.6 is as follows:
in order to solve the problem that the content of byproducts is high under the conditions of high temperature and strong alkali of a compound II and 4, 6-dichloro-2-methylpyrimidine, DIEA with weak alkalinity is selected as an alkaline reagent by controlling different reaction conditions, so that the reaction temperature is reduced, the generation of the byproducts is reduced, the yield of a main product compound is reduced, the catalyst is expensive, and the cost is increased.
Disclosure of Invention
In view of the above disadvantages of the prior art, the present invention aims to provide a method for preparing dasatinib monohydrate, which is used to solve the problems of the prior art that the reaction conditions for preparing dasatinib monohydrate are harsh, the cost is high, the dasatinib monohydrate is not easy to purify, and the method is not suitable for industrial mass production.
To achieve the above objects and other related objects, the present invention is achieved by the following technical solutions.
The invention firstly claims a preparation method of dasatinib monohydrate, wherein dasatinib reacts in an ethanol aqueous solution to obtain dasatinib monohydrate, and the reaction route is as follows:
according to the preparation method of the dasatinib monohydrate, dasatinib is added into an ethanol water solution and heated and refluxed until the dasatinib is completely dissolved, inorganic impurities are removed by filtration while the dasatinib is hot, then the temperature is reduced to a temperature suitable for generating crystal water, the temperature is reduced until products are completely separated out, and the dasatinib monohydrate is obtained through post-treatment.
According to the preparation method of dasatinib monohydrate, the concentration of the ethanol aqueous solution can be set according to needs, and preferably, the ethanol aqueous solution with the concentration of at least 60 wt% is adopted.
According to the preparation method of dasatinib monohydrate, the volume ratio of dasatinib to ethanol aqueous solution is 1: (1-20). In the volume ratio interval, the raw materials can be completely dissolved, and the post-treatment process only needs cooling crystallization if the solvent amount is less than 1: 20, may result in incomplete formation of the monohydrate.
According to the preparation method of the dasatinib monohydrate, the dasatinib is heated to 70-80 ℃ until the dasatinib is completely dissolved. In the temperature range, the product can be ensured to completely form monohydrate, partial product does not form monohydrate when the temperature is lower than 70 ℃, no influence on the reaction result is caused when the temperature is higher than 80 ℃, but the energy consumption required by the reaction is increased and the difficulty in subsequent treatment and temperature reduction is increased.
According to the preparation method of the dasatinib monohydrate, the dasatinib monohydrate is heated to 70-80 ℃ and kept for 1-5 hours. In the time interval, the products can be ensured to be completely monohydrate, and some products can be not monohydrate when the temperature is lower than 1 h; and after more than 5h, there will be some monohydrate product again, for example after 10-15h, increasing to 1.5 hydrate.
According to the preparation method of dasatinib monohydrate, the temperature of the reaction system is reduced to 50-60 ℃ to a temperature suitable for generating crystal water. The temperature plays an important role in the reaction progress in the preparation method of dasatinib monohydrate, and under the condition that other reaction conditions are not changed, the reaction temperature is over 60 ℃ or below 50 ℃ to greatly influence the formation of crystal water, and more preferably, the temperature is reduced to 55 ℃ as the product temperature.
According to the preparation method of the dasatinib monohydrate, the temperature is reduced to 50-60 ℃, and then the reaction system is kept for at least 8 hours, preferably 8-12 hours. The time in the preparation method of the dasatinib monohydrate plays an important role in the progress of the reaction, the reaction time is 4 hours under the condition that other reaction conditions are not changed, and only 0.5 crystal water can be formed when the reaction temperature is 55 ℃; the water of crystallization gradually increases with the reaction time.
According to the preparation method of the dasatinib monohydrate, the temperature is reduced by adopting a natural cooling mode. And then the temperature is reduced to the product temperature which is less than or equal to the room temperature. Preferably, the temperature is further reduced to 5-15 ℃ when the temperature of the reaction system is further reduced. More preferably, the temperature is further decreased to a temperature of 10 ℃ in the reaction system. Preferably, the temperature is reduced to 5-15 ℃ and then kept for at least 2h, so that the product is completely separated out.
According to the preparation method of the dasatinib monohydrate, cooling is accompanied by stirring.
According to the preparation method of dasatinib monohydrate, the post-treatment includes multiple steps of filtering, washing and drying. Preferably, the washing is to wash the filter cake with an aqueous ethanol solution, specifically, to wash the filter cake with an aqueous ethanol solution with a mass fraction of 50 wt%. More preferably, the volume of the ethanol aqueous solution is 1-2 times of that of the dasatinib. More preferably, the drying temperature is 50-60 ℃.
The structural formula of dasatinib described in the application is shown as formula II:
according to the preparation method of the dasatinib monohydrate, the dasatinib is generated by reacting a compound shown as a structural formula I with a compound a and a compound b, and the synthetic route is as follows:
according to the preparation method of dasatinib monohydrate, in the preparation of dasatinib, the reaction is carried out in the presence of an acid-binding agent. The acid-binding agent can neutralize hydrogen chloride generated in the final reaction process in the reaction, so that the reaction is better converted to a target product. Preferably, the acid scavenger is any one or more selected from triethylamine, diisopropylamine, pyridine, potassium carbonate and tri-n-butylamine.
According to the preparation method of the dasatinib monohydrate, in the preparation of dasatinib, the molar ratio of the acid-binding agent to the compound shown in the formula I is (2.5-8): 1. In the molar ratio interval, the reaction can be ensured to be carried out under the alkaline condition, otherwise, the raw materials cannot be completely reacted, the yield is influenced, and the purification difficulty is improved. More preferably, the molar ratio of the acid-binding agent to the compound shown in the formula I is 6: 1.
According to the preparation method of dasatinib monohydrate, in the preparation of dasatinib, the reaction is carried out in a reaction medium, and the reaction medium is an organic solvent. Preferably, the organic solvent is selected from one or more of acetonitrile, n-butanol, toluene and 1, 4-dioxane.
According to the preparation method of dasatinib monohydrate, in the preparation of dasatinib, the molar ratio of the compound shown as the structural formula I to the compound a is 1: (1.0-1.2). In this molar ratio range, the reaction proceeds smoothly, the amount of by-products is small, if the molar equivalent of the compound a is less than 1.0, the raw material remains, and if the molar equivalent of the compound a is greater than 1.2, the amount of by-products increases, which increases the difficulty of purification. More preferably, the molar ratio of the compound of formula I to compound a is 1: 1.05.
according to the preparation method of dasatinib monohydrate, the reaction time is 5-10 hours in the preparation of dasatinib. If the reaction time is longer than 5h, the raw materials can be reacted completely, and if the amplification effect exists in the factory amplification production, the reaction time is prolonged, and the reaction can be continued until the raw materials are completely reacted.
According to the preparation method of dasatinib monohydrate, in the preparation of dasatinib, the molar ratio of the compound represented by the structural formula I to the compound b is 1: (1.0-4.0). The reaction can be normally carried out in the molar ratio range; less than 1.0 molar equivalent of compound b leaves starting material that cannot be fully reacted; when the compound b is more than 4.0 molar equivalents, the by-products are increased, and the purification difficulty is increased. The reaction speed is relatively higher and the reaction yield is stable when the reaction speed is 2.5, and the treatment is simple. More preferably, the molar ratio of the compound of formula I to compound a is 1: 2.5.
according to the preparation method of the dasatinib monohydrate, the reaction temperature is 70-120 ℃ in the preparation of dasatinib. In this temperature range, the reaction can be smoothly and efficiently carried out, and if the temperature is lower than 70 ℃, the reaction speed is reduced, and the reaction temperature is lower than 40 ℃, and the reaction is basically not carried out.
According to the preparation method of dasatinib monohydrate, the reaction time is 5-10 hours in the preparation of dasatinib.
According to the preparation method of dasatinib monohydrate, the preparation method further comprises a post-treatment step in the preparation of dasatinib, wherein the post-treatment step comprises multiple steps of separation, filtration, washing or drying. More preferably, the separation is a quenching of the reaction with water, more preferably, the volume of water is at least 8 times the volume of the compound of formula I. More preferably, the washing is an ethanol wash cake. More preferably, the volume of the ethanol is 1-2 times of that of the compound shown in the structural formula I. More preferably, the drying is drying in a forced air oven. More preferably, the drying temperature is 50-60 ℃.
The technical scheme of the invention has the beneficial effects that:
the technical scheme provided by the invention can obtain the high-quality dasatinib monohydrate, avoids complicated separation and purification steps, is simple to operate, avoids the waste of raw materials, reduces the production cost, and is more suitable for industrial production.
Drawings
FIG. 1 is a scheme for the preparation of intermediate compound II in the examples
FIG. 2 is a preparation route of dasatinib monohydrate
FIG. 3 is a crude dasatinib purity profile in the examples
FIG. 4 is an example dasatinib monohydrate purity profile
Detailed Description
The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Test methods in which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the respective manufacturers.
When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
The compounds of formula I in the present application are prior art and can be obtained according to the following documents: friedrich C, Arnulf V, the chemistry of high-energy phosphors III, preparation of isothiourea phosphors and phosphors [ J ]. Chemische Berichte,1958,91: 919-.
In an exemplary embodiment of the present application, synthesis is performed using the route shown in fig. 1, with the following specific steps.
(1) Preparation of intermediate Compound II
N2Under protection, compound a (1.3KG,4.84mol) was weighed into a mechanically stirred 20L three-necked flask, 7.5L acetonitrile was added, stirred uniformly, compound I (752g,4.61mol) was added, potassium carbonate (3.8KG,27.66mol) was slowly added in portions, and stirred at room temperature for 4 hours. Then adding the compound b (1.5KG,11.5mol), heating and refluxing for 6 hours, cooling to room temperature, slowly adding 6.4L of water, stirring and centrifuging, washing and filtering a cake with 800ml of ethanol, and drying at 55 ℃ to obtain 1.83KG of white solid, wherein the yield is as follows: 81.3%, purity: 99.3 percent.
The analysis method of the intermediate compound II of the product of the step is as follows:
1. purity detection HPLC analysis method
1.1 instruments
HPLC, LC-20A, with UV detector
1.2 reagents
Acetonitrile (chromatographic grade)
Phosphoric acid (AR grade)
Child-haha pure water
1.3 preparation of sample solution
An appropriate amount of sample was weighed and dissolved in 20% acetonitrile/water to a sample concentration of about 0.5 mg/ml.
1.4 mobile phase arrangement
Phase A: 0.01% H3PO4/H2O
600mL of water is added into a 1L volumetric flask, 0.1mL of phosphoric acid is transferred into the volumetric flask, and water is added for dilution to a constant volume and is fully and uniformly mixed.
Phase B: acetonitrile
1.5 chromatographic conditions
1.6 System Adaptation
The blank is clean and there is no interference where the appearance of the main peak is unknown. (the signal-to-noise ratio of the interference peak is less than 10 or the interference peak area is less than the peak area of the main peak in the sensitivity solution, namely no interference is considered)
The signal-to-noise ratio S/N of the main peak in the sensitivity solution is ≧ 10.
1.7 calculation of results
And calculating the purity of the sample according to a peak area normalization method, and taking the average value of the two measurement results to report the final result if the RSD between the measurement results of each time is less than or equal to 2.0%.
(2) Preparation of compounds of formula III
The intermediate compound of formula II prepared above (1.3k g, 1V) and 80% aqueous ethanol (13L, 10V) were added to a 20.0L three-necked flask with mechanical stirring, followed by heating to 80 ℃ and a clearing reaction for 2 hours. When the temperature is reduced to 55 ℃, a small amount of solid is separated out and reacts for 10 hours. Cooling to 10 ℃, stirring for 2 hours, centrifuging, washing a filter cake with 1.3L of 50% ethanol, and drying at 55 ℃ to obtain 1.3kg of white solid, wherein the yield is as follows: 96.44%, purity: 99.88 percent.
The detection results of the final product determined as monohydrate in the examples of the present application are as follows:
through TGA (thermogravimetric analysis) detection, the weight loss rate of the monohydrate (theoretical weight loss rate of 3.56%) is confirmed to be 3.65% at 50-175 DEG C
The nuclear magnetic characterization results of dasatinib and the monohydrate thereof in the present example are as follows: HNMR (400MHz, DMSO-d6) ppm delta: 2.25(s, 3H, CH)3)，2.41(s，3H，CH3)，2.43(t，J＝6.2Hz，2H)，2.49(t，4H，CH2)，3.52～3.53(m，4H，CH2)，3.54～3.55(m，2H，CH2)，6.06(s，1H，CH)，7.27～7.28(m，1H，CH)，7.29～7.31。(m，1H，CH)，7.40(d，J＝7.5Hz，1H)，8.22(s，1H，CH)，9.85(s，1H，NH)。
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. The preparation method of the dasatinib monohydrate is characterized in that dasatinib reacts in an ethanol water solution to obtain the dasatinib monohydrate, and the reaction route is as follows:
2. the preparation method of dasatinib monohydrate according to claim 1, characterized by adding dasatinib into an aqueous ethanol solution, heating and refluxing until the dasatinib is completely dissolved, filtering while the solution is hot to remove inorganic impurities, then cooling the reaction system to a temperature suitable for generating crystal water, then cooling the reaction system until the product is completely precipitated, and then carrying out post-treatment to obtain dasatinib monohydrate.
3. The preparation method of dasatinib monohydrate according to claim 2, characterized by heating to a temperature of 70-80 ℃ in the reaction system to keep dasatinib completely dissolved; and/or the concentration of the ethanol water solution is not less than 60 wt%; and/or the volume ratio of the dasatinib to the ethanol aqueous solution is 1: (1-20).
4. The method for preparing dasatinib monohydrate according to claim 2, wherein the temperature of the reaction system is reduced to 50-60 ℃ to a temperature suitable for generating crystal water; and/or cooling to 5-15 ℃ when the temperature of the reaction system is reduced; and/or the temperature reduction is accompanied by stirring; and/or the post-treatment comprises a plurality of filtering, washing and drying.
5. The method for preparing dasatinib monohydrate according to claim 3, characterized in that the temperature of the reaction system is heated to 70-80 ℃ for 1-5 hours.
6. The preparation method of dasatinib monohydrate according to claim 4, characterized in that the temperature is reduced to 50-60 ℃ and then kept for at least 8 hours; and/or cooling the reaction system to 5-15 ℃ and keeping the temperature for at least 2 h.
7. The process for preparing dasatinib monohydrate according to claim 1, which comprises reacting a compound represented by the formula i with a compound a and a compound b, wherein the synthetic route is as follows:
8. the process for the preparation of dasatinib monohydrate according to claim 7, characterized in that the reaction is carried out in the presence of an acid scavenger; and/or the reaction is carried out in a reaction medium, wherein the reaction medium is an organic solvent; and/or further comprising a post-treatment step comprising a plurality of separating, filtering, washing or drying.
9. The process for preparing dasatinib monohydrate according to claim 7, wherein the molar ratio of the compound represented by the formula i to the compound a is 1: (1.0-1.2); and/or the molar ratio of the compound represented by the formula I to the compound b is 1: (1.0-4.0); the reaction time is 5-10 h; and/or the reaction temperature is 70-120 ℃.
10. The process for preparing dasatinib monohydrate according to claim 8, wherein the acid scavenger is any one or a combination of more selected from triethylamine, diisopropylamine, pyridine, potassium carbonate, and tri-n-butylamine; and/or the molar ratio of the acid-binding agent to the compound of the formula I is (2.5-8) to 1; and/or the organic solvent is selected from one or more of acetonitrile, n-butanol, toluene and 1, 4-dioxane.
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2020
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| WO2010139980A1 (en) * | 2009-06-03 | 2010-12-09 | Generics [Uk] Limited | Process for preparing crystalline dasatinib monohydrate |
| CN103059013A (en) * | 2011-10-18 | 2013-04-24 | 北京本草天源药物研究院 | New crystal of Dasatinib monohydrate and preparation method thereof |
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