阅读说明：本技术 一种博舒替尼1,3-丙二醚类二聚体杂质及其制备方法 (Bosutinib 1, 3-propylene diether dimer impurity and preparation method thereof ) 是由 姚继明 许毅 王蓉蓉 黄辉 刘宏 于 2020-12-16 设计创作，主要内容包括：本发明公开了一种博舒替尼1,3-丙二醚类二聚体杂质及其合成工艺,该合成工艺简单,纯度高、原料简单易得,制备的成品纯度可以达到99％以上,能够为博舒替尼的质量控制提供合格的杂质对照品。(The invention discloses a bosutinib 1, 3-propylene diether dimer impurity and a synthesis process thereof, wherein the synthesis process is simple, the purity is high, the raw materials are simple and easy to obtain, the purity of a prepared finished product can reach more than 99%, and a qualified impurity reference substance can be provided for quality control of bosutinib.)

1. The bosutinib 1, 3-propylene diether dimer impurity is characterized in that the structural formula of the compound is shown as a formula I

2. A process for preparing bosutinib 1, 3-propanediol dimer impurity compound according to claim 1, wherein the preparation route is as follows:

3. the preparation method according to claim 2, comprising the following steps:

1) mixing and stirring a formula II, DMAP, triethylamine, acetic anhydride and a reaction solvent, and then stirring at room temperature for reaction, wherein an esterification reaction is carried out to obtain a formula III, wherein the reaction formula is as follows:

2) the formula III prepared in the step 1) is subjected to a reduction reaction under the action of Pd/C and ammonium formate to prepare a formula IV, and the reaction formula in the step 2) is as follows:

3) carrying out addition reaction on the formula IV prepared in the step 2) and the formula V under the catalysis of triethyl orthoformate to generate a formula VI, wherein the reaction formula in the step 3) is as follows:

4) under the action of phosphorus oxychloride, cyclizing the formula VI prepared in the step 3), and hydrolyzing to generate a formula VII, wherein the reaction formula in the step 4) is as follows:

5) coupling the formula VII prepared in the step 4) with 1, 3-dibromopropane under the action of potassium carbonate to prepare a target compound formula I, wherein the reaction formula in the step 5) is as follows:

4. the method according to claim 3, wherein the molar ratio of the compound of formula II, DMAP, triethylamine and acetic anhydride in step 1) is 1: (0.2-0.5): (1.5-3): (1.5-3), wherein the reaction solvent is tetrahydrofuran.

5. The process according to claim 3, characterized in that the mass ratio of formula III, ammonium formate and Pd/C of step 2) is 1: (1.2-2): (0.15-0.4), and the reaction solvent is isopropanol and tetrahydrofuran.

6. A production method according to claim 3, wherein the molar ratio of the triethyl orthoformate of formula iv to formula v of step 3) is 1: (3-4): (0.9-1.5) and the reaction solvent is isopropanol.

7. The preparation method according to claim 3, wherein the molar ratio of the formula VI to the phosphorus oxychloride in the step 4) is 1 (2-3), and the reaction solvent is sulfolane.

8. The preparation method according to claim 3, wherein the molar ratio of the formula VII, the 1, 3-dibromopropane and the potassium carbonate in the step 5) is 1 (0.5-1.2): (2-3) the reaction solvent is DMF.

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a bosutinib 1, 3-propylene diether dimer impurity and a preparation method thereof.

Background

The type and content of impurities in the drug have great influence on the curative effect and safety of the drug, so the drug impurity spectrum must be comprehensively analyzed in the process of drug process development. The impurity profile is a general description of all known and unknown impurities present in a pharmaceutical product and includes not only identified impurities (i.e., impurities for which structural characteristics have been confirmed), specific impurities (i.e., identified or unidentified impurities for which a quality standard specifies an examination and has its own limits), but also potential impurities (i.e., impurities that may theoretically be generated during production or storage and are not necessarily present in the actual product).

The chemical name of bosutinib is: 4- [ (2, 4-dichloro-5-methoxyphenyl) amino ] -6-methoxy-7- [3- (4-methyl-1-piperazine) propoxy ] -3-quinolinecarbonitrile, Cas NO:380843-75-4, having the chemical structure shown in the formula:

bosutinib (SKI 606), developed by Wyeth Pharmaceuticals, usa, is a potent dual protein kinase Src/Abl inhibitor. Bosutinib (Bosutinib) was FDA approved for the treatment of adult chronic, accelerated or catastrophe philadelphia chromosome positive Chronic Myelogenous Leukemia (CML), drug resistant or intolerant patients to previous treatments, on day 9, month 4 of 2012. Trade name: bosulif. Most CML patients have philadelphia chromosome gene mutations that result in bone marrow production of tyrosine kinases that trigger bone marrow production of excessive, malformed, unhealthy white blood cells, i.e., granulocytes. Granulocytes can fight infection. Bosutinib (Bosulif) acts by blocking the signal that tyrosine kinases stimulate bone marrow to accelerate the production of malformed unhealthy granulocytes.

The currently common synthetic route of the bosutinib process is as follows:

according to the existing bosutinib process synthetic route and impurity spectrum analysis, the structure shown in the formula I of the invention is a potential process impurity in the bosutinib synthetic process, and the scientific evaluation on quality, safety and efficiency is required before the medicine is on the market.

Disclosure of Invention

The invention aims to provide a synthesis process of bosutinib process impurity formula I, which is simple, high in purity, simple and easily available in raw materials, and capable of providing qualified impurity reference substances for quality control of bosutinib.

The specific technical scheme is as follows:

the preparation route of the bosutinib 1, 3-propylene diether dimer impurity is as follows:

the method comprises the following specific steps:

1) mixing and stirring a formula II, DMAP, triethylamine, acetic anhydride and a reaction solvent, and then stirring at room temperature for reaction, wherein an esterification reaction is carried out to obtain a formula III, wherein the reaction formula is as follows:

2) the formula III prepared in the step 1) is subjected to a reduction reaction under the action of Pd/C and ammonium formate to prepare a formula IV, and the reaction formula in the step 2) is as follows:

3) carrying out addition reaction on the formula IV prepared in the step 2) and the formula V under the catalysis of triethyl orthoformate to generate a formula VI, wherein the reaction formula in the step 3) is as follows:

4) under the action of phosphorus oxychloride, cyclizing the formula VI prepared in the step 3), and hydrolyzing to generate a formula VII, wherein the reaction formula in the step 4) is as follows:

5) coupling the formula VII prepared in the step 4) with 1, 3-dibromopropane under the action of potassium carbonate to prepare a target compound formula I, wherein the reaction formula in the step 5) is as follows:

wherein in the step 1, the mol ratio of the formula II, DMAP, triethylamine and acetic anhydride is 1: (0.2-0.5): (1.5-3): (1.5-3), stirring at room temperature for 0.5-1.5 h by taking tetrahydrofuran as a solvent, evaporating the solvent under reduced pressure, adding dichloromethane and water for washing, separating liquid, washing an organic phase by sequentially using 1mol/L dilute hydrochloric acid and 10% potassium carbonate aqueous solution, collecting an organic phase, drying by using anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain a compound shown in the formula III.

In step 2, the mass ratio of the formula III to ammonium formate to Pd/C (mass fraction of 10%) is 1: (1.2-2): (0.15-0.4), the solvent is isopropanol and tetrahydrofuran, stirring and reacting for 16-17 h at room temperature, filtering, and concentrating the filtrate under reduced pressure to obtain the compound IV.

Wherein in the step 3, the molar ratio of the triethyl orthoformate to the triethyl orthoformate in the formula IV is 1: (3-4): (0.9-1.5) and the solvent is isopropanol, heating to reflux reaction for 5-6 h, cooling to room temperature, filtering and drying to obtain the compound shown in the formula VI.

In the step 4, the molar ratio of the compound VI to phosphorus oxychloride is 1 (2-3), the reaction solvent is sulfolane, the reaction temperature is 100-110 ℃, the reaction is carried out for 10-17h, then the cooling is carried out to 0-5 ℃, a potassium hydroxide aqueous solution is added, the stirring reaction is carried out for 10-11 h at room temperature, the reaction solution is washed twice by dichloromethane, the water phase is collected, the pH value of the water phase is adjusted to 5-6, a large amount of solid is separated out, then the filtering and drying are carried out, and the compound VII can be obtained, and can be further purified by column chromatography.

In the step 5, the molar ratio of the formula VII, the 1, 3-dibromopropane and the potassium carbonate is 1 (0.5-1.2): (2-3) reacting with a reaction solvent DMF at the reaction temperature of 50-55 ℃ for 12-17 h, adding a proper amount of water, stirring, crystallizing, filtering, drying to obtain a crude product of the target compound I, and further purifying by column chromatography to obtain a qualified product of the target compound.

The beneficial technical effects are as follows:

the invention discloses a synthesis process of bosutinib 1, 3-propylene diether dimer impurities, which is simple in synthesis process, high in purity and easy to obtain raw materials, and the purity of a prepared finished product can reach more than 99%, so that a qualified impurity reference substance can be provided for quality control of bosutinib.

Drawings

FIG. 1 is a liquid phase diagram of the compound of formula I prepared in example 1.

FIG. 2 is a MS spectrum of the compound of formula I prepared in example 1.

FIG. 3 is a hydrogen spectrum of the compound of formula I prepared in example 1.

FIG. 4 is a carbon spectrum of the compound of formula I prepared in example 1.

Detailed Description

The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.

Example 1

1) Synthesis of formula III:

adding 5.0g of tetrahydrofuran shown in the formula II, 50mL into a 250mL three-necked bottle, stirring 0.72g (0.2eq) of DMAP, 6.0g (2.0eq) of triethylamine and 6.0g (2.0eq) of acetic anhydride at room temperature for 0.5-1.5 h, evaporating the organic solvent under reduced pressure, adding 50mL of dichloromethane and 50mL of tap water, carrying out phase separation, washing the organic phase with 50mL of 1M hydrochloric acid and 50mL of 10% aqueous solution respectively, adding 6.0g of sodium sulfate into the organic phase, drying, and evaporating the organic phase to obtain 5.9g (94.2%) of gray solid.

2) Synthesis of formula iv:

a250 mL three-necked flask was charged with 5.9g of formula III, 47mL of isopropanol, 47mL of THF, 7.0g of ammonium formate, 1.0g of Pd/C (10%) and stirred for 16-17 h, filtered, rinsed with THF, and the solvent was evaporated under reduced pressure to give 4.8g (96.0%) of a yellow solid of formula IV (with a small amount of acetyl groups removed).

3) Synthesized according to formula VI:

adding 4.8g of triethyl orthoformate shown in the formula IV, 11.8g (3eq) and 6.2g (0.9eq) of isopropanol shown in the formula V, 58mL into a 250mL three-neck flask, stirring, heating to reflux for 5-6 h, cooling to room temperature, stirring for 2h, filtering, rinsing with a small amount of isopropanol, and drying by blowing at 45 ℃ for 24h to obtain 6.3g (yield 61.2%) of formula VI.

4) Synthesis of formula vii:

5.4g of sulfolane of the formula VI, 43.2g (30.0eq) are added into a 250mL three-necked flask, heated to 100 ℃ and then added dropwise

3.7g of phosphorus oxychloride (2.0eq), cyclization at 110 ℃ for 10-17h, cooling to 0-5 ℃ in an ice bath, adding 8.1g of KOH (12.0eq) and 175mL of water solution, dissolving the system, stirring for 10-11 h, pre-extracting twice with 50mL of dichloromethane, adjusting the pH value of a water phase to 5-6, precipitating a large amount of solid, filtering, rinsing with proper amount of water, and blowing and drying at 45 ℃ for 24h to obtain 4.0g of brown solid which is not purified and directly fed into the next step.

5) The synthesis of formula I:

adding 4.00g of the formula VII into a 500mL three-necked bottle, adding 1.05g (0.5eq) of 1, 3-dibromopropane, 2.82g (2.0eq) of potassium carbonate and 105g of DMF, heating to 50-55 ℃, reacting for 12-15 h, adding 320mL of water, precipitating yellow solid, filtering, rinsing with appropriate amount of water, drying overnight by blowing at 45 ℃, and carrying out column chromatography to obtain 320mg of a target product (formula I).

FIG. 1 is an HPLC chart of formula I obtained in example 1, and it can be seen that the purity of the objective product is 99.5%.

FIGS. 2 to 4 are the mass spectrum, the hydrogen spectrum and the carbon spectrum, respectively, of formula I obtained in example 1, the following are the spectra:

confirmation of structure of bosutinib 1, 3-propylene diether dimer impurity compound

Mass Spectrometry (AGILENT API 150EX LC/MS Mass Spectroscopy, ESI (+), 75V)

MS(ESI)：821.64[M+H⁺]See fig. 2.

The nuclear magnetic hydrogen spectrum (H1-NMR) data are shown in figure 3.

The nuclear magnetic carbon spectrum (C13-NMR) data are shown in figure 4.

Number of carbon atoms	Chemical shift	Carbon atom species
			5,30	154.48	Quaternary carbon
12,41	153.06	Quaternary carbon
			17,48	151.33	Quaternary carbon
6,35	149.88	Quaternary carbon
			1,39	146.20	Tertiary carbon
3,32	136.64	Quaternary carbon
			15,43	130.32	Quaternary carbon
19,46	123.59	Tertiary carbon
			20,45	120.88	Quaternary carbon
14,44	117.41	Quaternary carbon
			8,33	114.03	Quaternary carbon
18,47	113.03	Quaternary carbon
			4,31	110.00	Tertiary carbon
16,19	102.35	Tertiary carbon
			7,34	86.81	Tertiary carbon
11,40	65.60	Quaternary carbon
			10,37	57.28	Primary carbon
24,52	56.74	Primary carbon
			26,28	55.39	Secondary carbon
27	28.64	Secondary carbon

Example 2

1) Synthesis of formula III:

a250 mL three-necked flask is charged with 5.0g of formula II, 50mL of tetrahydrofuran, 1.44g (0.4eq) of DMAP, 4.5g (1.5eq) of triethylamine, 6.0g (2.0eq) of acetic anhydride, stirred at room temperature for 1-2 h, the organic solvent is evaporated under reduced pressure, 50mL of dichloromethane and 50mL of tap water are added, the phases are separated, the organic phase is washed with 50mL of 1M hydrochloric acid and 50mL of 10% aqueous potassium carbonate solution, 6.0g of sodium sulfate is added to the organic phase for drying, and the organic phase is evaporated to dryness to obtain 5.5g (88%) of a gray solid.

2) Synthesis of formula iv:

a250 mL three-necked flask was charged with 5.2g of formula III, 41mL of isopropanol, 41mL of THF, 9.36g of ammonium formate, 1.56g of Pd/C (10% of the total), stirred for 16h, filtered, rinsed with THF, and the solvent was evaporated under reduced pressure to give 4.2g (96.0%) of a yellow solid of formula IV (with a small amount of deacetylated product).

3) Synthesized according to formula VI:

4.2g of formula IV, 10.3g (3eq) of triethyl orthoformate, 6.0g (1eq) of formula V and 50mL of isopropanol are added into a 250mL three-necked flask, stirred and heated to reflux for 5h, cooled to room temperature, stirred for 2h, filtered, rinsed by a small amount of isopropanol and dried by blowing at 45 ℃ for 24h to obtain 5.5g (yield 61.2%) of formula VI.

4) Synthesis of formula vii:

adding 4.7g of sulfolane (30.0eq) of the formula VI and 37.6g of sulfolane (30.0eq) into a 250mL three-neck flask, heating to 110 ℃ at 100-.

5) The synthesis of formula I:

adding 0.88g of the formula VII into a 50mL three-necked bottle, adding 0.46g (1.0eq) of 1, 3-dibromopropane, 0.62g (2.0eq) of potassium carbonate and 23g of DMF, heating to 50-55 ℃, reacting for 15-17 h, adding 70mL of water, separating out a yellow solid, filtering, rinsing with appropriate amount of water, drying overnight by blowing at 45 ℃, and carrying out column chromatography to obtain 210mg of a target product (formula I); HPLC purity 99.2%.

Example 3

1) Synthesis of formula III:

15.0g of tetrahydrofuran of the formula II, 150mL, 3.24g (0.3eq) of DMAP, 27.0g (2.0eq) of triethylamine and 27.0g (2.0eq) of acetic anhydride are added into a 500mL three-necked flask, the mixture is stirred at room temperature for 1-1.5 h, the organic solvent is evaporated under reduced pressure, 150mL of dichloromethane and 150mL of tap water are added, the phases are separated, the organic phase is washed with 150mL of 1M hydrochloric acid and 150mL of 10% aqueous potassium carbonate solution respectively, 18.0g of sodium sulfate is added into the organic phase for drying, and the organic phase is evaporated to dryness to obtain 18.0g (94.2%) of gray solid.

2) Synthesis of formula iv:

a250 mL three-necked flask is added with 18.0g of formula III, 140mL of isopropanol, 140mL of THF, 36.0g of ammonium formate and 7.2g of Pd/C (10%), stirred for 16-17 h, filtered, rinsed with THF, and the solvent is evaporated under reduced pressure to obtain 14.0g (96.0%) of a yellow solid of formula IV.

3) Synthesized according to formula VI:

14.0g of triethyl orthoformate of the formula IV, 45.8g (4eq) and 30.0g (1.5eq) of isopropyl alcohol of the formula V and 170mL are added into a 250mL three-necked flask, stirred and heated to reflux for 5h, cooled to room temperature and stirred for 2h, filtered, rinsed by a small amount of isopropyl alcohol and dried by blowing at 45 ℃ for 24h to obtain 19.3g (yield 64.0%) of the formula VI.

4) Synthesis of formula vii:

adding 18.0g of sulfolane (30.0eq) with the formula VI and 144.0g into a 250mL three-neck flask, heating to 110 ℃ and dropwise adding

18.5g of phosphorus oxychloride (3.0eq), cyclization at 110 ℃ for 16h, cooling to 0-5 ℃ in an ice bath, adding 27.0g of KOH (12.0eq) and 583mL of water solution, dissolving the system, stirring for 10h, pre-extracting twice with 165mL of dichloromethane, adjusting the pH value of the water phase to 5-6, separating out a large amount of solid, filtering, rinsing with proper amount of water, blowing and drying at 45 ℃ for 24h to obtain 13.3g of brown solid, and obtaining the target product 4.0g of the formula VII through column chromatography.

5) The synthesis of formula I:

adding 4.0g of the formula VII into a 500mL three-necked flask, adding 2.4g (1.2eq) of 1, 3-dibromopropane, 4.2g (3.0eq) of potassium carbonate and 105g of DMF, heating to 50-55 ℃, reacting for 15-17 h, adding 320mL of water, precipitating yellow solid, filtering, rinsing with appropriate amount of water, drying overnight by blowing at 45 ℃, and purifying the obtained solid by column chromatography to obtain 1.2g of a target product (formula I), wherein the HPLC purity is 99.1%.

The foregoing is a more detailed description of the invention, taken in conjunction with the specific preferred embodiments thereof, and it is not intended that the invention be limited to the specific embodiments described. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.