WO2022127327A1 - Bosutinib 1,3-propanediether dimer impurity and preparation method therefor - Google Patents

Abstract

Disclosed in the present invention are a bosutinib 1,3-propanediether dimer impurity and a synthesis process thereof. The synthesis process is simple, the purity is high, raw materials are simple and easy to obtain, the purity of a prepared finished product can reach 99% or above, and a qualified impurity reference substance can be provided for quality control of bosutinib.

Description

A kind of bosutinib 1,3-propanediether dimer impurity and preparation method thereof technical field

The invention relates to the technical field of medicines, in particular to a bosutinib 1,3-propanediether dimer impurity and a preparation method thereof.

Background technique

The type and content of impurities in a drug have a significant impact on the efficacy and safety of the drug. Therefore, a comprehensive analysis of the drug impurity profile must be carried out during the process of drug process development. The impurity profile is a general description of all known and unknown impurities present in a drug product, including not only identified impurities (that is, impurities whose structural characteristics have been confirmed), specific impurities (that is, those that are specified in the specification and have their own limits) Standard identified or unidentified impurities), but also potential impurities (that is, impurities that may be theoretically speculated to be generated during production or storage, but not necessarily present in actual products).

Bosutinib Chemical Name: 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperidine oxazine) propoxy]-3-quinolinecarbonitrile, Cas NO:380843-75-4, has the chemical structure shown in the following formula:

Bosutinib (SKI 606), developed by Wyeth Pharmaceuticals, is a potent dual inhibitor of protein kinase Src/Abl. Bosutinib was approved by the FDA on September 4, 2012 for the treatment of adults with chronic, accelerated, or blast phase Philadelphia chromosome-positive chronic myeloid leukemia (CML) that is resistant or intolerant to prior therapy affected patients. Trade name: Bosulif. Most people with CML have a genetic mutation in the Philadelphia chromosome that causes the bone marrow to produce tyrosine kinase, an enzyme that triggers the bone marrow to produce too many malformed, unhealthy white blood cells called granulocytes. Granulocytes fight infection. Bosutinib (Bosulif) works by blocking a tyrosine kinase signal that stimulates the bone marrow to accelerate the production of malformed and unhealthy granulocytes.

The commonly used synthetic route of bosutinib technology is as follows:

According to the existing bosutinib process synthesis route combined with impurity spectrum analysis, the structure of formula I of the present invention shows a potential process impurity in the bosutinib synthesis process, and the quality, safety and efficacy of the drug must be scientifically evaluated before it goes on the market. .

SUMMARY OF THE INVENTION

The object of the present invention is to provide a synthesis process of bosutinib process impurity formula I, the synthesis process is simple, the purity is high, the raw materials are simple and easy to obtain, and the qualified impurity reference substance can be provided for the quality control of bosutinib.

The specific technical solutions are as follows:

The preparation route of bosutinib 1,3-propanediether dimer impurities is as follows:

Specific steps are as follows:

1) After mixing and stirring formula II, DMAP, triethylamine, acetic anhydride and the reaction solvent, the reaction is stirred at room temperature, and the esterification reaction occurs to obtain formula III, and the reaction formula is as follows:

2) Formula IV can be obtained by reducing the formula III prepared in step 1) under the action of Pd/C and ammonium formate, and the reaction formula in step 2) is as follows:

3) Under the catalysis of triethyl orthoformate, the formula IV obtained in step 2) and formula V are added to generate formula VI, and step 3) reaction formula is as follows:

4) under the effect of phosphorus oxychloride, step 3) the obtained formula VI is cyclized and then hydrolyzed to generate formula VII, step 4) reaction formula is as follows:

5) Under the effect of potassium carbonate, the formula VII prepared in step 4) is coupled with 1,3-dibromopropane to obtain the target compound formula I, and the reaction formula in step 5) is as follows:

Wherein in step 1, the molar ratio of formula II, DMAP, triethylamine and acetic anhydride is 1:(0.2～0.5):(1.5～3):(1.5～3), the solvent is tetrahydrofuran, and the stirring is carried out at room temperature for 0.5～1.5h After the solvent was evaporated under reduced pressure, dichloromethane and water were added to wash, and the organic phase was washed with 1 mol/L dilute hydrochloric acid and 10% potassium carbonate aqueous solution in turn. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. dry solvent to obtain compound formula III.

Wherein in step 2, the mass ratio of formula III, ammonium formate and Pd/C (mass fraction 10%) is 1:(1.2～2):(0.15～0.4), the solvent is isopropanol and tetrahydrofuran, and the reaction is stirred at room temperature for 16～ 17h, filtered, the filtrate was concentrated under reduced pressure to obtain compound formula IV.

Wherein in step 3, the molar ratio of formula IV, triethyl orthoformate and formula V is 1:(3～4):(0.9～1.5), the solvent is isopropanol, the temperature is raised to reflux reaction for 5～6h, and cooled to After room temperature, filter and dry to obtain compound formula VI.

Wherein in step 4, the molar ratio of formula VI and phosphorus oxychloride is 1:(2～3), the reaction solvent is sulfolane, the reaction temperature is 100～110 ℃, after 10～17h of reaction, cooling to 0～5 ℃, adding The aqueous potassium hydroxide solution is stirred for 10-11 hours at room temperature, the reaction solution is washed twice with dichloromethane, the aqueous phase is collected, the pH of the aqueous phase is adjusted to 5-6, a large amount of solids are precipitated, filtered and dried to obtain compound formula VII, which can be used Column chromatography was used for further purification.

Wherein in step 5, the molar ratio of formula VII, 1,3-dibromopropane and potassium carbonate is 1:(0.5～1.2):(2～3), reaction solvent DMF, reaction temperature 50～55 ℃, reaction 12～ After 17 hours, adding an appropriate amount of water, stirring and crystallization, filtering and drying, the crude product of the target compound of formula I can be obtained, and the qualified product of the target compound can be obtained by further purification by column chromatography.

Beneficial technical effects:

The invention discloses a synthesis process of bosutinib 1,3-propanediether dimer impurities. The synthesis process is simple, the purity is high, the raw materials are simple and easy to obtain, the purity of the prepared product can reach more than 99%, and the To provide a qualified impurity reference for the quality control of bosutinib.

Description of drawings

Figure 1 is the liquid phase spectrum of the compound of formula I prepared in Example 1.

Figure 2 is the MS spectrum of the compound of formula I prepared in Example 1.

Figure 3 is the hydrogen spectrum of the compound of formula I prepared in Example 1.

Figure 4 is the carbon spectrum of the compound of formula I prepared in Example 1.

Detailed ways

The specific embodiments are described below by way of examples, and the above-mentioned contents of the present invention are further described in detail. However, it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples.

Example 1

1) Synthesis of formula III:

Add 5.0g of formula II, 50mL of tetrahydrofuran, 0.72g (0.2eq) of DMAP, 6.0g (2.0eq) of triethylamine, 6.0g (2.0eq) of acetic anhydride to a 250mL three-necked flask, stir at room temperature for 0.5-1.5h, and then reduce the pressure. The organic solvent was evaporated to dryness, 50 mL of dichloromethane and 50 mL of tap water were added, and the phases were separated. The organic phase was washed with 50 mL of 1M hydrochloric acid and 50 mL of 10% potassium carbonate aqueous solution. The organic phase was dried by adding 6.0 g of sodium sulfate, and the organic phase was evaporated to dryness to obtain 5.9 g (94.2%) of grey solid.

2) Synthesis of formula IV:

5.9g of formula III, 47mL of isopropanol, 47mL of THF, 7.0g of ammonium formate, 1.0g of Pd/C (10%) were added to a 250mL three-necked flask, stirred for 16-17h, filtered, rinsed with THF, evaporated to dryness under reduced pressure, 4.8 g (96.0%) of a yellow solid of formula IV (with a small amount of acetyl off product) were obtained.

3) Synthesis of formula VI:

Add 4.8g of formula IV, 11.8g (3eq) of triethyl orthoformate, 6.2g (0.9eq) of formula V, and 58mL of isopropanol to a 250mL three-necked flask with stirring and heating to reflux for 5-6h, cooling to room temperature and stirring for 2h, Filtered, rinsed with a small amount of isopropanol, and dried by blowing at 45° C. for 24 h to obtain 6.3 g (yield 61.2%) of formula VI.

4) Formula VII synthesis:

5.4g of formula VI and 43.2g of sulfolane (30.0eq) were added to a 250mL three-necked flask, heated to 100-110°C, and added dropwise.

3.7g of phosphorus oxychloride (2.0eq), cyclized at 100-110°C for 10-17h, cooled to 0-5°C in an ice bath, added with an aqueous solution of 8.1g KOH (12.0eq) and 175mL of water, the system was dissolved and stirred for 10 ~11h, pre-extracted twice with 50mL of dichloromethane, adjusted the pH of the aqueous phase to 5-6, a large amount of solid was precipitated, filtered, rinsed with an appropriate amount of water, and dried at 45°C for 24h by blasting to obtain 4.0g of brown solid, unpurified, directly Cast next.

5) Synthesis of formula I:

Add 4.00g of formula VII to a 500mL three-necked flask, add 1.05g (0.5eq) of 1,3-dibromopropane, 2.82g (2.0eq) of potassium carbonate, 105g of DMF, heat to 50～55℃ and react for 12～ After 15 h, 320 mL of water was added to precipitate a yellow solid, which was filtered, rinsed with an appropriate amount of water, and dried overnight at 45°C with air blowing.

Figure 1 is the HPLC chart of formula I obtained in Example 1, and it can be known that the purity of the target product is 99.5%.

Figures 2-4 are the mass spectrum, hydrogen spectrum and carbon spectrum of Formula I obtained in Example 1, respectively, and the following is the spectrum analysis:

Structure confirmation of bosutinib 1,3-propanediether dimer impurity compound

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

MS (ESI): 821.64 [M+H ⁺ ], see Figure 2.

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

proton number	Chemical shift (ppm)	multiplicity	number of protons
13,42	9.64	s	2
1,39	8.44	s	2
16,19,46,49	7.80	d	4
4,7,31,34	7.37	d	4
26,28	4.39	t	4
10,37	3.96	s	6
24,52	3.87	s	6
27	2.51	s	2

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

carbon number	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:

In a 250mL three-necked flask, add 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, stir at room temperature for 1-2h, evaporate under reduced pressure Dry the organic solvent, add 50 mL of dichloromethane and 50 mL of tap water, and separate the phases. The organic phase is washed with 50 mL of 1M hydrochloric acid and 50 mL of 10% aqueous potassium carbonate solution. The organic phase is dried by adding 6.0 g of sodium sulfate, and the organic phase is evaporated to dryness to obtain 5.5 g (88%) grey solid.

2) Synthesis of formula IV:

5.2g of formula III, 41mL of isopropanol, 41mL of THF, 9.36g of ammonium formate, 1.56g of Pd/C (10%) were added to a 250mL three-necked flask, stirred for 16h, filtered, rinsed with THF, and evaporated to dryness under reduced pressure to obtain 4.2 g (96.0%) of a yellow solid of formula IV (with a small amount of acetyl off product).

3) Synthesis of formula VI:

In a 250mL three-necked flask, add 4.2g of formula IV, 10.3g (3eq) of triethyl orthoformate, 6.0g (1eq) of formula V, and 50mL of isopropanol with stirring and heating to reflux for 5h, cooling to room temperature, stirring for 2h, filtration, and a small amount of Rinse with isopropanol, and dry at 45° C. for 24 h by air blowing to obtain 5.5 g (yield 61.2%) of formula VI.

4) Formula VII synthesis:

Add 4.7g formula VI and 37.6g sulfolane (30.0eq) to a 250mL three-necked flask, heat to 100-110°C, add dropwise

4.0g of phosphorus oxychloride (2.5eq), cyclized at 100-110°C for 10-17h, cooled to 0-5°C in an ice bath, added with an aqueous solution of 7.0g KOH (12.0eq) and 150mL of water, the system was dissolved and stirred for 10 ~11h, pre-extracted twice with 45mL of dichloromethane, adjusted the pH of the water phase to 5-6, a large amount of solid was precipitated, filtered, rinsed with an appropriate amount of water, and dried at 45°C for 24h by blasting to obtain 3.5g of brown solid, which was obtained by column chromatography Target product 1.0 g of formula VII.

5) Synthesis of formula I:

Add 0.88g of formula VII to a 50mL three-necked flask, add 0.46g (1.0eq) of 1,3-dibromopropane, 0.62g (2.0eq) of potassium carbonate, and 23g of DMF, heat to 50～55℃ and react for 15～ After 17 h, 70 mL of water was added to precipitate a yellow solid, which was filtered, rinsed with an appropriate amount of water, and dried overnight at 45°C with air blowing. 210 mg of the target product (Formula I) was obtained by column chromatography;

Example 3

1) Synthesis of formula III:

Add 15.0g of formula II, 150mL of tetrahydrofuran, 3.24g (0.3eq) of DMAP, 27.0g (2.0eq) of triethylamine, 27.0g (2.0eq) of acetic anhydride to a 500mL three-necked flask, stir at room temperature for 1-1.5h, and then reduce the pressure. The organic solvent was evaporated to dryness, 150 mL of dichloromethane and 150 mL of tap water were added, and the phases were separated. The organic phase was washed with 150 mL of 1M hydrochloric acid and 150 mL of 10% potassium carbonate aqueous solution. The organic phase was dried by adding 18.0 g of sodium sulfate, and the organic phase was evaporated to dryness to obtain 18.0 g (94.2%) of grey solid.

2) Synthesis of formula IV:

18.0g of formula III, 140mL of isopropanol, 140mL of THF, 36.0g of ammonium formate, 7.2g of Pd/C (10%) were added to a 250mL three-necked flask, stirred for 16-17h, filtered, rinsed with THF, evaporated to dryness under reduced pressure, 14.0 g (96.0%) of a yellow solid of formula IV was obtained.

3) Synthesis of formula VI:

In a 250mL three-necked flask, add 14.0g of formula IV, 45.8g (4eq) of triethyl orthoformate, 30.0g (1.5eq) of formula V, and 170mL of isopropanol with stirring and heating to reflux for 5h, cooling to room temperature, stirring for 2h, filtration, Rinse with a small amount of isopropanol, and blow dry at 45° C. for 24 hours to obtain 19.3 g (yield 64.0%) of formula VI.

4) Formula VII synthesis:

Add 18.0g of formula VI and 144.0g of sulfolane (30.0eq) to a 250mL three-necked bottle, heat to 100-110°C, dropwise add

18.5g of phosphorus oxychloride (3.0eq) was cyclized at 100-110°C for 16h, cooled to 0-5°C in an ice bath, and an aqueous solution of 27.0g KOH (12.0eq) and 583mL of water was added, the system was dissolved, stirred for 10h, and used 165mL of dichloromethane was pre-extracted twice, the pH of the water phase was adjusted to 5-6, a large amount of solid was precipitated, filtered, rinsed with an appropriate amount of water, and dried at 45°C for 24h to obtain 13.3g of brown solids. The target product 4.0 was obtained by column chromatography. Formula VII of g.

5) Synthesis of formula I:

Add 4.0g of formula VII to a 500mL three-necked flask, add 2.4g (1.2eq) of 1,3-dibromopropane, 4.2g (3.0eq) of potassium carbonate, 105g of DMF, heat to 50～55℃ and react for 15～ After 17 h, 320 mL of water was added to separate out a yellow solid, which was filtered, rinsed with an appropriate amount of water, and dried overnight at 45°C by blowing.

The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field of the present invention, without departing from the concept of the present invention, some simple deductions or substitutions can be made, which should be regarded as belonging to the protection scope of the present invention.

Claims (8)

1. A bosutinib 1,3-propanediether dimer impurity, characterized in that the compound structural formula is shown in formula I

   
2. A preparation method of bosutinib 1,3-propanediether dimer impurity compound as claimed in claim 1, wherein the preparation route is as follows:

   
3. preparation method according to claim 2, is characterized in that, concrete steps are:

   1) After mixing and stirring formula II, DMAP, triethylamine, acetic anhydride and the reaction solvent, the reaction is stirred at room temperature, and the esterification reaction occurs to obtain formula III, and the reaction formula is as follows:

   

   2) Formula IV can be obtained by reducing the formula III prepared in step 1) under the action of Pd/C and ammonium formate, and the reaction formula in step 2) is as follows:

   

   3) Under the catalysis of triethyl orthoformate, the formula IV obtained in step 2) and formula V are added to generate formula VI, and step 3) reaction formula is as follows:

   

   4) under the effect of phosphorus oxychloride, step 3) the obtained formula VI is cyclized and then hydrolyzed to generate formula VII, step 4) reaction formula is as follows:

   

   5) Under the effect of potassium carbonate, the formula VII prepared in step 4) is coupled with 1,3-dibromopropane to obtain the target compound formula I, and the reaction formula in step 5) is as follows:

   
4. The preparation method according to claim 3, wherein the molar ratio of formula II, DMAP, triethylamine and acetic anhydride in the step 1) is 1:(0.2～0.5):(1.5～3):( 1.5-3), the reaction solvent is tetrahydrofuran.
5. The preparation method according to claim 3, wherein the mass ratio of formula III, ammonium formate and Pd/C in the step 2) is 1:(1.2～2):(0.15～0.4), and the reaction solvent is isopropanol and tetrahydrofuran.
6. The preparation method according to claim 3, wherein the molar ratio of formula IV, triethyl orthoformate and formula V in step 3) is 1:(3-4):(0.9-1.5), and the reaction The solvent is isopropanol.
7. The preparation method according to claim 3, wherein the molar ratio of formula VI and phosphorus oxychloride in the step 4) is 1:(2～3), and the reaction solvent is sulfolane.
8. The preparation method according to claim 3, is characterized in that, the molar ratio of described step 5) formula VII, 1,3-dibromopropane and potassium carbonate is 1:(0.5～1.2):(2～3), The reaction solvent was DMF.

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