CN112608278A - Bosutinib 1, 4-piperazine dimer impurity and preparation method thereof - Google Patents
Bosutinib 1, 4-piperazine dimer impurity and preparation method thereof Download PDFInfo
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- CN112608278A CN112608278A CN202011487515.0A CN202011487515A CN112608278A CN 112608278 A CN112608278 A CN 112608278A CN 202011487515 A CN202011487515 A CN 202011487515A CN 112608278 A CN112608278 A CN 112608278A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
Abstract
The invention discloses a bosutinib 1, 4-piperazine 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 the prepared finished product can reach more than 96%, and a qualified impurity reference substance can be provided for quality control of bosutinib.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a bosutinib 1, 4-piperazine 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 synthesis process of the bosutinib 1, 4-piperazine dimer impurity comprises the following steps:
the preparation route is as follows:
the method comprises the following specific steps:
1) mixing 2- (3-chloropropoxy) -1-methoxy-4-nitrobenzene (formula II), Pd/C (mass fraction of 10%) and a reaction solvent, heating, and carrying out hydrogenation reaction at normal pressure to generate 3- (3-chloropropoxy) -4-methoxyaniline (formula III), wherein the reaction formula in step 1) is as follows:
2) carrying out addition reaction on the 3- (3-chloropropoxy) -4-methoxyaniline (formula III) prepared in the step 1) and 2-cyano-N- (2, 4-dichloro-5-methoxyphenyl) acetamide (formula IV) under the catalysis of triethyl orthoformate to generate (E) -3- (((3- (3-chloropropoxy) -4-methoxyphenyl) amino) -2-cyano-N- (2, 4-dichloro-5-methoxyphenyl) acrylamide (formula V), wherein the reaction formula in the step 2) is as follows:
3) under the action of phosphorus oxychloride, cyclizing the (E) -3- (((3- (3-chloropropoxy) -4-methoxyphenyl) amino) -2-cyano-N- (2, 4-dichloro-5-methoxyphenyl) acrylamide (formula V) prepared in the step 2) to generate 7- (3-chloropropoxy) -4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinoline-3-nitrile (formula VI), wherein the reaction formula of the step 3) is as follows:
4) coupling the 7- (3-chloropropoxy) -4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinoline-3-carbonitrile prepared in the step 3) with anhydrous piperazine under the action of potassium carbonate to prepare a target compound 7,7' - ((((piperazine-1, 4-diylbis (propane-3, 1-diyl)) bis (oxy)) bis (4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinoline-3-carbonitrile) (formula I), wherein the reaction formula in the step 4) is as follows:
wherein in the step 1), the mass ratio of the formula II to Pd/C (mass fraction of 10%) is 1: (0.2-0.5), selecting tetrahydrofuran as a reaction solvent, carrying out hydrogenation for 15-18 h at 50-55 ℃ under normal pressure, cooling to room temperature, filtering Pd/C, and concentrating the solvent under reduced pressure to constant weight to obtain the compound of formula III.
In the step 2), the molar ratio of the triethyl orthoformate to the formula IV is 1 (3-4) to 0.9-1.5, isopropanol is selected as a reaction solvent, the reaction is carried out for 5-6 hours after heating to reflux, a solid is precipitated after cooling to room temperature, and the formula V is obtained after filtering.
In the step 3), the molar ratio of the formula V to phosphorus oxychloride is 1 (3-5), sulfolane is selected as a reaction solvent, the reaction temperature is 100-105 ℃, the reaction is carried out for 16-18 h, the temperature is reduced to 0-5 ℃, then water is added for crystallization, and the formula VI is obtained by filtering.
In the step 4), the molar ratio of the anhydrous piperazine and the potassium carbonate in the formula VI is 1 (0.5-1) to (3.0-4.0), N-dimethylformamide is selected as a solvent, the reaction temperature is 100-105 ℃, the reaction is carried out for 6-10 hours, then the mixture is cooled to room temperature, water is added for crystallization, the mixture is filtered and dried to obtain a crude product in the formula I, and the crude product is purified by column chromatography to obtain a qualified product.
The beneficial technical effects are as follows:
the invention discloses a synthesis process of bosutinib 1, 4-piperazine 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 96%, 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 12.0g of formula II, 2.7g of 10% wet Pd/C (mass fraction of 10%) and 150mL of methanol into a 250mL three-necked bottle, heating to 50-55 ℃, carrying out normal-pressure hydrogenation for 17-18 h, cooling to room temperature, filtering to remove Pd/C, carrying out reduced-pressure evaporation to dryness of an organic solvent to obtain 10.0g of formula III, and directly feeding the reactant into the next reaction.
2) Synthesis of formula iv:
adding 10g of triethyl orthoformate shown in the formula III, 20.2g (3eq) into a 250mL three-neck flask, stirring and heating 10.6g (0.9eq) of triethyl orthoformate shown in the formula IV and 132mL of isopropanol to reflux for 5-6 h, cooling to room temperature, stirring for 2h, filtering, and leaching with proper amount of isopropanol to obtain 10.0g (yield 46.0%) of the formula V.
3) Synthesized according to formula VI:
adding 7.5g of sulfolane (30.0eq) of the formula V and 55.8g into a 500mL three-neck flask, heating to 100-plus 105 ℃, dropwise adding 18.9g of phosphorus oxychloride (4.0eq), cyclizing at 100-plus 105 ℃ for 16-17 h, cooling to 0-5 ℃ in an ice bath, adding 170mL of tap water, precipitating a large amount of solids, filtering, rinsing with proper amount of water, and drying by blowing at 45 ℃ for 24h to obtain 6.0g (yield 83.0%) of the formula VI.
4) BN-05 synthesis:
adding 4.5g of the formula VI, 0.42g of anhydrous piperazine (0.5eq), 3.0g of sodium carbonate (3.0eq) and 90mL of DMF into a 250mL three-necked flask, heating to 100 ℃ and 105 ℃, stirring for 8-9 h, cooling to room temperature, adding 90mL of tap water to precipitate a solid, filtering, and carrying out forced air drying at 45 ℃ overnight to obtain 3.0g of a yellow solid. And (3) carrying out dry-method sample loading on 2.8g of the product for column chromatography, and collecting the target product to obtain 1.0g of the target product, wherein the HPLC purity is 96.7%.
The structure of the bosutinib piperazine dimer impurity compound is confirmed:
mass Spectrometry (WatersXE VOTeD Mass Spectrometry, ESI (+), 75V; ESI (-), 75V)
MS(ESI):947.71[M+H]+;945.75[M-H]-See fig. 2.
The nuclear magnetic hydrogen spectrum (H1-NMR) data are shown in figure 3.
Proton number | Chemical shift (ppm) | Multiplicity of properties | Number of protons |
17,51 | 9.64 | |
2 |
1,46 | 8.41 | |
2 |
4,7,40,43 | 7.78 | |
4 |
20,23,54,57 | 7.32 | |
4 |
11,37 | 4.19 | |
4 |
14,18,50,61,13,35 | 3.90 | |
16 |
30,31,33,34 | 2.51-2.46 | |
8 |
12,36 | 1.97 | |
4 |
Nuclear magnetic carbon spectrum (C13-NMR) data (see FIG. 4)
Example 2
1) Synthesis of formula III:
adding 2.5g of formula II, 0.50g of Pd/C (10% by mass) and 32mL of tetrahydrofuran into a 250mL three-necked flask, heating to 50-55 ℃, hydrogenating for 16-17 h under normal pressure, cooling to room temperature, filtering to remove Pd/C, evaporating the organic solvent under reduced pressure to obtain 2.3g of formula III, and directly feeding the reactant into the next reaction.
2) The synthesis of formula V:
2.3g of triethyl orthoformate shown in the formula III, 5.4g (3.5eq) of triethyl orthoformate, 2.7g (1.0eq) of triethyl orthoformate shown in the formula IV and 30mL of isopropanol are added into a 100mL three-neck flask, stirred and heated to reflux for 5 hours, cooled to room temperature and stirred for 2 hours, filtered, and rinsed by using a proper amount of isopropanol, so that 4.1g (yield 82.3%) of the triethyl orthoformate shown in the formula V is obtained.
3) Synthesized according to formula VI:
adding 4.1g of sulfolane (30.0eq) of the formula V and 30.9g into a 250mL three-neck flask, heating to 100-plus 105 ℃, dropwise adding 7.9g of phosphorus oxychloride (3.0eq), cyclizing at 100-plus 105 ℃ for 17-18 h, cooling to 0-5 ℃ in an ice bath, adding 95mL of tap water, precipitating a large amount of solids, filtering, rinsing with proper amount of water, and drying by blowing at 45 ℃ for 24h to obtain 3.5g (yield 88.0%) of the formula VI.
4) The synthesis of formula I:
3.0g of the formula VI, 0.56g of anhydrous piperazine (1.0eq), 2.0g of sodium carbonate (3.0eq) and 60mL of DMF are added into a 250mL three-necked flask, heated to 100 ℃ and 105 ℃, stirred for 8h, cooled to room temperature, added with 180mL of tap water to precipitate a solid, filtered, and dried by blowing at 45 ℃ overnight to obtain 2.2g of a yellow solid. And 2.2g of the product is subjected to column chromatography by a dry method, and a target product is collected to obtain 0.7g of the target product, wherein the HPLC purity is 97.0%.
Example 3
1) Synthesis of formula III:
adding 8.0g of formula II, 4.0g of Pd/C (10% by mass) and 100mL of tetrahydrofuran into a 250mL three-necked flask, heating to 50-55 ℃, hydrogenating for 15-16 h under normal pressure, cooling to room temperature, filtering to remove Pd/C, evaporating the organic solvent under reduced pressure to obtain 7.2g of formula III, and directly feeding the reactant into the next reaction.
2) Synthesis of formula iv:
adding 7.2g of triethyl orthoformate shown in the formula III, 14.5g (3eq) into a 250mL three-neck flask, adding 12.7g (1.5eq) of triethyl orthoformate shown in the formula IV and 95mL of isopropanol, stirring and heating to reflux for 4-5 h, cooling to room temperature, stirring for 2h, filtering, and leaching with proper amount of isopropanol to obtain 13.6g (yield 86.1%) of formula V.
3) VI synthesis:
adding 13.0g of sulfolane (30.0eq) of the formula V and 97.0g into a 250mL three-neck flask, heating to 100-105 ℃, dropwise adding 37.0g of phosphorus oxychloride (4.5eq), cyclizing for 16h at 100-105 ℃, cooling to 0-5 ℃ in an ice bath, adding 300mL of tap water, precipitating a large amount of solid, filtering, rinsing with proper amount of water, and drying for 24h at 45 ℃ by blowing air to obtain 11.0g (yield 88.0%) of the formula VI.
4) The synthesis of formula I:
10.0gBN-04, 0.93g of anhydrous piperazine (0.5eq), 8.9g of sodium carbonate (4.0eq) and 200mL of DMF are added into a 250mL three-necked flask, heated to 100 ℃ and 105 ℃, stirred for 8h, cooled to room temperature, added with 600mL of tap water to precipitate a solid, filtered, and dried by blowing at 45 ℃ overnight to obtain 7.4g of a yellow solid. And (3) taking 7.0g of the product, performing dry-process sample loading, performing column chromatography, and collecting the target product to obtain 2.2g of the target product with the purity of 96.5%.
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.
Claims (7)
3. the preparation method according to claim 2, comprising the following steps:
1) mixing a formula II, Pd/C and a reaction solvent, heating, and carrying out a normal pressure hydrogenation reaction to generate a formula III, wherein the reaction formula in the step 1) is as follows:
2) under the catalysis of triethyl orthoformate, carrying out addition reaction on the formula III prepared in the step 1) and the formula IV to generate a formula V, wherein the reaction formula in the step 2) is as follows:
3) under the action of phosphorus oxychloride, the formula V prepared in the step 2) is cyclized to generate a formula VI, and the reaction formula in the step 3) is as follows:
4) coupling the formula VI prepared in the step 3) with anhydrous piperazine under the action of potassium carbonate to prepare a target compound formula I,
step 4) the reaction formula is as follows:
4. the method according to claim 3, wherein in the step 1), the mass ratio of the formula II to Pd/C is 1: (0.2-0.5) and the reaction solvent is tetrahydrofuran.
5. The preparation method according to claim 3, wherein in the step 2), the molar ratio of the triethyl orthoformate to the triethyl orthoformate of the formula III is 1 (3-4) to (0.9-1.5), and the reaction solvent is isopropanol.
6. The preparation method according to claim 3, wherein in the step 3), the molar ratio of the formula V to the phosphorus oxychloride is 1 (3-5), and the reaction solvent is sulfolane.
7. The preparation method of claim 3, wherein in the step 4), the molar ratio of the piperazine of formula VI to the potassium carbonate is 1 (0.5-1) to (3.0-4.0), and the solvent is N, N-dimethylformamide.
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CN113135852A (en) * | 2021-04-30 | 2021-07-20 | 中国科学院长春应用化学研究所 | Preparation method of 4-aminoquinoline compound |
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