CN112552236A - Bosutinib 1, 3-propylene diether dimer impurity and preparation method thereof - Google Patents
Bosutinib 1, 3-propylene diether dimer impurity and preparation method thereof Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 25
- 239000002145 L01XE14 - Bosutinib Substances 0.000 title claims abstract description 22
- 229960003736 bosutinib Drugs 0.000 title claims abstract description 20
- 239000000539 dimer Substances 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 claims abstract description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 8
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 claims description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical group O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 6
- 238000007259 addition reaction Methods 0.000 claims description 2
- -1 bosutinib 1, 3-propanediol dimer Chemical class 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 17
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 abstract description 15
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 3
- 229910052799 carbon Inorganic materials 0.000 description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- 238000001035 drying Methods 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 238000007664 blowing Methods 0.000 description 8
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 229940083476 bosulif Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 210000004214 philadelphia chromosome Anatomy 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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.
Description
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 | |
| 5,30 | 154.48 | Quaternary carbon |
| 12,41 | 153.06 | Quaternary carbon |
| 17,48 | 151.33 | Quaternary carbon |
| 6,35 | 149.88 | |
| 1,39 | 146.20 | |
| 3,32 | 136.64 | Quaternary carbon |
| 15,43 | 130.32 | Quaternary carbon |
| 19,46 | 123.59 | |
| 20,45 | 120.88 | Quaternary carbon |
| 14,44 | 117.41 | |
| 8,33 | 114.03 | Quaternary carbon |
| 18,47 | 113.03 | |
| 4,31 | 110.00 | Tertiary carbon |
| 16,19 | 102.35 | Tertiary carbon |
| 7,34 | 86.81 | |
| 11,40 | 65.60 | |
| 10,37 | 57.28 | Primary carbon |
| 24,52 | 56.74 | |
| 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.
Claims (8)
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.
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