CN115304587A - Preparation method of afatinib impurity - Google Patents
Preparation method of afatinib impurity Download PDFInfo
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- CN115304587A CN115304587A CN202110490623.1A CN202110490623A CN115304587A CN 115304587 A CN115304587 A CN 115304587A CN 202110490623 A CN202110490623 A CN 202110490623A CN 115304587 A CN115304587 A CN 115304587A
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- 239000012535 impurity Substances 0.000 title claims abstract description 28
- 229960001686 afatinib Drugs 0.000 title claims abstract description 24
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000011160 research Methods 0.000 claims abstract description 9
- 238000006722 reduction reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 102
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 20
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- 150000001408 amides Chemical class 0.000 claims description 2
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- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
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- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 2
- QQHNGZNHRRLNKI-UHFFFAOYSA-N methyl carbonobromidate Chemical compound COC(Br)=O QQHNGZNHRRLNKI-UHFFFAOYSA-N 0.000 claims description 2
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- ABUYPZMWYIVOKQ-UHFFFAOYSA-N phenyl carbonobromidate Chemical compound BrC(=O)OC1=CC=CC=C1 ABUYPZMWYIVOKQ-UHFFFAOYSA-N 0.000 claims description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- LKYFCJNDMTXBKT-UHFFFAOYSA-N propan-2-yl carbonobromidate Chemical compound CC(C)OC(Br)=O LKYFCJNDMTXBKT-UHFFFAOYSA-N 0.000 claims description 2
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims 1
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- 230000009435 amidation Effects 0.000 abstract 1
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- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 9
- 239000005038 ethylene vinyl acetate Substances 0.000 description 9
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 9
- USNRYVNRPYXCSP-JUGPPOIOSA-N afatinib dimaleate Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 USNRYVNRPYXCSP-JUGPPOIOSA-N 0.000 description 7
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
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- HIMWAPFLBWDJMH-SZQRVLIRSA-N 1-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-5-hydroxypyrrolidin-2-one Chemical group C1[C@@H](COC1)OC1=C(N2C(=O)CCC2O)C=C2C(NC3=CC=C(F)C(Cl)=C3)=NC=NC2=C1 HIMWAPFLBWDJMH-SZQRVLIRSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a preparation method of afatinib impurities. Afatinib or salt thereof is used as a raw material, and Afatinib impurity J is obtained through reactions such as hydrolysis, amidation, reduction and the like, so that a basis is provided for research on Afatinib related substances. The method is simple, the raw materials are easy to obtain, the product is easy to purify, the yield and the purity are high, and the product can be used as a reference substance in impurity detection.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of afatinib impurities.
Background
Afatinib maleate (Afatinib) is an oral molecular targeted drug developed and produced by the germany briegger invar company, has a strong and irreversible double inhibition effect on Epidermal Growth Factor Receptor (EGFR) and human epidermal growth factor receptor 2 (HER 2), is suitable for first-line treatment of advanced non-small cell lung cancer (NSCLC) and patients with HER2 positive advanced breast cancer, and is also a second-line and third-line target drug for treating EGFR-TKIS resistance.
In the production and storage processes of afatinib, process impurities, degradation impurities and the like can be generated to affect the quality of the medicine, so that the research on the impurities of afatinib and the development of a simple and efficient impurity directional synthesis route are performed to obtain a high-purity impurity reference substance, so that the medicine quality detection work is performed, and the medicine quality is ensured. The main alkaline degradation impurities of afatinib are compounds shown in formula J and formula 11, and are commonly used for quality research of afatinib drug products.
4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [ 4-hydroxy-1-oxo-2-buten-1-yl ] amino-7- ((s) -tetrahydrofuran-3-yloxy) -quinazoline, a compound of formula J, is a major basic degradation impurity of afatinib maleate. At present, although relevant documents report the synthesis method of the impurity, experiments prove that the problem that the structure of a final product does not conform to the actual situation exists. Chinese patent document CN106916147A discloses a method for preparing an afatinib impurity standard substance, which uses afatinib API to synthesize the impurity through hydrolysis under alkaline conditions, but the synthesis method is verified, and the structure of the final product is 1- (4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -5-hydroxypyrrolidin-2-one, i.e. the compound shown in formula 11, and the nuclear magnetic spectrum provided in the patent document has 6 methylene hydrogens between chemical shifts 1.5 and 3 consistent with the characteristics of the compound shown in formula 11, but the compound shown in formula J (only 2 methylene hydrogens between chemical shifts 1.5 and 3, and the methylene hydrogen connected with hydroxyl group is in a lower field position) is not synthesized. The above-mentioned conclusion was also verified in journal of "A controlled, effective and robust process for the synthesis of an epidermal growth factor receptor inhibitor: afatinib Dimaleate" [ Chem Rep,2019,1 (1): 3-12 (DOI: 10.25082/CR.2019.01.001) ] and "preparation and structure speculation of degradation impurities of Afatinib maleate raw drug substance" (chemical world, 2019,60 (3), 177-181).
The invention provides a brand new synthesis method of impurity J, and the map representation is consistent with the structure, thereby having important significance for the quality control and the impurity research of afatinib maleate.
Disclosure of Invention
The invention provides a preparation method of a compound shown in a formula J, which comprises the following steps:
1) Hydrolyzing the compound A or the salt thereof under the action of a compound a1 to obtain a compound B;
2) Reacting the compound C with a compound C1 to obtain a compound D;
3) Reacting the compound B with the compound D to prepare a compound E;
4) The compound E and a compound E1 are subjected to reduction reaction to obtain a compound shown as a formula J;
according to an embodiment of the invention, said compound a1 in step 1) may be an acid, which may be a mineral acid, such as (concentrated) hydrochloric acid and/or (concentrated) sulfuric acid, preferably (concentrated) hydrochloric acid;
according to embodiments of the invention, the concentration of the compound a1 may be 1 to 12mol/L, for example 6 to 12mol/L, exemplary 2mol/L, 3mol/L, 4mol/L, 5mol/L, 6mol/L, 7mol/L, 8mol/L;
according to an embodiment of the present invention, the salt of compound a in step 1) may be the maleate salt of compound a (i.e. afatinib maleate);
according to an embodiment of the invention, the mass to volume ratio (g: mL) of said compound a or salt thereof to compound a1 in step 1) may be 1 (0.5-3), such as 1 (0.8-2), exemplified by 1;
according to an embodiment of the present invention, the solvent of the hydrolysis reaction of step 1) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, methanol, ethanol and isopropanol;
according to an embodiment of the present invention, the mass to volume ratio (g: mL) of the compound a or a salt thereof in step 1) to the solvent for the hydrolysis reaction in step 1) may be 1 (1-10), such as 1 (2-5), exemplified by 1;
according to an embodiment of the invention, the temperature of the hydrolysis reaction in step 1) is 60-80 ℃, such as 65-75 ℃, exemplary 70 ℃;
according to an embodiment of the invention, the hydrolysis reaction in step 1) is carried out for a period of 3 to 8 hours, such as 4 to 7 hours, illustratively 5 hours.
According to an embodiment of the present invention, the step 1) further comprises performing post-treatment on the reaction solution after the hydrolysis reaction is completed to obtain the compound B. For example, the post-processing includes: cooling the reaction solution (preferably to room temperature), pouring the reaction solution into ice water, adjusting the mixed solution to be alkaline (preferably pH = 8-9), stirring, adding dichloromethane for extraction, combining organic phases obtained by extraction, and washing, drying and purifying the organic phases to obtain the compound B. Preferably, the mixed solution is adjusted to be alkaline, and an aqueous sodium hydroxide solution is added to the mixed solution.
According to an embodiment of the present invention, the compound c1 in step 2) may be at least one of oxalyl chloride, thionyl chloride, phosphorus oxychloride and phosphorus trichloride, preferably thionyl chloride;
according to an embodiment of the invention, the molar ratio of compound C to compound C1 in step 2) may be 1 (1-5), such as 1 (2-3), exemplary 1;
according to an embodiment of the present invention, the solvent of the reaction of step 2) is selected from at least one of tetrahydrofuran, toluene, dichloromethane, chloroform and dichloroethane;
according to an embodiment of the invention, the mass to volume ratio (g: mL) of compound C in step 2) to the solvent of the reaction in step 2) may be 1 (5-20), for example 1 (8-12), exemplified by 1.
According to an embodiment of the invention, the reaction of step 2) is also carried out in the presence of a catalyst. For example, the catalyst is selected from DMF;
according to an embodiment of the invention, the temperature of the reaction in step 2) is 60-80 ℃, such as 65-75 ℃, exemplary 70 ℃;
according to an embodiment of the invention, the reaction time in step 2) is 3 to 8 hours, such as 4 to 7 hours, exemplary 5 hours;
according to an embodiment of the present invention, step 2) comprises: adding the compound C into a solvent, reducing the temperature of the system to-5-2 ℃ (preferably 0 ℃) in an inert atmosphere (preferably a nitrogen atmosphere), adding (preferably dropwise) the compound C1 into the system, adding (preferably dropwise) a catalyst into the system after the compound C1 is added, and heating and stirring for reaction.
According to an embodiment of the present invention, the step 2) further comprises post-treating the reaction solution after completion of the reaction. For example, the post-treatment comprises cooling the reaction solution (preferably to room temperature), and concentrating to dryness to obtain the compound D.
According to an embodiment of the invention, the molar ratio of compound B to compound D in step 3) may be 1 (1-5), such as 1 (2-3), exemplified by 1;
according to an embodiment of the present invention, the solvent of the reaction of step 3) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane and chloroform;
preferably, step 3) comprises: mixing the compound B with the solvent of the reaction in the step 3) to obtain a solution of the compound B; mixing the compound D with the solvent of the reaction in the step 3) to obtain a solution of the compound D; then dropwise adding the solution of the compound D into the solution of the compound B, and stirring for reaction;
preferably, the volume ratio of the solution of the compound B to the solution of the compound D is 1 (0.8-1.5), preferably 1;
preferably, the solution of the compound B is cooled to-30 ℃ to-10 ℃ (preferably to-20 ℃), and the solution of the compound D is dropwise added into the solution;
preferably, after the dropwise addition of the compound D solution is completed, stirring and raising the temperature to room temperature, and reacting for 1-4 hours;
according to an embodiment of the present invention, the mass to volume ratio (g: mL) of the compound B in step 3) to the total solvent in the reaction system of step 3) may be 1 (5-20), for example, 1 (8-12), exemplified by 1;
according to an embodiment of the invention, the reaction of step 3) is carried out in an oxygen-free atmosphere, for example a nitrogen atmosphere;
according to an embodiment of the present invention, step 3) further comprises obtaining said compound E after post-treatment after completion of the reaction; for example, the post-treatment comprises adding water to the reaction solution for quenching, stirring, filtering, and purifying to obtain the compound E.
According to an embodiment of the present invention, the compound e1 in step 4) may be selected from at least one of sodium borohydride, sodium borohydride acetate, sodium cyanoborohydride, potassium borohydride and lithium aluminum hydride, preferably sodium borohydride;
according to an embodiment of the invention, the molar ratio of compound E and compound E1 in step 4) may be 1 (0.5-5), e.g. 1 (0.8-3), exemplarily 1.8;
according to an embodiment of the present invention, the solvent of the reaction of step 4) is at least one of dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and acetonitrile;
according to an embodiment of the invention, the mass to volume ratio (g: mL) of compound E of step 4) to the total solvent of the reaction of step 4) may be 1 (2-15), for example 1 (3-10), exemplified by 1;
according to an embodiment of the present invention, the reaction of step 4) is performed in the presence of an esterification reagent, the esterification reagent reacts with carboxylic acid to obtain an activated ester, and the esterification reagent may be at least one selected from the group consisting of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, benzyl chloroformate, phenyl chloroformate, methyl bromoformate, ethyl bromoformate, isopropyl bromoformate, benzyl bromoformate, and phenyl bromoformate; preferably, the molar ratio of the compound E to the esterifying reagent may be 1 (0.5-5), such as 1 (0.8-3), exemplary 1;
according to an embodiment of the present invention, the process of the reaction of step 4) comprises: adding the compound E into the solvent for the reaction in the step 4), cooling to-5-2 ℃ (preferably 0 ℃), adding ethyl chloroformate into the system, then adding (preferably dropwise) the solution of the compound E1 into the system, and reacting at room temperature under stirring after the solution of the compound E1 is added. Preferably, the solution of the compound e1 is a mixed solution of THF and water of the compound e 1.
According to an embodiment of the present invention, the step 4) further comprises performing post-treatment on the reaction solution after the reaction is completed to obtain the compound J. For example, the post-treatment comprises adding the reaction solution into a saturated ammonium chloride solution, extracting after stirring (preferably extracting by adding EA), collecting an organic phase, and washing, drying and purifying the organic phase to obtain the compound J.
As an example, the compound of formula J is prepared by a process comprising the steps of:
1) Performing amide hydrolysis reaction on the compound A or salt thereof and concentrated hydrochloric acid to obtain a compound B;
2) Reacting the compound C under the action of thionyl chloride and a catalyst DMF to obtain a compound D;
3) Reacting the compound B with the compound D to obtain a compound E;
4) And reducing the compound E by sodium borohydride to obtain the compound shown in the formula J.
The invention also provides application of the preparation method in pharmaceutical process research, and the preparation method can be used for afatinib impurity research.
As used herein, "room temperature" means a temperature of 15 to 36 deg.C, for example, 25 deg.C.
Advantageous effects
The invention provides a new idea for synthesizing the alkali degradation impurity J of the afatinib or the salt thereof, and the synthesis method provided by the invention has the advantages of few reaction steps, simple process, easily obtained starting materials and high yield of target products. The method is real in operation and reliable in data, can really prepare the impurity J, has shorter steps, is easy to store the required materials, is harmless, is easy to purify the product, has higher yield and purity, can meet the preparation requirement of the impurity, and has important significance for the research on the afatinib or salt impurities thereof.
Drawings
FIG. 1 shows the pure impurity J in example 4 1 H NMR spectrum, solvent is deuterated DMSO;
FIG. 2 is a HPLC liquid chromatogram of the pure impurity J in example 4;
FIG. 3 is a high resolution mass spectrum of the pure impurity J in example 4.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
EXAMPLE 1 Synthesis of Compound B
The method comprises the following specific steps: firstly, 10g (0.014 mol) of afatinib maleate, i.e. the maleate of compound a, is added in portions to a mixed solvent of 20mL of ethanol and 20mL of concentrated hydrochloric acid, the temperature is raised to 70 ℃, the mixture is stirred for 5 hours, a TLC thin layer chromatography plate is used for monitoring (ammonia water is added for adjusting to be alkaline, methanol is added for diluting, a developing agent is DCM: meOH = 10.
EXAMPLE 2 Synthesis of Compound D
The method comprises the following specific steps: firstly, 4.27g (0.037 mol) of compound C is added into 40mL of toluene, nitrogen is replaced, the temperature is reduced to 0 ℃, 13.14g (0.11 mol) of thionyl chloride is added dropwise, after the addition of two drops of DMF, the temperature is increased to 70 ℃, stirring is carried out for 5 hours, a TLC thin-layer chromatography plate is used for monitoring (methanol is added for dilution, a developing agent: PE: EA = 1) reaction, when the compound C raw material completely disappears, the reaction liquid is reduced to room temperature, and the reaction liquid is directly concentrated to be dry to obtain 5.43g of compound D, yellow oily matter, and the yield is 96%.
EXAMPLE 3 Synthesis of Compound E
The method comprises the following specific steps: 5.43g (0.036 mol) of Compound D was added to 23mL of THF, the temperature was reduced to-20 ℃ by nitrogen substitution, 4.5g (0.012 mol) of Compound B in 23mL of THF was slowly added dropwise to the reaction system, after completion of addition, the temperature was slowly raised to room temperature and stirred for 2 hours, and the reaction of Compound B was completed by TLC plate monitoring (water and EA were added for extraction, EA phase was taken for detection, and developing agent: DCM: meOH = 10). Then, 5mL of water was added to the reaction solution to quench, the mixture was stirred for 10min, and a yellow solid was obtained by filtration, and after purification by dry silica gel column chromatography, compound E was obtained in a yield of 73% in a yield of 5.02 g.
EXAMPLE 4 Synthesis of Compound J
The specific steps are as follows, 5g of compound E is added into 30mL THF and cooled to 0 ℃, then ethyl chloroformate (1.3 g) is added dropwise, 670mg sodium borohydride is dissolved in a mixed solvent of 15mL THF and 15mL water after 10 minutes and is slowly dropped into the solution, after dropping, the solution is slowly raised to room temperature and stirred for 2 hours, TLC thin layer chromatography plate monitoring (water and EA are added for extraction, EA phase detection is carried out, developing solvent: DCM: meOH = 10) shows that the raw materials are reacted completely. Adding the reaction solution into a saturated ammonium chloride solution, stirring for 30min, adding EA (ethylene-vinyl acetate) for extraction, washing an organic phase with brine, drying, spin-drying, performing dry silica gel column chromatography, eluting a product with EA: meOH = 30.
As shown in fig. 1 1 H NMR(500MHz,DMSO-d6)δ9.81(s,1H),9.45(s,1H),8.94(s,1H),8.53(s,1H),8.12(dd,J＝6.8,2.6Hz,1H),7.79(m,1H),7.42(t,J＝9.1Hz,1H),7.24(s,1H),6.95(dt,J＝15.3,3.7Hz,1H),6.64(d,J＝15.3Hz,1H),5.29(m,1H),5.16(m,1H),4.28–4.15(m,2H),4.01(d,J＝3.3Hz,2H),3.93(q,J＝7.7Hz,1H),3.79(m,1H),2.36–2.28(m,1H),2.15(m,1H)。
The successful synthesis of compound J can be demonstrated by the characterization of figure 1, figure 2 and figure 3.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method of preparing a compound of formula J, comprising the steps of:
1) Hydrolyzing the compound A or the salt thereof under the action of the compound a1 to obtain a compound B;
2) Reacting the compound C with a compound C1 to obtain a compound D;
3) Reacting the compound B with the compound D to prepare a compound E;
4) The compound E and a compound E1 are subjected to reduction reaction to obtain a compound shown as a formula J;
2. the process according to claim 1, wherein the compound a1 in step 1) is an acid, and the acid is an inorganic acid such as hydrochloric acid and/or sulfuric acid;
preferably, the concentration of the compound a1 is from 1 to 12mol/L, for example from 6 to 12mol/L;
preferably, the salt of compound a in step 1) may be the maleate salt of compound a;
preferably, the mass-to-volume ratio (g: mL) of the compound A or the salt thereof to the compound a1 in the step 1) is 1 (0.5-3), for example, 1 (0.8-2);
preferably, the solvent for the hydrolysis reaction of step 1) is at least one selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, methanol, ethanol and isopropanol;
preferably, the mass-to-volume ratio of the compound A or the salt thereof in the step 1) to the solvent for the hydrolysis reaction in the step 1) is 1 (1-10) g: mL, for example, 1 (2-5) g: mL;
preferably, the temperature of the hydrolysis reaction in step 1) is 60-80 ℃, e.g. 65-75 ℃;
preferably, the hydrolysis reaction in step 1) is carried out for a period of 3 to 8 hours, for example 4 to 7 hours.
3. The preparation method according to claim 1 or 2, wherein the compound c1 in step 2) is at least one of oxalyl chloride, thionyl chloride, phosphorus oxychloride and phosphorus trichloride;
preferably, the molar ratio of the compound C to the compound C1 in the step 2) is 1 (1-5), such as 1 (2-3);
preferably, the solvent for the reaction of step 2) is selected from at least one of tetrahydrofuran, toluene, dichloromethane, chloroform and dichloroethane;
preferably, the mass-to-volume ratio of the compound C in step 2) to the solvent of the reaction in step 2) is 1 (5-20) g: mL, for example 1 (8-12) g: mL;
preferably, the reaction of step 2) is also carried out in the presence of a catalyst; for example, the catalyst is selected from DMF.
4. A method of preparation according to any one of claims 1 to 3, wherein the temperature of the reaction in step 2) is 60-80 ℃, such as 65-75 ℃;
preferably, the reaction time in step 2) is 3 to 8 hours, such as 4 to 7 hours.
5. The process according to any one of claims 1 to 4, wherein the molar ratio of compound B to compound D in step 3) is 1 (1-5), for example 1 (2-3);
preferably, the solvent for the reaction of step 3) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane and chloroform;
preferably, step 3) comprises: mixing the compound B with the solvent of the reaction in the step 3) to obtain a solution of the compound B; mixing the compound D with the solvent of the reaction in the step 3) to obtain a solution of the compound D; then dropwise adding the solution of the compound D into the solution of the compound B, and stirring for reaction;
preferably, the volume ratio of the solution of the compound B to the solution of the compound D is 1 (0.8-1.5);
preferably, the temperature of the solution of the compound B is reduced to-30 ℃ to-10 ℃, and the solution of the compound D is dripped into the solution;
preferably, after the dropwise addition of the compound D solution is completed, the solution is stirred to room temperature and reacted for 1 to 4 hours.
6. The preparation method according to any one of claims 1 to 5, wherein the mass-to-volume ratio of the compound B in the step 3) to the total solvent in the reaction system in the step 3) is 1 (5 to 20) g: mL, for example 1 (8 to 12) g: mL;
preferably, the reaction of step 3) is carried out in an oxygen-free atmosphere.
7. The preparation method according to any one of claims 1 to 6, wherein the compound e1 in step 4) is selected from at least one of sodium borohydride, sodium borohydride acetate, sodium cyanoborohydride, potassium borohydride and lithium aluminum hydride, preferably sodium borohydride;
preferably, the molar ratio of the compound E to the compound E1 in step 4) is 1 (0.5-5), for example 1 (0.8-3).
8. The method according to any one of claims 1 to 7, wherein the reaction in step 4) is carried out in the presence of an esterification reagent, and the esterification reagent may be at least one selected from the group consisting of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, benzyl chloroformate, phenyl chloroformate, methyl bromoformate, ethyl bromoformate, isopropyl bromoformate, benzyl bromoformate, and phenyl bromoformate;
preferably, the molar ratio of said compound E and said reaction with the esterifying reagent is 1 (0.5-5), for example 1 (0.8-3);
preferably, the solvent for the reaction of step 4) is at least one of dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and acetonitrile;
preferably, the mass-to-volume ratio of the compound E in step 4) to the total solvent in the reaction in step 4) is 1 (2-15) g: mL, for example 1 (3-10) g: mL.
9. The method of claim 1, comprising the steps of:
1) Performing amide hydrolysis reaction on the compound A and concentrated hydrochloric acid to obtain a compound B;
2) Reacting the compound C under the action of thionyl chloride and a catalyst DMF to obtain a compound D;
3) Reacting the compound B with the compound D to obtain a compound E;
4) And reducing the compound E by sodium borohydride to obtain the compound shown in the formula J.
10. The use of the preparation method of any one of claims 1-9 in pharmaceutical technology research, which can be used for afatinib impurity research.
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| CN111297865A (en) * | 2020-03-15 | 2020-06-19 | 黄泳华 | Use of heterocyclic compound-containing composition for preparing medicine for treating lung cancer |
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