CN113943273A - Preparation method of lung cancer drug AZD3759 - Google Patents
Preparation method of lung cancer drug AZD3759 Download PDFInfo
- Publication number
- CN113943273A CN113943273A CN202010694142.8A CN202010694142A CN113943273A CN 113943273 A CN113943273 A CN 113943273A CN 202010694142 A CN202010694142 A CN 202010694142A CN 113943273 A CN113943273 A CN 113943273A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- inert solvent
- under
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种肺癌药物AZD3759的制备方法。利用式Ⅷ化合物和式Ⅴ化合物为原料，经过水解反应、缩合反应、氨化反应、酸解反应、甲基化反应，得到式Ⅰ化合物AZD3759。该方法路线新颖、反应简便、环境友好、收率高，适宜工业化大生产。The invention provides a preparation method of lung cancer drug AZD3759. Using the compound of formula VIII and the compound of formula V as raw materials, through hydrolysis reaction, condensation reaction, ammoniation reaction, acidolysis reaction and methylation reaction, the compound AZD3759 of formula I is obtained. The method has novel route, simple reaction, environmental friendliness and high yield, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a novel lung cancer drug AZD 3759.
Background
Lung cancer is one of the most common cancers in china, with morbidity and mortality among all cancers. About 1/3 th of lung cancer occurs globally in china, with half of the lung cancer patients being advanced. Statistics show that 15% of patients with advanced lung cancer are combined with brain metastasis at the time of initial diagnosis. Brain metastases occur in about 50% of patients throughout the course of the disease. Brain metastasis is also a major therapeutic challenge for EGFR mutation-positive advanced non-small cell lung cancer (NSCLC).
Patients with EGFR mutation positive advanced non-small cell lung cancer have a very high incidence of brain metastases during treatment. Unfortunately, the efficacy of existing EGFR TKIs in brain metastasis patients is very limited. This is because most EGFR TKI drugs are substrates for P-glycoprotein (P-gp) or breast cancer drug-resistant protein (BCRP), and cannot effectively penetrate the blood brain barrier, and the intracranial drug concentration is very limited, only 1.13% to 16%, so that the intracranial metastasis focus cannot be effectively controlled. As a therapeutic drug designed by the Aslicon and used for treating the brain metastasis of the lung cancer, the AZD3759 blood-brain barrier transmittance is 100%, the drug has excellent performance in preclinical research and clinical tests, is hopefully officially approved, and is applied to the treatment of patients with the brain metastasis of the lung cancer.
The published patent US 2014255428 describes the synthetic route of the drug, and the final synthetic method of AZD3759 provides a synthetic method, but the synthetic route is long, the cost is high, the energy consumption is high, and the yield is low. Therefore, it is necessary to develop a new preparation method, which has the advantages of mild conditions, simple and convenient treatment, environmental friendliness, low cost and easy industrialization.
A process for the preparation of AZD3759 disclosed in US 2014255428:
wherein, the compound IV can be synthesized by the following steps:
in this method, the stability of the compound IV is poor, and even if a continuous reaction method is adopted, the yield and purity of the next reaction are affected. The deacetylation process of the compound shown in the formula VII is stronger in condition and more in side reaction.
Therefore, the preparation method of AZD3759, which has the advantages of novel route, simple and convenient reaction, environmental friendliness and high yield, is urgently needed in the field.
Disclosure of Invention
The invention aims to provide a preparation method of AZD3759, which has the advantages of novel route, simple and convenient reaction, environmental friendliness and high yield.
In a first aspect of the invention, there is provided a process for the preparation of a compound of formula I, said process comprising the steps of:
(1) carrying out hydrolysis reaction on the compound shown in the formula VIII in diluted hydrochloric acid to obtain a compound shown in the formula i;
(2) condensing a compound of formula i and a compound of formula XII in an inert solvent in the presence of a catalyst and a condensing agent to produce a compound of formula XI;
(3) in an inert solvent, carrying out ammoniation reaction on a compound of a formula XI and a compound of a formula X under an alkaline condition to obtain a compound of a formula III;
(4) in an inert solvent, carrying out acidolysis reaction on the compound of the formula III under an acidic condition to obtain a compound of a formula II;
(5) in an inert solvent, under the acidic condition, the compound of the formula II and formaldehyde carry out methylation reaction to obtain the compound of the formula I.
In another preferred example, in the step (1), the concentration of the hydrochloric acid is 2N-6N.
In another preferred embodiment, in step (1), the temperature of the hydrolysis reaction is 80 to 100 ℃, preferably 90 ℃.
In another preferred embodiment, in step (1), the amount of hydrochloric acid used is 5 to 20 times by volume, preferably 10 times by volume, the amount of formula VIII.
In another preferred embodiment, in the step (2), the catalyst is DMAP.
In another preferred embodiment, in step (2), the molar ratio of the compound of formula i to the compound of formula XII is 1: 0.8-1.2.
In another preferred embodiment, in said step (2), the molar ratio of said compound of formula i to the catalyst is from 8 to 12:0.8 to 1.2.
In another preferred embodiment, in step (2), the molar ratio of the compound of formula i to the compound of formula XII is 1: 0.8-1.2.
In another preferred embodiment, in the step (2), the inert solvent is selected from the group consisting of: 1, 4-dioxane, toluene, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, or a combination thereof.
In another preferred embodiment, in the step (2), the condensing agent is selected from the group consisting of: DCC, DIC, EDCI.
In another preferred embodiment, in the step (2), the reaction temperature is in the range of 20 to 60 ℃, more preferably 30 to 50 ℃.
In another preferred embodiment, the step (3) and the step (4) are carried out in the same reaction vessel.
In another preferred embodiment, in the step (3), the alkaline condition is provided by a reagent selected from the group consisting of: triethylamine, pyridine, morpholine, or a combination thereof.
In another preferred embodiment, in the step (3), the reaction time is 1 to 6 hours, preferably 2 to 8 hours, and more preferably 3 to 4 hours.
In another preferred embodiment, in the step (3), the reaction temperature is in a range of 65 to 90 ℃.
In another preferred example, in the step (3), the inert solvent is dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, 1, 4-dioxane, or a combination thereof.
In another preferred embodiment, in the step (3), the molar ratio of the compound of formula XI to the compound of formula X is 1: 0.8-1.2.
In another preferred embodiment, in said step (3), the molar ratio of said compound of formula XI to the base is 1: 0.8-1.2.
In another preferred example, in step (4), the acidic environment can be provided by the following reagents: dilute hydrochloric acid, hydrobromic acid, trifluoroacetic acid, hydrogen chloride and hydrogen bromide.
In another preferred embodiment, in step (4), the reaction temperature is selected from 10 to 60 ℃, preferably 20 to 30 ℃.
In another preferred example, in the step (4), the acid hydrolysis is performed in 0.8-1.2N diluted hydrochloric acid.
In another preferred embodiment, in the step (5), the molar amounts of formic acid and formaldehyde in the reaction are equivalent.
In another preferred embodiment, in the step (5), the molar ratio of the compound of formula II in the reaction to formic acid and formaldehyde is 1: 5-10.
In another preferred embodiment, in the step (5), the reaction temperature is in the range of 90 to 100 ℃.
In another preferred example, the method further comprises the steps of:
(6) reacting the compound shown in the formula V with triphosgene in an inert solvent under an alkaline condition, and hydrolyzing and acidifying to obtain the compound shown in the formula XII.
In another preferred embodiment, in step (6), the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, morpholine, or combinations thereof.
In another preferred embodiment, in step (6), the molar ratio of the compound of the formula V to triphosgene is from 1:0.8 to 1.5.
In another preferred embodiment, in step (6), the inert solvent is selected from the group consisting of: tetrahydrofuran, 1-methyl-tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, chloroform, or a combination thereof.
In another preferred embodiment, in step (6), the reaction temperature is in the range of 10 to 40 ℃, preferably 20 to 25 ℃.
In another preferred example, in the step (6), the temperature of the hydrolysis is 0-30 ℃.
In another preferred embodiment, in step (6), the hydrolysis is performed in the presence of a base, and the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, ammonia, or combinations thereof.
In another preferred embodiment, in the step (6), the acidifying agent is selected from the group consisting of: acetic acid, hydrochloric acid, hydrobromic acid, or a combination thereof.
In a second aspect of the present invention, there is provided a process for the preparation of formula XI below, said process comprising the steps of:
condensing the compound of formula i and the compound of formula XII in an inert solvent in the presence of a catalyst and a condensing agent to produce the compound of formula XI.
In a third aspect of the invention, there is provided a process for the preparation of a compound of formula I, said process comprising the steps of:
(3) in an inert solvent, carrying out ammoniation reaction on a compound of a formula XI and a compound of a formula X under an alkaline condition to obtain a compound of a formula III;
(4) in an inert solvent, carrying out acidolysis reaction on the compound of the formula III under an acidic condition to obtain a compound of a formula II;
(5) in an inert solvent, under the acidic condition, the compound of the formula II and formaldehyde carry out methylation reaction to obtain the compound of the formula I.
In another preferred embodiment, the method further comprises the steps of:
(2) condensing the compound of formula i and the compound of formula XII in an inert solvent in the presence of a catalyst and a condensing agent to produce the compound of formula XI.
In another preferred example, the method further comprises the steps of:
(6) reacting the compound shown in the formula V with triphosgene in an inert solvent under an alkaline condition, and hydrolyzing and acidifying to obtain the compound shown in the formula XII.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor develops a preparation method which has mild reaction conditions, simple and convenient treatment, environmental friendliness and low cost and is suitable for industrial mass production of AZD3759 through extensive and intensive research and a large amount of screening and testing. On the basis of this, the present invention has been completed.
Term(s) for
DMAP: 4-dimethylaminopyridine
DCC: dicyclohexylcarbodiimide
DIC: n, N' -diisopropylcarbodiimide
EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride
A compound of formula I: AZD3759
Preparation method
The preparation process of AZD3759 of the present invention will be specifically described below, but these specific processes do not limit the present invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
In each reaction step of the present invention, the ratio of the reactants, the reaction solvent, the reaction temperature, the reaction time, and the like may be selected according to the specific reactants.
The invention provides a preparation method of AZD3759, which comprises the following steps:
(1) in dilute hydrochloric acid, carrying out hydrolysis reaction on the compound shown in the formula VIII to obtain a compound shown in the formula i; the reaction temperature can be 80-100 ℃, and preferably 90 ℃; the concentration of hydrochloric acid is 2N-6N, more preferably 3N;
the amount of hydrochloric acid used is 5 to 20 times by volume, preferably 10 times by volume, of formula VIII.
(2) Condensing a compound of formula i and a compound of formula XII in an inert solvent in the presence of a catalyst and a condensing agent to produce a compound of formula XI; the inert solvent is selected from the group consisting of: 1, 4-dioxane, toluene, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, or a combination thereof; the catalyst is DMAP; the condensing agent is selected from the group consisting of: DCC, DIC, EDCI; the reaction temperature is in the range of 20 to 60 deg.C, more preferably 30 to 50 deg.C.
(3) In an inert solvent, carrying out ammoniation reaction on a compound of a formula XI and a compound of a formula X under an alkaline condition to obtain a compound of a formula III, and carrying out acidolysis reaction on the compound of the formula III in an inert solvent under an acidic condition to obtain a compound of a formula II; the step (3) and the step (4) can be continuously reacted in one reaction vessel; in the step (3), the alkaline condition can be provided by the following reagents: triethylamine, pyridine, morpholine, or a combination thereof; in the step (3), the reaction time is 1 to 6 hours, preferably 2 to 8 hours, and more preferably 3 to 4 hours; in the step (3), the reaction temperature is in the range of 65-90 ℃; in the step (3), the inert solvent is dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, 1, 4-dioxane, or a combination thereof; in step (4), the acidic environment may be provided by the following reagents: dilute hydrochloric acid, hydrobromic acid, trifluoroacetic acid, hydrogen chloride and hydrogen bromide. In another preferred embodiment, in step (4), the reaction temperature is selected from 10 to 60 ℃, preferably 20 to 30 ℃.
(4) Carrying out methylation reaction on a compound shown in a formula II and formaldehyde in an inert solvent under an acidic condition to obtain a compound shown in a formula I; in the step (5), the molar weight of formic acid and formaldehyde in the reaction is equivalent; in the step (5), the molar ratio of the compound in the formula II to formic acid and formaldehyde in the reaction is 1: 5-10; in the step (5), the reaction temperature is in the range of 90-100 ℃.
(5) Reacting a compound shown in the formula V with triphosgene in an inert solvent under an alkaline condition, and hydrolyzing and acidifying to obtain a compound shown in the formula XII; in step (6), reacting a compound of formula V with triphosgene, wherein the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, morpholine, or combinations thereof; in another preferred embodiment, in step (6), the molar ratio of the compound of the formula V to triphosgene is from 1:0.8 to 1.5. In the step (6), the inert solvent is selected from the group consisting of: tetrahydrofuran, 1-methyl-tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, chloroform, or a combination thereof; in the step (6), the reaction temperature range is 10-40 ℃, preferably 20-25 ℃; in the step (6), the hydrolysis temperature is 0-30 ℃; in step (6), the base required for hydrolysis is selected from: sodium hydroxide, potassium hydroxide, ammonia, or a combination thereof; in step (6), the acidifying agent is selected from: acetic acid, hydrochloric acid, hydrobromic acid, or a combination thereof.
The main advantages of the invention include:
1. the preparation method has mild reaction conditions, does not need harsh reaction conditions such as high temperature and the like, and is suitable for industrial production;
2. the method is simple and convenient to process and easy to amplify;
3. the invention is environment-friendly and has small environmental protection pressure;
4. the method has high yield and low cost;
5. the invention has novel route and avoids the influence of the prior patent.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
Reagent
DCC purchased from Saen chemical technology (Shanghai) Co., Ltd
30% of formaldehyde: purchased from Saen chemical technology (Shanghai) Co., Ltd
Examples
EXAMPLE 1 preparation of Compound (i)
Compound (VIII) (25.3g, 0.1mol) and 3N hydrochloric acid (250ml) were charged into a 500ml reaction flask, and the temperature was raised to 90 ℃ to react for 9 hours. After cooling to room temperature, hydrochloric acid was concentrated to a low volume, 100ml of water was added, the mixture was neutralized with dilute aqueous ammonia to PH 4, and ethyl acetate was added for extraction, followed by concentration to obtain 20.5g of compound (i) in 97% molar yield, ms (esi): [ M ] ═ 210.6.
Example 2 preparation of Compound (XI)
A1L reaction flask was charged with compound (i) (16.9g, 0.08mol), tetrahydrofuran (200ml), compound (XII) (19.5g, 0.08mol), DCC (16.5g, 0.08mol) and DMAP (0.1g, 0.008mol), and the mixture was heated to 40 ℃ for reaction for 6 hours, TLC monitored the disappearance of the substrate, cooled to room temperature, the reaction mixture was filtered, concentrated and ethyl acetate (200ml) was added. The residue was dissolved in ethyl acetate, washed with water, and concentrated to give 33.2g of the compound (XI) in 95% molar yield. Ms (esi): and M is 436.9.
EXAMPLE 3 preparation of Compound (II)
A1L reaction flask was charged with 21.8g (0.05 mol) of compound (XI), 21.8g (g), 300ml of isopropanol, 7.3g (g), 0.05mol of compound (X), and 5.05g (0.05 mol) of triethylamine, and the mixture was dissolved by stirring, and the mixture was heated to reflux for 3 hours, and monitored by TLC for completion of the reaction, and the reaction mixture was concentrated to dryness, 200ml of ethyl acetate was added, and 1N diluted hydrochloric acid (200ml) was added thereto, and the mixture was warmed to room temperature, stirred for 2 hours, and monitored by TLC for substrate depletion, and the pH was adjusted to slightly basic with diluted ammonia water, and ethyl acetate solution was separated, and after drying sodium sulfate in ethyl acetate solution, the mixture was concentrated to dryness to obtain 21.4g of a solid with a molar yield of 96%. Ms (esi): and M is 445.87.
EXAMPLE 4 preparation of Compound (I)
Adding compound (II) (19.3g, 0.043mol), formic acid (16g, 0.35mol), 30% formaldehyde (35g, 0.35mol) and purified water (175ml) into 250ml, heating to 100 ℃, reacting for 3h, controlling the reaction in TLC to be finished, cooling to 0 ℃, adjusting the pH to 9 by using dilute ammonia water, separating out a solid, filtering, adding 750ml of ethyl acetate and 250ml of 10% potassium carbonate aqueous solution into the obtained solid, stirring to separate out an organic phase, washing by using 250ml of water, drying the organic phase by using anhydrous sodium sulfate, removing the ethyl acetate under reduced pressure, adding 25ml of n-hexane and 25ml of ethyl acetate into the residue, heating to reflux, cooling to slowly separate out crystals, filtering the obtained solid, and drying in vacuum to obtain 17.8g of white solid with the molar yield of 90%. Ms (esi): [ M +1 ]]＝460.5。1H-NMR(400MHz,CDCl3):8.70(s,1H)，8.40-8.43(m,1H)，7.66(s,1H)，7.51(m,1H)，7.25(s,1H)，7.71-7.15(m,2H)，4.47(br,1H)，4.06-4.13(br，1H),3.91(s，3H)，3.40(br,1H),2.87(1H)，2.73(1H)，2.34(m，4H)，2.12(br，1H)，1.46(br，3H)。
Example 5 preparation of Compound (XII)
Adding the compound (V) (20.0g, 0.1mol), triphosgene (29.7g, 0.1mol), dichloromethane (300ml) and triethylamine (10.1g, 0.1mol) into a 500ml reaction bottle at 0 ℃, heating to 20-25 ℃, reacting for 24 hours, after the reaction is finished, slowly pouring a dilute sodium hydroxide aqueous solution into the reaction liquid, controlling the temperature to be not more than 30 ℃, stirring for 30 minutes, adjusting the pH to 6, adding dichloromethane (100 ml), stirring, separating liquid, concentrating the dichloromethane layer to obtain 22.0g of the compound (XII), wherein the molar yield is 90%.
MS(ESI)：[M]＝244.20。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A process for the preparation of a compound of formula I, said process comprising the steps of:
(1) carrying out hydrolysis reaction on the compound shown in the formula VIII in diluted hydrochloric acid to obtain a compound shown in the formula i;
(2) condensing a compound of formula i and a compound of formula XII in an inert solvent in the presence of a catalyst and a condensing agent to produce a compound of formula XI;
(3) in an inert solvent, carrying out ammoniation reaction on a compound of a formula XI and a compound of a formula X under an alkaline condition to obtain a compound of a formula III;
(4) in an inert solvent, carrying out acidolysis reaction on the compound of the formula III under an acidic condition to obtain a compound of a formula II;
(5) in an inert solvent, under the acidic condition, the compound of the formula II and formaldehyde carry out methylation reaction to obtain the compound of the formula I.
2. The method of claim 1, wherein in step (2), the catalyst is DMAP.
3. The method according to claim 1, wherein in the step (3), the alkaline condition is provided by a reagent selected from the group consisting of: triethylamine, pyridine, morpholine, or a combination thereof.
4. The method of claim 1, wherein in step (4), the acidic environment is provided by the following reagents: dilute hydrochloric acid, hydrobromic acid, trifluoroacetic acid, hydrogen chloride and hydrogen bromide.
5. The method of claim 1, further comprising the step of:
(6) reacting the compound shown in the formula V with triphosgene in an inert solvent under an alkaline condition, and hydrolyzing and acidifying to obtain the compound shown in the formula XII.
6. The method according to claim 7, wherein in the step (6), the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, morpholine, or combinations thereof.
7. The method according to claim 1, wherein in the step (6), the hydrolysis is carried out in the presence of a base selected from the group consisting of: sodium hydroxide, potassium hydroxide, ammonia, or combinations thereof.
8. A process for the preparation of formula XI, comprising the steps of:
condensing the compound of formula i and the compound of formula XII in an inert solvent in the presence of a catalyst and a condensing agent to produce the compound of formula XI.
9. A process for the preparation of a compound of formula I, said process comprising the steps of:
(3) in an inert solvent, carrying out ammoniation reaction on a compound of a formula XI and a compound of a formula X under an alkaline condition to obtain a compound of a formula III;
(4) in an inert solvent, carrying out acidolysis reaction on the compound of the formula III under an acidic condition to obtain a compound of a formula II;
(5) in an inert solvent, under the acidic condition, the compound of the formula II and formaldehyde carry out methylation reaction to obtain the compound of the formula I.
10. The method of claim 11, further comprising the step of:
(2) condensing the compound of formula i and the compound of formula XII in an inert solvent in the presence of a catalyst and a condensing agent to produce the compound of formula XI.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010694142.8A CN113943273A (en) | 2020-07-17 | 2020-07-17 | Preparation method of lung cancer drug AZD3759 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010694142.8A CN113943273A (en) | 2020-07-17 | 2020-07-17 | Preparation method of lung cancer drug AZD3759 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113943273A true CN113943273A (en) | 2022-01-18 |
Family
ID=79326816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010694142.8A Pending CN113943273A (en) | 2020-07-17 | 2020-07-17 | Preparation method of lung cancer drug AZD3759 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113943273A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105209456A (en) * | 2013-03-06 | 2015-12-30 | 阿斯利康(瑞典)有限公司 | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor |
| CN108329276A (en) * | 2018-04-23 | 2018-07-27 | 江苏兢业制药有限公司 | Hete rocyclic derivatives and its preparation and use |
| CN108658946A (en) * | 2017-03-28 | 2018-10-16 | 焦玉奇 | Novel quinazoline inhibitor |
| CN109438423A (en) * | 2018-09-12 | 2019-03-08 | 通化师范学院 | A kind of new method of the synthesis technology of lung cancer target compound AZD-3759 |
| CN110590683A (en) * | 2019-10-11 | 2019-12-20 | 山东四环药业股份有限公司 | A kind of preparation method of targeted drug AZD3759 intermediate |
| CN110903283A (en) * | 2018-09-17 | 2020-03-24 | 南京雷正医药科技有限公司 | Substituted quinazoline compound, pharmaceutical composition containing compound and application of compound |
-
2020
- 2020-07-17 CN CN202010694142.8A patent/CN113943273A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105209456A (en) * | 2013-03-06 | 2015-12-30 | 阿斯利康(瑞典)有限公司 | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor |
| CN108658946A (en) * | 2017-03-28 | 2018-10-16 | 焦玉奇 | Novel quinazoline inhibitor |
| CN108329276A (en) * | 2018-04-23 | 2018-07-27 | 江苏兢业制药有限公司 | Hete rocyclic derivatives and its preparation and use |
| CN109438423A (en) * | 2018-09-12 | 2019-03-08 | 通化师范学院 | A kind of new method of the synthesis technology of lung cancer target compound AZD-3759 |
| CN110903283A (en) * | 2018-09-17 | 2020-03-24 | 南京雷正医药科技有限公司 | Substituted quinazoline compound, pharmaceutical composition containing compound and application of compound |
| CN110590683A (en) * | 2019-10-11 | 2019-12-20 | 山东四环药业股份有限公司 | A kind of preparation method of targeted drug AZD3759 intermediate |
Non-Patent Citations (1)
| Title |
|---|
| QINGBEI ZENG: "Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 20, 27 August 2015 (2015-08-27), pages 8200 - 8215, XP055483844, DOI: 10.1021/acs.jmedchem.5b01073 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9845315B2 (en) | Method for preparing Afatinib and intermediate thereof | |
| JP7685292B2 (en) | Edoxaban key intermediate and its synthesis method | |
| CN106749446B (en) | A kind of intermediate of epirubicin hydrochloride compound V | |
| CN112279838B (en) | Preparation method of pyrroltinib | |
| CN112979544B (en) | Preparation method of cabozitinib or salt thereof | |
| CN113943273A (en) | Preparation method of lung cancer drug AZD3759 | |
| CN108424389A (en) | A kind of preparation method of Ivabradine impurity | |
| CN108707163B (en) | A kind of preparation method of stevioside aglycone | |
| CN114014863B (en) | Preparation method of bone marrow protective agent traasiril | |
| CN115872906A (en) | Levatinib impurity and preparation method thereof | |
| CN116396226A (en) | Preparation method of agoraphobia and intermediate compound thereof | |
| CN114195739B (en) | High-purity roxatidine acetate hydrochloride, intermediate thereof and preparation method thereof | |
| CN101298448B (en) | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl ] phenol | |
| CN116675651A (en) | Synthesis method and application of impurity of midazolam | |
| CN117164600A (en) | Preparation method of ADC drug toxin irinotecan derivative Dxd | |
| CN119059990B (en) | Preparation method of 1-carbamic acid tert-butyl piperazine | |
| CN114262327A (en) | Preparation process of HER2 small-molecule inhibitor picatinib | |
| CN111808156A (en) | Beta-nicotinamide riboside chloride crystal form 1A and crystal form 1B and preparation method thereof | |
| CN105566429B (en) | Preparation method of obeticholic acid type 1 | |
| CN112778189A (en) | (3R,4S) -N-substituent-3-carboxylic acid-4-ethyl pyrrolidine, intermediate and lapatinib | |
| CN112898297B (en) | Polysubstituted biquinoline compound and preparation method and application thereof | |
| CN116332935B (en) | Synthesis method of folic acid | |
| CN116239503B (en) | A preparation method and use of lopinavir impurity T | |
| CN114560845B (en) | Crystal form alpha of quinoline compound, and preparation method and application thereof | |
| CN112341354B (en) | A kind of synthetic method of PMS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220118 |