CN112375043B - Method for preparing dacomitinib - Google Patents
Method for preparing dacomitinib Download PDFInfo
- Publication number
- CN112375043B CN112375043B CN202011342561.1A CN202011342561A CN112375043B CN 112375043 B CN112375043 B CN 112375043B CN 202011342561 A CN202011342561 A CN 202011342561A CN 112375043 B CN112375043 B CN 112375043B
- Authority
- CN
- China
- Prior art keywords
- reaction
- chloro
- methoxy
- dacomitinib
- compound
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The invention discloses a method for preparing dacomitinib, which takes 2-bromo-4-methoxy-5-nitrobenzonitrile as a starting material and is subjected to addition reaction with 3-chloro-4-fluoroaniline and formamideCyclizing, reducing with thiourea dioxide and acylating with (E) -4- (piperidine-1-yl) -2-butenoic acid to obtain the critinib, the raw materials are cheap and easy to obtain, the synthetic process route is short, the total yield is high, a noble metal hydrogenation catalyst is not used, the production cost is low, the operation is safe and simple, and the use of toxic and harmful POCl is avoided3And SOCl2And the method has no pollution to the environment, and provides an efficient and green process route for realizing the industrial scale production of the dacomitinib.
Description
Technical Field
The invention relates to synthesis of dacomitinib, in particular to a method for preparing dacomitinib by taking 2-bromo-4-methoxy-7-nitrobenzonitrile as an initial raw material through addition, cyclization, reduction and acylation reactions, and belongs to the technical field of organic synthesis.
Background
Dacomitinib (Dacomitinib), chemical name N- {4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-yl } -4- (piperidin-1-yl) -2-butenamide, chemical structure as follows:
dacomitinib is a potent, irreversible Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor developed by the american pfizer company, approved by the U.S. Food and Drug Administration (FDA) in 2018 month 9 for first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) patients carrying EGFR activating mutations, and is also a potential therapeutic agent for head and neck cancer, brain tumors, squamous cell carcinoma of the skin, pulmonary hypertension, and the like.
The literature reports that the synthetic route of dacomitinib is mainly as follows: (1) using 2-amino-4-fluorobenzoic acid as raw material, making cyclization with formamide, nitrifying with nitric acid-sulfuric acid and SOCl2Chlorination, nucleophilic substitution with 3-chloro-4-fluoroaniline, methoxylation with sodium methoxide, catalytic hydrogenation of Raney Ni, and acylation with 4-piperidine-2-butenoyl chloride to obtain dactinotinib with a total yield of 49.8% (Chenghaibo, Xubin, Zhang bin, et al., university of pharmacy 2014, 45(2): 165-169); (2) takes 7-fluoro-6-nitro-4 (3H) -quinazolinone as raw material and is subject to methoxylation and POCl3/SOCl2Chlorination, nucleophilic substitution with 3-chloro-4-fluoroaniline, Raney Ni catalytic hydrogenation, acylation with 4-bromo-2-butenamide, and nucleophilic substitution with piperidine to obtain dacomitinib with a total yield of 46.3% (Chua, Yun Huan, Wang Fei, et al, J. Med. Kol. Industrial., 2014, 45(2): 107-; (3) takes 4-hydroxy-6-amino-7-methoxy quinazoline as a raw material, and is condensed with 4-piperidine-2-butenoyl chloride, substituted with methylsulfonyl chloride and condensed with 3-chloro-4-fluoroaniline to obtain the cotinib with the total yield of 58.6 percent (Zhai Fumin, malus spectabilis, Hosper. Var. Schott., and the like. CN 106008372[ P106008372 ]]2016-10-12); (4) by (E)N' - (2-cyano-5-methoxy-4-nitrophenyl) -N, N-dimethylformamidine, starting from Pd/C catalyzed hydrogenation, acylation with 4- (1-piperidinyl) -2-butenoic acid, condensation with 3-chloro-4-fluoroaniline and Dimroth rearrangement, gave rise to Krtinib with a total yield of 58.5% (Yu S, Diat O. ACS Symposium Series, 2016, 1239: 235-252). The method (1) and the method (2) have the advantages of cheap and easily obtained raw materials, mild reaction conditions, multiple process steps and use of toxic and harmful POCl3And SOCl2A large amount of waste acid and waste gas are generated, the method is not friendly to the environment, and potential safety hazards exist in nitration reaction and hydrogenation catalysts. The methods (3) and (4) have short synthesis process route and higher yield of target products, but have difficult raw material source, use precious metal catalyst and higher production cost. Therefore, the development of the dacomitinib synthesis process has important research significance, short process route, high yield of target products, simple reaction operation, cheap and non-toxic reagents, environmental friendliness and easy industrial production.
Disclosure of Invention
The invention provides a preparation method of dactinib, which takes 2-bromo-4-methoxy-5-nitrobenzonitrile (I) as a starting material and obtains the dactinib (V) through addition, cyclization, reduction and acylation reactions.
The invention is realized by the following technical scheme:
a method for preparing dacomitinib, comprising the steps of:
(1) adding the compound I, 3-chloro-4-fluoroaniline and glacial acetic acid into a single-mouth bottle, stirring and dissolving, and heating and refluxing to react until the reaction is complete. Cooling the reaction liquid to room temperature, and carrying out reduced pressure distillation to remove acetic acid to obtain a compound II which is directly used for the next reaction;
(2) and (3) adding formamide, a catalyst, a ligand and alkali into the reaction product II in the last step, and heating to react completely. Cooling the reaction liquid to room temperature, pouring into ice water, carrying out suction filtration, washing with water, and carrying out vacuum drying to obtain a compound III;
(3) adding the compound III and ethanol into a three-neck flask, adding a sodium hydroxide solution (5mol/L) under stirring, heating to the reaction temperature, adding thiourea dioxide in batches, adding the thiourea dioxide within 1h, and continuing to perform heat preservation reaction until the reaction is complete. After the reaction liquid is cooled, carrying out reduced pressure distillation to remove ethanol, carrying out cooling crystallization in an ice water bath, carrying out suction filtration, washing with water, and carrying out vacuum drying to obtain a compound IV;
(4) adding (E) -4- (piperidine-1-yl) -2-butenoic acid, alkali and anhydrous dichloromethane into a three-neck bottle, adding a condensing agent under the cooling of an ice bath, stirring for reacting for 1h, adding a compound IV, and stirring at room temperature for reacting completely. And washing the reaction solution with a citric acid solution (mass fraction of 10%), a saturated sodium bicarbonate solution and a saturated saline solution in sequence, drying over anhydrous magnesium sulfate, evaporating under reduced pressure to remove the solvent, recrystallizing the residue with anhydrous ethanol, and drying under vacuum to obtain the critinib (V).
The specific chemical reaction formula is described as follows:
in the preparation method of dacomitinib, the molar ratio of the compound I and the 3-chloro-4-fluoroaniline in the step (1) is 1: 1-1.5, preferably 1: 1; the dosage of the glacial acetic acid is 2-5 mL/mmol of the compound I, and preferably 4mL/mmol of the compound I; and carrying out reflux reaction for 5-8 h, preferably 6 h.
In the step (2), the using amount of formamide is 4-8 mL/mmol of the compound I, and preferably 5mL/mmol of the compound I; the base used is potassium carbonate, or potassium phosphate, preferably potassium carbonate; the dosage of alkali is 200-300% (mole fraction), preferably 250% (mole fraction); the catalyst is copper acetate, hydrated copper acetate or hydrated copper sulfate, preferably hydrated copper acetate; the dosage of the catalyst is 5 to 20 percent (mole fraction), preferably 10 percent (mole fraction); the ligand is L-proline or phenanthroline, preferably L-proline; the dosage of the ligand is 10 percent to 30 percent (mole fraction), and the preferred dosage is 20 percent (mole fraction); the reaction temperature is 140-160 ℃, and preferably 160 ℃; the reaction time is 2-4 h, preferably 2.5 h.
In the step (3), the molar ratio of the compound III to thiourea dioxide is 1: 2-5, preferably 1: 4; the dosage of ethanol is 2-5 mL/mmol of compound III, preferably 3mL/mmol of compound III; the dosage of the sodium hydroxide solution (5mol/L) is 1-2 mL of mmol compound III, preferably 1.6mL/mmol compound III; the reaction temperature is 30-60 ℃, and preferably 60 ℃; the reaction time is 0.5-2 h, preferably 1 h.
In the step (4), the molar ratio of (E) -4- (piperidine-1-yl) -2-butenoic acid to the compound IV is 1: 1-1.5, preferably 1: 1; the base is triethylamine or diisopropylethylamine, preferably triethylamine; the molar ratio of the alkali to the compound IV is 1-3: 1, preferably 2: 1; the using amount of the anhydrous dichloromethane is 10-20 mL/mmol of the compound IV, preferably 15mL/mmol of the compound IV; the condensing agent is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBt), Dicyclohexylcarbodiimide (DCC) or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), preferably EDCI/HOBt; the molar ratio of the condensing agent to the compound IV is 1-1.5: 1, preferably 1.2: 1; the reaction time is 12-20 h, preferably 16 h.
In the invention, acetic acid can promote the addition reaction of 3-chloro-4-fluoroaniline and the compound I to obtain a product II, the acetic acid is removed by reduced pressure distillation after the reaction is finished, and the residue is directly used for the next reaction without separation and purification. The catalytic activity of the Cu (II) salt on the cyclization reaction is better than that of the Cu (I) salt, the crystallization water in the Cu (II) salt can promote the cyclization reaction, the yield of a compound III is obviously improved, and the catalytic effect of hydrated copper acetate is best; the catalytic activity for the cyclization reaction gradually increases with increasing catalyst usage. Both L-proline and phenanthroline can generate a synergistic catalytic effect with a catalyst, so that the catalytic effect of hydrated copper acetate/L-proline is better. The yield of compound III was higher when K2CO3 was used as a base compared to K3PO 4. Formamide is used as a reactant and a solvent, so that the cyclization reaction can be promoted to be smoothly carried out, and the increase of the dosage is beneficial to the improvement of the yield of the compound III. The temperature has great influence on the cyclization reaction, the cyclization reaction is difficult to carry out when the temperature is low, the speed of the cyclization reaction is accelerated when the temperature is increased, side reactions are caused when the temperature is higher than 160 ℃, and the yield of the compound III is reduced. The reaction time is prolonged to facilitate the completion of the cyclization reaction.
In the invention, thiourea dioxide generates sulfinic acid with strong reducibility under the alkaline condition, has controllable reduction effect, good water solubility, good stability, high safety and no pollution, and can be used as an excellent reducing agent for aromatic nitro compounds. The thiourea dioxide excess can promote the complete reduction of the nitro group. The temperature is increased, so that thiourea dioxide is decomposed into sulfinic acid with strong reducibility under the alkaline condition, and the yield of the compound IV is obviously increased. The thiourea dioxide has very high reduction potential under the alkaline condition, the reduction reaction can be completed within 1 hour, and the yield of the compound IV is basically unchanged after the reaction time is prolonged.
In the present invention, the use of toxic and harmful SOCl in the production is avoided2The amide is prepared by an active ester method. DCC, BOP and EDCI/HOBt can effectively promote the compound IV and (E) -4- (piperidine-1-yl) -2-butenoic acid to have acylation reaction, and EDCI/HOBt is a condensing agent, so that the side reaction is less, the yield of dactinoib is high, and the post-treatment is simple. Triethylamine as base can better promote the completion of acylation reaction. When the amount of the carboxylic acid is insufficient, the acylation reaction cannot be completely carried out; the excess carboxylic acid results in acylation of the amino group at the 4-position to form a 4, 6-diacylated by-product. The acylation reaction can be carried out at low temperature, but the reaction time is longer; the reaction time is short at reflux temperature, but a diacylation side reaction occurs. The reaction can be completed after 16h at room temperature, and the reaction time is prolonged without obvious increase of the yield of the critinib.
Compared with the prior art, the method adopts 2-bromo-4-methoxy-5-nitrobenzonitrile as an initial raw material, and the obtained product reaches the critinib (V) through addition, cyclization, reduction and acylation reactions, and has the advantages of low price and easy obtainment of the raw material, short process route, high total yield, no use of noble metal hydrogenation catalyst, low production cost, safe and simple operation, and avoidance of use of toxic and harmful POCl3And SOCl2The method has no pollution to the environment, and provides an efficient and green process route for realizing the industrial scale production of the dacomitinib.
Detailed Description
The present invention is further illustrated by the following examples, which are provided for the purpose of illustration only and are not to be construed as limiting the invention.
EXAMPLE 1 Synthesis of Compound II
5.14g (20mmol) of Compound I, 2.92g (20mmol) of 3-chloro-4-fluoroaniline and 80mL of glacial acetic acid were charged in a single-neck flask, dissolved by stirring, and then heated under reflux for 6 hours. And cooling the reaction liquid to room temperature, and distilling under reduced pressure to remove acetic acid to obtain a bright yellow solid II which is directly used for the next reaction without separation and purification.
EXAMPLE 2 Synthesis of Compound III
To the reaction product II obtained in the previous step, 100mL of formamide, 7.00g (50mmol) of potassium carbonate, 4.36g (24mmol) of copper acetate monohydrate, 0.92g (8mmol) of L-proline was added, and the mixture was reacted at 160 ℃ for 2.5 hours. The reaction solution was cooled to room temperature, poured into 500mL of ice water, filtered, washed with water, and vacuum dried at 45 ℃ for 24h to give 5.52g of yellow solid III, yield 79.1%.
EXAMPLE 3 Synthesis of Compound IV
4.16g (12mmol) of the compound III and 36mL of ethanol are added into a three-neck flask, 19.2mL of 5mol/L sodium hydroxide solution is added under stirring, the temperature is heated to 50 ℃, 5.18g (48mmol) of thiourea dioxide is added in portions within 1h, and the reaction is continued for 1h at 50 ℃. After the reaction liquid is cooled, ethanol is removed by reduced pressure distillation, the reaction liquid is cooled and crystallized in an ice water bath, filtered, washed and dried in vacuum at 45 ℃ for 24 hours to obtain 3.67g of off-white solid IV, and the yield is 96.0%.
Example 4 Synthesis of dacomitinib (V)
A three-necked flask was charged with 1.69g (10mmol) of (E) -4- (piperidin-1-yl) -2-butenoic acid, 2.8mL (20mmol) of triethylamine, and 150mL of anhydrous dichloromethane, and then 1.62g (12mmol) of HOBt and 2.30g (12mmol) of EDCI were added thereto in this order under cooling with ice, followed by stirring for 1 hour, 3.19g (10mmol) of the compound IV was added thereto, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was washed with a citric acid solution (mass fraction: 10%), a saturated sodium bicarbonate solution, and a saturated saline solution (3 × 100mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and the residue was recrystallized from anhydrous ethanol and dried under vacuum at 45 ℃ for 24 hours to obtain 4.25g of the target compound v, with a yield of 90.4% and a purity of 99.2% [ HPLC normalization: column Diamonsil C18 column (4.6 mm. times.250 mm, 5 μm); mobile phase 0.1mol/L ammonium acetate-methanol (25: 75); the flow rate is 1.0 ml/min; the detection wavelength is 250 nm; column temperature 25 deg.C ].
Claims (1)
1. A method of preparing dacomitinib, characterized by comprising the steps of:
(1) adding 20mmol of 2-bromo-4-methoxy-5-nitrobenzonitrile (I), 20mmol of 3-chloro-4-fluoroaniline and 80mL of glacial acetic acid into a single-mouth bottle, stirring for dissolving, and heating for reflux reaction for 6 hours; cooling the reaction liquid to room temperature, and distilling under reduced pressure to remove acetic acid to obtain N- (3-chloro-4-fluorophenyl) -2-bromo-4-methoxy-5-nitrobenzamidine (II), wherein the N- (3-chloro-4-fluorophenyl) -2-bromo-4-methoxy-5-nitrobenzamidine (II) is directly used for the next reaction without separation and purification;
(2) adding 100mL of formamide, 50mmol of potassium carbonate, 24mmol of copper acetate monohydrate and 8mmol of L-proline into the reaction product II in the last step, and reacting at 160 ℃ for 2.5 h; cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, carrying out suction filtration, washing with water, and carrying out vacuum drying to obtain N- (3-chloro-4-fluorophenyl) -7-methoxy-6-nitro quinazoline-4-amine (III);
(3) adding 12mmol of compound III and 36mL of ethanol into a three-neck flask, adding 19.2mL of 5mol/L sodium hydroxide solution while stirring, heating to 50 ℃, adding 48mmol of thiourea dioxide in batches, completing the addition within 1h, and continuing to react for 1h at 50 ℃; after the reaction liquid is cooled, ethanol is removed by reduced pressure distillation, and the reaction liquid is cooled and crystallized in an ice-water bath, filtered, washed and dried in vacuum to obtain N- (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4, 6-diamine (IV);
(4) adding 10mmol of (E) -4- (piperidine-1-yl) -2-butenoic acid, 20mmol of triethylamine and 150mL of anhydrous dichloromethane into a three-necked bottle, sequentially adding 12mmol of 1-hydroxybenzotriazole (HOBt) and 12mmol of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) under ice bath cooling, stirring for reacting for 1h, adding 10mmol of a compound IV, and stirring for reacting for 16h at room temperature; washing the reaction solution with a citric acid solution with the mass fraction of 10%, a saturated sodium bicarbonate solution and a saturated saline solution in sequence, drying with anhydrous magnesium sulfate, removing the solvent by evaporation under reduced pressure, recrystallizing the residue with anhydrous ethanol, and drying in vacuum to obtain the critinib (V).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011342561.1A CN112375043B (en) | 2020-11-26 | 2020-11-26 | Method for preparing dacomitinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011342561.1A CN112375043B (en) | 2020-11-26 | 2020-11-26 | Method for preparing dacomitinib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112375043A CN112375043A (en) | 2021-02-19 |
| CN112375043B true CN112375043B (en) | 2022-03-08 |
Family
ID=74588386
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011342561.1A Active CN112375043B (en) | 2020-11-26 | 2020-11-26 | Method for preparing dacomitinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112375043B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113354623B (en) * | 2021-04-28 | 2024-04-05 | 上海高准医药有限公司 | Preparation method of ilaprazole key intermediate 5- (1H-pyrrole-1-yl) -2-mercaptobenzimidazole |
| CN113214210B (en) * | 2021-05-10 | 2022-03-04 | 合肥立方制药股份有限公司 | Preparation method of dihydroquercetin |
| CN113185485B (en) | 2021-05-10 | 2022-03-04 | 合肥立方制药股份有限公司 | Semi-synthesis method of dihydroquercetin |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288758A (en) * | 2013-05-16 | 2013-09-11 | 苏州明锐医药科技有限公司 | Preparation method of dacomitinib (I) |
| CN103304492A (en) * | 2013-06-20 | 2013-09-18 | 湖南欧亚生物有限公司 | Synthesis method of EGFR (epidermal growth factor receptor) inhibitor Dacomitinib |
| CN106008372A (en) * | 2016-03-16 | 2016-10-12 | 江苏悦兴药业有限公司 | Preparation method and key intermediate of dacomitinib |
| CN109206377A (en) * | 2018-09-19 | 2019-01-15 | 江苏食品药品职业技术学院 | A kind of new method preparing the fluoro- 6- nitro -4- quinazoline amine of N- (the chloro- 4- fluorophenyl of 3-) -7- |
-
2020
- 2020-11-26 CN CN202011342561.1A patent/CN112375043B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288758A (en) * | 2013-05-16 | 2013-09-11 | 苏州明锐医药科技有限公司 | Preparation method of dacomitinib (I) |
| CN103304492A (en) * | 2013-06-20 | 2013-09-18 | 湖南欧亚生物有限公司 | Synthesis method of EGFR (epidermal growth factor receptor) inhibitor Dacomitinib |
| CN106008372A (en) * | 2016-03-16 | 2016-10-12 | 江苏悦兴药业有限公司 | Preparation method and key intermediate of dacomitinib |
| CN109206377A (en) * | 2018-09-19 | 2019-01-15 | 江苏食品药品职业技术学院 | A kind of new method preparing the fluoro- 6- nitro -4- quinazoline amine of N- (the chloro- 4- fluorophenyl of 3-) -7- |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112375043A (en) | 2021-02-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112375043B (en) | Method for preparing dacomitinib | |
| CA2852771C (en) | Process for preparing quinoline derivatives | |
| AU2017215801B2 (en) | TLR7 agonist crystalline form a, preparation method and use thereof | |
| US20040067969A1 (en) | Syntheses of quinazolinones | |
| CA2514933A1 (en) | Preparation of substituted quinazolines | |
| WO2016202125A1 (en) | Azd9291 intermediate and preparation method therefor | |
| WO2017133687A1 (en) | Tlr7 agonist trifluoroacetate salt and crystalline form b thereof, preparation methods and uses | |
| CN106928236A (en) | A kind of synthesis technique of Rui Boxini | |
| KR20050042502A (en) | Process for the preparation of 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline | |
| CN104529895B (en) | Synthetic method of replacing nitrogen-containing heterocyclic compound | |
| EP3527556B1 (en) | Method for preparing deuterated imidazole diketone compound | |
| CN105646374B (en) | A kind of preparation method of erlotinib Hydrochloride | |
| CN101351459A (en) | Method for producing 4(3H)-quinazolinone derivative | |
| CN106045980B (en) | A kind of quinazoline derivant and preparation method thereof | |
| CN107118215A (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediates | |
| CN112390750B (en) | Quinolinone compounds as selective phosphodiesterase 2 inhibitors and preparation method thereof | |
| CN109206377B (en) | Novel method for preparing N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine | |
| WO2014183560A1 (en) | Afatinib and preparation method of intermediate thereof | |
| CN1078466A (en) | Benzoxazine ketone and benzo buprofezin with cardiovascular effect | |
| US20230002322A1 (en) | New chemical process for making 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine a key intermediate of nt-814 | |
| CN112409272A (en) | Preparation method and application of 6-chloro-7-bromo-4 (3H) -quinazolinone | |
| CN112979544A (en) | Preparation method of cabozantinib or salt thereof | |
| JPS6310955B2 (en) | ||
| Fiorito et al. | Ultrasound-promoted synthesis of 4 (3H)-quinazolines under Yb (OTf) 3 catalysis | |
| CN104693071A (en) | N-hydroxyl-N'-benzyl octanediamide preparation method |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20210219 Assignee: Jiangsu Roer Pharmaceutical Co.,Ltd. Assignor: JIANGSU FOOD & PHARMACEUTICAL SCIENCE COLLEGE Contract record no.: X2022320000321 Denomination of invention: A method for preparing dactyltinib Granted publication date: 20220308 License type: Common License Record date: 20221210 |