CN107522690B - Preparation method of Osimetinib - Google Patents
Preparation method of Osimetinib Download PDFInfo
- Publication number
- CN107522690B CN107522690B CN201610445669.0A CN201610445669A CN107522690B CN 107522690 B CN107522690 B CN 107522690B CN 201610445669 A CN201610445669 A CN 201610445669A CN 107522690 B CN107522690 B CN 107522690B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- formula
- water
- acetonitrile
- 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
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a preparation method of Osimertinib, and the raw material 3-chloropropionic acid related by the invention has low toxicity, stable property, easily available source, mild reaction condition and simple operation, and can obtain a high-purity product at high yield, thereby being suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a synthesis method of Osimetinib.
Background
Osimertinib, also known as AZD9291, chemically known as N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-propenamide, is an oral, irreversible, third-generation EGFR inhibitor (EGFR-TKI) developed by asikang, british, which is on the market by FDA accelerated approval on 11/13/2015 for the treatment of EGFR T790M mutant non-small cell lung cancer (NSCLC).
The document CN 103702990B et al describes two reaction routes:
route one is as follows:
in the first route, acryloyl chloride with high toxicity is used as a raw material, the flash point is low, volatile and highly toxic gas exists, the risk that explosive substances are easily formed when the acryloyl chloride contacts air exists, the acryloyl chloride does not meet the standard of green chemistry, and the product is difficult to purify, has low yield and is not suitable for industrial production.
Route two is as follows:
Disclosure of Invention
The invention provides a method for synthesizing Osimetinib, which comprises the following steps:
wherein the content of the first and second substances,
step I: carrying out condensation reaction on the compound of the formula A, a condensing agent and 3-chloropropionic acid to obtain a compound of a formula B;
step II: the compound of formula B undergoes a self-elimination reaction to provide a compound of formula C.
Step I is to prepare a compound shown in a formula B by condensing a compound shown in a formula A and 3-chloropropionic acid, wherein a condensing agent for the reaction is selected from one or more of 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), N, N ' -Carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI) and 1-Hydroxybenzotriazole (HOBT). In a preferred embodiment, the molar ratio of the condensing agent HATU to the compound A is 1-2.5: 1, preferably 1.3 to 1.5: 1.
the reaction temperature in the step I is-10-40 ℃, and the reaction time is 1-19 h. The preferable reaction temperature is-10 ℃, and the reaction time is 1-8 h.
The reaction solvent in the step I is one or more of acetone, acetonitrile, dichloromethane, N-Dimethylformamide (DMF) and N, N-Dimethylacetamide (DMAC). In a preferred embodiment, the solvent is dichloromethane.
In the step I, the molar ratio of the 3-chloropropionic acid to the compound A is 0.9-1.3: 1, more preferably 1 to 1.1: 1.
and (3) after the reaction in the step I is finished, adjusting the pH value of the system to 7-8 by using an alkali substance, extracting and washing the reaction system by using water, and distilling an organic phase under reduced pressure to obtain a compound B. The added alkali substance is selected from one or more of N, N-Diisopropylethylamine (DIPEA), triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, and preferably is triethylamine.
In the reaction in the step II, the alkaline reagent is one or more selected from triethylamine and N, N-diisopropylethylamine, and the feeding molar ratio of the alkaline reagent to the compound B is 1-10: 1.
And (3) adding water to precipitate the Osimetinib after the reaction is finished, wherein the reaction solvent in the step (II) is acetonitrile.
A specific reaction process of the step I is as follows: and (3) putting 3-chloropropionic acid and dichloromethane into a reaction bottle, cooling to-10 ℃, sequentially adding HATU and the compound A, and reacting at-10 ℃. And after the reaction is finished for about 4-5 hours, adding water and triethylamine to adjust the pH value to 7-8. Separating and extracting, washing the organic layer with water, and distilling under reduced pressure to obtain the compound B.
A specific reaction process of the step II is as follows: and dissolving the compound B in acetonitrile, adding triethylamine, and heating to 60-70 ℃. And after about 8-10 hours of reaction, dropwise adding water at 60-70 ℃, cooling to room temperature after dropwise adding, stirring for 2-3 hours, filtering, washing a filter cake with a mixed solution (1:1) of acetonitrile and water, and drying in vacuum to obtain a compound C.
In the designed synthetic route, the compound of the formula A, a condensing agent and 3-chloropropionic acid are subjected to condensation reaction to obtain a compound of the formula B, and the compound of the formula B is subjected to self elimination reaction to obtain a target product of the formula C. The 3-chloropropionic acid related to the raw material has low toxicity, stable property, easily obtained source, mild reaction condition and simple operation, and can obtain a high-purity product at high yield, thereby being suitable for industrial production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention will be described in more detail hereinafter by means of examples, which are intended to be illustrative further and should not be construed as limiting the invention.
The reaction scheme for each of the following examples is as follows:
example 1:
the first step is as follows: preparation of 3-chloro-N- [2- [ 2-dimethylaminoethyl (methyl) amino ] -4-methoxy-5- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] propanamide (B).
3-Chloropropionic acid (15.3g, 0.141mol), acetone (700ml), CDI (25.13g, 0.155mol), feed A (70g, 0.157mol) were added sequentially in a 2L three-necked flask, the temperature being kept below 10 ℃ during the addition. Reacting for 11h, adding DIPEA and water (700ml), adjusting the pH to 7-8, stirring, separating, taking down the organic layer of the lower layer, and discarding the upper layer. The organic layer was washed twice with water (700ml) and distilled under reduced pressure to give compound B.
The second step is that: preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-propenamide (C).
Adding acetonitrile (700ml) into the compound B prepared in the first step, adding triethylamine (15.15g, 0.15mol) into the system, heating to 70 ℃, stirring for reaction for 10.5h, dripping water (700ml), cooling and stirring. Filtration, cake washing with acetonitrile and water mixture, vacuum drying gave compound C (69.58g, 0.139mol), HPLC purity: 99.72 percent. The total yield of the two steps is 88.7%.
Example 2:
the first step is as follows: preparation of 3-chloro-N- [2- [ 2-dimethylaminoethyl (methyl) amino ] -4-methoxy-5- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] propanamide (B).
3-chloropropionic acid (22.15g, 0.204mol), acetonitrile (700ml), ECDI (75.24g, 0.393mol), stream A (70g, 0.157mol) were charged sequentially in a 2L three-necked flask, the temperature being maintained below 10 ℃ during the addition. Reacting for 11h, adding potassium hydroxide and water (700ml), adjusting the pH value to 7-8, stirring, separating, taking down the organic layer of the lower layer, and discarding the upper layer. The organic layer was washed twice with water (700ml) and distilled under reduced pressure to give compound B.
The second step is that: preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-propenamide (C).
Adding acetonitrile (700ml) into the compound B prepared in the first step, adding triethylamine (79.43g, 0.785mol) into the system, heating to 70 ℃, stirring for reaction for 10.5h, dripping water (700ml), cooling and stirring. Filtration, cake washing with acetonitrile and water mixture, and vacuum drying gave compound C (70.99g, 0.142mol), HPLC purity: 99.76 percent. The total yield of the two steps is 90.5%.
Example 3:
the first step is as follows: preparation of 3-chloro-N- [2- [ 2-dimethylaminoethyl (methyl) amino ] -4-methoxy-5- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] propanamide (B).
3-Chloropropionic acid (18.74g, 0.173mol), DMF (700ml), HOBT (42.43g, 0.314mol), feed A (70g, 0.157mol) were added sequentially in a 2L three-necked flask, the temperature being maintained below 10 ℃ during the addition. Reacting for 11h, adding sodium hydroxide and water (700ml), adjusting the pH value to 7-8, stirring, separating, taking down the organic layer of the lower layer, and discarding the upper layer. The organic layer was washed twice with water (700ml) and distilled under reduced pressure to give compound B.
The second step is that: preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-propenamide (C).
Adding acetonitrile (700ml) into the compound B prepared in the first step, adding diethylamine (80.38g, 1.1mol) into the system, heating to 70 ℃, stirring for reaction for 10.5h, dripping water (700ml), cooling and stirring. Filtration, cake washing with acetonitrile and water mixture, vacuum drying gave compound C (70.2g, 0.141mol), HPLC purity: 99.81 percent. The total yield of the two steps is 89.5%.
Example 4:
the first step is as follows: preparation of 3-chloro-N- [2- [ 2-dimethylaminoethyl (methyl) amino ] -4-methoxy-5- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] propanamide (B).
3-Chloropropionic acid (17.04g, 0.157mol), DMF (350ml), DMAC (350ml), HATU (44.77g, 0.118mol), HBTU (44.75g, 0.118mol) and feed A (70g, 0.157mol) were added in succession to a 2L three-necked flask, the temperature being maintained below 10 ℃ during the addition. Reacting for 11h, adding sodium carbonate and water (700ml), adjusting the pH to 7-8, stirring, separating, taking down the organic layer of the lower layer, and discarding the upper layer. The organic layer was washed twice with water (700ml) and distilled under reduced pressure to give compound B.
The second step is that: preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-propenamide (C).
Adding acetonitrile (700ml) into the compound B prepared in the first step, adding diethylamine (114.8g, 1.57mol) into the system, heating to 70 ℃, stirring for reaction for 10.5h, dripping water (700ml), cooling and stirring. Filtration, cake washing with acetonitrile and water mixture, vacuum drying gave compound C (69.4g, 0.139mol), HPLC purity: 99.77 percent. The total yield of the two steps is 88.5 percent.
Example 5:
the first step is as follows: preparation of 3-chloro-N- [2- [ 2-dimethylaminoethyl (methyl) amino ] -4-methoxy-5- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] propanamide (B).
3-Chloropropionic acid (17.5g, 0.161mol), methylene chloride (700ml), HATU (89.5g, 0.236mol), feed A (70g, 0.157mol) were charged sequentially in a 2L three-necked flask, with the temperature maintained below 10 ℃ during the addition. Reacting for 11h, adding triethylamine and water (700ml), adjusting the pH value to 7-8, stirring, separating, taking down the organic layer of the lower layer, and discarding the upper layer. The organic layer was washed twice with water (700ml) and distilled under reduced pressure to give compound B.
The second step is that: preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-propenamide (C).
Adding acetonitrile (700ml) into the compound B prepared in the first step, adding triethylamine (47.9g, 0.473mol) into the system, heating to 70 ℃, stirring for reaction for 10.5h, dripping water (700ml), cooling and stirring. Filtration, cake washing with acetonitrile and water mixture, and vacuum drying gave compound C (70.04g, 0.14mol), HPLC purity: 99.79 percent. 1 H-NMR(DMSO-d 6 )：10.26(1H,s)，9.24(1H,s)，8.71(1H,s)，8.35(1H,d)，8.25(1H,d)，7.94(1H,s)，7.51(1H,d)，7.24(2H,m)，7.16(1H,m)，7.04(1H,s)，6.44(1H,m)，6.30(1H,dd)，5.78(1H,dd)，3.91(3H,s)，3.87(3H,s)，2.87(2H,t)，2.71(3H,s)，2.27(2H,t)，2.19(6H,s)；MS：[M+1] + 500. The total yield of the two steps is as follows:89.3％。
example 6:
the first step is as follows: preparation of 3-chloro-N- [2- [ 2-dimethylaminoethyl (methyl) amino ] -4-methoxy-5- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] propionamide (B): sequentially adding 3-chloropropionic acid (162.8g, 1.5mol), dichloromethane (6500ml), HATU (830g, 2.19mol) and material A (650g, 1.46mol) into a 20L three-necked bottle at-10 ℃, reacting for 9h, adding triethylamine (500ml) and water (6500ml) to adjust the pH to 7-8, stirring, separating, taking the lower organic layer, and discarding the upper layer. The organic layer was washed twice with water (6500ml), and distilled under reduced pressure to give Compound B.
The second step: n- [2- [ [2- (dimethylamino) ethyl ] methyl]Methylamino radical]-4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl]Amino group]Phenyl radical]-preparation of 2-acrylamide (C): adding acetonitrile (4000ml) into the compound B prepared in the first step, adding triethylamine (450g, 4.45mol) into the system, heating to 60-70 ℃, stirring for reaction for 4.5h, dripping water (6500ml), cooling and stirring. Filtration, cake washing with a mixture of acetonitrile and water, and vacuum drying gave compound C (638.3g, 1.28mol), MS: [ M +1 ]] + 500. HPLC purity: 99.80 percent. The total yield of the two steps is as follows: 87.5 percent.
Example 7:
the first step is as follows: preparation of 3-chloro-N- [2- [ 2-dimethylaminoethyl (methyl) amino ] -4-methoxy-5- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] propionamide (B): adding dichloromethane (29.4L), 3-chloropropionic acid (734.5g, 6.77mol), HATU (3.26Kg, 8.6mol) and a material A (2.94Kg, 6.6mol) into a 100L reaction kettle in sequence, controlling the temperature to be minus 10-10 ℃, reacting for 10h, adding triethylamine (1.35Kg, 13.35mol) and water (29.4L) to adjust the pH to be 7-8, stirring, taking a lower organic layer, and discarding an upper layer. The organic layer was washed twice with water (29.4L) and distilled under reduced pressure to give Compound B.
The second step is that: n- [2- [ [2- (dimethylamino) ethyl ] methyl]Methylamino radical]-4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl]Amino group]Phenyl radical]-preparation of 2-acrylamide (C): acetonitrile (29.4L) was added to the compound B prepared in the first step, and triethylamine (2.0Kg, 19.78mol) was added to the system in litersHeating to 60-70 ℃, stirring for reaction for 13.5h, dripping water (29.4L), cooling and stirring. Filtration, cake washing with acetonitrile and water mixture, vacuum drying to give compound C (2.87kg, 5.75mol), MS: [ M +1 ]] + 500. HPLC purity: 99.81 percent. The total yield of the two steps is as follows: 87.1 percent.
Claims (2)
1. A preparation method of Osimetinib is characterized by comprising the following steps:
step I: carrying out condensation reaction on the compound of the formula A, a condensing agent and 3-chloropropionic acid, wherein the reaction temperature in the step I is-10 ℃, after the reaction in the step I is finished, adjusting the pH value of a reaction system to 7-8 by using an alkali substance, extracting and washing by using water, and distilling and drying an organic phase to obtain a compound of the formula B; the alkali substance is selected from potassium hydroxide, the condensing agent is selected from EDCI, the reaction solvent is selected from acetonitrile, and the molar ratio of the condensing agent to the compound of the formula A is 2.5: 1, the molar ratio of the 3-chloropropionic acid to the compound of the formula A is 1.3: 1;
step II: carrying out self-elimination reaction on the compound shown in the formula B in the presence of an alkaline reagent to obtain Osimetinib shown in a formula C;
the specific reaction process is as follows: dissolving the compound B in acetonitrile, adding triethylamine, and heating to 60-70 ℃; after 10 hours of reaction, dripping water at 60-70 ℃, cooling to room temperature after dripping, stirring for 2-3 hours, and filtering, wherein the volume ratio of acetonitrile to water for a filter cake is 1:1, and drying in vacuum to obtain a compound C.
2. The preparation method according to claim 1, wherein the molar ratio of the alkaline agent to the compound B in step II is 1-10: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610445669.0A CN107522690B (en) | 2016-06-20 | 2016-06-20 | Preparation method of Osimetinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610445669.0A CN107522690B (en) | 2016-06-20 | 2016-06-20 | Preparation method of Osimetinib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107522690A CN107522690A (en) | 2017-12-29 |
| CN107522690B true CN107522690B (en) | 2022-08-05 |
Family
ID=60733891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610445669.0A Active CN107522690B (en) | 2016-06-20 | 2016-06-20 | Preparation method of Osimetinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107522690B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108218839A (en) * | 2018-03-20 | 2018-06-29 | 上药康丽（常州）药业有限公司 | A kind of preparation method of antitumor drug AZD9291 |
| US11639344B2 (en) | 2018-05-15 | 2023-05-02 | InventisBio Co., Ltd. | EGFR inhibitors |
| CN110698461B (en) * | 2018-07-09 | 2024-04-05 | 上海翰森生物医药科技有限公司 | Preparation method of third-generation EGFR inhibitor |
| CN115433169B (en) * | 2022-11-07 | 2023-04-18 | 北京鑫开元医药科技有限公司 | Preparation method of oxitinib mesylate dimer |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102009001438A1 (en) * | 2009-03-10 | 2010-09-16 | Bayer Schering Pharma Aktiengesellschaft | New carbonylamino-substituted anilino-pyrimidine compounds are tyrosine kinase-2 inhibitors, useful for treating diseases associated with inflammatory conditions e.g. bronchitis, rheumatoid arthritis, psoriasis and Guillain Barre syndrome |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN105153122A (en) * | 2015-08-27 | 2015-12-16 | 上海圣考医药科技有限公司 | [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt |
| CN105461695A (en) * | 2014-09-29 | 2016-04-06 | 齐鲁制药有限公司 | Pyrimidine or triazine derivative, and preparation method and use thereof |
-
2016
- 2016-06-20 CN CN201610445669.0A patent/CN107522690B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102009001438A1 (en) * | 2009-03-10 | 2010-09-16 | Bayer Schering Pharma Aktiengesellschaft | New carbonylamino-substituted anilino-pyrimidine compounds are tyrosine kinase-2 inhibitors, useful for treating diseases associated with inflammatory conditions e.g. bronchitis, rheumatoid arthritis, psoriasis and Guillain Barre syndrome |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN105461695A (en) * | 2014-09-29 | 2016-04-06 | 齐鲁制药有限公司 | Pyrimidine or triazine derivative, and preparation method and use thereof |
| CN105153122A (en) * | 2015-08-27 | 2015-12-16 | 上海圣考医药科技有限公司 | [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107522690A (en) | 2017-12-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107522690B (en) | Preparation method of Osimetinib | |
| CN101812060B (en) | Simple novel method for preparing high-purity Sprycel, and intermediate compound | |
| CN101845045A (en) | Novel method for synthesizing dasatinib | |
| CN105198821B (en) | Lip river former times replaces the preparation method of Buddhist nun | |
| CN104059025A (en) | Novel intermediate used for preparation of avanafil and preparation method thereof | |
| CN105753944B (en) | His Wei of Dacca and its derivative prepare intermediate | |
| CN101985442A (en) | Convenient and quick method for preparing high-purity imatinib and mesylate thereof | |
| CN105859686B (en) | Refining method of dabigatran etexilate free alkali | |
| CN107311893B (en) | The synthetic method of temperature-sensitive sensitizer N- tolysulfonyl-N '-(3- tolysulfonyl phenyl) urea | |
| CN106565607B (en) | A kind of synthetic method of N-BETA-Alanyl-L-histidine | |
| CN105130887A (en) | Regorafenib preparation method | |
| JP2019147763A (en) | Manufacturing method of proline amide compound | |
| CN105085595B (en) | A kind of method of deacylation base protection 2,6 halosubstituted purine nucleosides of synthesis | |
| CN112457304B (en) | Preparation method of nifuratel | |
| CN112979544A (en) | Preparation method of cabozantinib or salt thereof | |
| CN108456202B (en) | Preparation method of azilsartan with low amide impurity content | |
| CN106905177A (en) | A kind of preparation method of the biphenyl propionic acid ethyl ester derivative hydrochloride of 2 amino 3 | |
| CN106632347B (en) | Preparation method of pyrrolopyrazine compound and salt thereof | |
| CN102153518A (en) | Preparation method of Gefitinib | |
| CN110698381A (en) | Method for synthesizing N- (benzyloxycarbonyl) succinimide by one-pot two-phase method | |
| CN106995446B (en) | Preparation method of Bruton's tyrosine kinase inhibitor | |
| CN104211705B (en) | A kind of preparation method of sldenafil | |
| CN108774210A (en) | A method of preparing high-purity imatinib | |
| CN112442038B (en) | Industrial preparation method of pemetrexed disodium | |
| CN110229099B (en) | Method for preparing sorafenib key intermediate |
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 | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20201230 Address after: 570311 No. 2 Yaogu No. 3 Road, Xiuying District, Haikou City, Hainan Province Applicant after: Hainan Simcere Pharmaceutical Co.,Ltd. Applicant after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Applicant before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |