CN107522690A - A kind of Osimertinib preparation method - Google Patents
A kind of Osimertinib preparation method Download PDFInfo
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- CN107522690A CN107522690A CN201610445669.0A CN201610445669A CN107522690A CN 107522690 A CN107522690 A CN 107522690A CN 201610445669 A CN201610445669 A CN 201610445669A CN 107522690 A CN107522690 A CN 107522690A
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- 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
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Abstract
The invention provides a kind of Osimertinib preparation method, and the chloropropionic acid toxicity of raw material 3 is low involved by invention, and property is stable, and source is easy to get, and reaction condition is gentle, simple to operate, while energy high productivity obtains the product of high-purity, is adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of organic synthesis, it is related to Osimertinib synthetic method.
Background technology
Osimertinib, also known as AZD9291, the entitled N- of chemistry [2- [[2- (dimethylamino) ethyl] methylamino]-
4- methoxyl groups -5- [[4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides are Britain Ahs
A kind of oral, irreversible, third generation EGFR inhibitor (EGFR-TKI) of this sharp Kanggong department exploitation, FDA was in 2015 11
Accelerated approval listing on the moon 13, for treating the non-small cell lung cancer (NSCLC) of EGFR T790M mutation.
The documents such as the B of CN 103702990 describe two kinds of reaction schemes：
Route one is as follows：
Route one employs the very big acryloyl chloride of toxicity as raw material, and its flash-point is low, volatile hypertoxicity gas, exists and connects
Tactile air easily forms the risk of explosive substance, does not meet the standard of Green Chemistry, and the more difficult purifying of product, and yield is relatively low,
Be not suitable for industrialized production.
Route two is as follows：
Route
3- chlorpromazine chlorides used in two equally have high toxicity, low-flash, severe reaction conditions, to equipment requirement height.
The content of the invention
The invention provides a kind of Osimertinib synthetic methods, its synthetic route is：
Wherein,
Step I：Formula A compounds carry out condensation reaction with condensing agent and 3- chloropropionic acids, obtain formula B compounds；
Step II：Formula B compounds carry out itself elimination reaction, obtain formula C compounds.
Step I is that formula A compounds are condensed formula B compounds with 3- chloropropionic acids, and the condensing agent of the reaction is selected from 2- (7- idols
Nitrogen BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), BTA-N, N, N', N'- tetramethyl
Urea hexafluorophosphoric acid ester (HBTU), N, N'- carbonyl dimidazoles (CDI), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides
(EDCI), the one or more of I-hydroxybenzotriazole (HOBT).In a kind of preferred scheme, condensing agent HATU and A compounds
Mol ratio be 1~2.5：1, preferably 1.3~1.5：1.
Reaction temperature in step I is -10~40 DEG C, and the reaction time is 1~19h.Preferable reaction temperature is -10~10
DEG C, the reaction time is 1~8h.
In step I reaction dissolvent be acetone, acetonitrile, dichloromethane, N,N-dimethylformamide (DMF), N, N- dimethyl
The one or more of acetamide (DMAC).In a kind of preferred scheme, solvent selects dichloromethane.
In step I, the mol ratio of 3- chloropropionic acids and A compounds is 0.9~1.3：1, more preferably 1~1.1：1.
After step I reactions terminate, with alkaloid substance regulation system pH value to 7~8, reaction system carries out extracting and washing with water,
It is evaporated under reduced pressure organic phase and obtains compound B.The alkaloid substance of addition is selected from N, N- diisopropylethylamine (DIPEA), triethylamine, hydrogen-oxygen
Change the one or more in potassium, sodium hydroxide, potassium carbonate, sodium carbonate, preferably triethylamine.
In step II reactions, one or more of the described alkaline reagent in triethylamine, DIPEA,
Itself and compound B molar ratio are 1~10:1.
Reaction dissolvent described in step II is acetonitrile, and after reaction terminates, adding water precipitates precipitation Osimertinib.
A kind of step I specific course of reaction is as follows：By in 3- chloropropionic acids, dichloromethane input reaction bulb, -10 are cooled to
~10 DEG C, HATU and compound A are sequentially added, keeping temperature is -10~10 DEG C of reactions.After reaction in about 4~5 hours terminates, add
Enter water, triethylamine regulation pH=7~8.Liquid separation is extracted, and organic layer is washed with water, and vacuum distillation obtains compound B.
A kind of step II specific course of reaction is as follows：Compound B is dissolved in acetonitrile, adds triethylamine, it is warming up to 60~
70℃.After reaction in about 8~10 hours terminates, water is added dropwise at 60~70 DEG C, room temperature is cooled to after completion of dropwise addition, stirring 2~3 is small
When, filter, filter cake acetonitrile and water mixed liquid (1:1) wash, compound C is obtained after vacuum drying.
In the synthetic route that the present invention designs, condensation reaction is carried out with formula A compounds and condensing agent and 3- chloropropionic acids, obtained
Formula B compounds, B compounds carry out itself elimination reaction, obtain formula C target products.Raw material 3- chloropropionic acids poison involved in the present invention
Property it is low, property is stable, and source is easy to get, and reaction condition is gentle, simple to operate, at the same can high productivity obtain the production of high-purity
Product, it is adapted to industrialized production.
Specific embodiment
The present invention will be in being hereafter exemplarily used for furtherly by embodiment more detailed description, these embodiments
It is bright, and be not construed as limiting the present invention.
The reaction scheme of following embodiment is as follows：
Embodiment 1：
The first step：The chloro- N- of 3- [2- [2- dimethylaminoethyls (methyl) amino] -4- methoxyl groups -5- [[4- (1- methyl Yin
Diindyl -3- bases) pyrimidine -2-base] amino] phenyl] propionamide (B) preparation.
Sequentially added in 2L there-necked flasks 3- chloropropionic acids (15.3g, 0.141mol), acetone (700ml), CDI (25.13g,
0.155mol), material A (70g, 0.157mol), charging process keeping temperature are less than 10 DEG C.11h is reacted, adds DIPEA and water
(700ml) regulation pH is 7~8 and stirred, and liquid separation, takes lower organic layer, discards upper strata.Organic layer is washed with water (700ml)
Twice, it is evaporated under reduced pressure and obtains compound B.
Second step：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl isophthalic acids H-
Indol-3-yl) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides (C) preparation.
Acetonitrile (700ml) is added into the preparation-obtained compound B of the first step, triethylamine is added into system
(15.15g, 0.15mol), 70 DEG C, stirring reaction 10.5h are warming up to, instill water (700ml) and be added dropwise, cooling stirring.Cross
Filter, filter cake are washed with acetonitrile and water mixed liquid, and compound C (69.58g, 0.139mol), HPLC purity are obtained after vacuum drying：
99.72%.Two step total recoverys 88.7%.
Embodiment 2：
The first step：The chloro- N- of 3- [2- [2- dimethylaminoethyls (methyl) amino] -4- methoxyl groups -5- [[4- (1- methyl Yin
Diindyl -3- bases) pyrimidine -2-base] amino] phenyl] propionamide (B) preparation.
3- chloropropionic acids (22.15g, 0.204mol), acetonitrile (700ml), ECDI are sequentially added in 2L there-necked flasks
(75.24g, 0.393mol), material A (70g, 0.157mol), charging process keeping temperature are less than 10 DEG C.11h is reacted, adds hydrogen
Potassium oxide and water (700ml) regulation pH are 7~8 and stirred, and liquid separation, take lower organic layer, discard upper strata.By organic layer water
(700ml) is washed twice, and vacuum distillation obtains compound B.
Second step：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl isophthalic acids H-
Indol-3-yl) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides (C) preparation.
Acetonitrile (700ml) is added into the preparation-obtained compound B of the first step, triethylamine is added into system
(79.43g, 0.785mol), 70 DEG C, stirring reaction 10.5h are warming up to, instill water (700ml) and be added dropwise, cooling stirring.Cross
Filter, filter cake are washed with acetonitrile and water mixed liquid, and compound C (70.99g, 0.142mol), HPLC purity are obtained after vacuum drying：
99.76%.Two step total recoverys 90.5%.
Embodiment 3：
The first step：The chloro- N- of 3- [2- [2- dimethylaminoethyls (methyl) amino] -4- methoxyl groups -5- [[4- (1- methyl Yin
Diindyl -3- bases) pyrimidine -2-base] amino] phenyl] propionamide (B) preparation.
Sequentially added in 2L there-necked flasks 3- chloropropionic acids (18.74g, 0.173mol), DMF (700ml), HOBT (42.43g,
0.314mol), material A (70g, 0.157mol), charging process keeping temperature are less than 10 DEG C.React 11h, add sodium hydroxide and
Water (700ml) regulation pH is 7~8 and stirred, and liquid separation, takes lower organic layer, discards upper strata.Organic layer is washed with water (700ml)
Wash twice, vacuum distillation obtains compound B.
Second step：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl isophthalic acids H-
Indol-3-yl) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides (C) preparation.
Acetonitrile (700ml) is added into the preparation-obtained compound B of the first step, diethylamine is added into system
(80.38g, 1.1mol), 70 DEG C, stirring reaction 10.5h are warming up to, instill water (700ml) and be added dropwise, cooling stirring.Filtering,
Filter cake is washed with acetonitrile and water mixed liquid, and compound C (70.2g, 0.141mol), HPLC purity are obtained after vacuum drying：
99.81%.Two step total recoverys 89.5%.
Embodiment 4：
The first step：The chloro- N- of 3- [2- [2- dimethylaminoethyls (methyl) amino] -4- methoxyl groups -5- [[4- (1- methyl Yin
Diindyl -3- bases) pyrimidine -2-base] amino] phenyl] propionamide (B) preparation.
Sequentially added in 2L there-necked flasks 3- chloropropionic acids (17.04g, 0.157mol), DMF (350ml), DMAC (350ml),
HATU (44.77g, 0.118mol), HBTU (44.75g, 0.118mol) material A (70g, 0.157mol), charging process keep temperature
Degree is less than 10 DEG C.11h is reacted, sodium carbonate is added and water (700ml) regulation pH is 7~8 and stirred, liquid separation, take lower organic layer,
Discard upper strata.Organic layer is washed twice with water (700ml), vacuum distillation obtains compound B.
Second step：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl isophthalic acids H-
Indol-3-yl) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides (C) preparation.
Acetonitrile (700ml) is added into the preparation-obtained compound B of the first step, diethylamine is added into system
(114.8g, 1.57mol), 70 DEG C, stirring reaction 10.5h are warming up to, instill water (700ml) and be added dropwise, cooling stirring.Cross
Filter, filter cake are washed with acetonitrile and water mixed liquid, and compound C (69.4g, 0.139mol), HPLC purity are obtained after vacuum drying：
99.77%.Two step total recoverys 88.5%.
Embodiment 5：
The first step：The chloro- N- of 3- [2- [2- dimethylaminoethyls (methyl) amino] -4- methoxyl groups -5- [[4- (1- methyl Yin
Diindyl -3- bases) pyrimidine -2-base] amino] phenyl] propionamide (B) preparation.
3- chloropropionic acids (17.5g, 0.161mol), dichloromethane (700ml), HATU are sequentially added in 2L there-necked flasks
(89.5g, 0.236mol), material A (70g, 0.157mol), charging process keeping temperature are less than 10 DEG C.11h is reacted, adds three
Ethamine and water (700ml) regulation pH are 7~8 and stirred, and liquid separation, take lower organic layer, discard upper strata.By organic layer water
(700ml) is washed twice, and vacuum distillation obtains compound B.
Second step：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl isophthalic acids H-
Indol-3-yl) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides (C) preparation.
Acetonitrile (700ml) is added into the preparation-obtained compound B of the first step, triethylamine is added into system
(47.9g, 0.473mol), 70 DEG C, stirring reaction 10.5h are warming up to, instill water (700ml) and be added dropwise, cooling stirring.Cross
Filter, filter cake are washed with acetonitrile and water mixed liquid, and compound C (70.04g, 0.14mol), HPLC purity are obtained after vacuum drying：
99.79%.1H-NMR(DMSO-d6)：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.Two step total recoverys：89.3%.
Embodiment 6：
The first step：The chloro- N- of 3- [2- [2- dimethylaminoethyls (methyl) amino] -4- methoxyl groups -5- [[4- (1- methyl Yin
Diindyl -3- bases) pyrimidine -2-base] amino] phenyl] propionamide (B) preparation：At -10~10 DEG C, add successively in 20L there-necked flasks
Enter 3- chloropropionic acids (162.8g, 1.5mol), dichloromethane (6500ml), HATU (830g, 2.19mol), material A (650g,
1.46mol), 9h is reacted, triethylamine (500ml) is added and water (6500ml) regulation pH is 7~8 and stirred, liquid separation that removing layer has
Machine layer, discards upper strata.Organic layer is washed twice with water (6500ml), vacuum distillation obtains compound B.
Second step：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl isophthalic acids H-
Indol-3-yl) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides (C) preparation：To the preparation-obtained compound of the first step
Acetonitrile (4000ml) is added in B, triethylamine (450g, 4.45mol) is added into system and is warming up to 60~70 DEG C, stirring reaction
4.5h, instill water (6500ml), cooling stirring.Filtering, filter cake are washed with acetonitrile and water mixed liquid, and compound is obtained after vacuum drying
C (638.3g, 1.28mol), MS：[M+1]+=500.HPLC purity：99.80%.Two step total recoverys：87.5%.
Embodiment 7：
The first step：The chloro- N- of 3- [2- [2- dimethylaminoethyls (methyl) amino] -4- methoxyl groups -5- [[4- (1- methyl Yin
Diindyl -3- bases) pyrimidine -2-base] amino] phenyl] propionamide (B) preparation：Dichloromethane is sequentially added into 100L reactors
(29.4L), 3- chloropropionic acids (734.5g, 6.77mol), HATU (3.26Kg, 8.6mol), material A (2.94Kg, 6.6mol), control
Temperature -10~10 DEG C processed, 10h is reacted, add triethylamine (1.35Kg, 13.35mol) and water (29.4L) regulation pH as 7~8 simultaneously
Stirring, takes lower organic layer, discards upper strata.Organic layer is washed twice with water (29.4L), and vacuum distillation obtains compound B.
Second step：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl isophthalic acids H-
Indol-3-yl) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides (C) preparation：To the preparation-obtained compound of the first step
Acetonitrile (29.4L) is added in B, triethylamine (2.0Kg, 19.78mol) is added into system and is warming up to 60~70 DEG C, stirring reaction
13.5h, instill water (29.4L), cooling stirring.Filtering, filter cake are washed with acetonitrile and water mixed liquid, and compound is obtained after vacuum drying
C (2.87kg, 5.75mol), MS：[M+1]+=500.HPLC purity：99.81%.Two step total recoverys：87.1%.
Claims (12)
1. a kind of Osimertinib preparation method, it is characterised in that it comprises the following steps：
Step I：Formula A compounds carry out condensation reaction with condensing agent and 3- chloropropionic acids, obtain formula B compounds；
Step II：Formula B compounds carry out itself elimination reaction in the presence of alkaline reagent, obtain shown in formula C
Osimertinib；
2. synthetic method according to claim 1, it is characterised in that described condensing agent is selected from the 2- (nitrogen of 7- azos benzo three
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), BTA-N, N, N', N'- tetramethylurea hexafluorophosphoric acid
Ester (HBTU), N, N'- carbonyl dimidazoles (CDI), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDCI) and 1- hydroxyls
One or more in BTA (HOBt), preferably 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluoros
Phosphate (HATU).
3. synthetic method according to claim 1, it is characterised in that the reaction temperature in described step I is -10~40
DEG C, preferably -10~10 DEG C.
4. synthetic method according to claim 1, it is characterised in that reaction dissolvent in described step I be selected from acetone,
One or more in acetonitrile, dichloromethane, DMF, DMA, preferably dichloromethane.
5. synthetic method according to claim 1, it is characterised in that in described step I, condensing agent and formula A compounds
Mol ratio is 1~2.5：1, preferably 1.3~1.5：1.
6. synthetic method according to claim 1, it is characterised in that in described step I, 3- chloropropionic acids and formula A compounds
Mol ratio be 0.9~1.3：1, preferably 1~1.1：1.
7. synthetic method according to claim 1, it is characterised in that after described step I reactions terminate, adjusted with alkaloid substance
PH value of reaction system is saved to after 7~8, with water extracting and washing, organic phase distillation is dried to obtain compound B.
8. synthetic method according to claim 7, it is characterised in that described alkaloid substance be selected from DIPEA,
One or more in triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, preferably triethylamine.
9. synthetic method according to claim 1, it is characterised in that the alkaline reagent in described step II is selected from three second
Amine, N, the one or more in N- diisopropylethylamine.
10. synthetic method according to claim 1, it is characterised in that alkaline reagent and compound in described step II
B molar ratio is 1~10:1.
11. synthetic method according to claim 1, it is characterised in that the reaction dissolvent in described step II is acetonitrile.
12. synthetic method according to claim 1, it is characterised in that after described step II reactions terminate, adding water makes
Separate out solid Osimertinib.
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Cited By (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 |
| WO2019218987A1 (en) * | 2018-05-15 | 2019-11-21 | Inventisbio Shanghai Ltd. | Egfr inhibitors |
| CN110698461A (en) * | 2018-07-09 | 2020-01-17 | 上海翰森生物医药科技有限公司 | Preparation method of third-generation EGFR inhibitor |
| CN115433169A (en) * | 2022-11-07 | 2022-12-06 | 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 |
Non-Patent Citations (4)
| Title |
|---|
| 吴梧桐 主编: "《生物制药工艺学 第4版》", 31 August 2015, 中国医药科技出版社 * |
| 吴梧桐主编: "《生物化学 第二版》", 31 March 2010, 中国医药科技出版社 * |
| 曾戎: "《多糖基高分子-药物轭合物的设计、合成、表征和评价》", 31 May 2011, 华南理工大学出版社 * |
| 王永红 等: "《综合化学实验》", 31 August 2009, 浙江大学出版社 * |
Cited By (7)
| 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 |
| WO2019218987A1 (en) * | 2018-05-15 | 2019-11-21 | Inventisbio Shanghai Ltd. | Egfr inhibitors |
| CN112119074A (en) * | 2018-05-15 | 2020-12-22 | 益方生物科技（上海）有限公司 | EGFR inhibitors |
| US11639344B2 (en) | 2018-05-15 | 2023-05-02 | InventisBio Co., Ltd. | EGFR inhibitors |
| CN110698461A (en) * | 2018-07-09 | 2020-01-17 | 上海翰森生物医药科技有限公司 | Preparation method of third-generation EGFR inhibitor |
| 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 |
| CN115433169A (en) * | 2022-11-07 | 2022-12-06 | 北京鑫开元医药科技有限公司 | Preparation method of oxitinib mesylate dimer |
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| CN107522690B (en) | 2022-08-05 |
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