CN108218754B - Preparation method of 2- (2,5-difluorophenyl) pyrrolidine - Google Patents
Preparation method of 2- (2,5-difluorophenyl) pyrrolidine Download PDFInfo
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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Abstract
The invention provides a preparation method of 2- (2,5-difluorophenyl) pyrrolidine, which comprises the following steps: (1) reacting the pyrrolidine with N-chlorosuccinimide to generate 1-chloropyrrolidine; (2) carrying out elimination reaction on the 1-chloropyrrolidine generated in the step (1) in a sodium methoxide solution to generate 3, 4-dihydro-2H-pyrrole; (3) and (3) reacting the 3, 4-dihydro-2H-pyrrole generated in the step (2) with a Grignard reagent of 2, 5-difluorobromobenzene to obtain 2- (2,5-difluorophenyl) pyrrolidine. The preparation method of the 2- (2,5-difluorophenyl) pyrrolidine has the advantages of reasonable synthesis process design, cheap reagent, convenient purchase, no heavy metal pollution, mild reaction conditions, low raw material cost, no need of special equipment, simple and convenient operation, low energy consumption and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of a drug intermediate, in particular to a preparation method of 2- (2,5-difluorophenyl) pyrrolidine.
Background
Larotrectinib (LOXO-101) sulfate, chemical name: (S) -N- (5- ((R) -2- (2,5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3-hydroxypyrolidine-1-carboxamide sulfate, CAS number: 1223405-08-0, the structural formula is as follows,
larotrectinib (LOXO-101) sulfate is an orally available, selective, ATP-competitive, potent inhibitor of the tropomyosin receptor kinase TRK, previously qualified by the FDA as a breakthrough medication on day 13/7 of 2016, for use in non-surgically resectable or metastatic solid tumors in adults and children that are TRK fusion gene mutation positive. Larotrectinib has been shown to have a long lasting anti-tumor activity and good tolerability in Trk fusion cancers of a wide range of ages and tumor types. Larotrectinib would be the first therapeutic drug to be developed and approved simultaneously in adults and children and the first tumor-targeted therapy in a molecular sense spanning all traditionally defined tumor types.
2- (2,5-difluorophenyl) pyrrolidine, CAS: 886503-15-7, which is an important intermediate for LOXO-101 synthesis and has the following structural formula,
at present, the preparation method of the compound has three methods as follows:
the method comprises the following steps: according to patent CN102224153A, a synthesis method is provided, as follows:
the synthesis process uses expensive reagents such as laburnine, palladium acetate and the like, so the synthesis cost is high; and the process needs low temperature (-78-65 ℃), has great requirements on industrial equipment and has great energy consumption.
The second method comprises the following steps: according to patent CN104114553A, a synthesis process is provided, as follows:
the synthesis process uses titanium ethoxide which is a hazardous chemical in a controlled type, and the process needs low temperature (-78 ℃), has great requirements on industrial equipment and has great energy consumption.
The third method comprises the following steps: another synthesis process is provided according to patent CN104114553A, as follows:
the synthesis process takes 2-pyrrolidone as a raw material, the total yield is about 36 percent, wherein, the last step is as follows: sodium borohydride is added into the methanol aqueous solution at room temperature, the reaction is violent, the control is not easy, and the operation is dangerous.
Therefore, the preparation process of the 2- (2,5-difluorophenyl) pyrrolidine has the following defects: the first method has high reagent cost, low reaction temperature (-78 to-65 ℃), high equipment requirement, high energy consumption and no contribution to industrialization; the method II uses the titanium ethoxide which is a tubular dangerous chemical, has low reaction temperature (-78 ℃), high equipment requirement and high energy consumption, and is not suitable for industrial production; the third method has violent reaction, is not easy to control and is dangerous to operate.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a preparation method of 2- (2,5-difluorophenyl) pyrrolidine.
In order to achieve the purpose, the invention adopts the technical scheme that: a preparation method of 2- (2,5-difluorophenyl) pyrrolidine comprises the following steps:
(1) reacting the pyrrolidine with N-chlorosuccinimide to generate 1-chloropyrrolidine;
(2) carrying out elimination reaction on the 1-chloropyrrolidine generated in the step (1) in a sodium methoxide solution to generate 3, 4-dihydro-2H-pyrrole;
(3) and (3) reacting the 3, 4-dihydro-2H-pyrrole generated in the step (2) with a Grignard reagent of 2, 5-difluorobromobenzene to obtain 2- (2,5-difluorophenyl) pyrrolidine.
The specific reaction route is as follows:
according to the steps, the obtained 2- (2,5-difluorophenyl) pyrrolidine is used as a racemate, and the chiral R-2- (2,5-difluorophenyl) pyrrolidine can be obtained by performing salt formation, crystallization and resolution on D-malic acid.
As a preferred embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, in the step (3), the temperature of the reaction of 3, 4-dihydro-2H-pyrrole with the grignard reagent of 2, 5-difluorobromobenzene is 0 to 50 ℃.
As a preferred embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, in the step (3), the temperature of the reaction of 3, 4-dihydro-2H-pyrrole with the grignard reagent of 2, 5-difluorobromobenzene is 10 to 25 ℃.
The reaction temperature is close to room temperature and relatively more economical.
As a preferred embodiment of the method for producing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, in the step (3), the molar ratio of 3, 4-dihydro-2H-pyrrole to 2, 5-difluorobromobenzene as the grignard reagent is: 3, 4-dihydro-2H-pyrrole: 2, 5-difluorobromobenzene is prepared from (1: 1) - (1: 2).
As a preferred embodiment of the method for producing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, in the step (3), the molar ratio of 3, 4-dihydro-2H-pyrrole to 2, 5-difluorobromobenzene as the grignard reagent is: 3, 4-dihydro-2H-pyrrole: 2, 5-difluorobromobenzene comprises Grignard reagent of 1: 1-1: 1.5.
The atom utilization rate is higher when the reaction is carried out at the mixture ratio.
In a preferred embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, in step (3), the reaction time of 3, 4-dihydro-2H-pyrrole with the grignard reagent of 2, 5-difluorobromobenzene is 4 to 16 hours.
As a preferred embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, in step (1), the temperature of the reaction of pyrrolidine with N-chlorosuccinimide is 20 ℃.
As a preferable embodiment of the method for producing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, in the step (2), the reaction temperature of 1-chloropyrrolidine in a sodium methoxide solution is 0 ℃.
The invention has the beneficial effects that: the invention provides a preparation method of 2- (2,5-difluorophenyl) pyrrolidine. The preparation method of the 2- (2,5-difluorophenyl) pyrrolidine has the advantages of reasonable synthesis process design, cheap reagent, convenient purchase, no heavy metal pollution, mild reaction conditions, low raw material cost, no need of special equipment, simple and convenient operation, low energy consumption and suitability for industrial production.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
In an embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present embodiment comprises the following steps:
(1) and 1-chloropyrrolidine preparation: adding N-chlorosuccinimide (43.37g, 325mmol, 1.1eq) and 160mL of methyl tert-butyl ether into a reaction bottle with a thermometer under the protection of nitrogen, stirring and cooling to below 20 ℃, slowly dropping pyrrolidine (21.00g, 295mmol, 1.0eq), stirring and reacting at room temperature for 24 hours, and stopping reaction; adding 80mL of water, stirring to dissolve clearly, standing for layering, washing an organic layer with 80mL of 20% saline water, drying with anhydrous magnesium sulfate, and evaporating the solvent at a temperature of not higher than 25 ℃ under reduced pressure to obtain 31.00g of light yellow oily substance, namely 1-chloropyrrolidine, wherein the yield is 99%;
(2) and 3, 4-dihydro-2H-pyrrole: in a reaction bottle with a thermometer, under the protection of nitrogen, adding 30% sodium methoxide (102.31g, 568mmol and 2eq), stirring and cooling to 0 ℃, slowly dropwise adding 1-chloropyrrolidine (30.00g, 284mmol and 1.0eq), after the addition, keeping the temperature and reacting for 1 hour, then heating to room temperature, stirring and reacting for 2 hours, adding water, stirring and dissolving, extracting for three times by 3X 100mL methyl tert-butyl ether, combining organic phases, washing with brine, drying with anhydrous magnesium sulfate, and evaporating to remove the solvent to obtain 17.25g of light yellow oily substance, namely 3, 4-dihydro-2H-pyrrole with the yield of 88%;
(3) and 2- (2,5-difluorophenyl) pyrrolidine: in a reaction bottle provided with a reflux pipe, a constant-pressure dropping filter funnel and a thermometer, under the protection of nitrogen, magnesium chips (3.00g, 125mmol, 1.4eq) and anhydrous tetrahydrofuran (20 mL, 1-bromoethane (0.2mL) are sequentially added, 2, 5-difluorobromobenzene (20.00g, 104mmol, 1.2eq, dissolved in 40mL of anhydrous THF) is dropped by about one fourth, the mixture is stirred and heated to 45 ℃, the mixture is stirred for 0.5 hour, the reaction is started, 2, 5-difluorobromobenzene solution is continuously dropped slowly, after the completion of the addition, the reaction is kept warm for 2 hours, the temperature is reduced to 25 ℃, 3, 4-dihydro-2H-pyrrole (6.00g, 87mol, 1.0eq) is dropped, after the reaction is completed, the reaction is kept warm at 25 ℃ for 8 hours, sodium hydroxide solution is added for dissolution, dichloromethane is extracted twice, organic layers are combined, brine is washed, anhydrous magnesium sulfate is dried, the solvent is evaporated under reduced pressure, and yellow oily matter 13.2g is obtained, namely, the yield of the 2- (2,5-difluorophenyl) pyrrolidine is 83 percent.
The product obtained in this example was characterized by HNMR, and the nuclear magnetic data is:1H-NMR(400MHz,CDCl3),δppm:6.75～7.05(m,2H),7.18～7.26(m,1H),4.41(dd,J＝7.6,4.0Hz,1H),3.03～3.55(m,2H),1.45～1.93(m,4H)，MS(m/z),([M+H]+),184.05. Therefore, the obtained product is the target compound 2- (2,5-difluorophenyl) pyrrolidine.
Example 2
In an embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present embodiment comprises the following steps:
(1) and 1-chloropyrrolidine preparation: the same as example 1;
(2) and 3, 4-dihydro-2H-pyrrole: the same as example 1;
(3) and 2- (2,5-difluorophenyl) pyrrolidine: in a reaction bottle provided with a reflux pipe, a constant-pressure dropping filter funnel and a thermometer, under the protection of nitrogen, magnesium chips (2.54g, 104mmol, 1.2eq) and anhydrous tetrahydrofuran (20 mL) and 1-bromoethane (0.2mL) are sequentially added, 2, 5-difluorobromobenzene (16.80g, 87mmol, 1.0eq and dissolved in 35mL of anhydrous THF) is dropped by about one fourth, the mixture is stirred and heated to 45 ℃, the mixture is stirred for 0.5 hour, the reaction is started, 2, 5-difluorobromobenzene solution is continuously dropped slowly, after the completion of the addition, the reaction is kept warm for 2 hours, the temperature is reduced to 0 ℃, 3, 4-dihydro-2H-pyrrole (6.00g, 87mol and 1.0eq) is dropped, after the reaction is completed, the reaction is kept warm at 0 ℃, the mixture is added with sodium hydroxide solution and dissolved clear, dichloromethane is extracted twice, organic layers are combined, brine is washed, anhydrous magnesium sulfate is dried, the solvent is evaporated under reduced pressure, 12.85g of yellow oily matter is obtained, namely, the yield of the 2- (2,5-difluorophenyl) pyrrolidine is 81 percent.
Example 3
In an embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present embodiment comprises the following steps:
(1) and 1-chloropyrrolidine preparation: the same as example 1;
(2) and 3, 4-dihydro-2H-pyrrole: the same as example 1;
(3) and 2- (2,5-difluorophenyl) pyrrolidine: in a reaction bottle provided with a reflux pipe, a constant-pressure dropping filter funnel and a thermometer, under the protection of nitrogen, magnesium chips (3.80g, 156mmol, 1.8eq) and anhydrous tetrahydrofuran (20 mL) and 1-bromoethane (0.2mL) are sequentially added, 2, 5-difluorobromobenzene (25.10g, 130mmol, 1.5eq and dissolved in 50mL anhydrous THF) is dropped by about one fourth, the mixture is stirred and heated to 45 ℃, the mixture is stirred for 0.5 hour, the reaction is started, 2, 5-difluorobromobenzene solution is continuously dropped slowly, after the completion of the addition, the reaction is kept warm for 2 hours, the temperature is reduced to 25 ℃, 3, 4-dihydro-2H-pyrrole (6.00g, 87mol and 1.0eq) is dropped, after the reaction is completed, the reaction is kept warm at 25 ℃ for 8 hours, sodium hydroxide solution is added for dissolution, dichloromethane is extracted twice, organic layers are combined, brine is washed, anhydrous magnesium sulfate is dried, the solvent is evaporated under reduced pressure, and yellow oily matter 12.50g is obtained, this was found to be 2- (2,5-difluorophenyl) pyrrolidine with a yield of 78%.
Example 4
In an embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present embodiment comprises the following steps:
(1) and 1-chloropyrrolidine preparation: the same as example 1;
(2) and 3, 4-dihydro-2H-pyrrole: the same as example 1;
(3) and 2- (2,5-difluorophenyl) pyrrolidine: in a reaction bottle provided with a reflux pipe, a constant-pressure dropping filter funnel and a thermometer, under the protection of nitrogen, magnesium chips (5.07g, 209mmol, 2.4eq) and anhydrous tetrahydrofuran (20 mL) and 1-bromoethane (0.2mL) are sequentially added, 2, 5-difluorobromobenzene (33.58g, 174mmol, 2.0eq, dissolved in 65mL anhydrous THF) is dropped by about one fourth, the mixture is stirred and heated to 45 ℃, the mixture is stirred for 0.5 hour, the reaction is started, the 2, 5-difluorobromobenzene solution is continuously and slowly dropped, after the completion of the addition, the temperature is kept for 2 hours, the temperature is reduced to 25 ℃, 3, 4-dihydro-2H-pyrrole (6.00g, 87mol, 1.0eq) is dropped, after the completion of the addition, the temperature is kept at 25 ℃, the reaction is stirred for 8 hours, sodium hydroxide solution is added, dichloromethane is dissolved and extracted twice, organic layers are combined, washed by brine, dried by anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, 14.34g of yellow, namely, the yield of the 2- (2,5-difluorophenyl) pyrrolidine is 90%.
Example 5
In an embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present embodiment comprises the following steps:
(1) and 1-chloropyrrolidine preparation: the same as example 1;
(2) and 3, 4-dihydro-2H-pyrrole: the same as example 1;
(3) and 2- (2,5-difluorophenyl) pyrrolidine: in a reaction bottle provided with a reflux pipe, a constant-pressure dropping filter funnel and a thermometer, under the protection of nitrogen, magnesium chips (3.00g, 125mmol, 1.4eq) and anhydrous tetrahydrofuran (20 mL, 1-bromoethane (0.2mL) are sequentially added, 2, 5-difluorobromobenzene (20.00g, 104mmol, 1.2eq, dissolved in 40mL of anhydrous THF) is dropped, the mixture is stirred and heated to 45 ℃, the mixture is stirred for 0.5 hour, the reaction is started, 2, 5-difluorobromobenzene solution is continuously dropped slowly, after the completion of the addition, the reaction is kept warm for 2 hours, 3, 4-dihydro-2H-pyrrole (6.00g, 87mol, 1.0eq) is dropped, after the completion of the addition, the reaction is kept warm at 50 ℃ for 4 hours, the mixture is cooled to room temperature, sodium hydroxide solution is added for dissolution, dichloromethane is extracted twice, organic layers are combined, brine is washed, anhydrous magnesium sulfate is dried, the solvent is evaporated under reduced pressure, and yellow oily matter 14.02g is obtained, this was found to be 2- (2,5-difluorophenyl) pyrrolidine with a yield of 88%.
Example 6
In an embodiment of the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present invention, the method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to the present embodiment comprises the following steps:
(1) and 1-chloropyrrolidine preparation: the same as example 1;
(2) and 3, 4-dihydro-2H-pyrrole: the same as example 1;
(3) and 2- (2,5-difluorophenyl) pyrrolidine: in a reaction bottle provided with a reflux pipe, a constant-pressure dropping filter funnel and a thermometer, under the protection of nitrogen, magnesium chips (3.00g, 125mmol, 1.4eq) and anhydrous tetrahydrofuran (20 mL, 1-bromoethane (0.2mL) are sequentially added, 2, 5-difluorobromobenzene (20.00g, 104mmol, 1.2eq, dissolved in 40mL of anhydrous THF) is dropped by about one fourth, the mixture is stirred and heated to 45 ℃, the mixture is stirred for 0.5 hour, the reaction is started, 2, 5-difluorobromobenzene solution is continuously dropped slowly, after the completion of the addition, the temperature is kept for reaction for 2 hours, the temperature is reduced to 10 ℃, the mixture is dropped by 3, 4-dihydro-2H-pyrrole (6.00g, 87mol, 1.0eq) is dropped, after the completion of the reaction is kept at 10 ℃, the temperature is dropped to room temperature, sodium hydroxide solution is added for clear, dichloromethane is extracted twice, organic layers are combined, washed by brine, the anhydrous magnesium sulfate is dried, the solvent is evaporated under reduced pressure, 14.82g of yellow oily substance is obtained, namely the 2- (2,5-difluorophenyl) pyrrolidine is obtained, and the yield is 93%.
The 2- (2,5-difluorophenyl) pyrrolidine obtained in the example is used for preparing 2- (2,5-difluorophenyl) pyrrolidine-D-malate, and the specific steps are as follows:
the 2- (2,5-difluorophenyl) pyrrolidine obtained in this example was dissolved in 150mL of ethanol, heated to 65 ℃, D-malic acid (7.5g,56.0mmol) was added, cooled to room temperature, and seeded with 100mg of R-2- (2,5-difluorophenyl) pyrrolidine-D-malate at 55 ℃. Filtration and drying of 15.3g of 2- (2,5-difluorophenyl) pyrrolidine-D-malate with 30mL of ethanol gave a yield of 61% and a value of 75% ee by chiral liquid chromatography. By the same crystallization procedure, the ee value can be increased to 95% with an overall yield of 35%.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (7)
1. A preparation method of 2- (2,5-difluorophenyl) pyrrolidine is characterized by comprising the following steps:
(1) reacting the pyrrolidine with N-chlorosuccinimide to generate 1-chloropyrrolidine;
(2) carrying out elimination reaction on the 1-chloropyrrolidine generated in the step (1) in a sodium methoxide solution to generate 3, 4-dihydro-2H-pyrrole;
(3) and (3) reacting the 3, 4-dihydro-2H-pyrrole generated in the step (2) with a Grignard reagent of 2, 5-difluorobromobenzene at constant temperature of 0-50 ℃ to obtain 2- (2,5-difluorophenyl) pyrrolidine.
2. The method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to claim 1, wherein in step (3), the reaction temperature of 3, 4-dihydro-2H-pyrrole and the grignard reagent of 2, 5-difluorobromobenzene is 10 to 25 ℃.
3. The process for preparing 2- (2,5-difluorophenyl) pyrrolidine according to claim 1, wherein in step (3), the molar ratio of 3, 4-dihydro-2H-pyrrole to 2, 5-difluorobromobenzene is: 3, 4-dihydro-2H-pyrrole: 2, 5-difluorobromobenzene is prepared from (1: 1) - (1: 2).
4. The process for preparing 2- (2,5-difluorophenyl) pyrrolidine according to claim 1, wherein in step (3), the molar ratio of 3, 4-dihydro-2H-pyrrole to 2, 5-difluorobromobenzene is: 3, 4-dihydro-2H-pyrrole: 2, 5-difluorobromobenzene comprises Grignard reagent of 1: 1-1: 1.5.
5. The method for preparing 2- (2,5-difluorophenyl) pyrrolidine according to claim 1, wherein in step (3), the reaction time of 3, 4-dihydro-2H-pyrrole and the grignard reagent of 2, 5-difluorobromobenzene is 4-16H.
6. The process for preparing 2- (2,5-difluorophenyl) pyrrolidine according to claim 1, wherein in step (1), the temperature for the reaction of pyrrolidine with N-chlorosuccinimide is 20 ℃.
7. The process for producing 2- (2,5-difluorophenyl) pyrrolidine according to claim 1, wherein in the step (2), the reaction temperature of 1-chloropyrrolidine in a sodium methoxide solution is 0 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102056927A (en) * | 2008-05-13 | 2011-05-11 | Irm责任有限公司 | Fused nitrogen containing heterocycles and compositions thereof as kinase inhibitors |
| CN102224153A (en) * | 2008-09-22 | 2011-10-19 | 阵列生物制药公司 | Substituted imidazo[1,2b]pyridazine compounds as trk kinase inhibitors |
| WO2013088257A1 (en) * | 2011-12-12 | 2013-06-20 | Dr. Reddy's Laboratories Ltd. | Substituted heterocyclic compounds as tropomyosin receptor kinase a (trka) inhibitors |
| CN107207514A (en) * | 2014-12-15 | 2017-09-26 | 康联制药有限公司 | Fused ring heteroaryl compound and its purposes as TRK inhibitor |
-
2018
- 2018-01-23 CN CN201810066842.5A patent/CN108218754B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102056927A (en) * | 2008-05-13 | 2011-05-11 | Irm责任有限公司 | Fused nitrogen containing heterocycles and compositions thereof as kinase inhibitors |
| CN102224153A (en) * | 2008-09-22 | 2011-10-19 | 阵列生物制药公司 | Substituted imidazo[1,2b]pyridazine compounds as trk kinase inhibitors |
| WO2013088257A1 (en) * | 2011-12-12 | 2013-06-20 | Dr. Reddy's Laboratories Ltd. | Substituted heterocyclic compounds as tropomyosin receptor kinase a (trka) inhibitors |
| CN104114553A (en) * | 2011-12-12 | 2014-10-22 | 雷迪博士实验室有限公司 | Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (Trk) inhibitors |
| CN107207514A (en) * | 2014-12-15 | 2017-09-26 | 康联制药有限公司 | Fused ring heteroaryl compound and its purposes as TRK inhibitor |
Non-Patent Citations (4)
| Title |
|---|
| Chemical hybridizing agents. Synthesis of racemic cis- and trans-methanoproline;Willy D. Kollmeyer等;《ACS Symposium Series》;19871231;第355卷;第401-408页 * |
| Four-component condensation: a new versatile method for the synthesis of substituted prolyl peptides;Ruth F. Nutt等;《J. Am. Chem. Soc.》;19821231;第104卷(第21期);第5852-5853页 * |
| Regioselective Addition Reactions of Organometallic Reagents with 3-Benzylidene Heterocyclic Imines Leading to the Synthesis of Pyrrolizidines;Duy H. Hua等;《J. Org. Chem.》;19891231;第54卷(第22期);第5399-5402页 * |
| Synthesis of 1-(3-dimethylaminopropyl)-2-substituted spiro[cycloalkane-1,3-indolines];Jose Gonzalo Rodriguez等;《J. Chem. Soc. Perkin. Trans.》;19881231(第12期);第3243-3247页 * |
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