CN105461640B - A kind of preparation method of tyrosine kinase inhibitor - Google Patents
A kind of preparation method of tyrosine kinase inhibitor Download PDFInfo
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- CN105461640B CN105461640B CN201510871586.3A CN201510871586A CN105461640B CN 105461640 B CN105461640 B CN 105461640B CN 201510871586 A CN201510871586 A CN 201510871586A CN 105461640 B CN105461640 B CN 105461640B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Abstract
The present invention relates to a kind of tyrosine kinase inhibitor RociletinibN [3 [[2 [[4 (piperazinyl of 4 acetyl group 1) 2 methoxyphenyls] amino] 5 (trifluoromethyl) 4 pyrimidine radicals] amino] phenyl] the new preparation method of 2 acrylamides, creative use compound（Ⅶ）Key intermediate of (trifluoromethyl) pyrimidine of 2 [[4 (piperazinyl of 4 acetyl group 1) 2 methoxyphenyls] amino] 4 chlorine 5 as synthesis Rociletinib, can make target product and isomeric by-products ratio in reaction system reach 4:More than 1, the drawbacks of of a relatively high selectivity avoids more existing synthetic method accessory substance, polishing purification difficulty well.Preparation method of the present invention is simple to operate, and favorable reproducibility is economic and environment-friendly, can prepare the high Rociletinib of purity, and total recovery reaches 60~65%, is adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of tyrosine kinase inhibitor-Rociletinib is new
Preparation method.
Background technology
Rociletinib（CO-1686, N- [3- [[2- [[4- (4- acetyl group -1- piperazinyls) -2- methoxyphenyls] ammonia
Base] -5- (trifluoromethyl) -4- pyrimidine radicals] amino] phenyl] -2- acrylamides, see compound 1 in reaction equation one）It is Clovis
Oncology companies third generation tyrosine kinase inhibitor, non-small cell lung cancer is mutated mainly for T790M has been produced（NSCLC）
Irreversible EGF-R ELISA（EGFR）Inhibitor.Research shows that Rociletinib is a kind of oral efficient junket
Histidine kinase inhibitor, it can be produced by Cys797 at the ATP binding pockets with EGFR tyrosine kinase domains irreversible common
Valence link is combined so as to suppress protein kinase activity.More importantly Rociletinib can selective depression EGFR activated mutants（Such as
L858R）It is mutated with acquired resistance（Such as T790M）, and the effect to Wild type EGFR is very weak, therefore effectively can reduce or keep away
Exempt from because targeting Wild type EGFR and caused by toxicity, be expected to turn into treatment carry EGFR activated mutants NSCLC patient two wires
Medication.
This patent document CN103269704A of A Wei rummies is built in west, and《Chinese Journal of Pharmaceuticals》, 2014,45
(8)：The method for preparing Rociletinib and intermediate is reported in 710-713, sees reaction equation one.However, on the synthesis road
In the preparation process of line compound 2, the disubstituted accessory substance of piperazine is more, and reaction controlling difficulty is big, and yield is low；In addition, compound 5
Preparation process in, in reaction system, the target product of 4 nucleophilic displacement of fluorine of pyrimidine and the accessory substance of 2 nucleophilic displacement of fluorine of pyrimidine
Ratio be almost 1:1, and both solubility are extremely similar, purifying difficulty is larger, and yield is relatively low；Furthermore the preparation of compound 6
In use iron powder reducing nitro, produce iron cement, environmental pollution is serious.
Reaction equation one
To sum up, nearly all concentrated with reference to existing patent and document, the maximum difficult point of current Rociletinib synthetic methods
Synthesizing the intermediate 5 of above-mentioned route, the chloro- 5- trifluoromethyl pyrimidines -4- amine of N- (3- nitrobenzophenones) -2-, title intermediate with
The ratio of its accessory substance isomers is almost 1:1, it is purified, and difficulty is big, and yield is low, and is not solved effectively for a long time,
This brings many puzzlements to pharmaceutical developments person, it would therefore be highly desirable to develop a new synthetic route to solve the above problems.
The content of the invention
In view of the above-mentioned problems, the present invention provides a kind of simple to operate, favorable reproducibility, system economic and environment-friendly, product purity is high
Standby tyrosine kinase inhibitor-Rociletinib new method.
To solve problem above, grope by substantial amounts of experiment, the present invention is achieved through the following technical solutions：
The design of synthetic route of the present invention such as following formula：
Reaction equation two
Reaction equation three
Compound in formula（Ⅱ）, compound（Ⅲ）, compound（Ⅵ）, compound (VIII) and compound（Ⅷ'）It is commercially available,
For the reliable raw material of steady quality being easy to get.The use compound of the invention（Ⅶ）As synthesis Rociletinib's
Key intermediate, overcome the problem not solved effectively for a long time.Those skilled in the art are known, 2,4 dichloro pyrimidines
Generation nucleophilic substitution, substituted activity order be 4 and be more than 2, but the present invention is in the presence of lewis acid etc., then adds
Upper nucleophilic attack reagent compound（Ⅴ）It own electronic cloud Density Distribution Feature, can take 2 nucleophilics of pyrimidine in reaction system
The target product in generation is compound（Ⅶ）Reach 4 with the isomeric by-products ratio of 4 nucleophilic displacement of fluorine of pyrimidine:More than 1, relatively
High selectivity avoids the drawbacks of more existing synthetic method accessory substance, polishing purification difficulty well, announces the present invention below
The detailed preparation method of patent.
Compound（Ⅳ）It can be prepared by existing method：With compound（Ⅱ）And compound（Ⅲ）For initiation material, warp
Nucleophilic substitution obtains compound（Ⅳ）.
Compound（Ⅴ）Can be by compound（Ⅳ）Prepared by palladium carbon catalytic hydrogenation.
Compound（Ⅶ）Compound can be passed through（Ⅴ）With compound（Ⅵ）It is made under Louis acid catalysis, conventional road
Lewis acid is the common lewis acid reagents, preferably zinc chloride such as zinc chloride, aluminium chloride or iron chloride；Conventional solvent is inertia
Solvent, such as aromatic hydrocarbons（Toluene etc.）, ethers（Ether, tetrahydrofuran etc.）, halo alkanes（Dichloromethane, chloroform etc.）, esters（Second
Acetoacetic ester etc.）, amide-type（Such as N,N-dimethylformamide, DMAC N,N' dimethyl acetamide）, sulfone class（Such as dimethyl sulfoxide (DMSO)）、
Nitrile（Acetonitrile etc.）, ketone（Such as acetone）, preferred tetrahydrofuran；Compound（Ⅵ）Dosage be usually compound（Ⅴ）Material
1~1.5 times of amount, lewis acidic dosage is generally in compound（Ⅴ）2~5 times of the amount of material, preferably 2~3 times；Reaction
Temperature is generally at 20~80 DEG C, preferably 20~50 DEG C；Reaction time is generally in 8~24h, preferably 16~24h.
Compound（Ⅶ）With（Ⅷ）Reaction obtains compound（Ⅰ）That is Rociletinib, reaction are generally entered in the system of alcohol
OK, conventional alcohol includes methanol, ethanol, isopropanol, n-butanol etc., preferably methanol；The compound（Ⅷ）For formula（Ⅶ）Chemical combination
1~1.5 times of the amount of thing material, the HCl dosages of hydrochloric acid are generally in compound（Ⅶ）1~6 times of the amount of material, preferably 2~4
Times.
Compound（Ⅶ）With（Ⅷ’）React to obtain compound（Ⅸ）, react and generally carried out in the system of alcohol, conventional alcohol bag
Include methanol, ethanol, isopropanol, normal propyl alcohol etc., preferably methanol；Compound（Ⅷ’）Dosage generally in compound（Ⅶ）Material
1~6 times, preferably 1~1.5 times of amount；Reaction temperature is generally at 20~80 DEG C, preferably 60~70 DEG C；Reaction time generally 8~
24h, preferably 5~10h.
Compound（Ⅸ）Deprotection reaction obtains compound（Ⅹ）, react generally in the system of alcohol or chloralkane to enter
OK；Conventional alcohol includes methanol, ethanol, isopropanol, normal propyl alcohol etc., preferably methanol；Conventional chloralkane include dichloromethane,
Chloroform, 1,2- dichloroethanes etc., preferably dichloromethane；Conventional acid is hydrochloric acid or trifluoroacetic acid, and sour effective dose is usual
In compound（Ⅸ）1~6 times of the amount of material, preferably 1~1.5 times；Reaction temperature is generally at 0~50 DEG C, preferably 20~30 DEG C；
Reaction time is generally in 0.5~10h, preferably 5~10h.
Compound（Ⅹ）React to obtain compound with acryloyl chloride（Ⅰ）That is Rociletinib, react generally in chloralkane
System in carry out, conventional chloralkane includes dichloromethane, chloroform, 1,2- dichloroethanes etc., preferably dichloromethane；It is conventional
Alkali include the inorganic base such as sodium carbonate, sodium acid carbonate, and the organic base such as pyridine, triethylamine, diisopropylethylamine, preferably three second
Amine, the dosage of alkali is generally in compound（Ⅹ）1~6 times of the amount of material, preferably 2~3 times；The dosage of acryloyl chloride is generally being changed
Compound（Ⅹ）1~6 times of the amount of material, preferably 1~1.5 times；Reaction temperature is generally at 20~50 DEG C, preferably 20~30 DEG C；Instead
Generally in 4~24h, preferably 4~5h between seasonable.
The present invention has following positive beneficial effect：
Preparation method of the present invention is simple to operate, and favorable reproducibility is economic and environment-friendly, and it is high can to prepare purity
Rociletinib, total recovery reach 60~65%, are adapted to industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.It is it should be appreciated that described herein specific
Embodiment only to explain the present invention, is not intended to limit the present invention.
The compound of embodiment 1（Ⅳ）The preparation of 2- methoxyl groups -4- (4- acetyl group -1- piperazinyls) nitrobenzene
Compound is added into dry 500mL there-necked flasks（Ⅱ）2- methoxyl group -4- fluoronitrobenzenes 140g (0.82mol),
Add 1,4- dioxane 150mL and compound（Ⅲ）Acetylpiperazine 500g (3.90mol), is heated to reflux 2~3h（100
℃）, TLC monitoring reactions, disappeared to raw material, reaction system concentrated after cooling, when being largely evaporated off to dioxane, add water
After 250mL, stir about 0.5h, filter, filter cake is eluted to obtain yellow solid with water 200mL, and 50~60 DEG C are dried to obtain product
217.56g yield 95%.
1HNMR:（d6-DMSO）, δ：2.12 (s, 3H)；3.61 (m, 4H)；3.66 (m, 4H)；3.95 (s, 3H)；6.59 (s,
1H)；6.64 (d, 1H)；7.99 (d, 1H).
The compound of embodiment 2（Ⅴ）The preparation of 2- methoxyl groups -4- (4- acetyl group -1- piperazinyls) aniline
Compound is added into dry 500mL reaction bulbs（Ⅳ）33g (0.11mol), 10%Pd/C 1.5g, without water beetle
Alcohol 150mL, stirring, after nitrogen displacement 3 times, normal pressure is passed through hydrogen stirring, and after reacting at room temperature 4h, TLC monitoring reactions finish, will
System filtering, concentration, obtain product 24.68g, yield 90%.
1HNMR:（d6-DMSO）, δ：2.02 (s, 3H)；2.85~2.94.61 (m, 4H)；3.52~3.56 (m, 4H)；3.74
(s, 3H)；4.28（B, 2H）；6.29 (d, 1H)；6.52~6.54 (d, 2H).
The compound of embodiment 3（Ⅶ）2- [[4- (4- acetyl group -1- piperazinyls) -2- methoxyphenyls] amino] -4- is chloro-
The preparation of 5- (trifluoromethyl) pyrimidine
（1）Nitrogen protection is lower to add zinc chloride 94.06g (0.69mol), anhydrous tetrahydro furan 350ml, control temperature in
15~20 DEG C, compound is slowly added dropwise（Ⅵ）The chloro- 5- trifluoromethyl pyrimidines 49.90g (0.23mol) of 2,4- bis- and 150mL tetrahydrochysenes
The mixed liquor of furans composition.Maintain this thermotonus 1h；
（2）By compound（Ⅴ）47.8g (0.19mol) is dissolved in 120mL anhydrous tetrahydro furans, is added drop-wise to above-mentioned preparation
In liquid, stirring reaction 30min, 116.37g (1.15mol) triethylamine is added dropwise, 20~24h, TLC monitoring are reacted at room temperature after adding
Reaction finishes, and is extracted 3 times with 100mL dichloromethane.Organic phase is washed, anhydrous sodium sulfate drying, concentrate, use acetonitrile：Acetone=
3：1 crystallize pink colour to faint yellow solid 84.03g, yield 85%.
1HNMR：（d6-DMSO）, δ：2.05 (s, 3H)；3.36 (m, 4H)；3.60 (m, 4H)；3.76 (s, 3H)；6.52 (s,
1H)；6.67 (d, 1H)；7.22 (d, 1H)；8.62 (m, 1H)；9.61 (b, 1H).
The compound of embodiment 4（Ⅹ）N- [3- [2- [[4- (4- acetyl group -1- piperazinyls) -2- methoxyphenyls] amino] -
5- (trifluoromethyl) -4- pyrimidine radicals] amino] aniline preparation
（1）By compound（Ⅶ）51.58g (0.12mol) and compound（Ⅷ’）N- (3- aminophenyls) tertiary fourth oxanamide
31.24g (0.15mol) is added in 200mL methanol, and room temperature adds 1 mol/L HCl (250mL), is slowly warming up to 60 DEG C instead
Answer 5~7h.Room temperature is dropped to, adds 200ml water, dichloromethane 300mL is extracted three times, organic phase is washed, saturated salt washing,
Sodium sulphate is dried.Removal of solvent under reduced pressure, methylene chloride/methanol are recrystallized to give off-white powder 56g, yield 90%, are compound
（Ⅸ）；
（2）By gained compound（Ⅸ）50g (0.12mol) adds 150mL dichloromethane, trifluoroacetic acid 27mL
(0.36mol), it is slowly heated to 40~50 DEG C and reacts 8~10 hours, obtain brown solid, dissociated with aqueous sodium carbonate, two
Chloromethanes extracts, and anhydrous sodium sulfate drying, is concentrated to give white solid 52.3g, yield 87%.
1HNMR：（d6-DMSO）, δ：2.05 (s, 3H)；3.13 (m, 4H)；3.39 (m, 4H)；3.60 (s, 3H)；4.97 (b,
2H)；6.37~6.39 (m, 2H)；6.62~6.64 (m, 2H)；6.64 (b, 2H)；6.97 (m, 1H)；7.56 (d, 1H)；8.10
(s, 1H)；8.15 (b, 1H)；8.24 (s, 1H).
The compound of embodiment 5（Ⅹ）N- [3- [2- [[4- (4- acetyl group -1- piperazinyls) -2- methoxyphenyls] amino] -
5- (trifluoromethyl) -4- pyrimidine radicals] amino] aniline preparation
（1）By compound (VII) 51.58g (0.12mol) and compound（Ⅷ’）N- (3- aminophenyls) tertiary fourth oxanamide
31.24g (0.15mol) is added in 200mL methanol, and room temperature adds 1mol/L HCl (250mL), is slowly warming up to 60 DEG C instead
Answer 5~7h.Room temperature is dropped to, adds 200mL water, with dichloromethane 300mL extractions three times, organic phase is washed, saturated salt washing,
Sodium sulphate is dried.Removal of solvent under reduced pressure, methylene chloride/methanol are recrystallized to give off-white powder 56g, yield 90%, are compound
（Ⅸ）；
（2）By gained compound（Ⅸ）50g (0.12mol) adds 150mL methanol, hydrochloric acid 30mL (0.36mol) and slowly added
40~50 DEG C of 8~10h of reaction of heat, reaction add 200mL methyl tertiary butyl ether(MTBE)s after terminating, separate out white solid, filtering, and filter cake is used
200mL methyl tertiary butyl ether(MTBE)s elute.Dark HCl, solid is obtained after drying, is dissociated successively with aqueous sodium carbonate, dichloromethane
Alkane extraction, anhydrous sodium sulfate drying, then white solid 49.95g is concentrated to give, yield 83%.
1HNMR：（d6-DMSO）, δ：2.05 (s, 3H)；3.13 (m, 4H)；3.39 (m, 4H)；3.60 (s, 3H)；4.97 (b,
2H)；6.37~6.39 (m, 2H)；6.62~6.64 (m, 2H)；6.64 (b, 2H)；6.97 (m, 1H)；7.56 (d, 1H)；8.10
(s, 1H)；8.15 (b, 1H)；8.24 (s, 1H).
The compound of embodiment 6（Ⅰ）N- [3- [[2- [[4- (4- acetyl group -1- piperazinyls) -2- methoxyphenyls] ammonia
Base] -5- (trifluoromethyl) -4- pyrimidine radicals] amino] phenyl] -2- acrylamides preparation
By compound（Ⅶ）51.58g (0.12mol) and compound（Ⅷ）N- (3- aminophenyls) acrylamide 29.20g
(0.18mol) is added in 200mL methanol, adds 1 mol/L HCl (250mL) at room temperature, is slowly warming up to 60 DEG C, reaction 5
~7h.Drop to room temperature, add 200mL water, extracted 3 times with dichloromethane 300mL, organic phase is washed, saturated sodium-chloride is washed, most
Dried afterwards with sodium sulphate.Removal of solvent under reduced pressure, obtains the white solid of class, and methylene chloride/methanol recrystallizes to obtain off-white powder
60.0g, purity 99.8%, yield 90%.
1HNMR：（d6-DMSO）, δ：2.08 (s, 3H)；3.10 (m, 4H)；3.60 (m, 4H)；3.81 (m, 4H)；5.81 (d,
1H)；6.32 (d, 2H)；6.51 (m, 1H)；6.64 (s, 1H)；7.22 (b, 1H)；7.32 (t, 1H)；7.52 (m, 2H)；7.62 (b,
2H) ；8.13 (s, 1H)；8.32 (s, 1H)；8.73 (b, 1H)；10.19 (b, 1H).
The compound of embodiment 7（Ⅰ）N- [3- [[2- [[4- (4- acetyl group -1- piperazinyls) -2- methoxyphenyls] amino] -
5- (trifluoromethyl) -4- pyrimidine radicals] amino] phenyl] and -2- acrylamides preparation
By compound（Ⅹ）40.12g (0.08mol) is dissolved in 280mL dichloromethane, adds 16.2g
（0.16mol）Triethylamine, acryloyl chloride 9.05g (0.10mol) is added dropwise under ice bath, then reacts at room temperature 4~5h.It is removed under reduced pressure
Solvent, residue add 200mL water, are filtered after stirring, obtain off-white powder, methylene chloride/methanol recrystallizes to obtain off-white color
Powder 41.0g, purity 99.6%, yield 92%.
1HNMR：（d6-DMSO）, δ：2.08 (s, 3H)；3.10 (m, 4H)；3.60 (m, 4H)；3.81 (m, 4H)；5.81 (d,
1H)；6.32 (d, 2H)；6.51 (m, 1H)；6.64 (s, 1H)；7.22 (b, 1H)；7.32 (t, 1H)；7.52 (m, 2H)；7.62 (b,
2H) ；8.13 (s, 1H)；8.32 (s, 1H)；8.73 (b, 1H)；10.19 (b, 1H).
The invention is not limited in above-mentioned embodiment, those skilled in the art can also make a variety of changes accordingly,
It is but any all to cover within the scope of the claims with equivalent or similar change of the invention.
Claims (7)
- A kind of 1. compound（Ⅰ）Preparation method, it is characterised in that comprise the following steps：（1）Prepare compound（Ⅶ）：The compound（Ⅶ）By compound（Ⅴ）With compound（Ⅵ） In atent solvent system, it is made through Louis acid catalysis；（2）Pass through compound（Ⅶ）Prepare compound（Ⅰ）：1）Compound（Ⅶ）With compound（Ⅷ’）Reacted, obtained in the system of alcohol（Ⅸ）；Compound（Ⅷ’）Dosage be compound（Ⅶ）1~1.5 times of the amount of material, reaction 60~70 DEG C of temperature, 5~10h of reaction time；2）By gained compound（Ⅸ）Progress deprotection reaction in the system of alcohol or chloralkane is added with acid and obtains compound （Ⅹ）；The effective dose of acid is compound（Ⅸ）1~1.5 times of the amount of material, instead It is 20~30 DEG C to answer temperature, and the reaction time is 5~10h；3）By gained compound（Ⅹ）, acryloyl chloride and alkali reacts in the system of chloralkane and obtains compound（Ⅰ）；Acryloyl The dosage of chlorine is compound（Ⅹ）1~1.5 times of the amount of material, the dosage of alkali is compound（Ⅹ）2~3 times of the amount of material, Reaction temperature is 20~30 DEG C, and the reaction time is 4~5h.
- 2. preparation method according to claim 1, it is characterised in that：The compound（Ⅴ）Preparation method include it is following Step：1）With compound（Ⅱ）And compound（Ⅲ）To rise Beginning raw material, nucleo philic substitution reaction obtain compound（Ⅳ）；2）Gained compound（Ⅳ）Compound is made through palladium carbon catalytic hydrogenation（Ⅴ）.
- 3. preparation method according to claim 1, it is characterised in that：The lewis acid is zinc chloride, aluminium chloride and chlorine Change at least one of iron, the atent solvent is aromatic hydrocarbons, ethers, halo alkanes, esters, amide-type, sulfone class, nitrile, ketone At least one of class solvent.
- 4. preparation method according to claim 3, it is characterised in that：The atent solvent is toluene, ether, tetrahydrochysene furan Mutter, dichloromethane, chloroform, ethyl acetate, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), acetonitrile, At least one of acetone.
- 5. preparation method according to claim 1, it is characterised in that：The compound（Ⅵ）Dosage be compound（Ⅴ） 1~1.5 times of the amount of material, the lewis acidic dosage are compound（Ⅴ）2~5 times of the amount of material, reaction temperature are 20~80 DEG C, the reaction time is 8~24h.
- 6. preparation method according to claim 5, it is characterised in that：The lewis acidic dosage is compound（Ⅴ）Thing 2~3 times of the amount of matter, reaction temperature are 20~50 DEG C, and the reaction time is 16~24h.
- 7. preparation method according to claim 1, it is characterised in that step 1）Or 2）The alcohol is methanol, ethanol, isopropyl At least one of alcohol and normal propyl alcohol；Step 2）The acid is hydrochloric acid or trifluoroacetic acid；Step 3）The alkali is sodium carbonate, carbon At least one of sour hydrogen sodium, pyridine, triethylamine and diisopropylethylamine；Step 3）The chloralkane is dichloromethane, chlorine At least one of imitative and 1,2- dichloroethanes.
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| CN106554347B (en) * | 2015-09-25 | 2020-10-30 | 浙江博生医药有限公司 | EGFR kinase inhibitor and preparation method and application thereof |
| CN105481779B (en) * | 2015-12-24 | 2019-01-25 | 南京华威医药科技集团有限公司 | Anticancer drug Rociletinib and its intermediate preparation |
| CN114213339B (en) * | 2021-12-20 | 2023-10-31 | 苏州康纯医药科技有限公司 | Preparation method of epidermal cell growth factor receptor mutation inhibitor |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and uses thereof |
| WO2014182593A1 (en) * | 2013-05-06 | 2014-11-13 | Clovis Oncology, Inc. | Salts of an epidermal growth factor receptor kinase inhibitor |
| CN104284584A (en) * | 2012-03-15 | 2015-01-14 | 西建阿维拉米斯研究公司 | Salts of epidermal growth factor receptor kinase inhibitor |
| WO2015117547A1 (en) * | 2014-02-04 | 2015-08-13 | Jiangsu Medolution Limited | Substituted pyrimidines useful as egfr-t790m kinase inhibitors |
| CN104860890A (en) * | 2015-04-29 | 2015-08-26 | 上海泓博智源医药技术有限公司 | T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs |
| WO2015158310A1 (en) * | 2014-04-18 | 2015-10-22 | 山东轩竹医药科技有限公司 | Tyrosine kinase inhibitor and uses thereof |
| CN105198821A (en) * | 2015-10-26 | 2015-12-30 | 苏州明锐医药科技有限公司 | Preparation method of Rociletinib |
-
2015
- 2015-12-02 CN CN201510871586.3A patent/CN105461640B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and uses thereof |
| CN104284584A (en) * | 2012-03-15 | 2015-01-14 | 西建阿维拉米斯研究公司 | Salts of epidermal growth factor receptor kinase inhibitor |
| WO2014182593A1 (en) * | 2013-05-06 | 2014-11-13 | Clovis Oncology, Inc. | Salts of an epidermal growth factor receptor kinase inhibitor |
| WO2015117547A1 (en) * | 2014-02-04 | 2015-08-13 | Jiangsu Medolution Limited | Substituted pyrimidines useful as egfr-t790m kinase inhibitors |
| WO2015158310A1 (en) * | 2014-04-18 | 2015-10-22 | 山东轩竹医药科技有限公司 | Tyrosine kinase inhibitor and uses thereof |
| CN104860890A (en) * | 2015-04-29 | 2015-08-26 | 上海泓博智源医药技术有限公司 | T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs |
| CN105198821A (en) * | 2015-10-26 | 2015-12-30 | 苏州明锐医药科技有限公司 | Preparation method of Rociletinib |
Non-Patent Citations (1)
| Title |
|---|
| CO-1686的合成;张姗等;《中国医药工业杂志》;20140831;第45卷(第8期);第710-713页 * |
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