CN109956940A - A kind of method that the rich former times cloth intermediate cyano reaction of pa prepares heteroaryl cyanide - Google Patents
A kind of method that the rich former times cloth intermediate cyano reaction of pa prepares heteroaryl cyanide Download PDFInfo
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- CN109956940A CN109956940A CN201910399411.5A CN201910399411A CN109956940A CN 109956940 A CN109956940 A CN 109956940A CN 201910399411 A CN201910399411 A CN 201910399411A CN 109956940 A CN109956940 A CN 109956940A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to technical field of organic synthesis, former times cloth intermediate is won to solve existing pa, especially there is pyrido [2,3-d] pyrimidin-7-ones skeleton compound, 6- cyanalation reaction cost height, low yield can lead to the problem of and provide a kind of method that the cyanalation reaction of such compound prepares heteroaryl cyanide to human body and the harmful cyanide ion of environment.This method uses the six cyano ferrous acid potassium (K of cyanylation agent of nonhazardous4[Fe(CN)6]) it is used as cyanogen source, in bis- [2- (diphenylphosphino) phenyl] ether palladium chloride (PdCl2(DPEPhos)) under catalytic action, efficient conversion is realized.The present invention is at low cost, and environmentally protective, reaction condition milder, yield is higher, and post-reaction treatment process will not be generated to human body and the harmful cyanide ion of environment, be of great significance to the research and industrialization development of pharmacy and related fields.
Description
Technical field
The present invention relates to technical field of organic synthesis more particularly to a kind of pa win the reaction of former times cloth intermediate cyanoization prepare it is miscellaneous
The method of aryl cyanide.
Background technique
It is a kind of efficient CDK4/6 inhibitor that pa, which wins former times cloth (Palbociclib), has broad spectrum anticancer activity, is the whole world
In the first heavy pound formula new drug in CDK inhibitor field.Pa, which wins former times cloth, to be had and entirely different first of antineoplastic mechanism before
The highly selective inhibitor of CDK4/6, in addition to advanced breast cancer, for other Several Kinds of Malignancy such as lymph cancer, lung cancer
Corresponding clinical trial is at melanoma etc..
In the early stage chemical synthesis research that pa wins former times cloth, its core skeleton pyrido [2,3-d] pyrimidine -7- is related generally to
The synthesis and modification of ketone compound, the compound 2,3 and 4 in reaction route I is to be related to the important intermediate of the skeleton.Chemical combination
Object 2 can obtain under lithium hexamethyldisilazide effect with ethyl acetate cyclization phonetic with core skeleton pyrido [2,3-d]
The compound 3 of pyridine -7- ketone, then react to obtain 6- bromo-derivatives 4 with N- bromo-succinimide.
The success that pa wins former times cloth will be such that pyrido [2,3-d] pyrimidin-7-ones class compound obtains in pharmaceutical chemistry research
More applications.And such compound makes its changes in modification more horn of plenty in the position after 6- bromos, wherein most common
Be bromo position cyanalation reaction.Because aryl cyanide itself is present in many dyestuffs, herbicide, agrochemicals
In product, drug and natural products.In pharmaceutical chemistry research, aryl cyanide is even more that can be converted into all kinds of to have bioactivity
Important intermediate.Due to the needs of diversified drug molecule design, the simple cyanalation method of aromatic ring has been unable to meet medicine
The demand of object synthesis, similar pa win the azepine of former times cloth intermediate pyrido [2,3-d] pyrimidin-7-ones class compound special in this way
The cyanalation reaction of aromatic ring needs more methodological studies and exploration.
Pyrido [2,3-d] pyrimidin-7-ones are the heterocyclic compounds of a kind of height electron deficient, this kind of compound with it is general
The aromatic compound of aromatic compound or electron rich is compared, and common cyanalation reaction condition is all difficult to realize.In existing literature,
The only a few studies cyanalation reaction that relates to similar structures, has all used cuprous cyanide (CuCN) as cyanylation agent, instead
Answer temperature relatively high.Part research, which has also been attempted, realizes cyanalation reaction with cyaniding tetraethyl ammonium, but the reagent price is high
It is expensive, and yield is not also high.
Disclosed in Chinese patent literature " 6- replace pyrido [2,3-D] pyrimidines as protein kinase suppression
Preparation ", application publication number CN108191857A, the invention N-Methyl pyrrolidone (NMP) is as solvent, in cyaniding Asia
Under copper effect, can the yield under 150 DEG C of heating condition with 34% obtain cyanalation product, but reaction needed for this method
Temperature is higher, it is necessary to excessive cuprous cyanide adsorb a large amount of products at high temperature so that yield reduce.
Although the above-mentioned prior art can obtain cyanalation product, yield is difficult to improve, and cyanogen source used, cyaniding
Cuprous and cyaniding tetraethyl ammonium, can all generate in last handling process to human body and the harmful cyanide ion of environment.So finding
It is extremely important that highly efficient catalyst system and safer cyanogen source prepare heteroaryl cyanide.
Summary of the invention
The present invention is in order to overcome existing pa to win former times cloth intermediate cyano reaction cost height, low yield, can generate to human body
It the problem of cyanide ion harmful with environment, provides a kind of pa and wins the intermediate cyano reaction of former times cloth and prepare heteroaryl cyanide
Method, cheap and environmentally protective, reaction condition milder, yield is higher, and post-reaction treatment process will not be generated to human body
Cyanide ion harmful with environment is of great significance to the research and industrialization development of pharmacy and related fields.
To achieve the goals above, the invention adopts the following technical scheme:
A kind of method that the rich former times cloth intermediate cyano reaction of pa prepares heteroaryl cyanide, according to following chemical reaction side
Formula carries out:
Under inert gas protection, by 6- haloperidid simultaneously [2,3-d] pyrimidin-7-ones class compound (I), cyanalation examination
Agent, catalyst, potassium acetate, n,N-Dimethylformamide and water are mixed in reaction flask, and heating stirring is to fully reacting after sealing；
Ethyl acetate is added after reaction solution is cooling, then uses saturated common salt water washing, mistake after gained organic phase is dried over anhydrous sodium sulfate
It filters and is concentrated, crude product obtains 6- cyanopyridine simultaneously [2,3-d] pyrimidin-7-ones class compound (II) after column chromatographs.
The present invention solves in current pharmaceutical synthesis and other chemical related fieldss, for phonetic with pyrido [2,3-d]
The problem of cyanalation reaction in the position 6- of the heterocyclic nitrogen compound of pyridine -7- ketone skeleton, and to it is other have not been studied have lack
The cyanalation reaction of the compound of electronics aromatic ring frame has instructive effect.Since all kinds of aryl or heteroaryl cyanide are in drug
It is the important intermediate for being converted into various bioactive molecules in chemical research, the present invention has largely expanded the model for the cyanide that can be synthesized
It encloses.Compared with prior art, reaction condition milder, yield is higher, and post-reaction treatment process will not be generated to human body and ring
The harmful cyanide ion in border is of great significance to the research and industrialization development of pharmacy and related fields.
Preferably, simultaneously [2,3-d] pyrimidin-7-ones class compound has following below formula to the 6- haloperidid:
Wherein, R1For methyl mercapto, amino that amino or alkyl, aryl, heterocycle, aromatic heterocyclic replace；R2For H or C1~
C10Alkyl；R3For C1~C10Alkyl or C3~C6Naphthenic base；X is bromine atom, chlorine atom or iodine atom.
Preferably, the cyanylation agent is six cyano ferrous acid potassium, chemical molecular formula K4[Fe(CN)6], usually
With trihydrate (K4[Fe(CN)6]·3H2O form) exists, and is also designated as potassium ferrocyanide, is a kind of pair of human body and environmentally friendly
, very safe cyanylation agent even can be used as anti-agglomerating agent and be added in edible salt.No matter this reagent sheet
The by-product formed after body or its participation reaction, all will not be to human body or environmental danger.The present invention be used only it is cheap and
Efficient cyanalation reaction can be realized as cyanogen source to six cyano ferrous acid potassium of environment nonhazardous, be that industry amplification is suitble to make
Ideal cyanalation reaction reagent.
Preferably, the catalyst is bis- [2- (diphenylphosphino) phenyl] ether palladium chloride (PdCl2(DPEPhos)),
Its chemical molecular formula is C36H28Cl2OP2Pd is a kind of biphosphine ligand palladium catalyst being commercialized, structural formula are as follows:
The complex compound catalyst PdCl that bis- [2- (diphenylphosphino) phenyl] ethers (DPEPhos) and palladium chloride are formed2
(DPEPhos) cyanalation reaction of the invention can effectively be optimized, because of bis- [2- (diphenylphosphino) phenyl] ethers and palladium chloride
The double phosphine coordinations of special wide angle, the aromatic compound to electron deficient is a kind of good catalyst system.
Therefore, it is low that the invention has the following beneficial effects: costs of material, environmentally protective, and reaction condition milder, yield is more
Height, and post-reaction treatment process will not generate the research to human body and the harmful cyanide ion of environment, to pharmacy and related fields
It is of great significance with industrialization development.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance of product made from embodiment 11H spectrogram.
Fig. 2 is the nuclear magnetic resonance of product made from embodiment 21H spectrogram.
Specific embodiment
Below by specific embodiment, and in conjunction with attached drawing, the technical solutions of the present invention will be further described.
In the present invention, if not refering in particular to, all devices and raw material is commercially available or the industry is common are following
Method in embodiment is unless otherwise instructed conventional method in that art.
Embodiment 1
According to following chemical equation, the bromo- 8- cyclopenta -5- methyl -2- methylsulfanyl pyridine of 6- is simultaneously [2,3-d] phonetic
The cyanalation reaction of pyridine -7- ketone prepares 6- cyano -8- cyclopenta -5- methyl -2- methylsulfanyl pyridine simultaneously [2,3-d] pyrimidin-7-ones:
Under inert gas protection, the bromo- 8- cyclopenta -5- methyl -2- methylsulfanyl pyridine of 6- is added into 25mL reaction flask
And [2,3-d] pyrimidin-7-ones (4,500mg, 1.41mmol), six cyano ferrous acid potassium trihydrates (298mg, 0.71mmol),
Bis- [2- (diphenylphosphino) phenyl] ether palladium chlorides (303mg, 0.42mmol), potassium acetate (69.3mg, 0.71mmol), N, N- bis-
Methylformamide (5mL) and water (0.5mL), reaction flask are heated and are stirred 7 hours at 100 DEG C after being sealed with rubber stopper.Reaction solution
Ethyl acetate is added after cooling, is filtered after then using saturated common salt water washing, gained organic phase to be dried over anhydrous sodium sulfate and dense
Contracting, the light yellow solid that crude product obtains after column chromatographs be 6- cyano -8- cyclopenta -5- methyl -2- methylsulfanyl pyridine simultaneously [2,
3-d] pyrimidin-7-ones (5,342mg, yield: 80.7%).
The nuclear magnetic resonance of product made from the present embodiment1H spectrogram is as shown in Figure 1:1H NMR(400MHz,CDCl3,ppm):δ
8.81(s,1H),5.98–5.89(m,1H),2.72(s,3H),2.63(s,3H),2.31–2.23(m,2H),2.12–2.05(m,
2H),1.92–1.84(m,2H),1.73–1.66(m,2H).
Embodiment 2
According to following chemical equation, the bromo- 8- cyclopenta -2- methylsulfanyl pyridine of 6- simultaneously [2,3-d] pyrimidin-7-ones cyanogen
Glycosylation reaction prepares 6- cyano -8- cyclopenta -2- methylsulfanyl pyridine simultaneously [2,3-d] pyrimidin-7-ones:
Under inert gas protection, the bromo- 8- cyclopenta -2- methylsulfanyl pyridine of 6- simultaneously [2,3- is added into 25mL reaction flask
D] pyrimidin-7-ones (4a, 680.5mg, 2mmol), six cyano ferrous acid potassium trihydrates (422.4mg, 1mmol), bis- [2- (two
Phenyl phosphino-) phenyl] ether palladium chloride (429.5mg, 0.6mmol), potassium acetate (98.1mg, 1mmol), n,N-Dimethylformamide
(7mL) and water (0.7mL), reaction flask are heated and are stirred 7 hours at 100 DEG C after being sealed with rubber stopper.It is added after reaction solution is cooling
Then ethyl acetate uses saturated common salt water washing, gained organic phase is filtered and is concentrated after being dried over anhydrous sodium sulfate, and crude product is through column
The light yellow solid obtained after chromatography be 6- cyano -8- cyclopenta -2- methylsulfanyl pyridine simultaneously [2,3-d] pyrimidin-7-ones (5a,
494.2mg, yield: 86.3%).
The nuclear magnetic resonance of product made from the present embodiment1H spectrogram is as shown in Figure 2:1H NMR(400MHz,CDCl3,ppm):δ
8.67(s,1H),8.09(s,1H),5.99–5.90(m,1H),2.64(s,3H),2.33–2.24(m,2H),2.11–2.04(m,
2H),1.95–1.86(m,2H),1.74–1.67(m,2H).
Embodiment 3
According to following chemical equation, 4- (6- (bromo- 8- cyclopenta -5- methyl -7- oxo -7, the 8- dihydropyridine of 6-
And [2,3-d] pyrimidine -2 --amino) pyridin-3-yl) cyanalation reaction preparation 4- (6- (the 6- cyano-of piperazine-1- t-butyl formate
8- cyclopenta-5- methyl-7- oxo-7,8- dihydro pyrido [2,3-d] pyrimidine -2 --amino) pyridin-3-yl) piperazine-1- first
Tert-butyl acrylate:
Under inert gas protection, 4- (6- (the bromo- 8- cyclopenta -5- methyl -7- oxo-of 6- is added into 25mL reaction flask
7,8- dihydro pyrido [2,3-d] pyrimidine -2 --amino) pyridin-3-yl) piperazine-1- t-butyl formate (4b, 584.5mg,
1mmol), six cyano ferrous acid potassium trihydrate (211.2mg, 0.5mmol), bis- [2- (diphenylphosphino) phenyl] ether palladium chlorides
(214.8mg, 0.3mmol), potassium acetate (49.1mg, 0.5mmol), n,N-Dimethylformamide (4mL) and water (0.4mL), instead
It heats and stirs 7 hours at 100 DEG C after answering bottle to be sealed with rubber stopper.Ethyl acetate is added after reaction solution is cooling, then with saturation
Brine It, gained organic phase are filtered and are concentrated after being dried over anhydrous sodium sulfate, and crude product obtains light yellow after column chromatographs
Solid is 6- cyano -8- cyclopenta -2- methylsulfanyl pyridine simultaneously [2,3-d] pyrimidin-7-ones (5b, 348mg, yield: 65.6%).
Comparative example 1
According to following chemical equation:
Select zinc cyanide (Zn (CN)2) it is used as cyanylation agent, in tris(dibenzylideneacetone) dipalladium (Pd2(dba)3) urge
Under change effect, with bis- (diphenylphosphino) ferrocene (DPPF) of 1,1'- for ligand, cyanalation reaction is carried out.
Comparative example 2
Comparative example 2 and the difference of comparative example 1 are: the zinc powder (Zn) activated being added in reaction system, remaining technique is complete
It is exactly the same.
Comparative example 3
Comparative example 3 and the difference of comparative example 1 are: the zinc powder (Zn) and zinc acetate (Zn activated being added in reaction system
(OAc)2) it is used as co-catalysis system, remaining technique is identical.
The reaction system of comparative example 1-3 and the results are shown in Table 1:
1. comparative example 1-3 of table obtains reaction system and result
| Number | Addition reaction reagent | As a result |
| Comparative example 1 | / | Raw material does not react |
| Comparative example 2 | Zn | Yield: 8.6%, the recycling of raw material 4 60.7% |
| Comparative example 3 | Zn,Zn(OAc)2 | Yield: 11.8%, the recycling of raw material 4 54% |
In order to avoid using this kind of toxicity of Cymag (NaCN), potassium cyanide (KCN) high, it be easy to cause the cyano of environmental pollution
Change reagent, present invention applicant selects zinc cyanide (Zn (CN) first2) reaction is attempted, the results are shown in Table 1, three (two
BENZYLIDENE ACETONE) two palladium (Pd2(dba)3) under catalytic action, with bis- (diphenylphosphino) ferrocene (DPPF) of 1,1'- for ligand,
Efficient cyanalation reaction can be carried out to pyridine nitrogen heterocycles halide using zinc cyanide.However, as shown in comparative example 1, it should
Condition cannot then react in pyrido [2,3-d] pyrimidin-7-ones skeleton of the invention.
The zinc powder (Zn) activated is added in comparative example 2, it is desirable to be able to it avoids reacting deactivation prob as caused by cyanide ion,
And zinc powder can remove the oxygen in reaction system, and palladium catalyst is made to be maintained at the efficient catalytic state of zeroth order, this condition energy
It enough carries out reaction, but product can only be obtained with 8.6% yield, and still have 60.7% raw material that cannot be converted.
Comparative example 3 uses zinc powder and zinc acetate (Zn (OAc)2) co-catalysis system because zinc acetate can make to be catalyzed
The more permanent activity of agent holding is until the reaction is complete.But such catalyst system improves very the substrate that the present invention studies
It is micro-, cyanalation product is only obtained with 11.8% yield, and there is 54% raw material to be recovered.
Comparative example 4
According to following chemical equation:
Cuprous cyanide (CuCN) is selected to be used as cyanylation agent, N-Methyl pyrrolidone (NMP) is used as solvent, reaction temperature
210 DEG C, carry out cyanalation reaction.
Comparative example 5
Comparative example 5 and the difference of comparative example 4 are: 150 DEG C of reaction temperature, remaining technique is identical.
Comparative example 6
Comparative example 6 and the difference of comparative example 4 are: 120 DEG C of reaction temperature, remaining technique is identical.
Comparative example 7
Comparative example 7 and the difference of comparative example 4 are: tetrakis triphenylphosphine palladium is added as catalyst, N, N- dimethyl methyl
Amide (DMF) is used as solvent, and 135 DEG C of reaction temperature, remaining technique is identical.
The reaction system of comparative example 4-7 and the results are shown in Table 2:
The reaction system and result of 2. comparative example 4-7 of table
| Number | Catalyst | Solvent | Temperature | Conversion ratioa | Yield |
| Comparative example 4 | / | NMP | 210℃ | 100% | 25.9% |
| Comparative example 5 | / | NMP | 150℃ | 100% | 34.2% |
| Comparative example 6 | / | NMP | 120℃ | ~50% | / |
| Comparative example 7 | Pd(PPh3)4 | DMF | 135℃ | 100% | 38.2% |
Present invention applicant uses more traditional cyanogen source, and cuprous cyanide (CuCN) attempts the cyanalation reaction, and
The research more refined is done.Since the method needs temperature higher, so selecting the higher N-Methyl pyrrolidone of boiling point
(NMP) it is used as solvent, discovery reaction at high temperature can convert completely raw material, but the excess cyaniding as necessary to the condition
Cuprous adsorption production easy at high temperature, and more impurity is generated, so the yield at 210 DEG C of comparative example 4 is only 25.9%；It is right
Yield can be increased to 34.2% when 5 temperature of ratio drops to 150 DEG C；The nearly half raw material unreacted at 120 DEG C of comparative example 6 is complete, produces
Product are difficult purified obtain.Tetrakis triphenylphosphine palladium is added as catalyst in comparative example 7, can make fully reacting at a lower temperature
Conversion, yield has also slightly been increased to 38.2%, and the n,N-Dimethylformamide (DMF) that solvent then uses boiling point relatively low is i.e.
It can.
Although the reaction method of comparative example 1-3 and comparative example 4-7 can obtain cyanalation product 5, yield is all difficult
It is improved, and cyanogen source used, zinc cyanide and cuprous cyanide, can all be generated to human body and environment in last handling process again
Harmful cyanide ion.So the highly efficient catalyst system of searching and safer cyanogen source are extremely important.
Comparative example 8-12
Comparative example 8-12 the difference from embodiment 1 is that: PdCl2(DPEPhos) catalyst equivalent, DMF:H2O
When reaction temperature is different for solvent volume, and referring specifically to table 3, remaining technique is identical.
3. comparative example 7-11 of table and embodiment 2 obtain reaction system and yield
aThe estimated value of thin-layer chromatography chromatography (TLC) colour developing；bIt is calculated according to the bromo raw material 4 that recycling obtains.
The conversion ratio and yield of above-mentioned comparative example and embodiment are recorded in table 3, analysis data can obtain:
Comparative example 8 uses the catalyst PdCl of 0.2 equivalent (20mol% of substrate feeding quantity)2(DPEPhos), in N, N-
Dimethylformamide (DMF) and water (volume ratio DMF:H2O=2:1 in mixed solvent system), only with 0.5 equivalent, (substrate adds
The 50mol% of doses) six cyano ferrous acid potassium reacted at 130 DEG C, discovery raw material can react quickly, but may be by
Excessively high in temperature, generation impurity is excessive, is difficult to isolate and purify to obtain product.9 reaction temperature of comparative example drops to 90 DEG C, reaction system
Although clean many, has nearly half raw material to be unable to fully reacting, still has no idea to be separated to purer product.Comparison
Example 10 controls reaction temperature at 100 DEG C, it is found that while the temperature condition is able to ascend conversion ratio, moreover it is possible to smoothly be separated to
34.2% product.But still thering is 30% raw material not converted to be recovered under the conditions of this, we are then repeating this
Find there is the insoluble matter for the catalyst that is similar in color to be suspended in reaction solution always in reaction system when condition.Comparative example 11 is by solvent
Proportion adjustment is to DMF:H2O=10:1, conversion ratio, which has, to be increased substantially, and also can obtain cyanalation product with 64.1% yield
5.Embodiment 2 is by catalyst PdCl2(DPEPhos) when equivalent is increased to 0.3, then realize 100% conversion ratio and
80.7% separation yield.Comparative example 12 only uses single dicyandiamide solution of DMF, and conversion ratio then reduces instead.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the present invention in any form, and is not surpassing
There are also other variations and modifications under the premise of technical solution documented by claim out.
Claims (4)
1. a kind of pa wins the method that the intermediate cyano reaction of former times cloth prepares heteroaryl cyanide, which is characterized in that in indifferent gas
Under body protection, by 6- haloperidid simultaneously [2,3-d] pyrimidin-7-ones class compound, cyanylation agent, catalyst, potassium acetate, N, N-
Dimethylformamide and water are mixed in reaction flask, and heating stirring is to fully reacting after sealing；Acetic acid is added after reaction solution is cooling
Then ethyl ester uses saturated common salt water washing, gained organic phase is filtered and is concentrated after being dried over anhydrous sodium sulfate, and crude product is chromatographed through column
After obtain 6- cyanopyridine simultaneously [2,3-d] pyrimidin-7-ones class compound.
2. a kind of pa according to claim 1 wins the method that the intermediate cyano reaction of former times cloth prepares heteroaryl cyanide,
It is characterized in that, simultaneously [2,3-d] pyrimidin-7-ones class compound has following below formula to the 6- haloperidid:
Wherein, R1For methyl mercapto, amino that amino or alkyl, aryl, heterocycle, aromatic heterocyclic replace；R2For H or C1~C10's
Alkyl；R3For C1~C10Alkyl or C3~C6Naphthenic base；X is bromine atom, chlorine atom or iodine atom.
3. a kind of pa according to claim 1 wins the method that the intermediate cyano reaction of former times cloth prepares heteroaryl cyanide,
It is characterized in that, the cyanylation agent is six cyano ferrous acid potassium.
4. a kind of pa according to claim 1 wins the method that the intermediate cyano reaction of former times cloth prepares heteroaryl cyanide,
It is characterized in that, the catalyst is bis- [2- (diphenylphosphino) phenyl] ether palladium chlorides, structural formula are as follows:
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102015704A (en) * | 2008-04-29 | 2011-04-13 | 霍夫曼-拉罗奇有限公司 | Pyrimidinyl pyridone inhibitors of JNK |
| WO2013046045A1 (en) * | 2011-09-27 | 2013-04-04 | Dr. Reddy's Laboratories, Ltd. | 5 - benzylaminomethyl - 6 - aminopyrazolo [3, 4 -b] pyridine derivatives as cholesteryl ester -transfer protein (cetp) inhibitors useful for the treatment of atherosclerosis |
| CN108191857A (en) * | 2017-01-24 | 2018-06-22 | 成都优赛丽医药科技有限公司 | Pyrido [2,3-D] pyrimidines of 6- substitutions are as kinases inhibitor |
-
2019
- 2019-05-14 CN CN201910399411.5A patent/CN109956940A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102015704A (en) * | 2008-04-29 | 2011-04-13 | 霍夫曼-拉罗奇有限公司 | Pyrimidinyl pyridone inhibitors of JNK |
| WO2013046045A1 (en) * | 2011-09-27 | 2013-04-04 | Dr. Reddy's Laboratories, Ltd. | 5 - benzylaminomethyl - 6 - aminopyrazolo [3, 4 -b] pyridine derivatives as cholesteryl ester -transfer protein (cetp) inhibitors useful for the treatment of atherosclerosis |
| CN108191857A (en) * | 2017-01-24 | 2018-06-22 | 成都优赛丽医药科技有限公司 | Pyrido [2,3-D] pyrimidines of 6- substitutions are as kinases inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| JEFFERY RICHARDSON 等: ""Improved Substrate Scope in the Potassium Hexacyanoferrate(II)-Based Cyanation for the Synthesis of Benzonitriles and Their Heterocyclic Analogues"", 《J. ORG. CHEM.》 * |
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