CN107793394A - A kind of serial key intermediate for producing selective PI3K inhibitor - Google Patents
A kind of serial key intermediate for producing selective PI3K inhibitor Download PDFInfo
- Publication number
- CN107793394A CN107793394A CN201710657049.8A CN201710657049A CN107793394A CN 107793394 A CN107793394 A CN 107793394A CN 201710657049 A CN201710657049 A CN 201710657049A CN 107793394 A CN107793394 A CN 107793394A
- Authority
- CN
- China
- Prior art keywords
- key intermediate
- pi3k inhibitor
- selective pi3k
- serial key
- producing selective
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CCCOCCNC([N+]=C(N1*COCC1)N=C)=C(C)Cc1c[n+]c([*+])cc1C(F)(F)F Chemical compound CCCOCCNC([N+]=C(N1*COCC1)N=C)=C(C)Cc1c[n+]c([*+])cc1C(F)(F)F 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The invention discloses a kind of serial key intermediate for producing selective PI3K inhibitor, structural formula is：OrThe synthesis technique of the present invention, avoids cumbersome operating process, simplifies reactions steps, and raw material is easy to get, and reaction is gentle, and cost is relatively low, is adapted to industrialized production, has wide market prospects.
Description
Technical field
The present invention relates to pharmaceutical field, specifically a kind of serial key intermediate for producing selective PI3K inhibitor.
Background technology
5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine is the exploitation of pharmacy giant Novartis
A kind of selective PI3K inhibitor, the entitled Buparlisib of English, code name is BKM120 or NVP-BKM120.BKM120 is acted on
In the cell line of releasing PI3K regulations, including when A2780, U87MG, MCF7 and DU145, there is antiproliferative activity, GI50 is
0.1-0.7nM(Burger MT,et al.ACS Med Chem Lett,2011,2(10),774–779).BKM120 inductions are more
Hair property myeloma cell (ARP1, ARK, MM.1S, MM1.R and U266) apoptosis, causes G1 phase cytosises, S phase Leukopenias.
BKM120 induces the primary MM Apoptosis of CD138+, and toxicity is relatively low when acting on CD138- stroma cells.BKM120 can cause
BimS upper mediation XIAP downward.(Zheng Y, et al.J Mol Med (Berl), 2011 Dec 30.) BKM120 is acted on
In Human Gastric carcinoma's cell line, mTOR downstream signals are reduced, there is antiproliferative activity.The stomach cancer that BKM120 acts on KRAS is thin
Born of the same parents are that can strengthen p-ERK or p-STAT3.BKM120 and STAT3 blocking agents are combined, and are acted on the cell of the KRAS containing mutation, are lured
Apoptosis is led, there is cooperative effect, but acting on KRAS wild-type cells does not have this effect.Explanation 5- [2,6- described above
Two (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine has a variety of active anticancers, and it is potential weight pound anticancer
Medicine.The structural formula of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine is as follows：
The synthesis of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] current document report of -4- (trifluoromethyl) -2- pyridine amine
Route mainly has following several：Route one (referring to patent WO2012109423),
By 2- amino -4- trifluoromethyls -5-
Bromo- pyridine carries out palladium catalysed cross coupling reaction with duplex pinacol borate, then carries out suzuki with the chlorine pyrimidine of double morpholines substitution
Coupling reaction obtains finished product.The route is overall more succinct, but has that two-step reaction yield is relatively low, final step atom economy
Property is very poor (see patent WO2012109423 pages 29), illustrates that the byproduct of reaction is more, while post-process purifying column chromatography
Isolated product, the production method for not being；Route two (referring to patent WO2012044727A2),
The chlorine pyrimidine that dimorpholine is substituted closes
As borate, then pyridine bromo- with 2- amino -4- trifluoromethyls -5- carries out suzuki coupling reactions, obtains target product.Should
The difficult point of route is the suzuki coupling reactions for synthesizing borate and final step.According to the ingredient proportion of report, finally
The Atom economy of one step coupling is bad, the problem of cost is higher be present；Route three (referring to patent WO2012044727A2), will
After the amino of the bromo- pyridines of 2- amino -4- trifluoromethyls -5- is protected with acetyl group, carry out parental materials with butyl lithium reagent and make
Boric acid, the boric acid and the chlorine pyrimidine of substitution carry out suzuki coupling reactions, are finally deprotected, obtain target product.The route
Core is synthesis boric acid., it is necessary to be substituted using n-BuLi in building-up process, as little as -78 DEG C of reaction temperature, producing
The defects of meeting energy consumption is larger in amplification, it is also higher to equipment requirement, while butyl lithium dosage is also big, is not preferable
Route
Therefore, research and develop it is new, be more suitable for industrialization, [2,6- bis- (4- morpholinyls) -4- are phonetic by the preparation 5- of low-carbon environment-friendly
Piperidinyl] -4- (trifluoromethyl) -2- pyridine amine method it is very necessary.
The content of the invention
It is an object of the invention to provide a kind of serial key intermediate for producing selective PI3K inhibitor, with solution
State the problem of being proposed in background technology.
To achieve the above object, the present invention provides following technical scheme：
A kind of serial key intermediate for producing selective PI3K inhibitor, structural formula are：
As the further scheme of the present invention：A kind of serial key intermediate for producing selective PI3K inhibitor, structure
Formula is：
As the further scheme of the present invention：A kind of serial key intermediate for producing selective PI3K inhibitor, it is middle
Body substituent X is bromine, and the structural formula of key intermediate is as follows：
As the further scheme of the present invention：A kind of serial key intermediate for producing selective PI3K inhibitor, it is middle
Body substituent Y is-OH, and the structural formula of key intermediate is as follows：
As the further scheme of the present invention：A kind of serial key intermediate for producing selective PI3K inhibitor, it is middle
Body substituent Y is-OC (CH3) 2-, and the structural formula of key intermediate is as follows：
A kind of preparation method for the serial key intermediate for producing selective PI3K inhibitor, it is characterised in that specific step
It is rapid as follows,After being reacted under the effect of the reagents such as lithium alkylide with borate, preparation is quenched in last acid：
A kind of preparation method for the serial key intermediate for producing selective PI3K inhibitor, it is characterised in that specific step
It is rapid as follows,In the presence of RMgBr isopropylmagnesium chloride, prepared with boron ester reagent reacting：
A kind of synthetic route for the serial key intermediate for producing selective PI3K inhibitor is：
A kind of reaction condition for the serial key intermediate synthetic route for producing selective PI3K inhibitor is in toluene, two
Reacted at least one solvent such as toluene, benzene, it is anti-with 2,5- acetyl butyryls progress reflux dewatering in the presence of p-methyl benzenesulfonic acid
Should.
Compared with prior art, the beneficial effects of the invention are as follows：The synthesis technique of the present invention, avoids cumbersome operation stream
Journey, reactions steps are simplified, and raw material is easy to get, reaction is gentle, and cost is relatively low, is adapted to industrialized production, has wide market
Prospect.
Brief description of the drawings
Fig. 1 is the HNMR figures of the finished product for the serial key intermediate preparation for producing selective PI3K inhibitor.
Fig. 2 is the MS figures of the finished product for the serial key intermediate preparation for producing selective PI3K inhibitor.
Fig. 3 is the HPLC figures of the finished product for the serial key intermediate preparation for producing selective PI3K inhibitor.
Embodiment
The technical scheme of this patent is described in more detail with reference to embodiment.
Fig. 1-3, a kind of serial key intermediate for producing selective PI3K inhibitor are referred to, its synthetic route is：Specifically comprise the following steps：
(1) 2- amino -4- trifluoromethyl -5- bromopyridines are taken off with 2.5- acetyl butyryls in the presence of p-methyl benzenesulfonic acid dehydration
Water reacts, and protects amino.
(2) amido protecting of 2- amino -4- trifluoromethyls -5- bromopyridines enters in solvent toluene either benzene or dimethylbenzene
OK.
(3) intermediate after amido protecting successively obtains pinacol borate key with RMgBr and boron ester reagent reacting
Intermediate, the intermediate is by suzuki reactions and dimorpholine chlorine substituted pyrimidines coupling reaction, then sloughs amido protecting, obtains 5-
[2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine.
(4) intermediate after amido protecting also can carry out coupling reaction with dimorpholine substituted pyrimidines borate, then slough ammonia
Base is protected, and obtains 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine.
The protection reaction (synthesis of compound 2) of amino：
2- amino -4- trifluoromethyl -5- bromopyridines (500g, 2.07mol) are added into 2000ml toluene, add 2,5-
Acetyl butyryl (283g, 2.48mol), p-methyl benzenesulfonic acid 50g is added at room temperature, stirs and is warming up to backflow, install water knockout drum,
After reflux water-dividing reacts 15 hours, there is no moisture to go out, and sampling carries out TLC (PE/EA=3/1) and shows that raw material conversion is complete.Drop
Temperature adds water 1500ml into reaction solution to 20-30 DEG C, and stirring is lower to adjust pH to 8-9, stirring with 10% sodium hydrate aqueous solution
Liquid separation is carried out afterwards and obtains organic phase, and organic phase obtains crude product after being concentrated under reduced pressure, and changes crude product petroleum ether 500ml mashing and mistake
Compound 2 is obtained after filter, is off-white color product 574g (yield 87%).
The reaction (synthesis of compound 3) that 5 bromines are substituted with pinacol borate：By after amido protecting compound 2 (500g,
1.57mol) add into 3000ml tetrahydrofurans, be cooled to 0-5 DEG C under stirring, the tetrahydrofuran that isopropylmagnesium chloride is added dropwise is molten
Liquid 850ml (2.0mol/L concentration, 1.70mol), stirs 2h at 0-10 DEG C after dripping off, (sampling water quenching is completed in TLC monitoring reactions
After going out, TLC is carried out：PE/EA=3/1).Converted added in the backward above reaction solution isopropoxy pinacol borate (350g,
1.88mol, 1.2 equivalents) and after being warming up to 50-60 DEG C of reaction 2-3 hour, sampling TLC monitoring reaction conversions are complete.It is cooled to 0
DEG C or so, saturated aqueous ammonium chloride 1000ml is added into reaction solution, stirs liquid separation, organic phase is washed with saturated sodium-chloride
Afterwards, it is concentrated to dryness, obtains drying after stirring in residue addition petroleum ether, be concentrated to give solid, a small amount of petroleum ether of the solid
It is 495g (yield 86%) that drying, which obtains the weight of yellow product 3, after washing.
The method A (synthesis of compound 6) of coupling reaction
Tetrahydrofuran 1000ml is added in clean 2000ml there-necked flasks, water 300ml is added, adds compound 3
(150g, 0.41mol) and compound 4 (116g, 0.41mol, 1.0 equivalent), adding potassium carbonate, (112g, 0.82mol, 2.0 work as
Amount), Pd (dppf) Cl2 (4.5g, 0.03w/w) is added, is added with nitrogen displacement air three times, then be warming up to 60-70 DEG C of reaction
4-5h, TLC (PE/EA=1/1) monitoring reaction are completed.Cooling, divides sub-cloud aqueous phase.Upper organic phase is collected, and is directly used in down
Single step reaction.
The method B (synthesis of compound 6) of coupling reaction
Tetrahydrofuran 500ml is added in clean 1000ml there-necked flasks, water 150ml is added, adds compound 3
(50g, 0.16mol) and compound 5 (60g, 0.16mol, 1.0 equivalent), adding potassium carbonate, (43g, 0.32mol, 2.0 work as
Amount), Pd (dppf) Cl2 (1.5g, 0.03w/w) is added, is added with nitrogen displacement air three times, then be warming up to 60-70 DEG C of reaction
4-5h, TLC (PE/EA=1/1) monitoring reaction are completed.Cooling, divides sub-cloud aqueous phase.Upper organic phase is collected, and is directly used in down
Single step reaction.
Deprotection reaction (compound 7：5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridines
The synthesis of amine)
The reaction solution about 1500ml that the method A of preceding step coupling reaction is obtained, add hydrochloric acid solution (5M, 600ml), stirring
And be warming up to 50-60 DEG C of reaction 4-5h, TLC (PE/EA=1/1) monitoring reaction and complete, reaction solution is concentrated, concentrate is in 10-
The lower sodium hydroxide (20% concentration) that adds of 20 DEG C of stirrings adjusts pH value to 8-9, separates out solid, filtering, collects filter cake.Gained filter cake
It is 2/1 to be recrystallized with ethyl acetate/petroleum ether, it is 105g to obtain product weight, white solid powder, purity 99.1%.MS
[M+1]：411；HNMR(D6-CDCl3):δ3.60-3.63(m,4H),3.74-3.81(m,12H),4.90(s,2H),4.24
(dd,1H),5.99(s,1H),6.79(s,1H),8.28(s,1H)。
The present invention operation principle be：The technical solution used in the present invention a, wherein synthetic route isAnother synthetic route isOn the bromopyridine of 2- amino -4- trifluoromethyls -5
After amido protecting is using the protection of 2,5- acetyl butyryls, makes boric acid or borate and 2,4- dimorpholine -6- chlorine pyrimidines are coupled；Or
After amino on the bromopyridine of person 2- amino -4- trifluoromethyls -5 is protected with 2,5- acetyl butyryls, directly with substituted pyrimidine boronic acid ester
Coupling reaction is carried out, halo is preferably bromo, and boric acid or borate are preferably pinacol borate, that is, are had：Used in the synthesis technique in new key
Mesosome is：The key intermediate is preferablyThe protection of the bit amino of pyridine 2, specially 2- amino-
4- trifluoromethyl -5- bromopyridines carry out dehydration with 2.5- acetyl butyryls in the presence of p-methyl benzenesulfonic acid dehydration；The bit amino of pyridine 2
Protection carried out in solvent toluene, benzene or dimethylbenzene；Intermediate after amido protecting can priority and RMgBr and boron ester
Reagent reacting obtains pinacol borate key intermediate, and the intermediate is even by suzuki reactions and dimorpholine chlorine substituted pyrimidines
Connection reaction, then amido protecting is sloughed, obtain 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridines
Amine；Intermediate after amido protecting can carry out coupling reaction with dimorpholine substituted pyrimidines borate, then slough amido protecting, obtain
5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires rather than described above limits, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.Any reference in claim should not be considered as to the involved claim of limitation.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that those skilled in the art should for clarity
Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
It is appreciated that other embodiment.
Claims (9)
1. a kind of serial key intermediate for producing selective PI3K inhibitor, it is characterised in that the structural formula is：
2. a kind of serial key intermediate for producing selective PI3K inhibitor, it is characterised in that the structural formula is：
3. according to the serial key intermediate for producing selective PI3K inhibitor described in claim 1, it is characterised in that institute
It is bromine to state intermediate substituent X, and the structural formula of key intermediate is as follows：
4. according to the serial key intermediate for producing selective PI3K inhibitor described in claim 2, it is characterised in that institute
It is-OH to state intermediate substituent Y, and the structural formula of key intermediate is as follows：
5. according to the serial key intermediate for producing selective PI3K inhibitor described in claim 2, it is characterised in that institute
It is-OC (CH3) 2- to state intermediate substituent Y, and the structural formula of key intermediate is as follows：
6. the preparation method of the serial key intermediate of the selective PI3K inhibitor of production according to claim 4, it is special
Sign is, comprises the following steps that,After being reacted under the effect of the reagents such as lithium alkylide with borate, last acid is quenched
Prepare：
7. the preparation method of the serial key intermediate of the selective PI3K inhibitor of production according to claim 5, it is special
Sign is, comprises the following steps that,In the presence of RMgBr isopropylmagnesium chloride, with boron ester reagent reacting system
It is standby：
8. according to the serial key intermediate for producing selective PI3K inhibitor described in claim 1, it is characterised in that institute
The synthetic route for stating intermediate is：
9. intermediate according to claim 8, it is characterised in that the synthetic route reaction condition is in toluene, diformazan
Reacted at least one solvent such as benzene, benzene, reflux dewatering reaction is carried out with 2,5- acetyl butyryls in the presence of p-methyl benzenesulfonic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710657049.8A CN107793394A (en) | 2017-08-03 | 2017-08-03 | A kind of serial key intermediate for producing selective PI3K inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710657049.8A CN107793394A (en) | 2017-08-03 | 2017-08-03 | A kind of serial key intermediate for producing selective PI3K inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107793394A true CN107793394A (en) | 2018-03-13 |
Family
ID=61531508
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710657049.8A Pending CN107793394A (en) | 2017-08-03 | 2017-08-03 | A kind of serial key intermediate for producing selective PI3K inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107793394A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103140479A (en) * | 2010-10-01 | 2013-06-05 | 诺华有限公司 | Manufacturing process for pyrimidine derivatives |
| CN104736532A (en) * | 2012-10-23 | 2015-06-24 | 诺华股份有限公司 | Improved process for manufacturing 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine |
| CN106458968A (en) * | 2014-04-22 | 2017-02-22 | 巴塞尔大学 | Novel manufacturing process for triazine, pyrimidine and pyridine derivatives |
| WO2017049498A1 (en) * | 2015-09-23 | 2017-03-30 | 前湾医药科技（深圳）有限公司 | Imidazopyridine compound and uses in preparation of pi3k inhibitor |
-
2017
- 2017-08-03 CN CN201710657049.8A patent/CN107793394A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103140479A (en) * | 2010-10-01 | 2013-06-05 | 诺华有限公司 | Manufacturing process for pyrimidine derivatives |
| CN104736532A (en) * | 2012-10-23 | 2015-06-24 | 诺华股份有限公司 | Improved process for manufacturing 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine |
| CN106458968A (en) * | 2014-04-22 | 2017-02-22 | 巴塞尔大学 | Novel manufacturing process for triazine, pyrimidine and pyridine derivatives |
| WO2017049498A1 (en) * | 2015-09-23 | 2017-03-30 | 前湾医药科技（深圳）有限公司 | Imidazopyridine compound and uses in preparation of pi3k inhibitor |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101456855B (en) | Method for preparing 1,3-propanesultone | |
| CN104496983A (en) | Palbociclib preparation method | |
| CN102584795A (en) | Preparing method of crizotinib | |
| CN107936029B (en) | Method for synthesizing Ribociclib | |
| CN110372578A (en) | A kind of new chlorphenamine maleate synthetic method | |
| CN104926798A (en) | High purity preparation method of Afatinib intermediate | |
| CN107793394A (en) | A kind of serial key intermediate for producing selective PI3K inhibitor | |
| CN106748716B (en) | A kind of new method for preparing 2,4,5 trifluoro benzene acetic acids | |
| CN107011347B (en) | A kind of synthetic method of chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 4- | |
| CN103864702A (en) | Method for preparing quinazolinone in water phase through microwave catalysis | |
| CN103204808A (en) | Biquinoline derivative, preparation method thereof and application thereof in preparing anticancer medicament | |
| Lu et al. | Syntheses, structures, catalytic and antitumor activities of a series of pyrimidine derivatives coordination complexes | |
| CN105949217A (en) | Preparation method of milbemycin oxime intermediate | |
| CN103896859B (en) | The technique of synthesizing cytimidine | |
| CN101066987B (en) | Preparation process of brivudine | |
| CN104496913B (en) | A method of preparing 5- substitution -2,4- dimethyl sulphur-based pyrimidines | |
| CN102070524A (en) | Method for preparing 3-cyano-4-halogenated quinoline derivatives | |
| CN101555248A (en) | Method for preparing poly-substituted 1, 5-naphthyridine compound | |
| CN102127093B (en) | Refining process for Cefotiam hexetil hydrochloride | |
| CN105541710B (en) | A kind of synthetic method of montelukast | |
| CN101935317B (en) | Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof | |
| CN104610180A (en) | Oteracil potassium preparation method | |
| CN109721587A (en) | A kind of method and its application preparing phthalyl Amlodipine | |
| CN105541711B (en) | A kind of preparation method of montelukast | |
| CN117964627A (en) | Preparation method of key intermediate of rebaudinib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180313 |
|
| RJ01 | Rejection of invention patent application after publication |