CN105777652A - Method for preparing 2,5-dichloro-4-(3-nitrophenoxy) pyrimidine - Google Patents
Method for preparing 2,5-dichloro-4-(3-nitrophenoxy) pyrimidine Download PDFInfo
- Publication number
- CN105777652A CN105777652A CN201610213309.8A CN201610213309A CN105777652A CN 105777652 A CN105777652 A CN 105777652A CN 201610213309 A CN201610213309 A CN 201610213309A CN 105777652 A CN105777652 A CN 105777652A
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- China
- Prior art keywords
- pyrimidine
- phenoxy
- nitro
- chloro
- bis
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- 0 *c1cccc(O)c1 Chemical compound *c1cccc(O)c1 0.000 description 1
- GIKMWFAAEIACRF-UHFFFAOYSA-N Clc(cnc(Cl)n1)c1Cl Chemical compound Clc(cnc(Cl)n1)c1Cl GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 1
- SEGZIOXGXFJLHD-UHFFFAOYSA-N [O-][N+](c1cccc(Oc(nc(nc2)Cl)c2Cl)c1)=O Chemical compound [O-][N+](c1cccc(Oc(nc(nc2)Cl)c2Cl)c1)=O SEGZIOXGXFJLHD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a method for preparing a drug intermediate, in particular to a method for preparing 2,5-dichloro-4-(3-nitrophenoxy) pyrimidine.A reaction is conducted on 2,4,5-trichloropyrimidin and 3-nitrophenol to prepare and obtain the final product 2,5-dichloro-4-(3-nitrophenoxy) pyrimidine.The method is simple and convenient to practice, the product is high in yield and purity, reaction conditions are mild, safety is high, and the method is especially suitable for industrial production.
Description
[technical field]
The present invention relates to a kind of pharmaceutical intermediate preparation method, be specifically related to a kind of 2, the chloro-4-of 5-bis-(3-nitro-phenoxy) is phonetic
The preparation method of pyridine.
[background technology]
WZ4002 is a kind of novel, Catastrophic selection EGFR inhibitor, acts on EGFR (L858R)/(T790M),
In BaF3 cell line, IC50 is 2nM/8nM；ERBB2 phosphorylation (T798I) do not had inhibitory action.Make on this clinical drug
For hepatocarcinoma and nonsmall-cell lung cancer disease aspect, WZ4002 compound molecular weight is 494.18, and its structural formula is as follows:
WZ4002 also suppresses other EGFR gene types, IC50 during as acted on E746_A750 and E746_A750/T790M
It is respectively 2 and 6nM.When WZ4002 acts on Wild type EGFR, IC50 is 32nM.WZ4002 acts on non-small cell
The phosphorylation of EGFR, AKT and ERK1/2 is suppressed during pulmonary carcinoma (NSCLC) cell.WZ4002 acts on expression not
With the phosphorylation of suppression EGFR during the NIH-3T3 cell of EGFRT790M mutation allele.Suppress with quinazoline ditosylate salt
Agent is compared, and the effect that WZ4002 acts on Wild type EGFR phosphorylation is low 100 times.WZ4002 suppresses restructuring
The effect of L858R/T790M proteinaceous EGFR kinase activity is more much higher than suppression Wild type EGFR, and HKI-272 and Gefitinib
Inhibition just contrary with WZ4002.Additionally, the H1975 cell of anti-Src TKI and the EGFR of HCC827 cell
Phosphorylation suppressed by third generation EGFR TKI WZ4002 completely.
2,5-bis-chloro-4-(3-nitro-phenoxy) pyrimidine is a kind of important intermediate of synthesis compound WZ4002, and its molecular weight is
286.071, structural formula is as follows:
The present invention will provide a kind of method of the synthesis chloro-4-of 2,5-bis-(3-nitro-phenoxy) pyrimidine.
[summary of the invention]
The technical problem to be solved is to provide a kind of method of the synthesis chloro-4-of 2,5-bis-(3-nitro-phenoxy) pyrimidine.
For achieving the above object, design a kind of 2, the preparation method of the chloro-4-of 5-bis-(3-nitro-phenoxy) pyrimidine, it is characterised in that
Controlling temperature is room temperature at 60 DEG C, and by 2,4,5-trichloropyrimidines add in the DMF solvent containing potassium carbonate, add 3-nitre
Base phenol, controls temperature 50-70 DEG C, reacts 1-3 hour；After reaction completely, pour reactant liquor into 10-15 times of volume
In clear water, taking organic compound layer and be dried concentration precipitation solid, filter, filter cake washes rear methanol drip washing with water and dries, prepares
The chloro-4-of 2,5-bis-(3-nitro-phenoxy) pyrimidine.
Reaction equation is shown below: added by the trichloropyrimidine of compound 2,4,5-shown in formula 1 in the DMF solvent containing potassium carbonate,
Add compound 3-nitrophenol shown in formula 2 to react, prepare compound 2 shown in formula 3,5-bis-chloro-4-(3-nitro
Phenoxy group) pyrimidine:
Described 2,4,5-trichloropyrimidine with 3-nitrophenol in (1.31-1.34): 1 ratio mixes.
The described DMF solvent concentration containing potassium carbonate is 0.4g/ml.
Controlling reaction temperature and be chosen to be 60 DEG C, the response time is set as 2 hours.
In course of reaction, completely, described TLC (PE:EA=10:1) refers to pass through in TLC (PE:EA=10:1) monitoring reaction
Whether thin layer chromatography technology carries out detection reaction complete, developing solvent be chosen as mixed system, PE refers to petroleum ether；EA is second
Acetoacetic ester；10 1 is the volume ratio of petroleum ether and ethyl acetate.
The present invention provide method, final production yield and purity can not only be significantly improved, also have simple to operate, reaction time is short,
Advantage is particularly suitable for industrialized production safely and efficiently.
[detailed description of the invention]
Unless otherwise defined, the present invention uses all technology and implication and the common skill of the technical field of the invention of scientific terminology
The implication that art personnel are generally understood that is identical.Generally, the present invention use name and following experimental technique be all well known in the art or
Commonly using, if not specializing, test reagent used in the embodiment of the present invention and material are all commercially available.In order to make this
Bright solved the technical problem that, technical scheme and beneficial effect clearer, below in conjunction with specific embodiment, to the present invention
It is further described.
Compound shown in compound shown in reaction Chinese style 1 of the present invention and formula 2 derives from commercially available, cheap and easy to get.
Embodiment 1:
Controlling temperature is at 50 DEG C, and the trichloropyrimidine of compound 2,4,5-shown in 132g formula 1 is added the 500ml containing 200g potassium carbonate
In DMF solvent, adding compound 3-nitrophenol shown in 100g formula 2, then controlling temperature is 60 DEG C, reacts 2 hours.
In course of reaction after TLC (PE:EA=10:1) monitoring reaction completely, reactant liquor is poured in the clear water of 15 times of volumes, take
Organic compound layer is dried concentration and separates out solid；Then filtering, filter cake washes rear methanol drip washing with water and dries, and prepares 188g formula
The chloro-4-of compound 2,5-shown in 3 bis-(3-nitro-phenoxy) pyrimidine.
Product detection data are as follows:
1H NMR 600MHz (DMSO d6) δ 8.84 (s, 1H), 8.38 (d, J=6.6Hz, 2H), 7.80 (d, J=6.6Hz,
2H)。
Embodiment 2:
Controlling temperature is at 60 DEG C, and the trichloropyrimidine of compound 2,4,5-shown in 66g formula 1 is added the 250ml containing 100g potassium carbonate
In DMF solvent, adding compound 3-nitrophenol shown in 50g formula 2, then controlling temperature is 70 DEG C, reacts 3 hours.
In course of reaction after TLC (PE:EA=10:1) monitoring reaction completely, reactant liquor is poured in the clear water of 10 times of volumes, take
Organic compound layer is dried concentration and separates out solid；Then filtering, filter cake washes rear methanol drip washing with water and dries, and prepares 92g formula
The chloro-4-of compound 2,5-shown in 3 bis-(3-nitro-phenoxy) pyrimidine.
Embodiment 3:
Controlling temperature is at 27 DEG C, and the trichloropyrimidine of compound 2,4,5-shown in 198g formula 1 is added the 750ml containing 300g potassium carbonate
In DMF solvent, adding compound 3-nitrophenol shown in 150g formula 2, then controlling temperature is 50 DEG C, reacts 3 hours.
In course of reaction after TLC (PE:EA=10:1) monitoring reaction completely, reactant liquor is poured in the clear water of 15 times of volumes, take
Organic compound layer is dried concentration and separates out solid；Then filtering, filter cake washes rear methanol drip washing with water and dries, and prepares 280g formula
The chloro-4-of compound 2,5-shown in 3 bis-(3-nitro-phenoxy) pyrimidine.
Embodiment 4:
Controlling temperature is at 40 DEG C, and the trichloropyrimidine of compound 2,4,5-shown in 106g formula 1 is added the 400ml containing 160g potassium carbonate
In DMF solvent, adding compound 3-nitrophenol shown in 80g formula 2, then controlling temperature is 60 DEG C, reacts 2 hours.
In course of reaction after TLC (PE:EA=10:1) monitoring reaction completely, reactant liquor is poured in the clear water of 13 times of volumes, take
Organic compound layer is dried concentration and separates out solid；Then filtering, filter cake washes rear methanol drip washing with water and dries, and prepares 150g formula
The chloro-4-of compound 2,5-shown in 3 bis-(3-nitro-phenoxy) pyrimidine.
Embodiment 5:
Controlling temperature is at 35 DEG C, and the trichloropyrimidine of compound 2,4,5-shown in 158g formula 1 is added the 600ml containing 240g potassium carbonate
In DMF solvent, adding compound 3-nitrophenol shown in 120g formula 2, then controlling temperature is 60 DEG C, and reaction 1.5 is little
Time.In course of reaction after TLC (PE:EA=10:1) monitoring reaction completely, reactant liquor is poured in the clear water of 12 times of volumes,
Take organic compound layer and be dried concentration precipitation solid；Then filtering, filter cake washes rear methanol drip washing with water and dries, and prepares 224g
The chloro-4-of compound 2,5-bis-shown in formula 3 (3-nitro-phenoxy) pyrimidine.
Embodiment 6:
Controlling temperature is at 45 DEG C, and the trichloropyrimidine of compound 2,4,5-shown in 80g formula 1 is added the 300ml containing 120g potassium carbonate
In DMF solvent, adding compound 3-nitrophenol shown in 60g formula 2, then controlling temperature is 60 DEG C, reacts 2 hours.
In course of reaction after TLC (PE:EA=10:1) monitoring reaction completely, reactant liquor is poured in the clear water of 11 times of volumes, take
Organic compound layer is dried concentration and separates out solid；Then filtering, filter cake washes rear methanol drip washing with water and dries, and prepares 150g formula
The chloro-4-of compound 2,5-shown in 3 bis-(3-nitro-phenoxy) pyrimidine.
It should be noted that, although the present invention is disclosed above with preferred embodiment, so it is not limited to the present invention, any ripe
Practise this those skilled in the art, without departing from the spirit and scope of the present invention, any amendment, equivalent and the improvement etc. made, all
Within protection scope of the present invention should being included in.
Claims (6)
1. one kind 2, the preparation method of the chloro-4-of 5-bis-(3-nitro-phenoxy) pyrimidine, it is characterised in that controlling temperature is that room temperature is to 60 DEG C
Under, by 2,4,5-trichloropyrimidines add in the DMF solvent containing potassium carbonate, add 3-nitrophenol, control temperature
50-70 DEG C, react 1-3 hour；After reaction completely, reactant liquor is poured in the clear water of 10-15 times of volume, take and organise
Compound layer is dried concentration and separates out solid, filters, and filter cake washes rear methanol drip washing with water and dries, and prepares 2,5-bis-chloro-4-(3-
Nitro-phenoxy) pyrimidine.
2. one 2 as claimed in claim 1, the preparation method of the chloro-4-of 5-bis-(3-nitro-phenoxy) pyrimidine, it is characterised in that anti-
Formula is answered to be shown below: compound shown in formula 1 and compound shown in formula 2 react compound shown in the formula of preparing 3:
3. one 2 as claimed in claim 1, the preparation method of the chloro-4-of 5-bis-(3-nitro-phenoxy) pyrimidine, it is characterised in that institute
State 2,4,5-trichloropyrimidine with 3-nitrophenol in (1.31-1.34): 1 ratio mixes.
4. one 2 as claimed in claim 1, the preparation method of the chloro-4-of 5-bis-(3-nitro-phenoxy) pyrimidine, it is characterised in that institute
Stating the DMF solvent concentration containing potassium carbonate is 0.4g/ml.
5. one 2 as claimed in claim 1, the preparation method of the chloro-4-of 5-bis-(3-nitro-phenoxy) pyrimidine, it is characterised in that control
Reaction temperature processed is chosen to be 60 DEG C, and the response time is set as 2 hours.
6. one 2 as claimed in claim 1, the preparation method of the chloro-4-of 5-bis-(3-nitro-phenoxy) pyrimidine, it is characterised in that anti-
Carrying out detection reaction by thin layer chromatography technology during Ying the most complete, developing solvent is petroleum ether and the second of volume ratio 10 1
The mixed system of acetoacetic ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610213309.8A CN105777652A (en) | 2016-04-07 | 2016-04-07 | Method for preparing 2,5-dichloro-4-(3-nitrophenoxy) pyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610213309.8A CN105777652A (en) | 2016-04-07 | 2016-04-07 | Method for preparing 2,5-dichloro-4-(3-nitrophenoxy) pyrimidine |
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| Publication Number | Publication Date |
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| CN105777652A true CN105777652A (en) | 2016-07-20 |
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|---|---|---|---|
| CN201610213309.8A Pending CN105777652A (en) | 2016-04-07 | 2016-04-07 | Method for preparing 2,5-dichloro-4-(3-nitrophenoxy) pyrimidine |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159742B (en) * | 2011-12-16 | 2015-08-12 | 北京韩美药品有限公司 | 5-chloropyrimide compounds and the application as EGFR tyrosine kinase inhibitor thereof |
| WO2015170600A1 (en) * | 2014-05-08 | 2015-11-12 | 東ソー・エフテック株式会社 | 5-(trifluoromethyl) pyrimidine derivative and production method therefor |
-
2016
- 2016-04-07 CN CN201610213309.8A patent/CN105777652A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159742B (en) * | 2011-12-16 | 2015-08-12 | 北京韩美药品有限公司 | 5-chloropyrimide compounds and the application as EGFR tyrosine kinase inhibitor thereof |
| WO2015170600A1 (en) * | 2014-05-08 | 2015-11-12 | 東ソー・エフテック株式会社 | 5-(trifluoromethyl) pyrimidine derivative and production method therefor |
Non-Patent Citations (3)
| Title |
|---|
| CHUN HAN，等: "Synthesis and evaluation of 2-anilinopyrimidines bearing 3-aminopropamides as potential epidermal growth factor receptor inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| DEBJIT BASU，等: "Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| ZHOU, WENJUN，等: "Discovery of selective irreversible inhibitors for EGFR-T790M", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160720 |
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| RJ01 | Rejection of invention patent application after publication |