CN109251205A - A method of efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine - Google Patents
A method of efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine Download PDFInfo
- Publication number
- CN109251205A CN109251205A CN201811231933.6A CN201811231933A CN109251205A CN 109251205 A CN109251205 A CN 109251205A CN 201811231933 A CN201811231933 A CN 201811231933A CN 109251205 A CN109251205 A CN 109251205A
- Authority
- CN
- China
- Prior art keywords
- compound
- pyrimidine
- reaction
- chlorine pyrazolo
- follows
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses the method that one kind efficiently synthesizes 5- chlorine pyrazolo [1,5-a] pyrimidine, synthetic routes are as follows: first reacts compound A with compound B, compound C is obtained, then by compound C and phosphorus oxychloride reaction, obtains compound D, as 5- chlorine pyrazolo [1,5-a] pyrimidine；Reaction equation are as follows:Synthesis condition of the invention is mild, post-processing effect on environment it is small, and this method concise in technology, raw material it is cheap and easy to get, it is easy to operate, be particularly well suited for industrialized production, have very extensive industrial applications prospect and market value.
Description
Technical field
The present invention relates to pharmaceutical intermediates to synthesize field, and in particular to a kind of scalable synthesis 5- chlorine pyrazolo [1,5-a]
The method of pyrimidine.
Background technique
Pyrazolo [1,5-a] pyrimidine class formation has important pharmaceutical activity meaning, and many new drug bioactive molecules all have
The mother nucleus structure.Such as phosphatidyl inositol kinase (PI3K) inhibitor compound 1 developed by Novartis Inc company, pass through
The key signal access for influencing tumour cell realizes good anticancer activity (WO2008/037477), which is exactly with pyrrole
Azoles simultaneously [1,5-a] pyrimidine be parent nucleus new drug bioactive molecule.For another example compound 2 is by Neurocrine Biosciences Inc
Cortico-trophin-releasing factor (CRF) (CRF) agonist compounds of company's exploitation, to the treatment extremely caused nerveous system of CRF
System disorder and depression have a good effect (WO2005063755), and pyrazolo [1,5-a] pyrimidine is also the pass of the compound
Bond structure.5- chlorine pyrazolo [1,5-a] pyrimidine (D) is to introduce a kind of heavy of pyrazolo [1,5-a] pyrimidine structure to drug molecule
Intermediate is wanted, the 5- position chlorine of compound D and 3- hydrogen can introduce different structure fragments by reaction, to synthesize difference
Pharmaceutical activity molecule.Compound 1, compound 2, compound D structural formula as shown in Formulas I, II, III:
5- chlorine pyrazolo [1,5-a] pyrimidine (compound D) synthesis technology of document (WO2011029027A1) report exists
Following defect: it is low that technique obtains target product D total recovery, and only 36%；The technique of synthetic intermediate C amplifying operation property is poor, deposits
In security risk；The synthesis technology of target product D, it is big that corrosive raw materials phosphorus oxychloride makees solvent usage, feeds intake and post-process peace
Full blast danger is high, and effect on environment is big, and the present invention is optimized for defective workmanship as above, and process overall yields of the invention are
76%, the technique of synthetic intermediate C directly reduces solvent usage by solvent of methanol solution of sodium methylate, and it is dense to increase reaction
Degree carries out reaction completely, and solvent methanol is evaporated off in addition post-processing selection, and is post-processed with cold water, reduces product in solvent
In loss, product yield increases；The phosphorus oxychloride that suitable equivalent is added in the synthesis technology of target product D both ensure that reaction
It sufficiently carries out reducing influence of the post-reaction treatment to environment again.Therefore the present invention develop it is a kind of it is easy to operate, total recovery is high,
Small 5- chlorine pyrazolo [1,5-a] pyrimidine (compound D) synthesis technology of effect on environment.
Summary of the invention
In view of the above-mentioned problems of the prior art, the object of the present invention is to provide one kind to efficiently synthesize 5- chlorine pyrazolo
The method of [1,5-a] pyrimidine, to be applied to industry's enlarging production.
To achieve the above object, the technical solution adopted by the present invention are as follows:
The method that one kind efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine, synthetic route are as follows:
Compound A is reacted with compound B first, obtains compound C, then by compound C and phosphorus oxychloride reaction, is obtained
To compound D, as 5- chlorine pyrazolo [1,5-a] pyrimidine；Reaction equation are as follows:
Specific steps are as follows:
Step 1, under anhydrous and oxygen-free gas nitrogen-less protection, in the methanol solution mixture of compound A and sodium methoxide,
Compound B is added, then carries out back flow reaction, after reaction, by reaction solution cold filtration, evaporating solvent under reduced pressure is obtained white
Color solid, as compound C；
Phosphorus oxychloride is added into the acetonitrile solution of compound C under anhydrous and oxygen-free gas nitrogen-less protection in step 2, into
Row back flow reaction, reaction solution clarification, evaporating solvent under reduced pressure obtain yellow solid, as compound D.
Preferably, in the step 1, the condition of back flow reaction are as follows: heat 65-70 DEG C back flow reaction 4 hours.
Preferably, in the step 1, obtained white solid is dissolved in 10 DEG C of water, adjusts pH value to 2, filters
To compound as white solid C.
Preferably, in the step 1, in the methanol solution of sodium methoxide, the mass fraction of sodium methoxide is 30%.
Preferably, in the step 2, the condition of back flow reaction are as follows: be heated to 85 DEG C of back flow reactions 2 hours.
Preferably, in the step 2, into yellow solid plus water removes residual thionyl chloride, and yellow solid is obtained by filtration
Compound D.
The beneficial effects of the present invention are: the solvent usage amount that the present invention synthesizes 5- chlorine pyrazolo [1,5-a] pyrimidine technique is small,
Synthesis condition is mild, post-processing effect on environment it is small, and this method concise in technology, raw material it is cheap and easy to get, it is easy to operate, be extremely suitable for
In industrialized production, there is very extensive industrial applications prospect and market value.
Detailed description of the invention
Fig. 1 is the H-NMR spectrum for the product Compound C that step 1 obtains in embodiment；
Fig. 2 is the H-NMR spectrum for the product Compound D that step 2 obtains in embodiment.
Specific embodiment
The method of a kind of high efficiency synthesis 5- chlorine pyrazolo [1,5-a] pyrimidine of the present invention, currently without other phases
Close patent literature report.
The present invention will be further described combined with specific embodiments below.According to following embodiments, can better understand
The present invention.However, as it will be easily appreciated by one skilled in the art that specific material proportion, process conditions described in embodiment and
Its result is merely to illustrate the present invention, without that should will not limit the present invention described in detail in claims.
Embodiment
The synthesis of 5- chlorine pyrazolo [1,5-a] pyrimidine, synthetic route are as follows:
Synthesis step are as follows:
Step 1, under anhydrous and oxygen-free gas nitrogen-less protection, to methanol solution (its of 1kg compound A and 2.7L sodium methoxide
In, in the methanol solution of sodium methoxide, the mass fraction of sodium methoxide is that 1.9kg compound B is added 30%) in mixture, heating,
Temperature is controlled at 65-70 DEG C, back flow reaction 4 hours, after reaction, by reaction solution cold filtration, evaporating solvent under reduced pressure is obtained
To white solid, after white solid is dissolved in 10 DEG C of 1.5L water, adjust pH value to 2,1.4kg white solid be obtained by filtration
Conjunction object C, yield 86%,1H-NMR(CDCl3, 400MHz): δ 5.89 (1H, d, J=1.6Hz), 5.95 (1H, d, J=
7.2Hz), 7.70 (1H, d, J=1.6Hz), 8.19 (1H, d, J=7.2Hz).
1kg compound C is dissolved in 2kg acetonitrile by step 2, under anhydrous and oxygen-free gas nitrogen-less protection, to the second of compound C
It is slowly added into 400g phosphorus oxychloride in nitrile solution, is heated to 85 DEG C, back flow reaction 2 hours, reaction solution clarification removed under reduced pressure molten
Agent obtains yellow solid, and 1kg water is slowly added into yellow solid, removes a small amount of residual thionyl chloride, 1kg yellow is obtained by filtration
Solid chemical compound D, yield 88%,1H-NMR (DMSO-d6,400MHz): δ 6.73 (1H, dd, J=2.0,0.8Hz), 7.13
(1H, d, J=7.2Hz), 8.29 (1H, d, J=2.4Hz), 9.18 (1H, dd, J=7.2,0.8Hz).
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (7)
1. the method that one kind efficiently synthesizes 5- chlorine pyrazolo [1,5-a] pyrimidine, it is characterised in that: synthetic route are as follows:
Compound A is reacted with compound B first, obtains compound C, then by compound C and phosphorus oxychloride reaction, is changed
Close object D, as 5- chlorine pyrazolo [1,5-a] pyrimidine；Reaction equation are as follows:
2. the method according to claim 1 for efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine, it is characterised in that: specific
Step are as follows:
Step 1, in the methanol solution mixture of compound A and sodium methoxide, is added under anhydrous and oxygen-free gas nitrogen-less protection
Then compound B carries out back flow reaction, after reaction, by reaction solution cold filtration, it is solid to obtain white for evaporating solvent under reduced pressure
Body, as compound C；
Step 2 is added phosphorus oxychloride into the acetonitrile solution of compound C, is returned under anhydrous and oxygen-free gas nitrogen-less protection
Stream reaction, reaction solution clarification, evaporating solvent under reduced pressure obtain yellow solid, as compound D.
3. the method according to claim 2 for efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine, it is characterised in that: described
In step 1, the condition of back flow reaction are as follows: heat 65-70 DEG C back flow reaction 4 hours.
4. the method according to claim 2 for efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine, it is characterised in that: described
In step 1, obtained white solid is dissolved in 10 DEG C of water, adjusts pH value to 2, compound as white solid C is obtained by filtration.
5. the method according to claim 2 for efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine, it is characterised in that: described
In step 1, in the methanol solution of sodium methoxide, the mass fraction of sodium methoxide is 30%.
6. the method according to claim 2 for efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine, it is characterised in that: described
In step 2, the condition of back flow reaction are as follows: be heated to 85 DEG C of back flow reactions 2 hours.
7. the method according to claim 2 for efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine, it is characterised in that: described
In step 2, into yellow solid plus water removes residual thionyl chloride, and yellow solid compound D is obtained by filtration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811231933.6A CN109251205A (en) | 2018-10-22 | 2018-10-22 | A method of efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811231933.6A CN109251205A (en) | 2018-10-22 | 2018-10-22 | A method of efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109251205A true CN109251205A (en) | 2019-01-22 |
Family
ID=65046608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811231933.6A Pending CN109251205A (en) | 2018-10-22 | 2018-10-22 | A method of efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109251205A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102271515A (en) * | 2008-10-31 | 2011-12-07 | 健泰科生物技术公司 | Pyrazolopyrimidine JAK inhibitor compounds and methods |
| CN104781251A (en) * | 2012-11-08 | 2015-07-15 | 百时美施贵宝公司 | Bicyclic heterocycle substituted pyridyl compounds useful as kinase modulators |
-
2018
- 2018-10-22 CN CN201811231933.6A patent/CN109251205A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102271515A (en) * | 2008-10-31 | 2011-12-07 | 健泰科生物技术公司 | Pyrazolopyrimidine JAK inhibitor compounds and methods |
| CN104781251A (en) * | 2012-11-08 | 2015-07-15 | 百时美施贵宝公司 | Bicyclic heterocycle substituted pyridyl compounds useful as kinase modulators |
Non-Patent Citations (2)
| Title |
|---|
| M. P. DWYER ET AL.: "Discovery of pyrazolo[1,5-a]pyrimidine-based Pim inhibitors:A template-based approach", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 章思规 等主编: "《精细有机化工制备手册》", 30 April 1994, 科学技术文献出版社 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Reddy et al. | PEG-SO3H catalyzed synthesis and cytotoxicity of α-aminophosphonates | |
| AU2016225781B2 (en) | Radioactive fluorine labeling precursor compound and method for manufacturing radioactive fluorine labeled compound using the same | |
| CN107176955A (en) | A kind of Ba Rui replaces the preparation method of Buddhist nun | |
| Khedar et al. | Copper triflate: An efficient catalyst for direct conversion of secondary alcohols into azides | |
| EP3741758A1 (en) | Bromodomain inhibitor compound and use thereof | |
| Łukasik et al. | Simple Synthesis of 2-Aminoaryliminophosphoranes from N-Aryl-2-nitrosoanilines and Their Application in 2-Aminobenzimidazole Synthesis | |
| US20120322995A1 (en) | beta-DIHYDROFURAN DERIVING COMPOUND, METHOD FOR PRODUCING beta-DIHYDROFURAN DERIVING COMPOUND OR beta-TETRAHYDROFURAN DERIVING COMPOUND, beta-GLYCOSIDE COMPOUND, METHOD FOR PRODUCING beta GLYCOSIDE COMPOUND, AND METHOD FOR PRODUCING 4'-ETHYNYL D4T AND ANALOGUE COMPOUNDS THEREOF | |
| CN109705094A (en) | A kind of preparation method of pyridine quinazoline | |
| CN109251205A (en) | A method of efficiently synthesizing 5- chlorine pyrazolo [1,5-a] pyrimidine | |
| CN104356110B (en) | A kind of the sulphur induction tetrazine compound of 3,6 aromatic heterocycle Asymmetrical substitute 1,2,4,5 and its synthetic method | |
| KR102203085B1 (en) | Method for synthesis of 1-alkyl-3,5-dinitro-1,2,4-triazole using continuous flow chemistry | |
| Du et al. | Copper (II)-Catalyzed C–N Coupling of Aryl Halides and N-Nucleophiles Promoted by Quebrachitol or Diethylene Glycol | |
| CN101735220A (en) | Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof | |
| JP5245408B2 (en) | Method for producing 1-substituted-5-acylimidazole compound | |
| Ledeti et al. | New azomethine derivatives of 3-substituted-4H-4-amino-5-ethoxycarbonyl-methylsulfanyl-1, 2, 4-triazoles as potential anti-inflammatory agents | |
| Arava et al. | An efficient synthesis of N-cyclopropylanilines by a Smiles rearrangement | |
| CN104230885A (en) | A preparing method of imatinib | |
| CN108840806B (en) | Preparation method of benzamide compound | |
| Bugera et al. | Synthesis and properties of α-bromomethyl-substituted β-ethoxyvinyl polyfluoroalkyl ketones | |
| CN100593538C (en) | Method for preparing N-substituted acryloyl-2,5-pyrrole-dione compound | |
| Shi et al. | Synthesis, Crystal Structure, and Antiproliferative Activity of Novel 7-Arylaminopyrazolo [1, 5-a] pyrimidine Derivatives Containing the Hydrazone Moiety | |
| CN103601719B (en) | 2, 2'-bipyridine-6, 6'-diformyl-quinolyl-2-amine derivative, and preparation method and applications thereof | |
| CN103030641A (en) | Preparation method of pemetrexed disodium key intermediate | |
| CN109912521B (en) | Method for synthesizing alkenyl-substituted 1,2, 3-triazole derivative in one step | |
| Tomczak et al. | A New Way to Obtain Risedronic Acid. |
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: 20190122 |
|
| RJ01 | Rejection of invention patent application after publication |