CN109320573A - A kind of green synthesis process of clofarabine - Google Patents
A kind of green synthesis process of clofarabine Download PDFInfo
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- CN109320573A CN109320573A CN201811374522.2A CN201811374522A CN109320573A CN 109320573 A CN109320573 A CN 109320573A CN 201811374522 A CN201811374522 A CN 201811374522A CN 109320573 A CN109320573 A CN 109320573A
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- Prior art keywords
- compound
- formula
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- clofarabine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The present invention relates to a kind of green synthesis process of clofarabine, include the following steps:
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of green synthesis process of clofarabine.
Background technique
Clofarabine (clofarabine) is a kind of fluoro nucleosides class drug, is approved by the FDA in the United States listing within 2004, faces
It is mainly used for treating leukemia of children on bed.At present there are many synthetic methods of clofarabine, but most methods need to use centre
Body --- bis--O- benzoyl of the bromo- 2- deoxidation -2- β of 1--fluoro- 3,5--D-arabinose.It is green that the present invention provides a kind of one kettle way
The method that color synthesizes above-mentioned intermediate, and be successfully applied in the synthesis technology of clofarabine.
Summary of the invention
The present invention provides a kind of green synthesis process of clofarabine, it is characterised in that includes the following steps:
(1) Formula II compound is dissolved in organic solvent, 40% hydrobromic acid, tetrabutyl ammonium fluoride is added under ice bath, stirs
After mixing reaction 3 hours, triethylamine trihydrofluoride is added, continues to be stirred to react 2-3 hours to get compound of formula I；
(2) formula III compound is dissolved in acetonitrile, potassium tert-butoxide, calcium hydride, the tert-butyl alcohol is added, be warming up to 60 DEG C of reactions 1
Hour after, be added compound of formula I, keep 60 DEG C the reaction was continued 10 hours to get formula IV compound；
(3) formula IV compound removes Bz under alkaline condition, obtains Formula V compound, i.e. clofarabine.
In step (1), every mM of Formula II compound uses 40% hydrobromic acid 5mL, uses tetrabutyl ammonium fluoride 2-
3mmol uses triethylamine trihydrofluoride 1-1.5mmol.The preferred methylene chloride of the organic solvent, THF.
In step (2), every mM of formula III compound is made using potassium tert-butoxide 1.2mmol using calcium hydride 1.2mmol
With tert-butyl alcohol 1.5mL, compound of formula I 1.2mmol is used.
In step (3), the methanol solution or NH of the sodium methoxide of the preferred pH9.0-10.0 of alkaline condition3/ MeOH is full
And solution.
Another embodiment of the present invention provides a kind of bromo- 2- deoxidation -2- β of one pot process 1--bis--O- benzene of fluoro- 3,5-
The method of formoxyl-D-arabinose (Formulas I), it is characterised in that include the following steps:
Formula II compound is dissolved in organic solvent, 40% hydrobromic acid, tetrabutyl ammonium fluoride are added under ice bath, stirring is anti-
After answering 3 hours, triethylamine trihydrofluoride is added, continues to be stirred to react 2-3 hours to get compound of formula I.
Wherein, every mM of Formula II compound is made using 40% hydrobromic acid 5mL using tetrabutyl ammonium fluoride 2-3mmol
With triethylamine trihydrofluoride 1-1.5mmol.The preferred methylene chloride of the organic solvent, THF.
Of the present invention 40% hydrobromic acid refers to that mass fraction is 40% hydrobromic acid solution.
Compared with the prior art, the advantages of the present invention are as follows: (1) present invention successfully completed by Formula II compound one kettle way
Preparation of compounds of formula I greatly reduces reaction step；(2) the present invention provides a kind of green high-efficient synthesis clofarabines
New process.
Specific embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments are only not supposed to be a limitation to the present invention or implementation principle for better understanding invention, reality of the invention
The mode of applying is not limited to the following contents.
Embodiment 1
Modus ponens II compound (1.0mmol) is dissolved in methylene chloride (10mL), and 40% hydrobromic acid is added under ice bath
(5mL), tetrabutyl ammonium fluoride (2mmol) after being stirred to react 3 hours, is added triethylamine trihydrofluoride (1.0mmol), continues
After being stirred to react 3 hours, methylene chloride dilution is added, is successively washed with saturated sodium bicarbonate, saturated sodium-chloride, anhydrous sodium sulfate
After dry, filtering, filtrate concentration, obtain light yellow oil (385mg, yield 91%, HPLC purity 76.2%, α/β are about 1/1,
Through1H NMR, MS confirmation are compound of formula I, and confirmation data and report are consistent).
Embodiment 2
Modus ponens II compound (1.0mmol) is dissolved in THF (10mL), and 40% hydrobromic acid (5mL), four fourths are added under ice bath
Base ammonium fluoride (3mmol) after being stirred to react 3 hours, is added triethylamine trihydrofluoride (1.5mmol), continues to be stirred to react 2 small
Shi Hou, be added methylene chloride dilution, successively wash with saturated sodium bicarbonate, saturated sodium-chloride, anhydrous sodium sulfate drying, filter,
Filtrate concentration after, obtain light yellow oil (398mg, yield 94%, HPLC purity 74.3%, α/β are about 1/1,1H NMR、MS
Data and embodiment 1 are consistent).
Embodiment 3
Modus ponens II compound (1.0mmol) is dissolved in methylene chloride (10mL), and 40% hydrobromic acid is added under ice bath
(5mL), triethylamine trihydrofluoride (1.0mmol), after being stirred to react 6 hours, TLC detection does not find α or beta comfiguration Formulas I chemical combination
Object.
Embodiment 4
Modus ponens III compound (1.0mmol) is dissolved in acetonitrile (10mL), and potassium tert-butoxide (1.2mmol), calcium hydride is added
(1.2mmol), the tert-butyl alcohol (1.5mL) is added compound of formula I (1.2mmol) after being warming up to 60 DEG C of reactions 1 hour, is kept for 60 DEG C
It after the reaction was continued 10 hours, is cooled to room temperature, filters, after filtrate tune pH to 6.0-7.0, concentration obtains formula IV through silica gel column chromatography
Compound (192mg, warp1H NMR, MS confirmation are formula IV compound, and confirmation data and report are consistent), in addition also obtain α configuration
By-product 186mg.
Embodiment 5
Modus ponens IV compound (1.0mmol) is dissolved in methanol, and sodium methoxide tune pH9.0-10.0 is added, is stirred to react at room temperature
2 hours, TLC detection formula IV compound completely disappeared, and cation exchange resin was added, after five minutes, filtering, filtrate are concentrated for stirring
Up to Formula V (clofarabine, white solid, 290mg, yield 95.5%,1H、13C NMR, MS data and report are consistent).
Embodiment 6
NH is added in formula IV compound (1.0mmol)3In/MeOH saturated solution (15mL), after stirring 6 hours at room temperature,
Be concentrated under reduced pressure, re-crystallizing in ethyl acetate obtain white solid (271mg, yield 89.2%,1H、13C NMR, MS data and clofarabine
Unanimously).
Claims (5)
1. a kind of synthesis technology of clofarabine, it is characterised in that include the following steps:
(1) Formula II compound is dissolved in organic solvent, 40% hydrobromic acid, tetrabutyl ammonium fluoride is added under ice bath, stirring is anti-
After answering 3 hours, triethylamine trihydrofluoride is added, continues to be stirred to react 2-3 hours to get compound of formula I；
(2) formula III compound is dissolved in acetonitrile, potassium tert-butoxide, calcium hydride, the tert-butyl alcohol is added, be warming up to 60 DEG C and react 1 hour
Afterwards, be added compound of formula I, keep 60 DEG C the reaction was continued 10 hours to get formula IV compound；
(3) formula IV compound removes Bz under alkaline condition, obtains Formula V compound, i.e. clofarabine.
2. synthesis technology described in claim 1, it is characterised in that in step (1), every mM of Formula II compound uses 40%
Hydrobromic acid 5mL use triethylamine trihydrofluoride 1-1.5mmol using tetrabutyl ammonium fluoride 2-3mmol.
3. synthesis technology described in claim 1, it is characterised in that the preferred methylene chloride of organic solvent described in step (1),
THF。
4. the described in any item synthesis technologies of claim 1-3, it is characterised in that in step (2), every mM of formula III compound
Using potassium tert-butoxide 1.2mmol, compound of formula I 1.2mmol is used using tert-butyl alcohol 1.5mL using calcium hydride 1.2mmol.
5. the described in any item synthesis technologies of claim 1-4, it is characterised in that in step (3), the alkaline condition is preferred
The methanol solution or NH of the sodium methoxide of pH9.0-10.03/ MeOH saturated solution.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811374522.2A CN109320573A (en) | 2018-11-17 | 2018-11-17 | A kind of green synthesis process of clofarabine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811374522.2A CN109320573A (en) | 2018-11-17 | 2018-11-17 | A kind of green synthesis process of clofarabine |
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| CN109320573A true CN109320573A (en) | 2019-02-12 |
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| CN201811374522.2A Pending CN109320573A (en) | 2018-11-17 | 2018-11-17 | A kind of green synthesis process of clofarabine |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531695A (en) * | 2009-03-02 | 2009-09-16 | 徐州瑞赛科技实业有限公司 | Method for synthesizing fluoro-oligonucleotide for preparing siRNA |
| CN101555267A (en) * | 2008-04-09 | 2009-10-14 | 杭州容立医药科技有限公司 | Synthesis method of clofarabine of nucleoside analogues |
| CN101584672A (en) * | 2009-07-17 | 2009-11-25 | 山东罗欣药业股份有限公司 | Clofarabine pharmaceutical composition freeze-dried powder injection and preparation method thereof |
| CN101775044A (en) * | 2010-01-04 | 2010-07-14 | 成都福瑞生物工程有限公司 | Method for preparing fluoro alpha-D-arabinofuranose compound |
| CN102167716A (en) * | 2011-03-22 | 2011-08-31 | 福州海王福药制药有限公司 | Synthesis method of clofarabine, midbody thereof and preparation method of midbody |
-
2018
- 2018-11-17 CN CN201811374522.2A patent/CN109320573A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101555267A (en) * | 2008-04-09 | 2009-10-14 | 杭州容立医药科技有限公司 | Synthesis method of clofarabine of nucleoside analogues |
| CN101531695A (en) * | 2009-03-02 | 2009-09-16 | 徐州瑞赛科技实业有限公司 | Method for synthesizing fluoro-oligonucleotide for preparing siRNA |
| CN101584672A (en) * | 2009-07-17 | 2009-11-25 | 山东罗欣药业股份有限公司 | Clofarabine pharmaceutical composition freeze-dried powder injection and preparation method thereof |
| CN101775044A (en) * | 2010-01-04 | 2010-07-14 | 成都福瑞生物工程有限公司 | Method for preparing fluoro alpha-D-arabinofuranose compound |
| CN102167716A (en) * | 2011-03-22 | 2011-08-31 | 福州海王福药制药有限公司 | Synthesis method of clofarabine, midbody thereof and preparation method of midbody |
Non-Patent Citations (3)
| Title |
|---|
| QING DAI，等: "Synthesis of DNA oligos containing 2"-deoxy-2"-fluoro-D-arabinofuranosyl-5-carboxylcytosine as hTDG inhibitor", 《TETRAHEDRON》 * |
| TSANN-LONG SU，等: "Improved Synthesis of α-D-Ribofuranosides via Stereoselective Alkylation of a Dibutylstannylene Derivative for Ready Access to the 2-Substituted 2-Deoxyarabinofuransides", 《J. ORG. CHEM.》 * |
| 陈磊，等: "氟取代核苷的合成——糖基氟化的研究进展", 《化工时刊》 * |
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Application publication date: 20190212 |