CN101153049A - Method of producing high purity clofarabine - Google Patents
Method of producing high purity clofarabine Download PDFInfo
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- CN101153049A CN101153049A CN 200610113470 CN200610113470A CN101153049A CN 101153049 A CN101153049 A CN 101153049A CN 200610113470 CN200610113470 CN 200610113470 CN 200610113470 A CN200610113470 A CN 200610113470A CN 101153049 A CN101153049 A CN 101153049A
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- compound
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- clofarabine
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- clofarex
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Abstract
The present invention relates to a preparation method of clofarabine. The present invention comprises that the mixture of 2-adenine chlorine and the compound of formula I is separated after reaction under the alkaline condition and an appropriate temperature; the basically pure compound of the formula III can be prepared after separation. The high-purity clofarabine can be gotten through hydrolysis under alkaline conditions.
Description
Technical field
The present invention relates to a kind of preparation method's of Clofarex, particularly a kind of high purity clofarabine preparation method.
Background technology
Clofarex (Clofarabine) is a kind of nucleosides purine class antimetabolite, is used for the treatment of children's recurrent or intractable acute lymphoblastic leukemia, is the first new drug of getting permission to be used for the treatment of leukemia of children in nearly ten years, and its structural formula is as shown below:
Leukemia, especially acute lymphoblastic leukemia are the modal malignant tumours of children and teenager.Although the curative ratio of leukemia of children is higher, the anti-leukemia medicine that is specifically designed to children does not also have, and grownup's medication is used for children can bring very big side effect, has a strong impact on children's physical and mental health and quality of life.Clofarex is a medicine that is specifically designed to leukemia of children, this medicine treatment curative ratio height, and patient's better tolerance does not have unpredictable untoward reaction.This medicine is got permission to examine fast in the U.S., has also embodied its potential clinical value.The annual newly-increased leukaemic people more than 40,000 of China is a child patient greatly wherein.Therefore the exploitation of Clofarex not only can reduce the misery of vast child patient, also will obtain good social benefit and economic benefit simultaneously.
Described a kind of preparation method of Clofarex among the WO03011877, may further comprise the steps:
Be prepared in this way, the first step product is the mixture of formula III compound " beta comfiguration isomer " and " α-type isomer ", selection and control by reaction conditions, the content of " α-type isomer " can be controlled at about 5%, but in actually operating, the content of α-type isomer is more than 10%.Because the physico-chemical property of Clofarex and its " α-type isomer " is very approaching, " α-type isomer " of Clofarex is difficult to remove in the end product that obtains, and then influences the purity of product Clofarex.
At document J.Med.Chem., 1992, Vol.35 among the No.2, has reported with the molecular sieve catalyst reaction that adopt the way of twice column chromatography to remove isomer at last, and adopt this method complicated operation loaded down with trivial details, refining yield has only 31.6%.Production efficiency is low, production cost is high.
Polarity and the solvability of Clofarex and its " α-type isomer " are very similar, are difficult to effective separation.Adopt that WO03011877 describes and other disclosed preparation Clofarex method, can not be economical, prepare effectively, refiningly obtain highly purified Clofarex.Therefore, be necessary to develop a kind of simple effectively, easy handling, prepare the method for high purity clofarabine economically.
Summary of the invention
The purpose of this invention is to provide a kind of simple effectively, the preparation method of easy handling, economic high purity clofarabine.
The invention provides a kind of preparation method of high purity clofarabine, comprise the mixture of step (1) with the compound of 2-chloroadenine and formula I, under alkaline condition and proper temperature, separate the reaction back in The suitable solvent, obtains the compound of pure substantially formula III;
And step (2) will be pure substantially compound hydrolysis under alkaline condition of formula III, obtain highly purified Clofarex, wherein R1 and R2 represent the acetyl or benzoyl base.
The present invention further provides a kind of preparation method of high purity clofarabine, the mixture of one or more in employing Virahol, chloroform, the acetonitrile is as the solvent of step (1).
The present invention further provides a kind of preparation method of high purity clofarabine, adopting volume ratio is 1: 1～1: 2, be preferably 1: 1.3～and 1: 1.5 Virahol and the mixture of acetonitrile be as solvent.
The present invention further provides a kind of preparation method of high purity clofarabine, adopting volume ratio is 1: 0.7～1: 1.3, be preferably 1: 0.9～and 1: 1.1 Virahol and the mixture of chloroform be as solvent.
The present invention further provides a kind of preparation method of high purity clofarabine, the proper temperature that can adopt is 0～50 ℃, preferred 25～35 ℃.
The present invention further provides a kind of preparation method of high purity clofarabine, alkaline environment when the compound of preparation formula III obtains the mixture of particular methanol sodium and hydrolith by adopting the mixture a kind of or that they are several in sodium methylate, sodium ethylate, sodium hydride and the hydrolith.
The present invention further provides a kind of preparation method of high purity clofarabine, the alkaline environment when the compound of preparation formula III is 1: 1～1: 5 by adopting molar ratio, and the hydrolith and the sodium methylate mixture that are preferably 1: 3 obtain.
Reaction conditions during the present invention synthesizes by control formula III intermediate is controlled the generation of its isomer.Isolate pure substantially III compound intermediate then, again through the synthetic Clofarex of hydrolysis dehydroxylation protecting group.Avoid the removal of after generating isomer, re-refining, and then more easily prepare highly purified Clofarex.
Adopt method of the present invention; can effectively reduce the content of " α-type isomer " impurity in the Clofarex product; avoided column chromatography to reach the repeatedly troublesome operation of recrystallization; can realize efficiently, large-scale production Clofarex economically, the yield of reaction is higher, controllability strong, the purity height of product, cost are lower.
Embodiment
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Embodiment 1
Under the nitrogen protection, add 12.9g 2-chloroadenine in the 500ml there-necked flask, 100ml Virahol and 75ml acetonitrile mix.Under the room temperature, add 3.2g sodium methylate and 3.4g hydrolith.The mixed solution of 100ml chloroform and 30.5g formula I compound is slowly splashed into.Room temperature reaction spends the night, and the TLC detection reaction finishes.Filter, filter cake washs with chloroform.Merge organic phase, anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates.Cooling crystallization, suction filtration, room temperature vacuum-drying gets solid (formula III compound) 27.6g.Yield 75%.
Embodiment 2
Formula III compound 18.8g, the lithium hydroxide 3.4g, acetonitrile 200ml and the water 350ml that obtain in the example 1 are joined in the 1L reaction flask.Mix stirring at room 3 hours.Regulate pH to 7～8 with acetic acid, concentrating under reduced pressure is removed acetonitrile, the residue cooling crystallization.Suction filtration, filter cake is pulled an oar with acetonitrile.Suction filtration, filter cake in 50 ℃ of vacuum-dryings to constant weight.Get 7.2g off-white color solid, yield is 65%.HPLC analyzes the " α-type isomer that does not detect Clofarex.
Embodiment 3
Under the nitrogen protection, add 12.9g 2-chloroadenine in the 500ml there-necked flask, 100ml Virahol and 50ml acetonitrile mix.Under the room temperature, add 3.2g sodium methylate and 3.4g hydrolith.The mixed solution of 130ml chloroform and 30.5g formula I compound is slowly splashed into.Room temperature reaction spends the night, and the TLC detection reaction finishes.Filter, filter cake washs with chloroform.Merge organic phase, anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates.Cooling crystallization, suction filtration, room temperature vacuum-drying gets solid (formula III compound) 27.6g.Yield 70%.According to the method hydrolysis among the embodiment 2, obtain product and analyze again through HPLC, Clofarex " content of α-type isomer is 2.0%.
Embodiment 4
Under the nitrogen protection, add 12.9g 2-chloroadenine in the 500ml there-necked flask, 100ml Virahol and 75ml acetonitrile mix.Under the room temperature, add 3.2g sodium methylate and 4.0g hydrolith.The mixed solution of 100ml chloroform and 30.5g formula I compound is slowly splashed into.Room temperature reaction spends the night, and the TLC detection reaction finishes.Filter, filter cake washs with chloroform.Merge organic phase, anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates.Cooling crystallization, suction filtration, room temperature vacuum-drying gets solid (formula III compound) 27.6g.Yield 75%.According to the method hydrolysis among the embodiment 2, obtain product and analyze again through HPLC, Clofarex " content of α-type isomer is 1.7%.
Embodiment 5
Under the nitrogen protection, add 12.9g 2-chloroadenine in the 500ml there-necked flask, 100ml Virahol and 75ml acetonitrile mix.Under the room temperature, add 3.2g sodium methylate and 3.4g hydrolith.The mixed solution of 100ml chloroform and 30.5g formula I compound is slowly splashed into.45 ℃ of reactions are spent the night, and the TLC detection reaction finishes.Filter, filter cake washs with chloroform.Merge organic phase, anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates.Cooling crystallization, suction filtration, room temperature vacuum-drying gets solid (formula III compound) 27.6g.Yield 69%.According to the method hydrolysis among the embodiment 2, obtain product and analyze again through HPLC, Clofarex " content of α-type isomer is 3.0%.
Embodiment 6
Under the nitrogen protection, add 14g 2-chloroadenine in the 500ml there-necked flask, 100ml Virahol and 75ml acetonitrile mix.Under the room temperature, add 3.2g sodium methylate and 3.4g hydrolith.The mixed solution of 100ml chloroform and 32g formula I compound is slowly splashed into.Room temperature reaction spends the night, and the TLC detection reaction finishes.Filter, filter cake washs with chloroform.Merge organic phase, anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates.Cooling crystallization, suction filtration, room temperature vacuum-drying gets the formula III compound.According to the method hydrolysis among the embodiment 2, obtain product and analyze again through HPLC, Clofarex " content of α-type isomer is 2.0%.
Claims (7)
1. the preparation method of a high purity clofarabine is characterized in that may further comprise the steps:
(1), with the compound of formula I and the mixture of 2-chloroadenine, under alkaline condition and proper temperature, separate reaction back in The suitable solvent, obtains the compound of pure substantially formula III;
(2), compound hydrolysis under alkaline condition of formula III that will be pure substantially, obtain highly purified Clofarex, wherein R1 and R2 represent the acetyl or benzoyl base.
2. method according to claim 1 is characterized in that described suitable solvent is one or more the mixture in Virahol, chloroform, the acetonitrile.
3. method according to claim 1 is characterized in that the volume ratio of Virahol and acetonitrile is 1: 1～1: 2 in the described suitable solvent, is preferably 1: 1.3～1: 1.5.
4. method according to claim 1 is characterized in that the two volume ratio of Virahol and chloroform in the described solvent is 1: 0.7～1: 1.3, is preferably 1: 0.9～1: 1.1.
5. method according to claim 1 is characterized in that described proper temperature is 0～50 ℃, preferred 25～35 ℃.
6. method according to claim 1, the alkaline environment when it is characterized in that the compound of preparation formula III in the step (1) is by adopting one or more acquisitions in sodium methylate, sodium ethylate, sodium hydride and the hydrolith, particular methanol sodium and hydrolith.
7. method according to claim 6, the alkaline environment when it is characterized in that the compound of preparation formula III in the step (1) is 1: 1～1: 5 by adopting molar ratio, the hydrolith and the sodium methylate mixture that are preferably 1: 3 obtain.
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| CN 200610113470 CN101153049A (en) | 2006-09-29 | 2006-09-29 | Method of producing high purity clofarabine |
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| CN 200610113470 CN101153049A (en) | 2006-09-29 | 2006-09-29 | Method of producing high purity clofarabine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830955A (en) * | 2009-03-13 | 2010-09-15 | 浙江海正药业股份有限公司 | Synthesizing process of antineoplastic agent clofarabine |
| CN102311472A (en) * | 2010-07-09 | 2012-01-11 | 神隆(昆山)生化科技有限公司 | Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine |
| CN103665075A (en) * | 2013-12-26 | 2014-03-26 | 南通康鑫药业有限公司 | Synthesis method of clofarabine |
| CN105601688A (en) * | 2015-12-23 | 2016-05-25 | 国药一心制药有限公司 | Preparation methods for clofarabine intermediate and clofarabine |
-
2006
- 2006-09-29 CN CN 200610113470 patent/CN101153049A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830955A (en) * | 2009-03-13 | 2010-09-15 | 浙江海正药业股份有限公司 | Synthesizing process of antineoplastic agent clofarabine |
| CN101830955B (en) * | 2009-03-13 | 2013-09-11 | 浙江海正药业股份有限公司 | Synthesizing process of antineoplastic agent clofarabine |
| CN102311472A (en) * | 2010-07-09 | 2012-01-11 | 神隆(昆山)生化科技有限公司 | Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine |
| CN102311472B (en) * | 2010-07-09 | 2014-09-03 | 神隆(昆山)生化科技有限公司 | Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine |
| CN103665075A (en) * | 2013-12-26 | 2014-03-26 | 南通康鑫药业有限公司 | Synthesis method of clofarabine |
| CN105601688A (en) * | 2015-12-23 | 2016-05-25 | 国药一心制药有限公司 | Preparation methods for clofarabine intermediate and clofarabine |
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