CN1453287A - One-kettle process of preparing 2,3'-anhydro-5'-O-(tert-pentenyl) thymidine and its derivative (oxo bridge compound) - Google Patents
One-kettle process of preparing 2,3'-anhydro-5'-O-(tert-pentenyl) thymidine and its derivative (oxo bridge compound) Download PDFInfo
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- CN1453287A CN1453287A CN 02117191 CN02117191A CN1453287A CN 1453287 A CN1453287 A CN 1453287A CN 02117191 CN02117191 CN 02117191 CN 02117191 A CN02117191 A CN 02117191A CN 1453287 A CN1453287 A CN 1453287A
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Abstract
The present invention is the one-kettle process of preparing 2, 3'-anhydro-5'-protected thymidine and its derivative with thymidine and its derivative as material. The method is easy to operate and high in yield, and is one new method of synthesizing the intermediate of Zidovudine and similar compound.
Description
Invention field
The present invention relates to 2; the new preparation method of 3`-dehydration-5`-O-(pivaloyl group) Thymine deoxyriboside and derivative (oxygen bridge material) thereof; this 2,3`-dehydration-5`-O-(pivaloyl group) Thymine deoxyriboside and derivative (oxygen bridge material) thereof can be used for synthetic zidovudine and similar compound.
Background of invention
Known compound AZT (3`-azido--3`-deoxythymidine) and derivative thereof can be used for treating virus and infectation of bacteria, be particularly useful for treating AIDS (referring to, for example: United States Patent (USP) 4,724,4,828,838,4,847,244,4,874,609,4,874,751,4,818,705,5,093,114 and 5,145,840).Its preparation has three kinds of methods substantially:
Method one, with thymidine be raw material production (referring to, for example: J.Org.Chem., 1964,
29, 2076; Tetrahedron Lett., 1989,30,1955; United States Patent (USP) 5,041,543, DE3,705,794 and WO93,07162).
Method two, its characteristics be make carbohydrate precursor that azido-replaces and the coupling of an activatory thymus pyrimidine alkali (referring to, for example: Tetrahedron Lett., 1988,29,5349; WO 9001492 A1; Tetrahedron, 1988,44,625; Synthesis, 1991,451; J.Org.Chem., 1991,56,2614; Tetrahedron Lett., 1991,32,1813).
Method three, employing D-wood sugar (referring to, for example: United States Patent (USP) 4,916,218, Japanese Patent 63255295, European patent 295090, and United States Patent (USP) 4,921,950) or the D-glucofuranose (referring to, for example: Carbohydr.Res., 1991,316,179) do raw material, guide base pairing to generate required β-anomer with 2`-Alpha-hydroxy (with the carboxylate form).Although this reaction to join sugared stereoselectivity higher, the selective protection that its sugar moieties is long and go to protect and be still one problem to be solved is arranged.In addition, the used reagent of these methods is also very expensive.
In the past, because thymidine costs an arm and a leg, so it is higher with the thymidine to be that starting raw material prepares the zidovudine cost.But along with the realization of thymidine suitability for industrialized production, this method becomes the effective ways of preparation zidovudine.This method common feature is after thymidine is protected, and makes oxygen bridge material through Mitsunobu reaction, introduces azido-again, and last hydrolysis makes zidovudine (referring to Tetrahedron Lett., 1989,30 (15), 1955; J.Med.Chem., 1978,21 (1), 109; J.Org.Chem., 1964,29,2076; US 5041543; DE 3608606; DE 3705794; WO 9001492).Oxygen bridge material is a common important intermediate in these class methods.
These existing technology all do not relate to or advise of the present invention is raw material with Thymine deoxyriboside and derivative thereof, obtains 2 through " one kettle way ", the Thymine deoxyriboside of 3`-dehydration-5`-protection and the novel method of derivative thereof.
Goal of the invention
The purpose of this invention is to provide a kind of easy and simple to handle, yield is high, be suitable for the new method of the intermediate of continuous production zidovudine and similar compound.
Summary of the invention
The present invention relates to the preparation method of following compound:
Flow process is as follows:
R wherein
1Be hydrogen or methyl, R
2Be known hydroxyl protecting group, R
3Be alkyl or aryl.
Preparation method of the present invention is divided into two stages: the stage one, in alkali organic solvent, after the 5` position hydroxyl of Thymine deoxyriboside and derivative thereof protected with known method, the SULPHURYL CHLORIDE that replaces with alkyl or aryl was reacted again, forms the compound that the 3`-alkylsulfonyl replaces; In the stage two, with the reaction solution of stage one preparation, without aftertreatments such as separation, purifying, only through simple filtering or without filtration, directly reaction under certain condition obtains oxygen bridge material.After according to this law resulting oxygen bridge material being carried out purifying, can obtain the high product of purity, and be used to prepare highly purified zidovudine and class formula compound thereof.
Method of the present invention has following advantage:
1. do not need in this law that Thymine deoxyriboside and derivative thereof to 3`, 5` protection separates, aftertreatment such as purifying, obtain oxygen bridge material and be to use " one kettle way " directly to react, reduced operation steps, be convenient to serialization production and reduced production cost;
2. after according to this law resulting oxygen bridge material being carried out purifying, can obtain the high product of purity, and can be used for preparing highly purified zidovudine and class formula compound thereof.
Embodiment
Embodiment 1
Under the nitrogen gas stream, in the 2L there-necked flask, add the 1L pyridine, add the 100g Thymine deoxyriboside under stirring, cooling, temperature is lower than 10 ℃ of dropping pivaloyl chloride 60ml in keeping, drip and finish, room temperature reaction to raw material point disappears, and (TLC detects, developping agent: chloroform: methyl alcohol=9: 1).Cooling, temperature is lower than 10 ℃ of dropping methylsulfonyl chloride 45ml in keeping.Drip and finish room temperature reaction 3～5 hours.Filter, a little pyridine washing has filtrate being transferred in the there-necked flask of reflux cooling pipe, is heated with stirring to 70～75 ℃ and keep this thermotonus to raw material point disappear (TLC detection, developping agent: chloroform: methyl alcohol=9: 1).Be spin-dried for solvent, add chloroform in resistates, stirring at room was filtered after 30 minutes, and filtrate is placed in refrigerator and spent the night.Next day, separate out white crystals.Filter, a little chloroform washing, 50～60 ℃ of drying under reduced pressure get white crystalline powder 100g, yield: 78%.mp215～217℃。
The proton nmr spectra data are as follows:
1H-NMR (300MHz, CDCl
3) δ: 1.16 (9H, s, pivaloyl-H), 1.81 (3H, s, 5-CH
3), 2.68 (2H, m, 2`a-H), 4.22 (2H, dd, 5`ab-H), 4.38 (1H, m, 4`-H), 5.19 (1H, brs, 3`-H), 5.54 (1H, d, 1`-H), 6.99 (1H, d, 6-H).
Embodiment 2
Under the nitrogen gas stream, in the 2L there-necked flask, adding 0.5L trichloromethane, the 0.5L triethylamine adds the 100g Thymine deoxyriboside under stirring, cooling, temperature is lower than 10 ℃ of dropping pivaloyl chloride 60ml in the maintenance, drips and finishes, and room temperature reaction is to raw material point disappearance (TLC detection).Cooling, temperature is lower than 10 ℃ of dropping methylsulfonyl chloride 45ml in keeping.Drip and finish room temperature reaction 3～5 hours.Reaction is finished, and being heated with stirring to refluxes and keep being back to raw material point disappears.Method according to embodiment 1 is carried out aftertreatment, gets white crystalline powder 107g, yield: 83%.mp215～217℃。
Embodiment 3
With 1, the 4-dioxane replaces the trichloromethane among the embodiment 2, repeats same operation, obtains the oxygen bridge material 111g of white crystalline powder, yield: 87%.mp215～217℃。
Claims (4)
1. the novel method for preparing general formula (1) compound:
General formula (1)
This method comprises:
With general formula (2) is raw material, after respectively 3`, 5` position hydroxyl being protected in alkali organic solvent, need not aftertreatment, directly carries out the Mitsunobu reaction and makes oxygen bridge material (1).
General formula (2)
R in general formula (1) and the general formula (2)
1Be hydrogen or methyl, R
2Be known hydroxyl protecting group.
2. the method for claim 1, starting raw material is a Thymine deoxyriboside.
3. the process of claim 1 wherein that used alkali organic solvent is the mixed solvent of organic basess such as pyridines, trialkyl amines or above-mentioned organic bases and halogenated hydrocarbon, ethers, ester class or organic solvent of ketone.
4. the method for claim 1 after the hydroxyl that it is characterized in that 3`, 5` position to Thymine deoxyriboside is protected, need not separated product, directly carries out the Mitsunobu reaction, makes highly purified oxygen bridge material.With the oxygen bridge material that makes with this method, can make highly purified zidovudine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02117191 CN1453287A (en) | 2002-04-25 | 2002-04-25 | One-kettle process of preparing 2,3'-anhydro-5'-O-(tert-pentenyl) thymidine and its derivative (oxo bridge compound) |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02117191 CN1453287A (en) | 2002-04-25 | 2002-04-25 | One-kettle process of preparing 2,3'-anhydro-5'-O-(tert-pentenyl) thymidine and its derivative (oxo bridge compound) |
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| CN 02117191 Pending CN1453287A (en) | 2002-04-25 | 2002-04-25 | One-kettle process of preparing 2,3'-anhydro-5'-O-(tert-pentenyl) thymidine and its derivative (oxo bridge compound) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103443115A (en) * | 2011-11-07 | 2013-12-11 | 上海迪赛诺药业有限公司 | Method for preparing zidovudine and intermediate thereof |
| CN104710490A (en) * | 2013-12-13 | 2015-06-17 | 安徽贝克联合制药有限公司 | Preparation method of zidovudine |
-
2002
- 2002-04-25 CN CN 02117191 patent/CN1453287A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103443115A (en) * | 2011-11-07 | 2013-12-11 | 上海迪赛诺药业有限公司 | Method for preparing zidovudine and intermediate thereof |
| CN103443115B (en) * | 2011-11-07 | 2015-09-23 | 上海迪赛诺药业有限公司 | Prepare the method for zidovudine and intermediate thereof |
| CN104710490A (en) * | 2013-12-13 | 2015-06-17 | 安徽贝克联合制药有限公司 | Preparation method of zidovudine |
| CN104710490B (en) * | 2013-12-13 | 2019-05-03 | 安徽贝克联合制药有限公司 | A kind of preparation method of Zidovudine |
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