CN103450148B - A kind of synthetic method of five-membered ring sulfate compound - Google Patents
A kind of synthetic method of five-membered ring sulfate compound Download PDFInfo
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Abstract
The invention belongs to technical field of organic chemistry, are related to a kind of synthetic method of five-membered ring sulfate compound.The technical solution adopted by the present invention is：3 compound of formula reacts 1 compound of synthesis formula with 2 compound of formula, and the equation of reaction is shown below：；Wherein, P1、P2It is hydroxyl protection base, R2=R3For halogen, imidazole radicals, R1For alkyl, aryl or aralkyl.This method is realized by single step reaction, safe and simple, and post-processing operation is simple, is suitble to industrialized production.
Description
Technical field
The invention belongs to technical field of organic chemistry, and in particular to sulphur ring technical field of chemistry.
Background technology
Five-membered ring sulfate compound, basic structure are sulfuric ester ring：
,
Carbon on its sulfuric ester ring has nucleopilic reagent very high reactivity, has in organic synthesis field and widely should
With.
Five-membered ring sulfate compound shown in formula I, No. CAS is 879551-01-6, is synthesis PSI-6130 i.e. 2 '-de-
The important intermediate of oxygen -2 '-fluoro- 2 '-carbon-methylcystein nucleoside compound, PSI-6130 are HCV（Hepatitis C Virus）
NS5B polymerase inhibitors has important application prospect in treatment liver cancer,
。
WO2008045419 and document 1 have reported the synthesis technology of five-membered ring sulfate compound synthesis PSI-6130,
Its synthetic route is as follows：
。
And synthesizing five-membered ring sulfuric ester has two big basic lines at present, a kind of is the derivatives reaction by sulfuric acid or sulfuric acid
It obtains, another kind is first synthesizing five-membered ring sulfite, then is oxidized to five-membered ring sulfuric ester.In WO2008045419 and text
The latter has been used in offering 1.
Synthetic route described in WO2008045419 and document 1 is as follows：
。
The synthetic route that WO2008045419 and document 1 describe all first passes through（2S, 3R）Ethyl -3-（（R）- 2,2- two
- 4 base of penta ring of methyl-1,3-dioxy）- 2,3- dihydroxy -2 Methylpropionic acid and thionyl chloride ring synthesizing five-membered ring sulfite,
Hypochlorite oxidation is used afterwards into five-membered ring sulfuric ester.
As can be seen that the synthesis route described in WO2008045419 and document 1 is realized by two-step reaction, it is first
First（2S, 3R）Ethyl -3-（（R）- 4 base of -2,2- dimethyl -1,3- dioxolanes）- 2,3- dihydroxy -2 Methylpropionic acid and two
Chlorine sulfoxide reaction generation cyclic sulfite, is then oxidized to Cyclic Sulfate, reaction need to pass through two with oxidant by cyclic sulfite
It walks to realize, it is cumbersome, and first step thionyl chloride, pollution is big, and second step uses oxidant, and security risk is big,
Secondary, about liquor natrii hypochloritis, commercialized liquor natrii hypochloritis's effective percentage content is low, causes production capacity small.
In view of reaction raw materials toxicity existing for the existing method for preparing the five-membered ring sulfuric acid ester compound is big, reaction step
Complexity, production capacity are small, it is therefore desirable to develop a kind of more economic, easy preparation method.
Document 1：An Efficient and Diastereoselective Synthesis of PSI-6130: A
Clinically Efficacious Inhibitor of HCV NS5B Polymerase；Journal of Organic
Chemistry, Volume 74, Issue 17, Pages 6819-6824,2009.
Invention content
The purpose of the present invention is to provide a kind of method that five-membered ring sulfuric acid ester compound is prepared through single step reaction, the party
Method is safe and simple, post-processes very simple, and production capacity is big, is suitble to industrialized production.
The technical solution adopted by the present invention is：3 compound of formula reacts 1 compound of synthesis formula, the side of reaction with 2 compound of formula
Formula is shown below：
,
Wherein, P1、P2It is hydroxyl protection base, R1For alkyl, aryl or aralkyl, R2=R3For halogen, imidazole radicals.
The P1、P2It is identical or can be differently independent hydroxyl protection base, as methoxy, benzyloxymethyl,
Tertiary butyl, benzyl, trimethylsilyl or t-butyldimethylsilyi.
The P1、P2Vicinal diols protecting group can also be formed together, and the vicinal diols protecting group refers to acetal, ketal
Or the protecting group of ortho acid ester-formin, such as ethylidene, isopropylidene, cyclopentylene or cyclohexylidene.
Preferably, the vicinal diols protecting group is isopropylidene.
The R1Can be alkyl, such as methyl, ethyl, propyl, isopropyl or butyl；Aryl, such as phenyl；Aralkyl, such as
The benzyl derivative of substituted base on benzyl or phenyl ring.
Preferably, the R1For phenyl, benzyl, ethyl.
It is highly preferred that the R1For ethyl.
Preferably, the R2=R3For chlorine or imidazole radicals.
In a kind of preferred embodiment provided by the invention, the technique of 1 compound of synthesis formula is：In organic solvent
In, in the presence of a base, 3 compound of formula reacts 1 compound of synthesis formula with 2 compound of formula.
The organic solvent can be esters, ethers, arene, alkanes or halogenated hydrocarbon.
Preferably, the esters are Ethyl formate, ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl propionate or third
The different methyl esters of acid；The ethers is methyl tertiary butyl ether(MTBE), tetrahydrofuran, isopropyl ether or amyl ether；The arene is toluene or two
Toluene；The alkanes are pentane, hexane or pentamethylene；The halogenated hydrocarbon is dichloromethane or chloroform.
The alkali can be organic base, such as secondary amine, tertiary amine；Can be inorganic base, such as alkali metal hydrogencarbonate, alkali metal carbon
Hydrochlorate.
Preferably, the alkali metal hydrogencarbonate is NaHCO3、KHCO3；The alkali carbonate is NaCO3、
KCO3。
3 compound of formula, 2 compound of formula, alkali charge ratio be preferably 1:（1~5）:（2~15）.
The mass volume ratio of 3 compound of formula and organic solvent is preferably 1:3~50.
It is highly preferred that the mass volume ratio of 3 compound of formula and organic solvent is 1:8~30.
In above-mentioned reaction, control temperature is preferably -20~50 DEG C.
It is highly preferred that controlled at 0~10 DEG C.
The present invention provides a kind of with sulfonic acid chloride or 1,1 '-sulphonyl diimidazole is reaction raw materials, with 2 compound of formula through one
The method that step reaction prepares five-membered ring sulfuric acid ester compound, this method is safe and simple, post-processes very simple, production capacity
Greatly, it is suitble to industrialized production.
Specific embodiment
For a further understanding of the present invention, with reference to embodiment to five-membered ring sulfate compound provided by the invention
Synthetic method is described in detail.It is to be appreciated that the description of these embodiments is only to be further described the present invention
Feature rather than the limitation to the scope of the invention or scope of the invention as claimed.
Embodiment 1：
200ml isopropyl acetates are added in the 500mL reaction bulbs of clean dried, put into 20g（2S, 3R）Ethyl -3-
（（R）- 4 base of -2,2- dimethyl -1,3- dioxolanes）- 2,3- dihydroxy -2 Methylpropionic acid, 40.8g triethylamines, stirring are molten
Solution.0-10 DEG C is cooled to, 18g sulfonic acid chlorides and 26ml isopropyl acetate mixed solutions is added dropwise at 0-10 DEG C.Drop finishes, and TLC tracking is anti-
Terminal is answered, reaction is finished, and is sequentially added 200g water, 200g saturated sodium carbonates, the washing of 200g saturated sodium-chloride water solutions, is added in 50g
Magnesium sulfate is dried 1 hour.It filters, filtrate is spin-dried for, and obtains 25g grease, yield 100%, GC=98.1%.
Embodiment 2：
200ml methyl tertiary butyl ether(MTBE)s are added in the 500mL reaction bulbs of clean dried, put into 20g（2S, 3R）Ethyl-
3-（（R）- 4 base of -2,2- dimethyl -1,3- dioxolanes）- 2,3- dihydroxy -2 Methylpropionic acid, 40.8g triethylamines, stirring
Dissolving.0-10 DEG C is cooled to, 18g sulfonic acid chlorides and 26ml methyl tertiary butyl ether(MTBE) mixed solutions is added dropwise at 0-10 DEG C.Drop finish, TLC with
Track reaction end,.Reaction is finished, and is sequentially added 200g water, 200g saturated sodium carbonates, the washing of 200g saturated sodium-chloride water solutions, is added
Enter 50g magnesium sulfate to dry 1 hour.It filters, filtrate is spin-dried for, and obtains 25g grease, yield 99%, GC=97.8%.
Embodiment 3：
200ml toluene is added in the 500mL reaction bulbs of clean dried, puts into 20g（2S, 3R）Ethyl -3-（（R）-2,
- 4 base of 2- dimethyl -1,3- dioxolanes）- 2,3- dihydroxy -2 Methylpropionic acid, 40.8g triethylamines, stirring and dissolving.Cooling
To 0-10 DEG C, 18g sulfonic acid chlorides and 26ml toluene mixed solutions is added dropwise at 0-10 DEG C.Drop finishes, and TLC tracking reaction ends, reaction is finished,
200g water, 200g saturated sodium carbonates, the washing of 200g saturated sodium-chloride water solutions are sequentially added, it is small to add in the drying 1 of 50g magnesium sulfate
When.It filters, filtrate is spin-dried for, and obtains 25g grease, yield 97%, GC=98.5%.
Embodiment 4：
200ml hexanes are added in the 500mL reaction bulbs of clean dried, put into 20g（2S, 3R）Ethyl -3-（（R）-2,
- 4 base of 2- dimethyl -1,3- dioxolanes）- 2,3- dihydroxy -2 Methylpropionic acid, 40.8g triethylamines, stirring and dissolving.Cooling
To 0-10 DEG C, 18g sulfonic acid chlorides and 26ml hexane mixed solutions is added dropwise at 0-10 DEG C.Drop finishes, and TLC tracking reaction ends, reaction is finished,
200g water, 200g saturated sodium carbonates, the washing of 200g saturated sodium-chloride water solutions are sequentially added, it is small to add in the drying 1 of 50g magnesium sulfate
When.It filters, filtrate is spin-dried for, and obtains 25g grease, yield 100%, GC=97.5%.
Embodiment 5：
200ml dichloromethane is added in the 500mL reaction bulbs of clean dried, puts into 20g（2S, 3R）Ethyl -3-
（（R）- 4 base of -2,2- dimethyl -1,3- dioxolanes）- 2,3- dihydroxy -2 Methylpropionic acid, 40.8g triethylamines, stirring are molten
Solution.0-10 DEG C is cooled to, 18g sulfonic acid chlorides and 26ml dichloromethane mixed solutions is added dropwise at 0-10 DEG C.Drop finishes, TLC tracking reactions
Terminal, reaction are finished, and are sequentially added 200g water, 200g saturated sodium carbonates, the washing of 200g saturated sodium-chloride water solutions, are added in 50g sulphur
Sour magnesium is dried 1 hour.It filters, filtrate is spin-dried for, and obtains 25g grease, yield 100%, GC=97.6%.
Embodiment 6：
200ml toluene is added in the 500mL reaction bulbs of clean dried, puts into 20g（2S, 3R）Ethyl -3-（（R）-2,
- 4 base of 2- dimethyl -1,3- dioxolanes）- 2,3- dihydroxy -2 Methylpropionic acid, 40.8gDMAP, stirring and dissolving.It is cooled to
10-20 DEG C, 26.6g 1,1 '-sulphonyl diimidazole and 26ml toluene mixed solutions is added dropwise at 10-20 DEG C.Drop finishes, TLC tracking reactions
Terminal, reaction are finished, and are sequentially added 200g water, 200g saturated sodium carbonates, the washing of 200g saturated sodium-chloride water solutions, are added in 50g sulphur
Sour magnesium is dried 1 hour.It filters, filtrate is spin-dried for, and obtains 24g grease, yield 93%, GC=97%.
Embodiment 7：
200ml isopropyl acetates are added in the 500mL reaction bulbs of clean dried, put into 20g（2S, 3R）Ethyl -3-
（（R）- 4 base of -2,2- dimethyl -1,3- dioxolanes）- 2,3- dihydroxy -2 Methylpropionic acid, 70g sodium carbonate, stirring and dissolving.
0-10 DEG C is cooled to, 18g sulfonic acid chlorides and 26ml isopropyl acetate mixed solutions is added dropwise at 0-10 DEG C.Drop finishes, and TLC tracking reaction is eventually
Point, reaction are finished, and are sequentially added 200g water, 200g saturated sodium carbonates, the washing of 200g saturated sodium-chloride water solutions, are added in 50g sulfuric acid
Magnesium is dried 1 hour.It filters, filtrate is spin-dried for, and obtains 22g grease, yield 85%, GC=90%.
Claims (9)
1. a kind of synthetic method of five-membered ring sulfate compound, which is characterized in that 3 compound of formula is deposited with 2 compound of formula in alkali
1 compound of production is reacted under the conditions,
Wherein, P1、P2It is hydroxyl protection base；R2=R3For halogen, imidazole radicals；R1For alkyl, aryl, aralkyl；The alkali is three
Ethamine or DMAP.
2. synthetic method according to claim 1, which is characterized in that the R2=R3For chlorine or imidazole radicals.
3. synthetic method according to claim 1, which is characterized in that the R1For methyl, ethyl, propyl, isopropyl, fourth
The benzyl derivative of substituted base on base, phenyl, benzyl or phenyl ring.
4. synthetic method according to claim 1, which is characterized in that the P1、P2It is identical or be differently independent hydroxyl
The vicinal diols protecting group that base protecting group is either formed together.
5. synthetic method according to claim 4, which is characterized in that the P1、P2It is identical or be differently methoxy methyl
Base, benzyloxymethyl, tertiary butyl, benzyl, trimethylsilyl or t-butyldimethylsilyi.
6. synthetic method according to claim 4, the vicinal diols protecting group is acetal form, Ketal form or ortho acid
The protecting group of ester-formin.
7. synthetic method according to claim 4, which is characterized in that the vicinal diols protecting group is ethylidene, sub- different
Propyl, cyclopentylene or cyclohexylidene.
8. synthetic method according to claim 1, which is characterized in that in organic solvent, 3 compound of formula and 2 chemical combination of formula
1 compound of object reaction synthesis formula.
9. synthetic method according to claim 8, which is characterized in that the organic solvent for Ethyl formate, ethyl acetate,
Isopropyl acetate, tert-butyl acetate, ethyl propionate or the different methyl esters of propionic acid, methyl tertiary butyl ether(MTBE), tetrahydrofuran, isopropyl ether, amyl ether,
Toluene, dimethylbenzene, pentane, hexane, pentamethylene, dichloromethane or chloroform.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210179943.6A CN103450148B (en) | 2012-06-04 | 2012-06-04 | A kind of synthetic method of five-membered ring sulfate compound |
| PCT/CN2013/076679 WO2013182028A1 (en) | 2012-06-04 | 2013-06-04 | Synthesis process for a five-membered ring sulphate compound |
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| CN201210179943.6A CN103450148B (en) | 2012-06-04 | 2012-06-04 | A kind of synthetic method of five-membered ring sulfate compound |
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| CN104045611A (en) * | 2014-04-04 | 2014-09-17 | 苏州景泓生物技术有限公司 | Method for preparing nucleoside polymerase inhibitor PSI-7977 intermediate |
| CN106810541A (en) * | 2016-12-30 | 2017-06-09 | 苏州诚和医药化学有限公司 | A kind of method that one-step method prepares Suo Feibuwei intermediates |
| CN109776487B (en) * | 2019-02-26 | 2021-09-24 | 武汉松石科技股份有限公司 | Preparation method of vinyl sulfate |
| CN111763200A (en) * | 2020-07-13 | 2020-10-13 | 香河昆仑化学制品有限公司 | Cyclic carbonic acid vinyl sulfate ester as lithium ion battery electrolyte additive and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101600725A (en) * | 2006-10-10 | 2009-12-09 | 法莫赛特股份有限公司 | The preparation nucleosides ribofuranosyl pyrimidines |
| WO2011074484A1 (en) * | 2009-12-18 | 2011-06-23 | Libramedicina, Inc. | PROCESS FOR PREPARING SUBSTITUTED 1-O-ACYL-2-DEOXY-2-FLUORO-4-THIO-β-D-ARABINOFURANOSES |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101600725A (en) * | 2006-10-10 | 2009-12-09 | 法莫赛特股份有限公司 | The preparation nucleosides ribofuranosyl pyrimidines |
| WO2011074484A1 (en) * | 2009-12-18 | 2011-06-23 | Libramedicina, Inc. | PROCESS FOR PREPARING SUBSTITUTED 1-O-ACYL-2-DEOXY-2-FLUORO-4-THIO-β-D-ARABINOFURANOSES |
Non-Patent Citations (1)
| Title |
|---|
| An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase;Peiyuan Wang et.al.;《J. Org. Chem.》;20090730;第74卷(第17期);第6821页scheme2 * |
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