CN105037453A - Preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside - Google Patents
Preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside Download PDFInfo
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- CN105037453A CN105037453A CN201510414117.9A CN201510414117A CN105037453A CN 105037453 A CN105037453 A CN 105037453A CN 201510414117 A CN201510414117 A CN 201510414117A CN 105037453 A CN105037453 A CN 105037453A
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- methyl
- isopropylidene
- deoxy
- glycosides
- ribofuranose
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- RNHBZJGMAYMLBE-MIDKJMSJSA-N CC([C@H]1OC(C)(C)O[C@H]11)OC1OC Chemical compound CC([C@H]1OC(C)(C)O[C@H]11)OC1OC RNHBZJGMAYMLBE-MIDKJMSJSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside. The method comprises: taking D-ribose as an initial material to obtain methyl-2,3-O-isopropylidene-D-ribofuranoside under the protection of methanol/acetone; reacting methyl-2,3-O-isopropylidene-D-ribofuranoside with paratoluensulfonyl chloride to obtain methyl-2,3-O-isopropylidene-5-O-paratoluenesulfonyl-D-ribofuranoside in alkaline condition, wherein the reaction is subjected to proper treatment and needs no purification; taking hexamethylphosphoric triamide or N,N-dimethyl-2-imidazolidinone as a reducing solvent; and using hydroboron for reduction to obtain methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside. The reducing reaction agent can be recycled; the reaction intermediates are subjected to proper treatment and need no purification; and the preparation method is simple to operate, wild in condition, and low in production cost.
Description
Technical field
The present invention relates to a kind of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides preparation method.
Background technology
Methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides is the key intermediate of synthesis antiviral capecitabine.Structure is as follows:
All have report in preparation method's document of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides and patent, general employing D-ribose is raw material, and through methyl alcohol, acetone protection, Tosyl chloride esterification, borohydride reduction obtain, and reaction principle is as follows:
World patent WO2010065586A2 reports; D-ribose is after methyl alcohol, acetone protection, and take triethylamine as acid binding agent, Tosyl chloride esterification obtains methyl-2; 3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides, this intermediate is dry after crystallization and purification in Virahol.Again using methyl-sulphoxide as reduction solvent, sodium borohydride reduction obtains methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides.This patent gained methyl-2,3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides needs a large amount of Virahol as recrystallisation solvent, also needs through operations such as filtration, dryings, complicated operation; And using methyl-sulphoxide as reduction solvent, during aftertreatment, foul smelling smell produces and reclaims difficulty, is difficult to circulation.
Summary of the invention
The object of the present invention is to provide methyl-2, the 3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides preparation method that a kind of easy and simple to handle, reductive condition environmental protection, reduction solvent are capable of circulation.
Technical solution of the present invention is:
A kind of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides preparation method, is characterized in that: comprise the following steps:
(1) D-ribose obtains methyl-2,3-O-isopropylidenes-D-RIBOSE glycosides through methyl alcohol, acetone protection in presence of an acid catalyst;
(2) then under alkaline condition and phase catalyst exist, methyl-2,3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides is obtained by reacting with Tosyl chloride; Add lower alcohol and destroy excessive Tosyl chloride, after adding water washing, the tosic acid low-carbon-ester that toluene generates with weak lye backflow removing;
(3) with HMPA or N, N-dimethyl-imidazolinone as reduction solvent, obtain methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides by borohydride reduction.
The acid catalyst that step (1) adopts is methylsulfonic acid.
The phase-transfer catalyst that step (2) adopts is triethyl benzyl ammonia chloride.
Lower alcohol in step (2) is methyl alcohol.
Weak lye in step (2) is saturated sodium bicarbonate aqueous solution.
Reduction reaction solvent of the present invention is capable of circulation, and reaction intermediate is through suitably process, and all without the need to purifying, simple, mild condition, environmental protection, production cost is low.
Below in conjunction with embodiment, the invention will be further described.
Embodiment
Embodiment 1:
50gD-ribose, 400ml methyl alcohol, 400ml acetone, 4g methylsulfonic acid is added in 1000ml there-necked flask, stir molten clear after, be warming up to backflow 2.5 hours, be cooled to room temperature, add triethylamine and adjust pH=7-8, concentrating under reduced pressure removing methyl alcohol, acetone, be cooled to 15-20 DEG C, the 50ml that adds water dilutes, and extracts with toluene 300ml+200ml.Combining methylbenzene phase, is cooled to 5-10 DEG C, adds 57.5g Tosyl chloride, 1g triethyl benzyl ammonia chloride; drip 54g50% sodium hydroxide solution; drip complete insulation reaction 4 hours, add 5ml methyl alcohol, continue reaction 1 hour; add 100ml × 2 and wash salt; toluene mutually in add 200ml saturated sodium bicarbonate aqueous solution temperature rising reflux 1 hour, be cooled to room temperature, phase-splitting; methyl-2,3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides toluene is makeed an appointment 550ml.
Embodiment 2:
Embodiment 1 gained methyl-2; 3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides toluene is makeed an appointment 550ml; concentrating under reduced pressure removes toluene; add 200mlHMPA; be warming up to 90-95 DEG C, slowly add 16.2g POTASSIUM BOROHYDRIDE in batches, finish insulation 4 hours; be cooled to 15-20 DEG C, drip 200ml shrend and to go out reaction.With 150ml × 3 petroleum ether extraction, merge sherwood oil phase, after 20ml water washing, concentrated removal sherwood oil, obtains methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides 50g, total recovery 80%, GC content 96.9%.
Embodiment 3:
Embodiment 1 gained methyl-2; 3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides toluene is makeed an appointment 550ml; concentrating under reduced pressure removes toluene; add 200mlDMI; be warming up to 90-95 DEG C, slowly add 16.2g POTASSIUM BOROHYDRIDE in batches, finish insulation 4 hours; be cooled to 15-20 DEG C, drip 200ml shrend and to go out reaction.With 150ml × 3 petroleum ether extraction, merge sherwood oil phase, after 20ml water washing, concentrated removal sherwood oil, obtains methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides 51g, total recovery 81%, GC content 97.5%.
Embodiment 4:
Embodiment 1 gained methyl-2; 3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides toluene is makeed an appointment 550ml; concentrating under reduced pressure removes toluene; add 200mlHMPA; be warming up to 90-95 DEG C, slowly add 11.4g sodium borohydride in batches, finish insulation 4 hours; be cooled to 15-20 DEG C, drip 200ml shrend and to go out reaction.With 150ml × 3 petroleum ether extraction, merge sherwood oil phase, after 20ml water washing, concentrated removal sherwood oil, obtains methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides 49g, total recovery 78%, GC content 97.2%.
Embodiment 5:
Embodiment 1 gained methyl-2; 3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides toluene is makeed an appointment 550ml; concentrating under reduced pressure removes toluene; add 200mlDMI; be warming up to 90-95 DEG C, slowly add 11.4g sodium borohydride in batches, finish insulation 4 hours; be cooled to 15-20 DEG C, drip 200ml shrend and to go out reaction.With 150ml × 3 petroleum ether extraction, merge sherwood oil phase, after 20ml water washing, concentrated removal sherwood oil, obtains methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides 51g, total recovery 81%, GC content 97.8%.
Embodiment 6:
Embodiment 2 gained reduction reaction raffinate aqueous phase and sherwood oil phase washing water merge about 450ml, atmospheric evaporation to 120 DEG C mutually, add 200ml toluene atmospheric pressure reflux and divide water to separate to anhydrous, be cooled to room temperature, filter, filter cake 50ml toluene wash, merging filtrate, after concentrating under reduced pressure removing toluene, obtain HMPA concentrated solution 170ml, underpressure distillation, recyclable HMPA160ml, the rate of recovery 80%, content 99%.After steaming water jacket use, recyclable HMPA190ml, the rate of recovery 95%, content 99%.
Embodiment 7:
Embodiment 3 gained reduction reaction raffinate aqueous phase and sherwood oil phase washing water merge about 450ml, atmospheric evaporation to 120 DEG C mutually, add 200ml toluene atmospheric pressure reflux and divide water to separate to anhydrous, be cooled to room temperature, filter, filter cake 50ml toluene wash, merging filtrate, after concentrating under reduced pressure removing toluene, obtain DMI concentrated solution 180ml, underpressure distillation, recyclable DMI170ml, the rate of recovery 85%, content 99%.After steaming water jacket use, recyclable DMI192ml, the rate of recovery 96%, content 99%.
Embodiment 8:
Embodiment 1 gained methyl-2; 3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides toluene is makeed an appointment 550ml; concentrating under reduced pressure removes toluene; add embodiment 6 gained 170mlHMPA concentrated solution, add 40mlHMPA, be warming up to 90-95 DEG C; slowly add 16.2g POTASSIUM BOROHYDRIDE in batches; finish insulation 4 hours, be cooled to 15-20 DEG C, drip 200ml shrend and to go out reaction.With 150ml × 3 petroleum ether extraction, merge sherwood oil phase, after 20ml water washing, concentrated removal sherwood oil, obtains methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides 50g, total recovery 80%, GC content 96.7%.
Embodiment 9:
Embodiment 1 gained methyl-2; 3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides toluene is makeed an appointment 550ml; concentrating under reduced pressure removes toluene; add embodiment 7 gained 180mlDMI concentrated solution, add 30mlDMI, be warming up to 90-95 DEG C; slowly add 16.2g POTASSIUM BOROHYDRIDE in batches; finish insulation 4 hours, be cooled to 15-20 DEG C, drip 200ml shrend and to go out reaction.With 150ml × 3 petroleum ether extraction, merge sherwood oil phase, after 20ml water washing, concentrated removal sherwood oil, obtains methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides 51g, total recovery 81%, GC content 97.6%.
Claims (4)
1. methyl-2, a 3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides preparation method, is characterized in that: comprise the following steps:
(1) D-ribose obtains methyl-2,3-O-isopropylidenes-D-RIBOSE glycosides through methyl alcohol, acetone protection in presence of an acid catalyst;
(2) then under alkaline condition and phase catalyst exist, methyl-2,3-O-isopropylidene-5-O-p-toluenesulfonyl-D-RIBOSE glycosides is obtained by reacting with Tosyl chloride; Add lower alcohol and destroy excessive Tosyl chloride, after adding water washing, the tosic acid low-carbon-ester that toluene generates with weak lye backflow removing;
(3) with HMPA or N, N-dimethyl-imidazolinone as reduction solvent, obtain methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides by borohydride reduction.
2. methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides preparation method according to claim 1, is characterized in that: the acid catalyst that step (1) adopts is methylsulfonic acid.
Methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides preparation method according to claim 1, is characterized in that: the phase-transfer catalyst that step (2) adopts is triethyl benzyl ammonia chloride.
3. methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides preparation method according to claim 1, is characterized in that: the lower alcohol in step (2) is methyl alcohol.
4. methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose glycosides preparation method according to claim 1, is characterized in that: the weak lye in step (2) is saturated sodium bicarbonate aqueous solution.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369736A (en) * | 2018-10-29 | 2019-02-22 | 广安凯特制药有限公司 | A kind of preparation method of high-purity capecitabine key intermediate |
| WO2024075025A1 (en) * | 2022-10-04 | 2024-04-11 | Hikal Limited | An industrial process for the preparation of substantially pure 2,3-o-isopropylidene-d-ribofuranose |
Citations (2)
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| CN101863931A (en) * | 2010-06-13 | 2010-10-20 | 启东东岳药业有限公司 | Method for preparing 5- deoxy-2,3- isopropylidene-D-ribose methylglucoside |
| CN103232498A (en) * | 2013-05-08 | 2013-08-07 | 浙江新三和医药化工股份有限公司 | Preparation method of 1-methyl-2,3-0-isopropylidene-5-deoxidized-D-ribofuranose |
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- 2015-07-14 CN CN201510414117.9A patent/CN105037453A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863931A (en) * | 2010-06-13 | 2010-10-20 | 启东东岳药业有限公司 | Method for preparing 5- deoxy-2,3- isopropylidene-D-ribose methylglucoside |
| CN103232498A (en) * | 2013-05-08 | 2013-08-07 | 浙江新三和医药化工股份有限公司 | Preparation method of 1-methyl-2,3-0-isopropylidene-5-deoxidized-D-ribofuranose |
Non-Patent Citations (2)
| Title |
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| 崇恩法等，: "以D-核糖为原料合成1,2,3-三-O-乙酰基-5-脱氧-D-呋喃核糖的研究.", 《化工时刊》 * |
| 马翔等，: "1,2,3- 三-O- 乙酰基-5- 脱氧-D- 呋喃核糖的制备.", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369736A (en) * | 2018-10-29 | 2019-02-22 | 广安凯特制药有限公司 | A kind of preparation method of high-purity capecitabine key intermediate |
| CN109369736B (en) * | 2018-10-29 | 2022-06-17 | 广安凯特制药有限公司 | Preparation method of high-purity capecitabine key intermediate |
| WO2024075025A1 (en) * | 2022-10-04 | 2024-04-11 | Hikal Limited | An industrial process for the preparation of substantially pure 2,3-o-isopropylidene-d-ribofuranose |
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