CN107501353A - A kind of preparation method of Fondaparinux sodium intermediate - Google Patents
A kind of preparation method of Fondaparinux sodium intermediate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
Abstract
The invention discloses a kind of preparation method of the Fondaparinux sodium intermediate shown in formula 1, comprise the following steps：1) compound shown in D gluconate dehydratases condensation production 6 is made；2) compound of the compound with acetate succinate imide ester under immobilized candida antarctica lipase catalysis shown in reaction production 5 shown in formula 6 is made；3) compound shown in formula 5 and toluene sulfochloride is made to react the compound shown in production 4 in the presence of acid binding agent；4) make the compound shown in formula 4 that cyclization and the deacetylated compound protected shown in reaction production 3 occur successively in the basic conditions；5) compound shown in formula 3 and pentaacetylglucose is made to react the compound shown in production 2 in the presence of Trimethlsilyltriflat；6) make the compound and benzaldehyde shown in formula 2, acetal protection reaction and the reaction of de- diacetyl group occur successively, produces；Its preparation process is few, selectivity is good, high conversion rate, simple to operate, suitable for large-scale production.
Description
Technical field
The invention belongs to carbohydrate chemistry field, applied to fine chemistry industry, medication chemistry industry, and in particular to a kind of sulphur reaches the liver last of the ten Heavenly stems
The preparation method of sodium intermediate.
Background technology
Fondaparinux sodium is a kind of artificial synthesized Carbohydrate drugs of heparin five (entitled fondaparinux of English
Sodium), be by first antithrombase dependence of French Sanofi Winthrop Industrie development and production Xa because
The indirect inhibitor of son.Chemical structural formula such as following formula a (represents 5 monose from left to right with D, E, F, G, H) respectively.
The fully synthetic route of Fondaparinux sodium is longer, and reaction step number is by 50 steps to more than 70 steps.Structure main at present
Strategy is (D+EF)+GH and two kinds of D+ (EF+GH), wherein, following structure (formula b) be introduced into one of the bglii fragments of EF bis- it is important in
Mesosome.
And the important intermediate (can be prepared in synthesis strategy current formula b) as the compound shown in following formula c for raw material
Obtain.
In the prior art in the relevant report of the synthetic method of intermediate (shown in formula b, formula c), patent of invention
US2016264609A1 is referred to a kind of synthetic method：
Wherein Formulas I is synthesized by following methods：
But in this synthetic route, formula III can just be obtained (shown in i.e. above-mentioned formula c by having to pass through two-step reaction as Formulas I
Intermediate), not only accessory substance is more for it, conversion ratio is low, and multiple reactions steps are intended to increase more consersion units,
And more operating times are needed, it is unfavorable for industrialized production.
For the compound shown in formula IV, one kind is disclosed in patent of invention US8461359B2 and is synthesized by D-Glucose
The method route of compound shown in formula IV：
But in this synthetic route, preparation process various (10 steps or so), selectivity and yield are undesirable, during preparation
Between it is longer, it is difficult to meet current demand.
The content of the invention
The technical problems to be solved by the invention are overcome the deficiencies in the prior art, there is provided a kind of improved Fondaparinux sodium
The preparation method of intermediate, its preparation process is few, selectivity is good, high conversion rate, simple to operate, suitable for large-scale production.
To solve above technical problem, a kind of technical scheme that the present invention uses is as follows：
A kind of preparation method of Fondaparinux sodium intermediate shown in formula 1, the preparation method comprise the following steps：
Step (1), make D-Glucose that the compound shown in the dehydration condensation production 6 of intramolecular occur,
Step (2), make compound shown in formula 6 and acetate succinate imide ester in immobilized candida antarctica lipase
Compound shown in the production that reacted under catalysis 5,
Step (3), the compound shown in formula 5 is set to be reacted with toluene sulfochloride in the presence of acid binding agent shown in production 4
Compound,
Step (4), make the compound shown in formula 4 that cyclization and deacetylated protection reaction generation occur successively in the basic conditions
Compound shown in formula 3,
Step (5), compound shown in formula 3 and pentaacetylglucose is set to exist in Trimethlsilyltriflat
Compound shown in lower reaction production 2,
Step (6), make compound and benzaldehyde shown in formula 2, acetal protection reaction occurs successively and de- diacetyl group is anti-
The Fondaparinux sodium intermediate shown in formula 1 should be prepared,
According to a preferred aspect of the present invention, in the step (6), make acetal protection reaction and de- diacetyl group anti-
Should carry out in next step in organic solvent, in mixed acid catalyst, the mixed acid by the concentrated sulfuric acid and p-methyl benzenesulfonic acid in mass ratio
1 ︰ 0.1~5 is formed, and wherein the concentrated sulfuric acid is the aqueous sulfuric acid that mass fraction is 70~98%；Described organic solvent is included and accounted for
5%~15% toluene of the organic solvent volume and account for the organic solvent volume ratio be 85%~95% DMF；Its
In, the volume ratio for controlling water and the organic solvent in initial action system is 0.005~0.04 ︰ 1.It is highly preferred that control
The volume ratio of water and the organic solvent in initial action system is 0.01~0.02 ︰ 1.It is further preferred that control starting
The volume ratio of water and the organic solvent in reaction system is 0.011~0.015 ︰ 1.
According to some preferred aspects of such scheme, in step (6), described organic solvent is also described organic comprising accounting for
Solvent volume is than the DMF for 85%~95%.It is highly preferred that described organic solvent by volume ratio 88%~92% DMF with
8%~12% toluene composition.
In the present invention, in the step (6), the content of control system reclaimed water and some first of addition in initial action
Benzene contributes to the lifting of reaction rate and conversion ratio.
According to some preferred aspects of such scheme, in step (6), the mixed acid and the chemical combination shown in the formula 2
The mass ratio that feeds intake of thing is 0.2~1 ︰ 1.It is highly preferred that the mixed acid and the mass ratio that feeds intake of the compound shown in the formula 2
For 0.3~0.8 ︰ 1.
According to some preferred aspects of such scheme, in step (6), the benzaldehyde reaches with the sulphur shown in the formula 2
The mass ratio that feeds intake of liver last of the ten Heavenly stems sodium intermediate is 0.2~0.8 ︰ 1.It is highly preferred that the benzaldehyde reaches liver with the sulphur shown in the formula 2
The mass ratio that feeds intake of last of the ten Heavenly stems sodium intermediate is 0.35~0.55 ︰ 1.
In certain specific embodiments of the invention, in step (6), shown in the organic solvent and the formula 2
The mass ratio that feeds intake of Fondaparinux sodium intermediate is 2~20 ︰ 1.
In some preferred embodiments of the present invention, in step (6), described reaction is -0.08~-0.1MPa's
Carried out under reduced pressure.
Further, in step (6), described reaction is carried out at being 35~55 DEG C in temperature.
In the step (6) of the present invention, under specific blend acid catalysis, in the presence of toluene and control starting is anti-
Answer and the sulphur that deacetylated protection and upper acetal protect a stepping to advance and be made shown in the formula 1 is reached into liver under the water content in system
Last of the ten Heavenly stems sodium intermediate, on the one hand, so that improving the selectivity of product in preparation process, reaction rate has also obtained significantly carrying
Rise, on the other hand, the increasing of stepwise reaction accessory substance, the increase in reaction time, the lifting of equipment cost are avoided, with existing skill
Preparation method in art is compared, and this not only reduces synthesis step, reduces time cost, equipment investment, simplifies operation, and
And ultimate yield has obtained obvious improvement.
In certain specific embodiments of the invention, in step (6), after the completion of reaction, alkaline matter, water are added
And toluene, stirring, it is the Fondaparinux sodium intermediate shown in the formula 1 to separate out solid
In certain specific embodiments of the invention, it is preferable that in the step (1), make in the presence of acid binding agent
D-Glucose generates the compound shown in the formula 6 with chloro- 1, the 3- methylimidazoles hydrochlorides of 2- in 0~5 DEG C of reaction.
Further, in the step (1), specific implementation process is：D-Glucose, triethylamine are dissolved in water,
Chloro- 1, the 3- methylimidazoles hydrochlorides of 2- are added, in 0~5 DEG C of reaction, reaction solution is concentrated, then adds acetonitrile, filtered, will
Gained filtrate concentrates, and produces the compound shown in described formula 6.
In certain specific embodiments of the invention, it is preferable that in the step (2), make the reaction 30 ± 1
Carried out at DEG C.
Further, in the step (2), specific implementation process is：Compound shown in formula 6 is dissolved in organic solvent
In, immobilized candida antarctica lipase, acetate succinate imide ester are added, in 30 ± 1 DEG C of reactions, is filtered, concentration will be dense
Contracting liquid is dissolved in dichloromethane, with salt pickling, then is washed, is then combined with organic phase, is concentrated, and adds toluene, is crystallized, filtering,
Produce the compound shown in described formula 5.
In the step (2) of the present invention, using commercially availableization immobilized candida antarctica lipase, and with acetate succinate acyl
Imines ester is as acylating reagent so that raw materials for production are cheap and easily-available, reduce production cost, and improve receipts compared with prior art
Rate.
In certain specific embodiments of the invention, it is preferable that in the step (3), by the compound shown in formula 5
It is dissolved in organic solvent, adds pyridine, add paratoluensulfonyl chloride, reacted at 20~25 DEG C, you can obtains shown in the formula 4
Compound.
Further, in the step (3), specific implementation process is：Compound shown in formula 5 is dissolved in organic solvent
In, pyridine is added, paratoluensulfonyl chloride is added, is reacted at 20~25 DEG C, hydrochloric acid is added, layering, organic phase is concentrated, then
Concentrate is dissolved in ethanol, adds petroleum ether, is crystallized, filtering, produces the compound shown in the formula 4.
In certain specific embodiments of the invention, it is preferable that in the step (4), control reaction system reclaimed water
Volume fraction be 3~6%, make the cyclization and it is deacetylated protection reaction stage by stage a step carry out.
Further, in the step (4), first make the compound shown in the formula 4 in the presence of sodium methoxide, 20
Ring-closure reaction occurs at~25 DEG C, the volume fraction for then adding water to reaction system reclaimed water is 3.5~5.5%, then 40~45
Deacetylated protection reaction occurs at DEG C, produces the compound shown in described formula 3.
Further, in the step (4), specific implementation process is：Compound shown in formula 4 is dissolved in organic molten
In agent, sodium methoxide is added, ring-closure reaction occurs at 20~25 DEG C, the volume fraction for then adding water to reaction system reclaimed water is
3.5~5.5%, then deacetylated protection reaction occurs at 40~45 DEG C, hydrochloric acid is then added, adjusts pH value 7~8, is concentrated,
Ethyl acetate is added in gained concentrate, is crystallized, filtering, produces the compound shown in described formula 3.
In the step (4) of the present invention, by the water content in control system, by cyclization, deacetylated protection stage by stage one
Step is completed, and reduces post-processing step, reduces energy consumption and loss, and improve yield.
In certain specific embodiments of the invention, it is preferable that in the step (5), make the change shown in the formula 3
Compound is anti-in the presence of 4A molecular sieves and Trimethlsilyltriflat, at 0~5 DEG C with pentaacetylglucose
Should, produce the compound shown in described formula 2.
Further, in the step (5), specific implementation process is：By the compound shown in formula 3, penta-acetyl Portugal
Grape sugar, 4A molecular sieves are added in organic solvent, are added Trimethlsilyltriflat, are reacted at 0~5 DEG C, add three
Ethamine, then filter, gained filtrate is washed, then organic phase is concentrated, eluted, produce the compound shown in described formula 2.
Due to the implementation of above-mentioned technical proposal, the present invention has the following advantages that compared with prior art：
The invention provides a kind of system as D-Glucose for the Fondaparinux sodium intermediate shown in initiation material formula 1
Standby route, its only by six-step process can compared with the required product that obtains of high yield, and it is simple to operate, step is few, selectivity is good, anti-
Mild condition is answered, is adapted to commercial Application.
Embodiment
The technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that described implementation
Example only part of the embodiment of the present invention, rather than whole embodiments.It is common based on the embodiment in the present invention, this area
The every other embodiment that technical staff is obtained under the premise of creative work is not made, belong to the model that the present invention protects
Enclose.
In the following embodiments, unless otherwise instructed, all raw materials are both from commercially available.
Fondaparinux sodium intermediate shown in formula 1：Compound shown in formula 2：Compound shown in formula 3：Compound shown in formula 4；Formula 5
Shown compound：Compound shown in formula 6：D-Glucose：
Embodiment 1 is as the compound shown in D-Glucose synthesis type 2
The preparation of compound shown in formula 6
D-Glucose 45g, water 1800ml, triethylamine 303.6g are added in toward reaction bulb, stirring is opened, is cooled to 0-5 DEG C, point
Criticize and add chloro- 1, the 3- methylimidazoles hydrochloride 170.1g of 2-, insulation reaction 30min at 0-5 DEG C, reaction solution decompression are controlled after adding
It is concentrated to dryness, adds 400ml acetonitriles, stir 1h, filtering, filter cake is washed with 100ml acetonitriles, and filtrate merges, and be concentrated under reduced pressure to obtain formula 6
Shown compound, it can be directly used for feeding intake in next step；
The preparation of compound shown in formula 5
Compound shown in formula 6 is dissolved in 1500ml pyridines, adds Novozym435 (immobilized candida antarctica fat
Fat enzyme) 20g, acetate succinate imide ester 47.2g, it is placed in shaking table and controls 30 ± 1 DEG C of reaction 48h, filtering, filtrate decompression is concentrated into
It is dry, then add the dissolving of 500ml dichloromethane, 500ml 1N watery hydrochloric acid is washed, and 500ml washings, is then combined with organic phase, and organic phase is dense
It is reduced to dry, adds toluene 200ml, stir 2h, separate out solid, filter, drying, obtain the compound 34.4g shown in formula 5；
The preparation of compound shown in formula 4
Compound 34.4g shown in formula 5 is dissolved in 2000ml dichloromethane, adds pyridine 39.9g, controls 20-25 DEG C, drop
Add paratoluensulfonyl chloride 32.1g dichloromethane 100ml solution.After dripping, insulated and stirred is reacted 48 hours, controls 20-25 DEG C
1N watery hydrochloric acid 500ml are added dropwise, layering, organic phase is concentrated under reduced pressure, concentrate is then dissolved in ethanol 100ml, stone is slowly added dropwise
Oily ether 500ml, 1h is stirred, separate out solid, filtering, filter cake dries to obtain compound 55.8g shown in formula 4；
The preparation of compound shown in formula 3
Compound shown in formula 4 is dissolved in 400ml tetrahydrofurans, sodium methoxide 33.6g is added, is stirred at 20-25 DEG C
2h is reacted, adds water 20ml, 40-45 DEG C of continuation stirring reaction 2h is warming up to, 1N hydrochloric acid is then added dropwise, adjusts pH to 7, is concentrated under reduced pressure into
It is dry, in gained concentrate plus ethyl acetate 100ml, 2h is stirred, solid separates out, filtering, dries to obtain compound shown in formula 3
21.3g；
As in the building-up process of the compound shown in D-Glucose synthesis type 3, compound shown in final described formula 3
Yield is 59.2%, purity 98.1%.
The preparation of compound shown in formula 2
Compound 21.3g shown in formula 3, pentaacetylglucose 57.6g, 4A molecular sieve 20g are added to dichloromethane
In 500ml, it is cooled to 0-5 DEG C, Trimethlsilyltriflat 32.8g is added dropwise, drips rear insulation reaction 16h, adds three second
Reaction is quenched in amine 29.9g, filtering, filtrate 250ml washings, organic phase is concentrated under reduced pressure into dry crude product, then rapid column chromatography
Purifying (being eluted with petrol ether/ethyl acetate=5/1) obtains the compound 56.9g shown in formula 2.
As in the building-up process of the compound shown in D-Glucose synthesis type 2, compound shown in final described formula 2
Yield is 48.0%, purity 97.5%.
The preparation of Fondaparinux sodium intermediate shown in the formula 1 of embodiment 2
Compound 56.9g shown in formula 2, water 3ml, toluene 30ml, benzaldehyde 25.5g are dissolved in 300ml dimethyl formyls
In amine, the concentrated sulfuric acid (mass fraction of sulfuric acid is 98%) 10g, water p-methyl benzenesulfonic acid 11.04g is added (wherein to toluene sulphur
The amount of acid is 10g), under -0.096MPa reduced pressure, 40-45 DEG C of stirring reaction 6h is controlled, adds 100ml unsaturated carbonate hydrogen
Sodium solution adjusts pH to 7-8, adds 600ml water and 300ml dilution with toluene, stirs 1h, and solid separates out, filtering, filter cake drying, produces institute
State the Fondaparinux sodium intermediate 45.0g shown in formula 1, yield 95.2%, purity 98.2%.
The preparation of Fondaparinux sodium intermediate shown in the formula 1 of embodiment 3
Compound 56.9g shown in formula 2, water 3ml, toluene 30ml, benzaldehyde 15.3g are dissolved in 300ml dimethyl formyls
In amine, the concentrated sulfuric acid (mass fraction of sulfuric acid is 98%) 10g, a water p-methyl benzenesulfonic acid 11.04g (wherein p-methyl benzenesulfonic acid are added
Amount be 10g), under -0.096MPa reduced pressure, control 40-45 DEG C of stirring reaction 6h, add 100ml saturated sodium bicarbonates
Solution adjusts pH to 7-8, adds 600ml water and 300ml dilution with toluene, stirs 1h, and solid separates out, filtering, filter cake drying, produces described
Fondaparinux sodium intermediate 16.5g shown in formula 1, yield 77.2%, purity 98.1%.
The preparation of Fondaparinux sodium intermediate shown in the formula 1 of embodiment 4
Compound 56.9g shown in formula 2, water 3ml, toluene 30ml, benzaldehyde 25.5g are dissolved in 300ml dimethyl formyls
In amine, the concentrated sulfuric acid (mass fraction of sulfuric acid is 98%) 10g, a water p-methyl benzenesulfonic acid 5.52g (wherein p-methyl benzenesulfonic acid are added
Measure as 5.0g), under -0.096MPa reduced pressure, 40-45 DEG C of stirring reaction 6h is controlled, it is molten to add 100ml saturated sodium bicarbonates
Liquid adjusts pH to 7-8, adds 600ml water and 300ml dilution with toluene, stirs 1h, and solid separates out, filtering, filter cake drying, produces the formula
Fondaparinux sodium intermediate 17.8g shown in 1, yield 83.1%, purity 98.0%.
Comparative example 1
It with embodiment 2, differs only in mixed acid (concentrated sulfuric acid and p-methyl benzenesulfonic acid) replacing with single pair substantially
Toluenesulfonic acid, product is not obtained.
Comparative example 2
It with embodiment 2, differs only in mixed acid (concentrated sulfuric acid and p-methyl benzenesulfonic acid) replacing with single sulphur substantially
Acid, product yield 28.3%, purity 96.1%.
Comparative example 3
It with embodiment 2, differs only in the addition of mixed acid not in the range of the ingredient proportion of the present invention, tool substantially
Body is concentrated sulfuric acid 10g, p-methyl benzenesulfonic acid 60g, product yield 54.1%, purity 96.3%.
Comparative example 4
It with embodiment 2, differs only in substantially and is not added with water in the compound and the course of reaction of benzaldehyde shown in formula 2
And toluene, product yield 49.3%, purity 95.7%.
Comparative example 5
It is substantially with embodiment 2, and the volume for differing only in the water added during initial action is 30ml, and product yield is
21.8%, purity 95.4%.
The present invention is described in detail above, its object is to allow the personage for being familiar with this art to understand this
The content of invention is simultaneously carried out, and it is not intended to limit the scope of the present invention, and the invention is not restricted to above-mentioned implementation
Example, the equivalent change or modification that all Spirit Essences according to the present invention are made, should all be included within the scope of the present invention.
Claims (10)
1. the preparation method of the Fondaparinux sodium intermediate shown in a kind of formula 1, it is characterised in that the preparation method includes as follows
Step：
Step (1), make D-Glucose that the compound shown in the dehydration condensation production 6 of intramolecular occur,
Step (2), compound shown in formula 6 and acetate succinate imide ester is set to be catalyzed in immobilized candida antarctica lipase
Under the compound that reacts shown in production 5,
Step (3), compound shown in formula 5 is set to react in the presence of acid binding agent the chemical combination shown in production 4 with toluene sulfochloride
Thing,
Step (4), make the compound shown in formula 4 that cyclization and deacetylated protection reaction production 3 occur successively in the basic conditions
Shown compound,
Step (5), make compound shown in formula 3 and pentaacetylglucose anti-in the presence of Trimethlsilyltriflat
The compound shown in production 2 is answered,
Step (6), make compound and benzaldehyde shown in formula 2, acetal protection reaction and de- diacetyl group reaction system occur successively
It is standby to obtain the Fondaparinux sodium intermediate shown in formula 1,
2. preparation method according to claim 1, it is characterised in that in the step (6), make acetal protection reaction and
De- diacetyl group reaction is carried out in next step in organic solvent, in mixed acid catalyst, and the mixed acid is by the concentrated sulfuric acid and to toluene
Sulfonic acid 1 ︰ 0.1~5 in mass ratio is formed, and wherein the concentrated sulfuric acid is the aqueous sulfuric acid that mass fraction is 70~98%；Described has
Solvent include 5%~15% toluene for accounting for the organic solvent volume and account for the organic solvent volume ratio for 85%~
95% DMF；Wherein, the volume ratio for controlling water and the organic solvent in initial action system is 0.005~0.04 ︰ 1.
3. the preparation method of the Fondaparinux sodium intermediate shown in formula 1 according to claim 2, it is characterised in that described
Mixed acid and the mass ratio that feeds intake of the compound shown in the formula 2 are 0.2~1 ︰ 1, control the water in initial action system and institute
The volume ratio for stating organic solvent is 0.01~0.02 ︰ 1, described organic solvent by the DMF of volume ratio 88%~92% and 8%~
12% toluene composition；The mass ratio that feeds intake of Fondaparinux sodium intermediate shown in the benzaldehyde and the formula 2 for 0.2~
0.8 ︰ 1, the mass ratio that feeds intake of the organic solvent and the Fondaparinux sodium intermediate shown in the formula 2 is 2~20 ︰ 1.
4. the preparation method of the Fondaparinux sodium intermediate shown in formula 1 according to claim 2, it is characterised in that described
Reaction carried out under -0.08~-0.1MPa reduced pressure, at 35~55 DEG C of temperature.
5. the preparation method of the Fondaparinux sodium intermediate shown in formula 1 according to claim 1, it is characterised in that in institute
State in step (1), D-Glucose is given birth to chloro- 1, the 3- methylimidazoles hydrochlorides of 2- in 0~5 DEG C of reaction in the presence of acid binding agent
Into the compound shown in the formula 6.
6. the preparation method of the Fondaparinux sodium intermediate shown in formula 1 according to claim 1, it is characterised in that in institute
State in step (2), the reaction is carried out at 30 ± 1 DEG C.
7. the preparation method of the Fondaparinux sodium intermediate shown in formula 1 according to claim 1, it is characterised in that in institute
State in step (3), the compound shown in formula 5 is dissolved in organic solvent, add pyridine, add paratoluensulfonyl chloride, 20~
Reacted at 25 DEG C, you can obtain the compound shown in the formula 4.
8. the preparation method of the Fondaparinux sodium intermediate shown in formula 1 according to claim 1, it is characterised in that in institute
State in step (4), the volume fraction for controlling reaction system reclaimed water is 3~6%, makes the cyclization and deacetylated protection reaction sublevel
One step of section is carried out.
9. the preparation method of the Fondaparinux sodium intermediate shown in formula 1 according to claim 8, it is characterised in that in institute
State in step (4), first make the compound shown in the formula 4 that ring-closure reaction occur in the presence of sodium methoxide, at 20~25 DEG C,
Then the volume fraction for adding water to reaction system reclaimed water is 3.5~5.5%, then deacetylated protection occurs instead at 40~45 DEG C
Should, produce the compound shown in described formula 3.
10. the preparation method of the Fondaparinux sodium intermediate shown in formula 1 according to claim 1, it is characterised in that in institute
State in step (5), make the compound shown in the formula 3 with pentaacetylglucose in 4A molecular sieves and trifluoromethanesulfonic acid trimethyl
Reacted in the presence of silicon ester, at 0~5 DEG C, produce the compound shown in described formula 2.
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| CN104144938A (en) * | 2012-02-02 | 2014-11-12 | 可靠生物医药公司 | An efficient and scalable process for the manufacture of fondaparinux sodium |
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| CN105622678A (en) * | 2014-11-05 | 2016-06-01 | 海门慧聚药业有限公司 | Novel technology for preparing disaccharide fragment of fondaparinux sodium intermediate |
| WO2017042092A1 (en) * | 2015-09-09 | 2017-03-16 | Sabic Global Technologies B.V. | Polyolefin compositions |
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| CN104144938A (en) * | 2012-02-02 | 2014-11-12 | 可靠生物医药公司 | An efficient and scalable process for the manufacture of fondaparinux sodium |
| WO2015070571A1 (en) * | 2013-11-14 | 2015-05-21 | 浙江海正药业股份有限公司 | Disaccharide intermediate and synthesis method thereof |
| CN105622678A (en) * | 2014-11-05 | 2016-06-01 | 海门慧聚药业有限公司 | Novel technology for preparing disaccharide fragment of fondaparinux sodium intermediate |
| WO2017042092A1 (en) * | 2015-09-09 | 2017-03-16 | Sabic Global Technologies B.V. | Polyolefin compositions |
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