CN107501353B - 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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- CN107501353B CN107501353B CN201710844125.6A CN201710844125A CN107501353B CN 107501353 B CN107501353 B CN 107501353B CN 201710844125 A CN201710844125 A CN 201710844125A CN 107501353 B CN107501353 B CN 107501353B
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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 methods of Fondaparinux sodium intermediate shown in formula 1, include the following steps：1) D gluconate dehydratases is made to be condensed 6 compound represented of production；2) 6 compound represented of formula reacts 5 compound represented of production with acetate succinate imide ester under immobilized candida antarctica lipase catalysis；3) 5 compound represented of formula reacts 4 compound represented of production with toluene sulfochloride in the presence of acid binding agent；4) under alkaline condition cyclization occurs successively for 4 compound represented of formula and 3 compound represented of production is reacted in deacetylated protection；5) 3 compound represented of formula reacts 2 compound represented of production with pentaacetylglucose in the presence of Trimethlsilyltriflat；6) 2 compound represented of formula and benzaldehyde, successively occur acetal protection reaction and de- diacetyl group reaction to get；Its preparation process is few, selectivity is good, high conversion rate, easy to operate, is suitable for large-scale production.
Description
Technical field
The invention belongs to carbohydrate chemistry field, it is 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 five Carbohydrate drugs of heparin (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 (respectively represents 5 monosaccharide from left to right) with D, E, F, G, H.
The fully synthetic route of Fondaparinux sodium is longer, and reaction step number is differed by 50 steps to more than 70 steps.Current main structure
Strategy is (D+EF)+GH and two kinds of D+ (EF+GH), wherein as lower structure (formula b) be introduced into one of bis- bglii fragments of EF it is important in
Mesosome.
And the important intermediate (can be prepared by following formula c compounds represented for raw material in synthesis strategy current formula b)
It obtains.
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：
However in this synthetic route, formula III can be obtained (shown in i.e. above-mentioned formula c by having to pass through two-step reaction just by Formulas I
Intermediate), not only by-product is more, conversion ratio is low, but also multiple reaction steps are intended to increase more consersion units,
And more operating times are needed, it is unfavorable for industrialized production.
For IV compound represented of formula, one kind is disclosed in patent of invention US8461359B2 and is synthesized by D-Glucose
The method route of IV compound represented of formula：
However in this synthetic route, preparation process various (10 steps or so), selectivity and yield are undesirable, when preparation
Between it is longer, it is difficult to meet current demand.
Invention content
The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a kind of improved Fondaparinux sodium
The preparation method of intermediate, preparation process is few, selectivity is good, high conversion rate, easy to operate, is suitable for large-scale production.
In order to solve the above technical problems, a kind of technical solution that the present invention uses is as follows：
The preparation method of Fondaparinux sodium intermediate, the preparation method shown in a kind of formula 1 include the following steps：
Step (1), 6 compound represented of dehydration condensation production for making D-Glucose generation intramolecular,
Step (2), 6 compound represented of formula and acetate succinate imide ester are in immobilized candida antarctica lipase
5 compound represented of the production that reacts under catalysis,
Step (3), 5 compound represented of formula are reacted in the presence of acid binding agent shown in production 4 with toluene sulfochloride
Compound,
Cyclization occurs successively under alkaline condition for step (4), 4 compound represented of formula and deacetylated protection reaction generates
3 compound represented of formula,
Step (5), 3 compound represented of formula and pentaacetylglucose exist in Trimethlsilyltriflat
Lower 2 compound represented of reaction production,
Step (6), 2 compound represented of formula and benzaldehyde, occur acetal protection reaction successively and de- diacetyl group is anti-
Fondaparinux sodium intermediate shown in formula 1 should be prepared,
According to a preferred aspect of the present invention, in the step (6), keep 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%；The organic solvent includes to account 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 of water and the organic solvent in control starting reaction system is 0.005~0.04 ︰ 1.It is highly preferred that control
The volume ratio for originating water and the organic solvent in reaction 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 said program, in step (6), the organic solvent is also described organic comprising accounting for
Solvent volume is than the DMF for 85%~95%.It is highly preferred that the organic solvent by volume ratio 88%~92% DMF with
8%~12% toluene composition.
In the present invention, in the step (6), originate react when control system in water content and be added some first
Benzene contributes to the promotion of reaction rate and conversion ratio.
According to some preferred aspects of said program, in step (6), the mixed acid and chemical combination shown in the formula 2
The mass ratio that feeds intake of object is 0.2~1 ︰ 1.It is highly preferred that the mass ratio that feeds intake of the mixed acid and 2 compound represented of the formula
For 0.3~0.8 ︰ 1.
According to some preferred aspects of said program, in step (6), the benzaldehyde is reached with 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 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), the reaction is -0.08~-0.1MPa's
It is carried out under reduced pressure.
Further, in step (6), the reaction carries out at being 35~55 DEG C in temperature.
In the step (6) of the present invention, in the presence of under specific blend acid catalysis, toluene and control starting is anti-
It answers and protects a stepping to advance deacetylated protection and upper acetal under the water content in system and sulphur shown in the formula 1 is made and reaches liver
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
It rises, on the other hand, the increasing of stepwise reaction by-product, the increase in reaction time, the promotion of equipment cost is avoided, with existing skill
Preparation method in art is compared, and this not only reduces synthesis steps, reduce time cost, equipment investment, simplifies operation, and
And ultimate yield has obtained apparent 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 Fondaparinux sodium intermediate shown in the formula 1 that solid, which is precipitated,
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, which is reacted with chloro- 1, the 3- methylimidazoles hydrochlorides of 2- at 0~5 DEG C, generates 6 compound represented of formula.
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, is reacted at 0~5 DEG C, reaction solution is concentrated, acetonitrile is then added, filtered, it will
Gained filtrate concentrates to get 6 compound represented of formula.
In certain specific embodiments of the invention, it is preferable that in the step (2), make the reaction 30 ± 1
It is carried out at DEG C.
Further, in the step (2), specific implementation process is：6 compound represented of formula is dissolved in organic solvent
In, immobilized candida antarctica lipase, acetate succinate imide ester is added, reacts, filters at 30 ± 1 DEG C, 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 toluene is added, and is crystallized, filtering,
Up to 5 compound represented of formula.
In the step (2) of the present invention, using commercially availableization immobilized candida antarctica lipase, acetate succinate acyl is used in combination
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 5 compound represented of formula
It is dissolved in organic solvent, pyridine is added, paratoluensulfonyl chloride is added, is reacted at 20~25 DEG C, you can obtain shown in the formula 4
Compound.
Further, in the step (3), specific implementation process is：5 compound represented of formula 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 concentrates organic phase, then
Concentrate is dissolved in ethyl alcohol, petroleum ether is added, crystallization is filtered to get 4 compound represented of the formula.
In certain specific embodiments of the invention, it is preferable that in the step (4), control water in reaction system
Volume fraction be 3~6%, so that the cyclization and deacetylated protection is reacted step progress stage by stage.
Further, in the step (4), first make 4 compound represented of the formula in the presence of sodium methoxide, 20
Ring-closure reaction occurs at~25 DEG C, the volume fraction for then adding water to water in reaction system is 3.5~5.5%, then 40~45
Deacetylated protection reaction occurs at DEG C to get 3 compound represented of formula.
Further, in the step (4), specific implementation process is：4 compound represented of formula 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 water in reaction system 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, concentrates,
Ethyl acetate is added in gained concentrate, crystallizes, filters to get 3 compound represented of formula.
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 post-processing step is reduced, and reduces energy consumption and loss, and improve yield.
In certain specific embodiments of the invention, it is preferable that in the step (5), make to change shown in the formula 3
It is anti-in the presence of 4A molecular sieves and Trimethlsilyltriflat, at 0~5 DEG C with pentaacetylglucose to close object
It should be to get 2 compound represented of formula.
Further, in the step (5), specific implementation process is：By 3 compound represented of formula, penta-acetyl Portugal
Grape sugar, 4A molecular sieves are added in organic solvent, and Trimethlsilyltriflat is added, is reacted at 0~5 DEG C, are added three
Then ethamine filters, gained filtrate is washed, then by organic phase concentration, elution to get 2 compound represented of formula.
Due to the implementation of above-mentioned technical proposal, the present invention has the following advantages that compared with prior art：
It is the system of Fondaparinux sodium intermediate shown in starting material formula 1 that the present invention provides a kind of by D-Glucose
Standby route, only by six-step process can compared with the required product that obtains of high yield, and it is easy to operate, step is few, selectivity is good, anti-
Mild condition is answered, commercial Application is suitble to.
Specific implementation mode
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
The every other embodiment that technical staff is obtained without making creative work belongs to the model that the present invention protects
It encloses.
In the following embodiments, unless otherwise instructed, all raw materials are both from commercially available.
Fondaparinux sodium intermediate shown in formula 1：2 compound represented of formula：3 compound represented of formula：4 compound represented of formula；
5 compound represented of formula：6 compound represented of formula：D-Glucose：
Embodiment 1 synthesizes 2 compound represented of formula by D-Glucose
The preparation of 6 compound represented of formula
D-Glucose 45g, water 1800ml, triethylamine 303.6g are added in toward reaction bulb, opens stirring, is cooled to 0-5 DEG C, point
It criticizes and chloro- 1, the 3- methylimidazoles hydrochloride 170.1g of 2- is added, insulation reaction 30min at 0-5 DEG C, reaction solution decompression are controlled after adding
It is concentrated to dryness, 400ml acetonitriles is added, stir 1h, filtering, filter cake is washed with 100ml acetonitriles, and filtrate merges, and formula 6 is concentrated under reduced pressure to obtain
Compound represented can be directly used for feeding intake in next step；
The preparation of 5 compound represented of formula
6 compound represented of formula is dissolved in 1500ml pyridines, Novozym435 (immobilized candida antarctica fat is added
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 dilute hydrochloric acid is washed, and 500ml washings are then combined with organic phase, and organic phase is dense
It is reduced to dry, adds toluene 200ml, stir 2h, solid is precipitated, filter, drying obtains 5 compound represented 34.4g of formula；
The preparation of 4 compound represented of formula
5 compound represented 34.4g of formula is dissolved in 2000ml dichloromethane, pyridine 39.9g is added, controls 20-25 DEG C, drop
Add the dichloromethane 100ml solution of paratoluensulfonyl chloride 32.1g.After dripping, insulated and stirred is reacted 48 hours, controls 20-25 DEG C
1N dilute hydrochloric acid 500ml are added dropwise, organic phase is concentrated under reduced pressure, concentrate is then dissolved in ethyl alcohol 100ml, stone is slowly added dropwise by layering
Oily ether 500ml stirs 1h, and solid, filtering is precipitated, and filter cake dries to obtain 4 compound represented 55.8g of formula；
The preparation of 3 compound represented of formula
4 compound represented of formula is dissolved in 400ml tetrahydrofurans, sodium methoxide 33.6g is added, is stirred at 20-25 DEG C
2h is reacted, adds water 20ml, is warming up to 40-45 DEG C and continues to be stirred to react 2h, 1N hydrochloric acid is then added dropwise, pH to 7 is adjusted, is concentrated under reduced pressure into
Dry, in gained concentrate plus ethyl acetate 100ml, stirring 2h, solid are precipitated, and 3 compound represented of formula is dried to obtain in filtering
21.3g；
In the building-up process for synthesizing 3 compound represented of formula by D-Glucose, final 3 compound represented of formula
Yield is 59.2%, purity 98.1%.
The preparation of 2 compound represented of formula
3 compound represented 21.3g of formula, 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, and organic phase is concentrated to dryness to obtain crude product, then rapid column chromatography by filtrate 250ml washings
It purifies (being eluted with petrol ether/ethyl acetate=5/1) and obtains 2 compound represented 56.9g of formula.
In the building-up process for synthesizing 2 compound represented of formula by D-Glucose, final 2 compound represented of formula
Yield is 48.0%, purity 97.5%.
The preparation of Fondaparinux sodium intermediate shown in 2 formula 1 of embodiment
2 compound represented 56.9g of formula, 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 the reduced pressure of -0.096MPa, 40-45 DEG C of control is stirred to react 6h, and 100ml unsaturated carbonate hydrogen is added
Sodium solution tune pH to 7-8 adds 600ml water and 300ml dilution with toluene, stirs 1h, and solid is precipitated, and filtering, filter cake is dried to get institute
State Fondaparinux sodium intermediate 45.0g shown in formula 1, yield 95.2%, purity 98.2%.
The preparation of Fondaparinux sodium intermediate shown in 3 formula 1 of embodiment
2 compound represented 56.9g of formula, 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 is added
Amount be 10g), under the reduced pressure of -0.096MPa, 40-45 DEG C of control is stirred to react 6h, and 100ml saturated sodium bicarbonates are added
Solution tune pH to 7-8 adds 600ml water and 300ml dilution with toluene, stirs 1h, and solid is precipitated, and filtering, filter cake is dried to get described
Fondaparinux sodium intermediate 16.5g shown in formula 1, yield 77.2%, purity 98.1%.
The preparation of Fondaparinux sodium intermediate shown in 4 formula 1 of embodiment
2 compound represented 56.9g of formula, 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 is added
Amount is 5.0g), under the reduced pressure of -0.096MPa, 40-45 DEG C of control is stirred to react 6h, and it is molten that 100ml saturated sodium bicarbonates are added
Liquid tune pH to 7-8 adds 600ml water and 300ml dilution with toluene, stirs 1h, and solid is precipitated, and filtering, filter cake is dried to get the formula
Fondaparinux sodium intermediate 17.8g shown in 1, yield 83.1%, purity 98.0%.
Comparative example 1
It differs only in mixed acid (concentrated sulfuric acid and p-methyl benzenesulfonic acid) replacing with single pair substantially with embodiment 2
Toluenesulfonic acid does not obtain product.
Comparative example 2
It differs only in mixed acid (concentrated sulfuric acid and p-methyl benzenesulfonic acid) replacing with single sulphur substantially with embodiment 2
Acid, product yield 28.3%, purity 96.1%.
Comparative example 3
It with embodiment 2, differs only in the additive amount of mixed acid not within the scope 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 differs only in substantially with embodiment 2 and is not added with water in 2 compound represented of formula and the reaction process of benzaldehyde
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 being added when starting reaction 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 field technology that can understand this
The content of invention is simultaneously implemented, and it is not intended to limit the scope of the present invention, and the present invention is not limited to above-mentioned implementations
, equivalent change or modification made by all Spirit Essences according to the present invention should be covered by the protection scope of the present invention.
Claims (8)
1. the preparation method of Fondaparinux sodium intermediate shown in a kind of formula 1, which is characterized in that the preparation method includes as follows
Step：
Step (1), 6 compound represented of dehydration condensation production for making D-Glucose generation intramolecular,
Step (2), 6 compound represented of formula and acetate succinate imide ester are catalyzed in immobilized candida antarctica lipase
Under react 5 compound represented of production,
Step (3), 5 compound represented of formula react chemical combination shown in production 4 with toluene sulfochloride in the presence of acid binding agent
Object,
Cyclization occurs successively under alkaline condition for step (4), 4 compound represented of formula and production 3 is reacted in deacetylated protection
Compound represented,
Step (5), 3 compound represented of formula and pentaacetylglucose are anti-in the presence of Trimethlsilyltriflat
2 compound represented of production is answered,
Acetal protection reaction and de- diacetyl group reaction system occur successively for step (6), 2 compound represented of formula and benzaldehyde
It is standby to obtain Fondaparinux sodium intermediate shown in formula 1,
In the step (6), acetal protection reaction and de- diacetyl group is made to react in organic solvent, under mixed acid catalyst
One step carries out, and the mixed acid is made of the concentrated sulfuric acid and p-methyl benzenesulfonic acid 1 ︰ 0.1~5 in mass ratio, and wherein the concentrated sulfuric acid is quality
The aqueous sulfuric acid that score is 70~98%；The mass ratio that feeds intake of the mixed acid and 2 compound represented of the formula is 0.2~
1 ︰ 1, the volume ratio that control originates water and the organic solvent in reaction system is 0.01~0.02 ︰ 1, the organic solvent
It is made of the DMF of volume ratio 88%~92% and 8%~12% toluene；The benzaldehyde reaches liver with sulphur shown in the formula 2
The mass ratio that feeds intake of last of the ten Heavenly stems sodium intermediate is 0.2~0.8 ︰ 1, among Fondaparinux sodium shown in the organic solvent and the formula 2
The mass ratio that feeds intake of body is 2~20 ︰ 1.
2. the preparation method of Fondaparinux sodium intermediate shown in formula 1 according to claim 1, which is characterized in that in institute
It states in step (6), the reaction carries out under the reduced pressure of -0.08~-0.1MPa, at 35~55 DEG C of temperature.
3. the preparation method of Fondaparinux sodium intermediate shown in formula 1 according to claim 1, which is characterized in that in institute
It states in step (1), D-Glucose is made to react life at 0~5 DEG C with chloro- 1, the 3- methylimidazoles hydrochlorides of 2- in the presence of acid binding agent
At 6 compound represented of the formula.
4. the preparation method of Fondaparinux sodium intermediate shown in formula 1 according to claim 1, which is characterized in that in institute
It states in step (2), the reaction is made to be carried out at 30 ± 1 DEG C.
5. the preparation method of Fondaparinux sodium intermediate shown in formula 1 according to claim 1, which is characterized in that in institute
It states in step (3), 5 compound represented of formula is dissolved in organic solvent, pyridine is added, paratoluensulfonyl chloride is added, 20~
It is reacted at 25 DEG C, you can obtain 4 compound represented of the formula.
6. the preparation method of Fondaparinux sodium intermediate shown in formula 1 according to claim 1, which is characterized in that in institute
It states in step (4), the volume fraction for controlling water in reaction system is 3~6%, and the cyclization and deacetylated protection is made to react sublevel
One step of section carries out.
7. the preparation method of Fondaparinux sodium intermediate shown in formula 1 according to claim 6, which is characterized in that in institute
It states in step (4), first makes 4 compound represented of the formula that ring-closure reaction occur in the presence of sodium methoxide, at 20~25 DEG C,
Then the volume fraction for adding water to water in reaction system is 3.5~5.5%, then deacetylated protection occurs instead at 40~45 DEG C
It should be to get 3 compound represented of formula.
8. the preparation method of Fondaparinux sodium intermediate shown in formula 1 according to claim 1, which is characterized in that in institute
It states in step (5), makes 3 compound represented of the formula with pentaacetylglucose in 4A molecular sieves and trifluoromethanesulfonic acid trimethyl
It is reacted to get 2 compound represented of formula in the presence of silicon ester, at 0~5 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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2017
- 2017-09-19 CN CN201710844125.6A patent/CN107501353B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
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| 磺达肝癸钠二糖中间体的合成工艺研究;韩健，等;《现代药物与临床》;20150630;第30卷(第6期);第605-609页 * |
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