CN105175460A - Preparation method for monosaccharide fragment intermediate of fondaparinux sodium as anticoagulant drug - Google Patents
Preparation method for monosaccharide fragment intermediate of fondaparinux sodium as anticoagulant drug Download PDFInfo
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Abstract
The invention provides a preparation method for a monosaccharide fragment intermediate of fondaparinux sodium as an anticoagulant drug, and the intermediate can be used in the preparation of the fondaparinux sodium as the anticoagulant drug. The method is easy to operate, can realize the kilogram-level preparation of fondaparinux sodium monosaccharide fragment A intermediate with single-optical activity, solves the technical bottleneck of conventional fondaparinux sodium fragment A synthesis, and is suitable for industrial production.
Description
Technical field
The present invention relates to field of medicine and chemical technology, relate to a kind of preparation method of anticoagulation medicine Fondaparinux sodium monose Segment A intermediate specifically.
Background technology
Thrombotic diseases is one of major disease that modern society's sickness rate is the highest.Wherein by surgical operation, wound (as on a large scale or the wound of lower limb), acute internal disease (as myocardial infarction, cerebral apoplexy), cancer therapy (as hormonotherapy, chemotherapy, radiotherapy) etc. the phlebothrombosis of bringing out become the third-largest cardiovascular disorder after acute coronary syndrome and cerebral apoplexy, serious threat human health at present.Main based on anti-freezing for venothrombotic prevention and treatment at present.Progressively substituted by anticoagulant of new generation because of the defect existed in Clinical practice in various degree with traditional anticoagulant that unfractionated heparin and warfarin are representative.
Fondaparinux sodium (
fondaparinux, GSK) be major target class with Xa factor, be the synthetic heparin-like oligosaccharide anticoagulant of unique listing at present, containing 5 monose in its structure, chemical structure is as follows.Compared with traditional anticoagulation medicine heparin, Fondaparinux sodium has obvious superiority: 1) prevention important organ operation and osseous surgery after blood coagulation, the heart obstruct and myocardial ischemia cause dead in clinical effectiveness be all better than heparin; 2) as highly selective Xa factor inhibitor, its mechanism of action does not relate to platelet activation, and therefore the side effect such as bleeding risk obviously reduces; 3) take enoxaparin as the unfractionated heparin depolymerization that the low molecular weight heparin of representative is mainly derived from chitterlings and extracts, its structure cannot clearly characterize, and limits by raw material supply; And Fondaparinux sodium is the single compound that pure chemistry synthesis obtains, molecular weight is determined, quality and quality comparatively biological products heparin are easy to control.Based on above advantage, since its listing, Fondaparinux sodium occupies critical role (Tran, A.H. in heparin class anticoagulation medicine market always; Lee, G.Ann.Pharmacother.2003,37,1632.).
But, as the anticoagulant relying on chemosynthesis completely, Fondaparinux sodium complex structure, existing synthetic route is all greater than 50 step (Chang, C.-H.; Lico, L.S.; Huang, T.-Y.; Lin, S.-Y.; Chang, C.-L.; Arco, S.D.; Hung, S.-C.Angew.Chem.Int.Ed.2014,53,9876), synthesis has challenge.In view of its patent expired in 2008, the synthesis of this medicine of effective implemention will have huge market potential, and the fragment connection strategy of efficient, the high stereoselectivity synthesis and development innovation of wherein setting up Fondaparinux sodium each monose fragment is the key technical problem needing present stage to solve.For the preparation of its A fragment, the technical bottleneck major embodiment of current existence is in being difficult to carry out high efficiency separation to its α, β-isomer in the process introducing 1-position methoxyl group, normally be converted by recrystallization or multi-step chemical and realize above-mentioned purpose (US4818816, US20050080042; CN103122012; Hung, S.-C.Angew.Chem.Int.Ed.2014,53,9876; Shen, J.; Zhao, W.; Wang, P.etal.Chem.Med.Chem.2014,9,1071), but there is the defect that overall combined coefficient is low, be difficult to realize suitability for industrialized production in various degree in existing method.
Summary of the invention
In view of this, the object of the invention is to provide a kind of method preparing Fondaparinux sodium A fragment intermediate, and its structural formula is such as formula shown in I.The method reaction yield is high, simple to operate, is suitable for suitability for industrialized production.
Wherein,
R is selected from blocking group: tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl or methyl-formiate base.
Compound I is the alpha-isomer of single optical activity.
For realizing object of the present invention, the present invention adopts following technical scheme:
Prepare a method for the Fondaparinux sodium A fragment intermediate of single optical activity, comprising:
Step 1, formula II crude compound generate formula III compound and formula IV compound under the effect of trivalent phosphine; Formula II crude compound is the mixture containing α, β-isomer;
The reaction solution of step 2, step 1 is not treated, and under organic bases or mineral alkali effect, the amino protecting group of formula III compound is protected, and obtains formula I, and formula IV compound does not react;
Step 3, separate type I and formula IV compound.
W-response route of the present invention is as follows:
Compound shown in formula II is prepared by document disclosed in prior art, such as reference method with D-Glucose amine hydrochlorate for raw material through 6 steps reaction preparation (Shen, J.; Zhao, W.; Wang, P.etal.Chem.Med.Chem.2014,9,1071).
As optimal technical scheme, trivalent phosphine described in step 1 is triphenylphosphine, tributylphosphine or trimethyl-phosphine.As preferred further, described trivalent phosphine is triphenylphosphine.
As optimal technical scheme, step 1 is carried out under the existence of suitable solvent and acid reagent.Acid reagent is for promoting that the hydrolysis of phosphinimine intermediate obtains compound III.
As optimal technical scheme, described acid reagent is silica gel, dilute hydrochloric acid, acetic acid,diluted or tosic acid.As preferred further, described acid reagent is silica gel.
As optimal technical scheme, solvent described in step 1 is water.As another optimal technical scheme, solvent described in step 1 is the mixed solvent that in tetrahydrofuran (THF), ether or toluene, any one and water form, and volume ratio is 10:1 ~ 1:10.As further preferred technical scheme, described solvent is water and tetrahydrofuran (THF) mixed solvent, and the volume ratio of water and tetrahydrofuran (THF) is 1:9.
As optimal technical scheme, the temperature of reaction of step 1 is 0 DEG C ~ 50 DEG C, preferred 20-30 DEG C, more preferably 25 DEG C.
As optimal technical scheme, blocking group described in step 2 is tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl or methyl-formiate base; Above-mentioned protecting group is modal amino protecting group, all can realize amido protecting, and do not affect subsequent operations under condition described in step 2.As preferably, in certain embodiments, described protecting group is carbobenzoxy-(Cbz).
As optimal technical scheme, mineral alkali described in step 2 is sodium bicarbonate, saleratus, salt of wormwood or sodium carbonate; Described organic bases is triethylamine or diisopropyl ethyl amine.Preferably, be sodium bicarbonate in certain embodiments.
As optimal technical scheme, formula I realizes being separated by silica gel column chromatography with formula IV compound.
From above technical scheme; the present invention utilizes two kinds of isomer of compound shown in formula II and phosphine to generate the difference of hydrolysis rate after imido grpup phosphine alkane intermediate; optionally alpha-isomer is converted into compound shown in formula III completely; and β-isomer is converted into and is not hydrolyzed imido grpup phosphine alkane intermediate shown in formula IV; subsequently by protecting the amido of compound shown in formula III further, realize the preparation of the Fondaparinux sodium A fragment of single optical activity.This method avoid and this step is separated to α, β of being difficult to be separated-isomer, use the method can realize the feather weight preparation of the Fondaparinux sodium monose Segment A of single optical activity, solve the technical bottleneck of existing Fondaparinux sodium A segment condense, be suitable for suitability for industrialized production.Formula I is known compound, can be further used for the preparation of Fondaparinux sodium intermediate, such as, and Li Zhenghai, CN104098619A; Lei, P.S.etal.Bioorg.Med.Chem.1998,6,1337.
Embodiment
The embodiment of the invention discloses a kind of method preparing the Fondaparinux sodium A fragment of single optical activity.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope method as herein described is changed or suitably change with combination, realize and apply the technology of the present invention.
In order to understand the present invention further, below in conjunction with embodiment, the present invention is described in detail.
The preparation of compound shown in embodiment 1 formula I
Preparation method's reference (Shen, the J. of compound shown in formula II; Zhao, W.; Wang, P.etal.Chem.Med.Chem.2014,9,1071) method, with D-Glucose amine hydrochlorate for raw material prepares through 6 step reactions.Compound shown in formula II is the crude product containing α, β-isomer mixture.By compound shown in formula II (300mg, 0.726mmol, α: β=77:22), triphenylphosphine (287mg, 1.5eq), 300mg silica gel is dissolved in THF:H
2in O=9:1 (5mL), react under room temperature.After reaction 24h, TLC monitors reaction raw materials completely dissolve, and reaction solution is directly added chloroformic acid benzyl ester (0.094mL, 1.5eq) and sodium bicarbonate (122mg under ice bath, 2eq), react 3h at 0 DEG C after, TLC monitoring display raw material reaction is complete.In reaction solution, add ethyl acetate and water, extraction (3mL × 2) merges organic layer afterwards.Organic layer sodium chloride solution washing (7mL × 2), anhydrous sodium sulfate drying, evaporated under reduced pressure.Silica gel column chromatography, PE:EA=5:1 to DCM:MeOH=50:1 gradient wash obtains I (200mg, 56.5%), IV (50mg, 11%).
Compound I: R
f=0.4 (PE/EA, 4/1, v/v),
1hNMR (600MHz, Acetone-d6): δ=8.08 – 8.06 (d, 2H, J=12.6Hz), 7.66 – 7.63 (t, 1H), 7.54 – 7.51 (t, 2H), 7.36 – 7.23 (m, 10H), 6.30 – 6.29 (d, 1H, J=9.6Hz), 5.14 – 5.12 (d, 1H, J=12Hz), 5.05 – 5.03 (d, 1H, J=12Hz), 4.93 – 4.91 (d, 1H, J=12Hz), 4.80 – 4.78 (d, 1H, J=13.2Hz), 4.72 (d, 1H, J=3.6Hz), 4.67 – 4.65 (d, 1H, J=13.8Hz), 4.53 – 4.50 (m, 1H), 3.90 – 3.70 (m, 4H), 3.39 (s, 3H).
13cNMR (150MHz, Acetone-d6): δ=165.8,156.2,139.4,137.4,133.0,130.3,129.3,128.6,128.3,128.0,127.7,127.6,127.5,127.1,99.1,80.5,74.4,71.1,71.0,70.2,65.8,63.9,55.1,54.4.
Compound IV: R
f=0.25 (DCM/MeOH, 50/1, v/v),
1hNMR (400MHz, CDCl
3): δ=8.01 – 7.99 (d, 2H, J=7.8Hz), 7.80 – 7.76 (m, 6H), 7.69 – 7.66 (t, 3H, J=7.8Hz), 7.55 – 7.52 (m, 7H), 7.42 – 7.39 (t, 2H, J=7.8Hz), 7.26 – 7.23 (m, 5H), 5.16 – 5.14 (d, 1H, J=11.4Hz), 5.00 – 4.99 (d, 1H, J=7.8Hz), 4.97 – 4.95 (d, 1H, J=11.4Hz), 4.61-4.58 (dd, 1H, J=12.0, 6.0Hz), 4.55 – 4.50 (m, 2H), 3.82 – 3.80 (m, 1H), 3.37 – 3.33 (t, 1H, J=9.6Hz), 3.10 (s, 3H), 2.66 – 2.61 (dd, 1H, J=18.0, 9.0Hz),
13cNMR (100MHz, CDCl
3): δ=166.9,138.9,134.2,134.1,134.0,133.9,133.0,129.8,129.5,129.4,128.3,128.2,127.5,127.4,122.9,122.2,102.9,82.4,82.3,75.2,73.7,72.0,64.0,59.5,56.3.
Compound III: R
f=0.39 (DCM/MeOH, 50/1, v/v),
1hNMR (400MHz, CDCl
3): δ=8.07 – 8.05 (d, 2H, J=7.2Hz), 7.59 – 7.56 (t, 1H, J=7.2Hz), 7.46 – 7.42 (t, 2H, J=8.0Hz), 7.37 – 7.29 (m, 5H), 4.96 – 4.93 (d, 1H, J=11.6Hz), 4.83 – 4.79 (dd, 2H, J=12.0,4.8Hz), 4.73 – 4.72 (d, 1H, J=3.6Hz), 4.46 – 4.42 (dd, 1H, J=12.0,2.0Hz), 3.87 – 3.83 (m, 1H), 3.57 – 3.43 (m, 2H), 3.41 (s, 3H), 2.79 – 2.76 (dd, 1H, J=9.2,3.6Hz);
13cNMR (100MHz, CDCl
3): δ=167.4,138.5,133.3,129.8,129.6,128.6,128.4,128.0,127.9,100.3,82.9,75.5,71.0,70.6,63.8,55.3,55.2.
Claims (10)
1. prepare a method for the Fondaparinux sodium A fragment intermediate of single optical activity, it is characterized in that, comprise the steps:
Step 1, formula II crude compound generate formula III compound and formula IV compound under the effect of trivalent phosphine; Formula II crude compound is the mixture containing α, β-isomer;
The reaction solution of step 2, step 1 is not treated, and under organic bases or mineral alkali effect, the amino protecting group of formula III compound is protected, and obtains formula I, and formula IV compound does not react;
Step 3, separate type I and formula IV compound.
2. method as claimed in claim 1, it is characterized in that, trivalent phosphine described in step 1 is triphenylphosphine, tributylphosphine or trimethyl-phosphine.
3. method as claimed in claim 1, is characterized in that, step 1 is carried out under the existence of suitable solvent and acid reagent.
4. method as claimed in claim 3, it is characterized in that, described acid reagent is silica gel, dilute hydrochloric acid, acetic acid,diluted or tosic acid.
5. method as claimed in claim 3, it is characterized in that, described solvent is water.
6. method as claimed in claim 3, it is characterized in that, described solvent is the mixed solvent that in tetrahydrofuran (THF), ether or toluene, any one and water form, and volume ratio is 10:1 ~ 1:10.
7. method as claimed in claim 1, it is characterized in that, the temperature of reaction of step 1 is 0 DEG C ~ 50 DEG C.
8. method as claimed in claim 1, it is characterized in that, protecting group described in step 2 is tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl or methyl-formiate base.
9. method as claimed in claim 1, it is characterized in that, mineral alkali described in step 2 is sodium bicarbonate, saleratus, salt of wormwood or sodium carbonate; Described organic bases is triethylamine or diisopropyl ethyl amine.
10. method as claimed in claim 1, it is characterized in that, formula I described in step 3 realizes being separated by silica gel column chromatography with formula IV compound.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461744A (en) * | 2020-03-30 | 2021-10-01 | 鲁南制药集团股份有限公司 | Purification method of fondaparinux sodium intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4818816A (en) * | 1981-04-28 | 1989-04-04 | Choay, S.A. | Process for the organic synthesis of oligosaccharides and derivatives thereof |
| US4987223A (en) * | 1981-12-23 | 1991-01-22 | Choay S.A. | Derivatives of the uronic acid |
| CN104098619A (en) * | 2014-03-25 | 2014-10-15 | 李正海 | Fondaparinux sodium disaccharide intermediate preparation method |
-
2015
- 2015-09-08 CN CN201510568046.8A patent/CN105175460B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4818816A (en) * | 1981-04-28 | 1989-04-04 | Choay, S.A. | Process for the organic synthesis of oligosaccharides and derivatives thereof |
| US4987223A (en) * | 1981-12-23 | 1991-01-22 | Choay S.A. | Derivatives of the uronic acid |
| CN104098619A (en) * | 2014-03-25 | 2014-10-15 | 李正海 | Fondaparinux sodium disaccharide intermediate preparation method |
Non-Patent Citations (1)
| Title |
|---|
| TIEHAI LI，等: ""Total Synthesis of Anticoagulant Pentasaccharide Fondaparinux"", 《CHEMMEDCHEM》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461744A (en) * | 2020-03-30 | 2021-10-01 | 鲁南制药集团股份有限公司 | Purification method of fondaparinux sodium intermediate |
| CN113461744B (en) * | 2020-03-30 | 2024-03-15 | 鲁南制药集团股份有限公司 | Purification method of fondaparinux sodium intermediate |
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