CN104151370B - A kind of synthetic method of Fondaparinux sodium intermediate - Google Patents
A kind of synthetic method of Fondaparinux sodium intermediate Download PDFInfo
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- CN104151370B CN104151370B CN201410256002.7A CN201410256002A CN104151370B CN 104151370 B CN104151370 B CN 104151370B CN 201410256002 A CN201410256002 A CN 201410256002A CN 104151370 B CN104151370 B CN 104151370B
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Abstract
The invention discloses the synthetic method of a kind of Fondaparinux sodium intermediate, including step be: with compound 3 as raw material, acetylating hydroxyl groups obtains compound 6, and described compound 6 is de-to methoxy-benzyl (PMB) with ammonium ceric nitrate, obtains Monomer C ring.By the way, the synthetic method of the Fondaparinux sodium intermediate of the present invention, with originally through 5 steps synthesis Monomer C chain rates relatively, simplify the synthetic route of Monomer C ring, reduce production cost, be suitable for large-scale industrial production.
Description
Technical field
The present invention relates to field of medicine and chemical technology, particularly relate to the important intermediate 1 of a kind of Fondaparinux sodium, 6-dehydration-
2-nitrine, the synthetic method of 3 acetyl group-β-D-Glucose.
Background technology
Fondaparinux sodium (Fondaparinux sodium) is the pentosan compound of the most first full chemical synthesis, is
The indirect suppression of first dependent Xa factor of antithrombase of France's Sanofi Winthrop Industrie development and production
Agent, No. CAS is 114870-03-0, and Chinese is entitled: methyl O-(2-deoxidation-6-O-sulfonic group-2-sulfoamido-α-D-glucopyra
Sugar)-(1 → 4)-O-(beta d glucopyranosiduronic acid)-(1 → 4)-O-(2-deoxidation-3,6-O-disulfonic acid base-2-sulfoamido-α-
D-glucopyranose)-(1 → 4)-O-(2-O-sulfonic group-α-L-pyrans iduronic acid)-(1 → 4)-2-deoxidation-6-O-sulfonic acid
Base-2-sulfoamido-α-D-glucopyranoside ten sodium salt, molecular formula is C31H43N3Na10O49S8, molecular weight is 1728, structure
For:。
Fondaparinux sodium is mainly used in preventing VTE, is the most efficient high selective Xa factor suppression
Agent.Factor Xa is the key link of the co-channel of blood coagulation " startup approach " and blood coagulation " amplification approach ", makes factor change
For fibrin ferment the formation that ultimately results in thrombus, it also it is the major target class of anticoagulant.Fondaparinux sodium with the ratio of 1:1 with anti-
Pentose structure on fibrin ferment (AT) combines and inhibiting factor Xa, but this combination is reversible, and Fondaparinux sodium activates one
After the AT of molecule, discharge and combine other AT molecule with prototype.After Fondaparinux sodium is combined with AT, make AT inhibiting factor Xa
Speed increase about 300 times.Inhibitory action to factor Xa have impact on the process of coagulation cascade reaction, and inhibits the shape of fibrin ferment
Become and the increase of thrombus.Semi-annular jade pendant reaches liver sodium in the last of the ten Heavenly stems and has more preferable anticoagulating active and longer partly declining compared with LMWHs (LWMH)
Phase (15-20h), (prothrombin a) inactivates, and to platelet function also without effect, energy is notable simultaneously will not to cause factor
Reduce hemorrhage side effect of Denging, and Clinical practice is convenient.But owing to synthesis is extremely complex, there are more than 50 step, production phase shape
Become bottleneck, cause product price costly, be unfavorable for that the popularization of medicine is with universal.
According in OL-5-4179, the synthetic route of Fondaparinux sodium intermediate Monomer A ring is:
。
According to Tetrahedron:A symmetry, 16 (2), 411-424;Report in 2005, Fondaparinux sodium intermediate
The synthetic route of Monomer C ring is:
。
According in CN101348509, the synthetic route of Fondaparinux sodium intermediate Monomer E ring is:。
The synthetic method synthetic reaction cost of above-mentioned technique is high, and reactions steps is longer.Accordingly, it would be desirable to in Fondaparinux sodium
The synthetic method of mesosome is developed.
Summary of the invention
The technical problem that present invention mainly solves is to provide the synthetic method of a kind of Fondaparinux sodium intermediate, this synthesis side
Method is effectively and reasonably and low cost.
For solving above-mentioned technical problem, the technical scheme that the present invention uses is: provide in the middle of a kind of Fondaparinux sodium
The synthetic method of body, including step be: with compoundFor raw material, acetylating hydroxyl groups
Compound, by described compoundUse ammonium ceric nitrate
De-to methoxy-benzyl (PMB), obtain Monomer C ring。
In a preferred embodiment of the present invention, described acetylating hydroxyl groups is addition aceticanhydride in the pyridine be dissolved with raw material
After, stir 1-3 hour at 20 DEG C.
In a preferred embodiment of the present invention, the described de-process to methoxy-benzyl is by compoundIt is dissolved in the mixed solvent of acetonitrile that volume ratio is 9:1 and water, at 0 DEG C, adds nitre
Acid cerium ammonium, is warmed up to 20 DEG C and reacts 1-3 hour.
The invention has the beneficial effects as follows: the synthetic method of the Fondaparinux sodium intermediate of the present invention, close through 5 steps with original
Become Monomer C chain rate relatively, simplify the synthetic route of Monomer C ring, reduce production cost, be suitable for large-scale industry
Metaplasia is produced.
Accompanying drawing explanation
For the technical scheme being illustrated more clearly that in the embodiment of the present invention, in embodiment being described below required for make
Accompanying drawing be briefly described, it should be apparent that, below describe in accompanying drawing be only some embodiments of the present invention, for
From the point of view of those of ordinary skill in the art, on the premise of not paying creative work, it is also possible to obtain other according to these accompanying drawings
Accompanying drawing, wherein:
Fig. 1 is the synthetic route chart of the Monomer C ring of the present invention.
Detailed description of the invention
Technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that described enforcement
Example is only a part of embodiment of the present invention rather than whole embodiments.Based on the embodiment in the present invention, this area is common
All other embodiments that technical staff is obtained under not making creative work premise, broadly fall into the model of present invention protection
Enclose.
Referring to Fig. 1, the present invention is that acetylating hydroxyl groups obtains chemical combination with the intermediate 3 synthesizing Monomer A ring as raw material
Thing 6, then compound 6 is taken off PMB with ammonium ceric nitrate, obtain product Monomer C ring.
Embodiment one:
The preparation process of compound 6 is:
Compound 3 (40 g, 0.13 mol) is dissolved in pyridine (240 mL, 2.98 mol), adds aceticanhydride
(80 ml, 0.85 mol) .This reactant liquor stirs 1-3 hour at 20 DEG C, is concentrated to give compound 6 (43 g, 94.5%).
Reaction equation is:。
Embodiment two:
The preparation process of compound Monomer C ring is:
Compound 6 (42.5 g, 0.12 mol) is dissolved in acetonitrile (475 mL) and water (55 ml), 0 DEG C
Lower addition ammonium ceric nitrate (166 g, 0.3 mol), reactant liquor reacts 1-3 hour at 20 DEG C, after having reacted through filtration,
Extraction, sodium bicarbonate aqueous solution are washed, and dry, concentrated pillar obtains compound C ring (21.5 g, 78%).
Reaction equation is:。
1H NMR (400 MHz, CDCl3) δ 5.42 (s, 1H), 4.88 – 4.81 (m, 1H), 4.58 (d,
J = 5.4 Hz, 1H), 4.11 – 4.08 (d, J = 8 Hz ,1H), 3.80 (dd, J = 7.5, 5.8 Hz,
1H), 3.60 (s, 1H), 3.45 (s, 1H), 3.04 (s, 1H), 2.10 (s, 3H)。
The foregoing is only embodiments of the invention, not thereby limit the scope of the claims of the present invention, every utilize this
Equivalent structure or equivalence flow process that bright description is made convert, or are directly or indirectly used in other relevant technology neck
Territory, is the most in like manner included in the scope of patent protection of the present invention.
Claims (2)
1. the synthetic method of a Fondaparinux sodium intermediate, it is characterised in that include that step is: with compoundFor raw material, acetylating hydroxyl groups obtains compound, by described
CompoundDe-to methoxy-benzyl with ammonium ceric nitrate, obtain Monomer C ring；The described de-process to methoxy-benzyl is by compound
It is dissolved in the mixed solvent of acetonitrile that volume ratio is 9:1 and water, at 0 DEG C, adds ammonium ceric nitrate, be warmed up to 20 DEG C of reaction 1-3 little
Time.
Synthetic method the most according to claim 1, it is characterised in that described acetylating hydroxyl groups is to the pyrrole being dissolved with raw material
After pyridine adds aceticanhydride, stir 1-3 hour at 20 DEG C.
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| CN201410256002.7A CN104151370B (en) | 2014-06-11 | 2014-06-11 | A kind of synthetic method of Fondaparinux sodium intermediate |
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| CN201410256002.7A CN104151370B (en) | 2014-06-11 | 2014-06-11 | A kind of synthetic method of Fondaparinux sodium intermediate |
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| CN104151370A CN104151370A (en) | 2014-11-19 |
| CN104151370B true CN104151370B (en) | 2016-09-07 |
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| CN110256321B (en) * | 2019-06-12 | 2021-05-28 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Preparation method and application of (2R,3S,4S) -4-amino-2-tetradecyl pyrrolidine-3-alcohol |
| CN110746471B (en) * | 2019-11-04 | 2021-06-25 | 江苏美迪克化学品有限公司 | Preparation method of fondaparinux sodium disaccharide intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008153394A2 (en) * | 2007-06-14 | 2008-12-18 | Academisch Medisch Centrum | Novel anti-inflammatory pro-drugs |
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2014
- 2014-06-11 CN CN201410256002.7A patent/CN104151370B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008153394A2 (en) * | 2007-06-14 | 2008-12-18 | Academisch Medisch Centrum | Novel anti-inflammatory pro-drugs |
Non-Patent Citations (2)
| Title |
|---|
| Total Synthesis of Anticoagulant Pentasaccharide Fondaparinux;Tiehai Li，等;《Chem. Med. Chem.》;20140411;第9卷;第1071-1080页 * |
| Use of Cerny Epoxides for the Accelerated Synthesis of Glycosaminoglycans;Sabine Arndt，等;《ORGANIC LETTERS》;20031007;第5卷(第22期);第4179-4182页 * |
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Effective date of registration: 20170313 Address after: 201201 Shanghai City, Pudong New Area Ruiqinglu No. 528 Building 9, No. 2 Patentee after: Shanghai Hongbo Zhiyuan pharmaceutical Limited by Share Ltd Address before: 215200 Jiangsu, Suzhou, Changan Road, No. 2358, science and Technology Park, building A, building, building 8 Patentee before: Suzhou Jinghong Biotechnology Co., Ltd. |
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