CN106632186A - Preparation method of zanamivir intermediate and preparation method of zanamivir - Google Patents
Preparation method of zanamivir intermediate and preparation method of zanamivir Download PDFInfo
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a preparation method of a zanamivir intermediate, namely an acetylation protected amino compound, and a preparation method of zanamivir. The preparation method of the zanamivir, provided by the invention, comprises the following steps: performing cyclization by taking sialic acid as a raw material and through group protection to produce a cyclization substance, treating the cyclization substance by a metal amino substance at one step to obtain the acetylation protected amino compound, and removing a hydroxyl protective agent acetic acid ester and removing guanidyl from imipyrozole reaction to obtain the zanamivir, wherein the process of treating the cyclization substance by the metal amino substance at one step to obtain the acetylation protected amino compound is great substantial breakthrough in preparation of the zanamivir, the synthesis steps are greatly shortened and the process operation is simplified. Ring opening is conducted by the cheap metal amino substance instead of expensive trimethylsilyl azid, so that the cost is reduced and the safety of the production process is guaranteed. According to thepreparation method of the zanamivir, provided by the invention, the total mass yield can reach 50 percent or above and is greatly increased as compared with that in the prior art.
Description
Technical field
The present invention relates to a kind of new preparation process of zanamivir intermediate, the invention further relates to a kind of system of zanamivir
Preparation Method, belongs to pharmaceutical chemistry technical field.
Background technology
Zanamivir (Zanamivir) is the first kind neuraminidase inhibitor being synthesized based on drug design, it
It is that few in number on the market at present two kinds are approved for treating A type and B-mode stream with Ao Ketawei (Osel tamivir)
The medicine of Influenza Virus.
Zanamivir, by Australian scientist's discovery than tower difficult to understand (Biota), in nineteen ninety Pueraria lobota was licensed in 1989
Lan Su SmithKlines company is used for clinical treatment.FDA approvals are obtained within 1999 and in U.S.'s listing, in the inhalant commodity of China's sale
Entitled musicality is clear.
Zanamivir, chemical name (4S, 5R, 6R) -5- acetylaminohydroxyphenylarsonic acid 4- guanidine radicals -6- ((1R, 2R) -1,2,3- tri- hydroxyls
Base-propyl group) -5,6- dihydro -4H- pyrans -2- carboxylic acids, chemical structural formula is as follows：
Zanamivir has various synthetic methods.Because sialic acid (N-acetyl-neuraminate) is using fermentation or enzymatic synthesis
After method industrialization success, because sialic acid price is than relatively low, by initiation material synthesis zanamivir of sialic acid a kind of Jing is become
The practical production method of Ji.
ZL96107757.3 patents are the Yuan Yan companies of zanamivir：Department more limited than tower scientific management difficult to understand of Australia
(BIOTA SCIENT MANAGEMENT (AU)) is in the Chinese patent applied and has been authorized.Patent protection Zha Na meter
Wei compound and its derivative；Also the antiviral application of these materials is protected, particularly for treating the purposes of influenza；And
Also protect the synthetic method of zanamivir.The patent synthesizes the route of zanamivir, is exactly that GlaxoSmithKline PLC company synthesis is pricked
The production line of Na meter Wei, concrete synthetic route is as follows：
With sialic acid (V) as raw material, the synthesis of the steps of Jing two obtains the sialic acid with protection group to ZL96107757.3 patents
(IV)；Then cyclocomplex (III) is generated；Recycle the azide open loops such as expensive trimethyl azide silicon to introduce required nitrogen
Atom, forms azido compound (IIa)；Jing is reduced, and obtains the amino substance (IIb) protected；Decarboxylate protection group methyl esters, is changed
Compound (II)；Then hydroxyl protection is removed, compound (Ia) is obtained；The upper croak base of last and miaow base pyrazoles reaction, obtains zanamivir
Compound (I).However, the method is not easy industrialization, reason is to employ nitrine during cyclocomplex (III) to (II)
Compound, trimethyl azide silicon is expensive, increases production cost, and the explosion danger that azide and intermediate are present,
Great danger is brought to large-scale industrial production.In addition, the patent is calculated according to sialic acid, gross mass yield only has
Less than 20%, yield is very low.
CN101704851A is related to a kind of serving as compound resisting highly pathogenic avian influenza zanamivir intermediate (5- acetylaminohydroxyphenylarsonic acids
3,5- dideoxy-D- glycerine base-D- galactolipin -2- bmap acid methyl esters) preparation method, but only optimize sialic acid
(V) methyl esters protects this step, and does not have substantial progress on the basis of patent ZL96107757.3.
CN102464640A makes certain improvements on the basis of ZL96107757.3 patents, that is, the amino substance protected
The process modification of (IIb) to zanamivir (I).ZL96107757.3 patents are the croak bases in final step, and
CN102464640A is first the amino in the amino substance (IIb) of protection to be converted into guanidine radicals with the reaction of miaow base pyrazoles, then ester group
Hydrolysis, Deprotection prepares zanamivir.The method is above going up croak base, does not meet atom economy, because miaow base pyrrole
Azoles is expensive, is above going up croak base, the inevitable many consumptions for going up croak base later of miaow base pyrazoles consumption, therefore the cost of the method
Will necessarily raise.
Therefore, seek a kind of not only safety but also the high zanamivir preparation method of low cost, yield, be zanamivir industry
One of preparation field technical problem urgently to be resolved hurrily.
The content of the invention
It is an object of the invention to provide a kind of amino-compound (Formula II) of zanamivir intermediate acetylization protection is new
Synthetic method, and the novel synthesis of zanamivir (Formulas I), the method shortens synthesis step, reduce production cost and
Production is dangerous, and yield greatly improved.
The invention provides a kind of amino-compound (Formula II) of zanamivir intermediate acetylization protection：(2R,3R,
4S) -3- acetylaminohydroxyphenylarsonic acids 4- amino -2- [(1R, 2R) -1,2,3- (triacetoxyl group) propyl group] -3,4- dihydro -2H- pyrans -6-
The preparation method of carboxylate, including：With metal amino thing and cyclocomplex (formula III)：(3aR, 4R, 7aR) -2- methyl -4- [(1S,
2R) -1,2,3- (triacetoxyl group) propyl group -4, [3,4, d] oxazole -6- carboxylate methyl esters react 7a- dihydro -3aH- pyrans, obtain
The amino-compound (Formula II) of acetylation protection
Wherein, the M in Formula II represents Na, K or Ca.
One of the invention concrete but non-limiting embodiment, methods described includes：To cyclocomplex (formula III)
Organic solvent solution in add metal amino thing, heating, under organic solvent reflux temperature react 6-8 hours, reaction is quenched,
Concentration, adds solvent dissolving, washing, concentrated solvent to filter to dry, recrystallization, and drying obtains the amino chemical combination of acetylation protection
Thing (Formula II).
One of the invention concrete but non-limiting embodiment, wherein, metal amino thing is Sodamide, amino
At least one in calcium or potassamide.
One of the invention concrete but non-limiting embodiment, wherein, cyclocomplex (formula III) and metal amino
The mass ratio of thing is 1：0.05-0.5.
Present invention also offers a kind of preparation method of zanamivir (Formulas I), including：Acetylation guarantor is prepared in aforementioned manners
The amino-compound (Formula II) of shield, by the amino-compound (Formula II) that obtained acetylation is protected hydroxy-protecting agent acetic acid is sloughed
Ester, then react with miaow base pyrazoles, obtain zanamivir (Formulas I)
Wherein, the M in Formula II represents Na, K or Ca.
Present invention also offers a kind of preparation method of zanamivir (Formulas I), including：
A () sialic acid (Formula V) generates the sialic acid with protection group (formula IV) through the radical protection to hydroxyl and carboxyl；
B the sialic acid of () with protection group (formula IV) carries out cyclization, generate cyclocomplex (formula III)；
C () cyclocomplex (formula III) reacts with metal amino thing, generate the amino-compound (Formula II) of acetylation protection；
Wherein, the M in Formula II represents Na, K or Ca
D the amino-compound (Formula II) of () acetylation protection sloughs hydroxy-protecting agent acetic acid esters, generate the dehydrogenation -4- of 2,3- bis-
Amino-N-acetyl-neuraminate (Formulas I a)；
Wherein, the M in Formula II represents Na, K or Ca
E () 2, (Formulas I a) and miaow base pyrazoles react the dehydrogenation -4- amino of 3- bis--N-acetyl-neuraminate, obtain zanamivir
(Formulas I)
One of the invention concrete but non-limiting embodiment, methods described includes：
A sialic acid (Formula V), methyl alcohol, strong acid ion exchange resin are stirred at room temperature 10-20 hours by (), to reaction
Solution of the liquid in dissolving clarification, filters out resin, and concentration methyl alcohol is to dry；Pyridine is added, to dimethylamino naphthyridine, under frozen water cooling
Aceticanhydride is added, 10-16 hours are stirred at room temperature, concentration pyridine is to dry；Dissolved with ethyl acetate, washing, concentration ethyl acetate to dry,
Obtain the sialic acid with protection group (formula IV)；
B () is added dropwise Trimethylsilyl trifluoromethanesulfonate in the ethyl acetate solution of the sialic acid with protection group (formula IV),
5-6 hours are reacted at 40-50 DEG C；Add water and reaction is quenched；Stirring, branch vibration layer, washing, concentration ethyl acetate obtains ring to dry
Compound (formula III)；
C () adds metal amino thing, heating, in organic solvent backflow in the organic solvent solution of cyclocomplex (formula III)
At a temperature of react 6-8 hours, reaction is quenched, concentrate, add solvent dissolving, washing, concentrated solvent to filter to dry, recrystallization, baking
It is dry, obtain the amino-compound (Formula II) of acetylation protection；
D amino-compound (Formula II) that () protects acetylation, in being added to suitable quantity of water, is added dropwise sodium hydroxide solution, room
Warm stirring reaction, the pH value for controlling reaction end is 10-11, and it is 4-5 to add acid-exchange resin to adjust PH, and condensed water is extremely
It is dry, recrystallisation from isopropanol is added, to filter, drying obtains the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (Formulas I a)；
E () (Formulas I a) in being added to suitable quantity of water, adds carbonic acid by the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate
Sodium, is subsequently adding miaow base pyrazole hydrochloride, and 6-8 hours are reacted at 30-40 DEG C；Part water is fallen in concentration, adds isopropanol, stirs
Mix, separate out pressed powder, filter, isopropanol washing, drying obtains zanamivir crude product, then is recrystallized by isopropanol-water,
Filter, drying obtains the zanamivir of pharmaceutical grade.
One of the invention concrete but non-limiting embodiment, wherein, in step (a), sialic acid (Formula V) with
Methyl alcohol, the mass ratio of strong acid ion exchange resin are 1：8-12：0.01-0.1；Sialic acid (Formula V) and pyridine, to dimethylamino
The mass ratio of pyridine is 1：8-12：0.01-0.05；Sialic acid (Formula V) is 1 with the mass ratio of aceticanhydride：1-3.
One of the invention concrete but non-limiting embodiment, wherein, in step (b), the saliva with protection group
Liquid acid (formula IV) is 1 with the mass ratio of ethyl acetate：2-8；Sialic acid with protection group (formula IV) and TFMS trimethyl
The mass ratio of estersil is 1：0.4-0.8.
One of the invention concrete but non-limiting embodiment, wherein, in step (c), metal amino thing is
At least one in Sodamide, amino calcium or potassamide；Cyclocomplex (formula III) is 1 with the mass ratio of metal amino thing：0.05-
0.5。
One of the invention concrete but non-limiting embodiment, wherein, 2,3- bis- dehydrogenation -4- amino-N- second
(Formulas I a) is 1 with the mass ratio of sodium carbonate to acyl neuraminic acid：1-1.5；Dehydrogenation -4- the amino of 2,3- bis--N-acetyl-neuraminate (formula
Ia it is) 1 with the mass ratio of miaow base pyrazole hydrochloride：0.5-0.6.
The beneficial effects are mainly as follows：
1. the present invention achieves breakthrough in zanamivir preparation process, by intermediate cyclocomplex (formula III) to
The amino-compound (Formula II) of another intermediate acetylization protection realizes one-step synthesis, with prior art GlaxoSmithKline PLC company by
The production line of cyclocomplex (III)-(IIa)-(IIb)-(II) three step synthesis is compared, and synthesis step is greatly shortened, and is simplified
Technological operation, is zanamivir preparation method is made that substantial significant improvement.
2. the present invention is with azide such as the costly and hazardous trimethyl azide silicon of cheap metal amino thing fictitious hosts,
Cyclocomplex (formula III) open loop, the amino-compound (Formula II) of one-step synthesis acetylation protection is set not only to significantly reduce and produce into
This, and avoid the explosive danger of the trinitride of raw material trimethyl azide silicon and generation, it is ensured that the peace of production technology
Quan Xing.
3. with the step of GlaxoSmithKline PLC company eight synthesis zanamivir finally only less than 20% gross mass yield compared with (press
Calculate according to sialic acid), the zanamivir preparation method of the present invention greatly improved yield, and gross mass yield is up to more than 50%.
4. the zanamivir preparation method of the present invention has obvious cost advantage and green syt advantage, and production technology is more
Simply, more convenient operation, is especially suitable for large-scale industrial production.
Specific embodiment
Provided hereinafter specific embodiment and further illustrate the present invention, but the present invention is not limited only to following enforcement
Mode.
The present invention obtains important breakthrough in zanamivir preparation process, does on the basis of ZL96107757.3 patents
Go out substantial improvement, prior art is straight by the three step synthetic routes of cyclocomplex (III)-(IIa)-(IIb)-(II)
Connect and replaced by (III)-(II) one-step synthesis, specifically process cyclocomplex (formula III) step with metal amino thing and obtain acetylation
The amino-compound (Formula II) of protection, reaction equation is as follows：
Wherein, the M in Formula II represents Na, K or Ca.
The invention provides a kind of preparation method of zanamivir (Formulas I), with sialic acid, i.e. N-acetyl-neuraminate (formula
V) it is raw material, through the radical protection to hydroxyl and carboxyl, obtains the sialic acid with protection group (formula IV)；Carry out again being cyclized instead
Should, generate cyclocomplex (formula III)；Cyclocomplex (formula III) is processed with metal amino thing, a direct step obtains the ammonia of acetylation protection
Based compound (Formula II)；Hydroxy-protecting agent acetic acid esters is sloughed again, obtains the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (formula
Ia)；Finally with the upper croak base of miaow base pyrazoles reaction, zanamivir (Formulas I) is obtained.Concrete synthetic route is as follows：
Wherein, the M in Formula II represents Na, K or Ca.
The zanamivir preparation method of the present invention is described in detail below：
(1) sialic acid (formula IV) of anamorphic zone protection group
Sialic acid (Formula V) is through the radical protection to hydroxyl and carboxyl, the sialic acid (formula IV) of anamorphic zone protection group.
By sialic acid (Formula V), methyl alcohol, strong acid ion exchange resin, 10-20 hours are stirred at room temperature, to reactant liquor
Solution in dissolving clarification；Filter out resin, concentration methyl alcohol is to dry；Pyridine is added, to dimethylamino naphthyridine (DMAP), ice water cooling
It is lower to add aceticanhydride, it is stirred at room temperature 10-16 hours, concentration pyridine is to dry；Dissolved with ethyl acetate, be washed with water and wash repeatedly, it is dense
Contracting ethyl acetate obtains the sialic acid with protection group (formula IV) to dry.The step yield about 98%.
Wherein, sialic acid (Formula V) and methyl alcohol, the mass ratio of strong acid ion exchange resin can be 1：8-12：0.01-
0.1。
Sialic acid (Formula V) can be 1 with pyridine, the mass ratio to dimethylamino naphthyridine (DMAP)：8-12：0.01-0.05.
Sialic acid (Formula V) can be 1 with the mass ratio of aceticanhydride：1-3.
(2) cyclocomplex (formula III) is synthesized
Sialic acid with protection group (formula IV) carries out cyclization, synthesis cyclocomplex (formula III).
To in the ethyl acetate solution of the sialic acid with protection group (formula IV), Trimethylsilyl trifluoromethanesulfonate is added dropwise
(TMSOTS), 5-6 hours are reacted at 40-50 DEG C；Add water and reaction is quenched；Stirring 30 minutes or so, branch vibration layer adds water to wash again
Wash once；Concentration ethyl acetate obtains cyclocomplex (formula III) to dry.The step yield about 90%.
Wherein, the sialic acid with protection group (formula IV) and the mass ratio of ethyl acetate can be 1：2-8.
Sialic acid with protection group (formula IV) can be 1 with the mass ratio of Trimethylsilyl trifluoromethanesulfonate (TMSOTS)：
0.4-0.8。
The water yield that addition is quenched is advisable with 0.5-1 times of the sialic acid with protection group (formula IV) quality.
(3) amino-compound (Formula II) of synthesis of acetylization protection
Cyclocomplex (formula III), the amino-compound (Formula II) of synthesis of acetylization protection are processed with metal amino thing.
The organic solvent such as anhydrous tetrahydro furan or toluene is added in cyclocomplex (formula III), metal amino thing is slowly added to,
6-8 hours are reacted in stirring, heating under the reflux temperature of organic solvent；Add water and reaction is quenched；Concentration, adds solvent such as acetic acid
Ethyl ester dissolves, and washes with water repeatedly, and concentrated solvent is to dry；Recrystallized with alcohol such as isopropanol etc., filtered, drying obtains acetylation
The amino-compound (Formula II) of protection.The step yield about 95%
Wherein, metal amino thing is typically at least one in Sodamide, amino calcium or potassamide.Cyclocomplex (formula III)
Can be 1 with the mass ratio of metal amino thing：0.05-0.5.
The amount of the organic solvent of dissolving cyclocomplex (formula III) can be 2-10 times of cyclocomplex (formula III) quality.
The water yield that addition is quenched is advisable with 0.5-1 times of cyclocomplex (formula III) quality.
The isopropanol of recrystallization is typically 4-6 times of cyclocomplex (formula III) quality.
(4) dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (Formulas I a) is synthesized
The amino-compound (Formula II) of acetylation protection sloughs hydroxy-protecting agent acetic acid esters, synthesizes the dehydrogenation -4- ammonia of 2,3- bis-
Base-N-acetyl-neuraminate (Formulas I a).
During the amino-compound (Formula II) that acetylation is protected is added into suitable quantity of water, the hydroxide of concentration about 10wt% is added dropwise
Sodium solution, is stirred at room temperature reaction, and the pH value for controlling reaction end is 10-11；It is 4-5 to add acid-exchange resin to adjust PH；
Condensed water adds recrystallisation from isopropanol to dry；Filter, drying obtains the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (formula
Ia).The step yield about 85%.
Wherein, the isopropanol of recrystallization can be 5-7 times of amino-compound (Formula II) quality of acetylation protection.
(5) zanamivir (Formulas I) is synthesized
(Formulas I a) and the upper croak base of miaow base pyrazoles reaction, synthesize Zha Na meter to 2,3- bis- dehydrogenation -4- amino-N-acetyl-neuraminate
Wei (Formulas I).
By the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate, (Formulas I a) is added in suitable quantity of water, adds sodium carbonate, so
Miaow base pyrazole hydrochloride is added afterwards；6-8 hours are reacted at 30-40 DEG C；Half water or so is fallen in concentration, adds isopropanol (about
10 times or so of 2,3- bis- dehydrogenation -4- amino-N-acetyl-neuraminate quality), stirring separates out pressed powder；Filter, isopropanol
Washing, drying obtains zanamivir crude product, then is recrystallized by isopropanol-water, filters, and drying obtains the Zha Na meter of pharmaceutical grade
Wei (Formulas I).The step yield about 70-80%.
Wherein, (Formulas I a) can be 1 with the mass ratio of sodium carbonate to the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate：1-
1.5。
(Formulas I a) can be the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate with the mass ratio of miaow base pyrazole hydrochloride
1：0.5-0.6.
Zanamivir prepared by said method, after testing, product purity is more than 99.0%, and single contaminant is less than 0.1%, symbol
Close pharmaceutical grade to require.The gross mass yield of the step of the above five can reach more than 50%.
With reference to specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.
Experimental technique above and used in following embodiments if no special instructions, is conventional method.
Material used, reagent etc. above and in following embodiments, if no special instructions, commercially obtain or
Prepared with known conventional method.
Embodiment 1
The amino-compound (Formula II) of synthesis of acetylization protection
Cyclocomplex (formula III) 120g, adds 1200g anhydrous tetrahydro furans, is slowly added to 20g potassamides.Stirring, heating,
React 7 hours under tetrahydrofuran reflux temperature.80g water quenchings are added to go out reaction.Concentration, adds ethyl acetate dissolving, uses every time
300g water washings three times, concentration ethyl acetate is to dry.550g recrystallisation from isopropanol is used, is filtered, drying obtains acetylation protection
Amino-compound (Formula II) 123g.Yield：93.1%.
Embodiment 2
(1) sialic acid (formula IV) of anamorphic zone protection group
Sialic acid (Formula V) 100g, methyl alcohol 1000g, strong acid ion exchange resin 5g；Stir 12 hours under room temperature, reaction
Solution of the liquid in dissolving clarification.HPLC detects that sialic acid normalization method content is 1.2%.Filter, filtrate concentrates methyl alcohol to dry, obtains
To methyl esters sialic acid.
Pyridine 1000g is added, to dimethylamino naphthyridine (DMAP) 3g, frozen water cooling is lower to add aceticanhydride 250g.It is stirred at room temperature
15 hours.HPLC detects that methyl esters sialic acid normalization method content is 0.3%.Concentration pyridine is to dry.Dissolved with 1000g ethyl acetate,
Every time with 300g water washings three times, concentration ethyl acetate is to dry.Obtain the sialic acid with protection group (formula IV) 169g.Yield：
97.9%.
(2) cyclocomplex (formula III) is synthesized
Sialic acid with protection group (formula IV) 169g, ethyl acetate 1000g, are added dropwise Trimethylsilyl trifluoromethanesulfonate
(TMSOTS) 80g, 45 DEG C are reacted 6 hours.85g water quenchings are added to go out reaction.Stirring 30 minutes, branch vibration layer adds 500g water again
Washed once.Concentration ethyl acetate is to dry.Obtain cyclocomplex (formula III) 117g.Yield 89.3%.
(3) amino-compound (Formula II) of synthesis of acetylization protection
Cyclocomplex (formula III) 117g, adds 1170g anhydrous tetrahydro furans, is slowly added to 15g Sodamides.Stirring, heating,
React 6 hours under tetrahydrofuran reflux temperature.80g water quenchings are added to go out reaction.Concentration, adds ethyl acetate dissolving, uses every time
300g water washings three times, concentration ethyl acetate is to dry.585g recrystallisation from isopropanol is used, is filtered, drying.Obtain acetylation protection
Amino-compound (Formula II) 118g.Yield：95.2%.
(4) dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (Formulas I a) is synthesized
Amino-compound (Formula II) 118g of acetylation protection, in being added to 1180g water, is added dropwise 10wt% NaOH molten
Liquid, is stirred at room temperature reaction, and side border ring detects the pH value of reactant liquor, and the pH value for controlling reaction end is 10-11.Add it is acid from
It is 4-5 that sub-exchange resin adjusts PH.Condensed water adds 710g recrystallisation from isopropanol to dry.Filter, drying, obtain the dehydrogenations of 2,3- bis--
4- amino-N-acetyl-neuraminate (Formulas I a) 66g.Yield：84.5%
(5) zanamivir (Formulas I) is synthesized
(Formulas I a) 66g in being added to 660g water, add sodium carbonate to 2,3- bis- dehydrogenation -4- amino-N-acetyl-neuraminate
66g, is subsequently adding miaow base pyrazole hydrochloride 36g.React 7 hours at 35 DEG C.330g water is fallen in concentration, adds 660g isopropanols,
Stirring, separates out pressed powder.Filter, isopropanol washing, drying obtains zanamivir crude product 67g.Pass through isopropanol-water weight again
Crystallization, filters, and drying obtains zanamivir (Formulas I) 55g of pharmaceutical grade.Yield：72.8%
HPLC is analyzed, and the zanamivir purity for preparing is more than 99.2%, and single contaminant is less than 0.1%.According to starting
Raw material sialic acid is calculated, and the total mass yield of zanamivir is 55%.
Embodiment 3
(1) sialic acid (formula IV) of anamorphic zone protection group
In 30L glass reaction kettles, sialic acid (Formula V) 2kg, methyl alcohol 20kg, strong acid ion exchange resin 100g are added；
Stir 10 hours under room temperature, solution of the reactant liquor in dissolving clarification.HPLC detects that sialic acid normalization method content is 1.0%.Cross
Filter, filtrate is transferred to 30L glass reaction kettles, and concentration methyl alcohol obtains methyl esters sialic acid to dry.
Pyridine 20kg is added, to dimethylamino naphthyridine (DMAP) 80g, frozen water cooling is lower to add aceticanhydride 5kg.It is stirred at room temperature 15
Hour.HPLC detects that methyl esters sialic acid normalization method content is 0.3%.Concentration pyridine is to dry.The dissolving of 20kg ethyl acetate is added,
Every time with 6L water washings three times, concentration ethyl acetate is to dry.Obtain the sialic acid with protection group (formula IV) 3.4kg.Yield：
98.6%.
(2) cyclocomplex (formula III) is synthesized
In 30L glass reaction kettles, the sialic acid with protection group (formula IV) 3.4kg, ethyl acetate 20kg are added, be added dropwise three
Fluorine methanesulfonic acid trimethylsilyl group (TMSOTS) 1.6kg, 40 DEG C are reacted 5 hours.1.8kg water quenchings are added to go out reaction.Stirring 30 minutes,
Branch vibration layer, adds 5kg water to washed once again.Concentration ethyl acetate is to dry.Obtain cyclocomplex (formula III) 2.4kg.Yield
90.1%.
(3) amino-compound (Formula II) of synthesis of acetylization protection
In 30L glass reaction kettles, cyclocomplex (formula III) 2.4kg is added, add 20kg anhydrous tetrahydro furans, it is slow to add
Enter 150g amino calcium.Stirring, heating is reacted 8 hours under tetrahydrofuran reflux temperature.1.7kg water quenchings are added to go out reaction.It is dense
Contracting, adds the dissolving of 20kg ethyl acetate, and every time with 6kg water washings three times, concentration ethyl acetate is to dry.Tied again with 10kg isopropanols
Crystalline substance, filters, drying.Obtain amino-compound (Formula II) 2.4kg of acetylation protection.Yield：94.5%.
(4) dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (Formulas I a) is synthesized
In 30L glass reaction kettles, amino-compound (Formula II) 2.4kg of acetylation protection is added, add 20kg water, drop
Plus 10wt% sodium hydroxide solutions, reaction is stirred at room temperature, side border ring detects the pH value of reactant liquor, controls the pH value of reaction end
For 10-11.It is 4-5 to add acid-exchange resin to adjust PH.Condensed water adds 12kg recrystallisation from isopropanol to dry.Filter, dry
It is dry, obtain the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (Formulas I a) 1.4kg.Yield：86.3%
(5) zanamivir
In 30L glass reaction kettles, the addition dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (Formulas I a) 1.4kg, plus
Enter to 15kg water, add sodium carbonate 1.3kg, be subsequently adding miaow base pyrazole hydrochloride 800g.React 6 hours at 40 DEG C.Concentration
Fall 8kg water, add 13kg isopropanols, stirring to separate out pressed powder.Filter, isopropanol washing, drying obtains zanamivir thick
Product 67g.Recrystallized by isopropanol-water again, filtered, drying obtains zanamivir (Formulas I) 1.2kg of pharmaceutical grade.Yield：
74.9%
HPLC is analyzed, and the zanamivir purity for preparing is 99.6%, and single contaminant is less than 0.1%.According to initial former
Material sialic acid is calculated, and the total mass yield of zanamivir is 60%.
The above is only the concrete application example of the present invention, protection scope of the present invention is not limited in any way.All employings
Equivalents or equivalence replacement and the technical scheme that formed, all fall within rights protection scope of the present invention.
Claims (11)
1. the amino-compound (Formula II) that a kind of zanamivir intermediate acetylization is protected：(2R, 3R, 4S) -3- acetylaminohydroxyphenylarsonic acid 4-
The preparation method of amino -2- [(1R, 2R) -1,2,3- (triacetoxyl group) propyl group] -3,4- dihydro -2H- pyrans -6- carboxylates,
Including：With metal amino thing and cyclocomplex (formula III)：(3aR, 4R, 7aR) -2- methyl -4- [(1S, 2R) -1,2,3- (triacetyls
Epoxide) propyl group -4, [3,4, d] oxazole -6- carboxylate methyl esters react 7a- dihydro -3aH- pyrans, obtain the amination of acetylation protection
Compound (Formula II)
Wherein, the M in Formula II represents Na, K or Ca.
2. method as claimed in claim 1, including：Metal amino thing is added in the organic solvent solution of cyclocomplex (formula III), plus
Heat, reacts 6-8 hours under organic solvent reflux temperature, and reaction is quenched, and concentrates, and adds solvent dissolving, washs, and concentrated solvent is extremely
Dry, recrystallization is filtered, and drying obtains the amino-compound (Formula II) of acetylation protection.
3. such as the method for claim 1 or 2, wherein, metal amino thing is at least in Sodamide, amino calcium or potassamide
Kind.
4. such as according to the method for claim 1 or 2, wherein, cyclocomplex (formula III) is 1 with the mass ratio of metal amino thing：0.05-
0.5。
5. a kind of preparation method of zanamivir (Formulas I), including：Acetylation protection is prepared with the arbitrary method of claim 1-4
Amino-compound (Formula II), by obtained acetylation protect amino-compound (Formula II) slough hydroxy-protecting agent acetic acid esters,
React with miaow base pyrazoles again, obtain zanamivir (Formulas I)
Wherein, the M in Formula II represents Na, K or Ca.
6. a kind of preparation method of zanamivir (Formulas I), including：
A () sialic acid (Formula V) generates the sialic acid with protection group (formula IV) through the radical protection to hydroxyl and carboxyl；
B the sialic acid of () with protection group (formula IV) carries out cyclization, generate cyclocomplex (formula III)；
C () cyclocomplex (formula III) reacts with metal amino thing, generate the amino-compound (Formula II) of acetylation protection；
Wherein, the M in Formula II represents Na, K or Ca
D the amino-compound (Formula II) of () acetylation protection sloughs hydroxy-protecting agent acetic acid esters, generate the dehydrogenation -4- ammonia of 2,3- bis-
Base-N-acetyl-neuraminate (Formulas I a)；
Wherein, the M in Formula II represents Na, K or Ca
E () 2, (Formulas I a) and miaow base pyrazoles react the dehydrogenation -4- amino of 3- bis--N-acetyl-neuraminate, obtain zanamivir (Formulas I)
7. method as claimed in claim 6, including：
A sialic acid (Formula V), methyl alcohol, strong acid ion exchange resin are stirred at room temperature 10-20 hours by (), be in reactant liquor
The solution of dissolving clarification, filters out resin, and concentration methyl alcohol is to dry；Pyridine is added, to dimethylamino naphthyridine, frozen water cooling is lower to be added
Aceticanhydride, is stirred at room temperature 10-16 hours, and concentration pyridine is to dry；Dissolved with ethyl acetate, washing, concentration ethyl acetate is obtained to dry
Sialic acid with protection group (formula IV)；
B () is added dropwise Trimethylsilyl trifluoromethanesulfonate in the ethyl acetate solution of the sialic acid with protection group (formula IV),
40-50 DEG C of reaction 5-6 hour；Add water and reaction is quenched；Stirring, branch vibration layer, washing, concentration ethyl acetate obtains cyclization to dry
Thing (formula III)；
C () adds metal amino thing, heating, in organic solvent reflux temperature in the organic solvent solution of cyclocomplex (formula III)
Lower reaction 6-8 hours, are quenched reaction, concentration, add solvent dissolving, washing, concentrated solvent to filter to dry, recrystallization, drying,
Obtain the amino-compound (Formula II) of acetylation protection；
D amino-compound (Formula II) that () protects acetylation, in being added to suitable quantity of water, is added dropwise sodium hydroxide solution, and room temperature is stirred
Mix reaction, the pH value for controlling reaction end is 10-11, it is 4-5 to add acid-exchange resin to adjust PH, condensed water to dry, plus
Enter recrystallisation from isopropanol, filter, drying obtains the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate (Formulas I a)；
E () (Formulas I a) in being added to suitable quantity of water, adds sodium carbonate, so by the dehydrogenation -4- amino of 2,3- bis--N-acetyl-neuraminate
Miaow base pyrazole hydrochloride is added afterwards, and 6-8 hours are reacted at 30-40 DEG C；Part water is fallen in concentration, adds isopropanol, stirring to separate out
Pressed powder, filters, isopropanol washing, and drying obtains zanamivir crude product, then is recrystallized by isopropanol-water, filters, and dries
It is dry, obtain the zanamivir of pharmaceutical grade.
8. method as claimed in claim 7, wherein, in step (a), sialic acid (Formula V) and methyl alcohol, strong acid ion exchange resin
Mass ratio is 1：8-12：0.01-0.1；Sialic acid (Formula V) is 1 with pyridine, the mass ratio to dimethylamino naphthyridine：8-12：
0.01-0.05；Sialic acid (Formula V) is 1 with the mass ratio of aceticanhydride：1-3.
9. method as claimed in claim 7, wherein, in step (b), the quality of the sialic acid with protection group (formula IV) and ethyl acetate
Than being 1：2-8；Sialic acid with protection group (formula IV) is 1 with the mass ratio of Trimethylsilyl trifluoromethanesulfonate：0.4-0.8.
10. such as the method for claim 6 or 7, wherein, in step (c), metal amino thing is Sodamide, amino calcium or potassamide
In at least one；Cyclocomplex (formula III) is 1 with the mass ratio of metal amino thing：0.05-0.5.
11. methods as claimed in claim 7, wherein, 2,3- bis- dehydrogenation -4- amino-N-acetyl-neuraminate (Formulas I a) and sodium carbonate
Mass ratio be 1：1-1.5；Dehydrogenation -4- the amino of the 2,3- bis--N-acetyl-neuraminate (matter of Formulas I a) and miaow base pyrazole hydrochloride
Amount ratio is 1：0.5-0.6.
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