CN106632186B - The preparation method of zanamivir intermediate and the preparation method of zanamivir - Google Patents
The preparation method of zanamivir intermediate and the preparation method of zanamivir Download PDFInfo
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Abstract
The present invention relates to the preparation methods of a kind of preparation method of the amino-compound of zanamivir intermediate acetylization protection and zanamivir.The preparation method of zanamivir of the present invention is using sialic acid as raw material, and by radical protection, cyclisation generates cyclocomplex; the amino-compound of acetylation protection is obtained with metal amino object processing one step of cyclocomplex; hydroxy-protecting agent acetic acid esters is sloughed again and guanylpyrazole reacts upper croak base, obtains zanamivir.Wherein, with the great substantive breakthroughs that the amino-compound that metal amino object processing one step of cyclocomplex obtains acetylation protection is in zanamivir preparation, synthesis step is greatly shortened, simplifies technological operation.The present invention trimethyl azide silicon open loop expensive with cheap metal amino object substitution, not only reduces cost, also ensures the safety of production technology.The preparation method gross mass yield of zanamivir of the present invention is greatly improved up to 50% or more than the prior art.
Description
Technical field
The present invention relates to a kind of new preparation process of zanamivir intermediate, and the invention further relates to a kind of systems of zanamivir
Preparation Method belongs to pharmaceutical chemistry technical field.
Background technique
Zanamivir (Zanamivir) is to design the first kind neuraminidase inhibitor being synthesized based on drug, it
With Ao Ketawei (Osel tamivir) be at present on the market two kinds few in number be approved for treatment A type and B-mode stream
The drug of Influenza Virus.
Zanamivir was found by Australia than the scientist of tower difficult to understand (Biota) in 1989, licensed to Pueraria lobota in nineteen ninety
The SmithKline Lan Su company is used for clinical treatment.Acquisition FDA approval in 1999 is simultaneously listed in the U.S., 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) -5,6- dihydro -4H- pyrans -2- carboxylic acid, chemical structural formula is as follows:
There are many synthetic methods for zanamivir.Since sialic acid (N-acetyl-neuraminate) is using fermentation or enzymatic synthesis
After method industrialization success, because sialic acid price is relatively low, synthesizing zanamivir as starting material using sialic acid becomes a kind of warp
It helps practical production method.
ZL96107757.3 patent is the Yuan Yan company 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 substances is protected, especially 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, specific synthetic route are as follows:
ZL96107757.3 patent for raw material, is synthesized through two steps with sialic acid (V), obtains the sialic acid with protecting group
(IV)；Then cyclocomplex (III) is generated；The azide open loops such as expensive trimethyl azide silicon are recycled to introduce required nitrogen
Atom is formed azido compound (IIa)；It is restored, the amino substance (IIb) protected；Decarboxylate protecting group methyl esters, is changed
It closes object (II)；Then hydroxyl protection is removed, compound (Ia) is obtained；Last and guanylpyrazole reacts upper croak base, obtains zanamivir
Compound (I).However, this method is not easy industrialization, the reason is that using nitrine during cyclocomplex (III) to (II)
Compound, trimethyl azide silicon is expensive, increases production cost, and explosion danger existing for azide and intermediate,
Great risk is brought to large-scale industrial production.In addition, the patent is calculated according to sialic acid, gross mass yield only has
20% hereinafter, yield is very low.
CN101704851A is related to a kind of serving as compound resisting highly pathogenic avian influenza zanamivir intermediate (5- acetylaminohydroxyphenylarsonic acid
3,5- dideoxy-D- glycerine base-D- galactolipin -2- bmap acid methyl esters) preparation method, however only optimize sialic acid
(V) methyl esters protects this step, and there is no substantive progress on the basis of patent ZL96107757.3.
CN102464640A makes certain improvements on the basis of ZL96107757.3 patent, that is, the amino substance protected
(IIb) to zanamivir (I) process modification.ZL96107757.3 patent is the croak base in final step, and
CN102464640A is first to react the amino in the amino substance of protection (IIb) with guanylpyrazole to be converted into guanidine radicals, then ester group
Zanamivir is prepared in hydrolysis, Deprotection.This method goes up croak base in front, atom economy is not met, because of amidino groups pyrrole
Azoles is expensive, in front upper croak base, and guanylpyrazole dosage is necessarily more than the dosage of upper croak base below, therefore the cost of this method
It will necessarily increase.
Therefore, seek the zanamivir preparation method a kind of not only safe but also at low cost, yield is high, be zanamivir industry
Preparation field one of the technical problems that are urgent to solve.
Summary of the invention
The object of the present invention is to provide a kind of the new of the amino-compound (Formula II) of zanamivir intermediate acetylization protection
The novel synthesis of synthetic method and zanamivir (Formulas I), this method shorten synthesis step, reduce production cost and
Risk is produced, yield greatly improved.
The present invention provides a kind of amino-compounds (Formula II) of zanamivir intermediate acetylization protection: (2R, 3R,
4S) -3- acetylaminohydroxyphenylarsonic acid 4- amino -2- [(1R, 2R) -1,2,3- (triacetoxyl group) propyl] -3,4- dihydro -2H- pyrans -6-
The preparation method of carboxylate, comprising: with metal amino object and cyclocomplex (formula III): (3aR, 4R, 7aR) -2- methyl -4- [(1S,
2R) -1,2,3- (triacetoxyl group) propyl -4,7a- dihydro -3aH- pyrans [3,4, d] oxazole -6- carboxylate methyl esters react, and obtain
The amino-compound (Formula II) of acetylation protection
Wherein, the M in Formula II indicates Na, K or Ca.
One according to the present invention specific but non-limiting embodiment, which comprises to cyclocomplex (formula III)
Organic solvent solution in be added metal amino object, heating, reacted 6-8 hours under organic solvent reflux temperature, quenching reaction,
Solvent dissolution, washing is added in concentration, and concentrated solvent is recrystallized to doing, filtered, and drying obtains the amino chemical combination of acetylation protection
Object (Formula II).
One according to the present invention specific but non-limiting embodiment, wherein metal amino object is Sodamide, amino
At least one of calcium or potassamide.
One according to the present invention specific but non-limiting embodiment, wherein cyclocomplex (formula III) and metal amino
The mass ratio of object is 1:0.05-0.5.
The present invention also provides a kind of preparation methods of zanamivir (Formulas I), comprising: prepares acetylation guarantor in aforementioned manners
The amino-compound (Formula II) that acetylation obtained is protected is sloughed hydroxy-protecting agent acetic acid by the amino-compound (Formula II) of shield
Ester, then reacted with guanylpyrazole, obtain zanamivir (Formulas I)
Wherein, the M in Formula II indicates Na, K or Ca.
The present invention also provides a kind of preparation methods of zanamivir (Formulas I), comprising:
(a) sialic acid (Formula V) generates the sialic acid (formula IV) with protecting group by the radical protection to hydroxyl and carboxyl；
(b) sialic acid with protecting group (formula IV) carries out cyclization, generates cyclocomplex (formula III)；
(c) cyclocomplex (formula III) is reacted with metal amino object, generates the amino-compound (Formula II) of acetylation protection；
Wherein, the M in Formula II indicates Na, K or Ca
(d) amino-compound (Formula II) of acetylation protection sloughs hydroxy-protecting agent acetic acid esters, generates 2,3-, bis- dehydrogenation -4-
Amino-N-acetyl-neuraminate (Formulas I a)；
Wherein, the M in Formula II indicates Na, K or Ca
(e) (Formulas I a) and guanylpyrazole react 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate, obtain zanamivir
(Formulas I)
One according to the present invention specific but non-limiting embodiment, which comprises
(a) by sialic acid (Formula V), methanol, strong acid ion exchange resin is stirred at room temperature 10-20 hours, until reaction
Liquid filters out resin in clear solution is dissolved, and concentration methanol is to dry；Pyridine is added, to dimethylamino naphthyridine, under ice water is cooling
Be added aceticanhydride, be stirred at room temperature 10-16 hour, concentration pyridine to do；Dissolved, washed with ethyl acetate, concentration ethyl acetate to dry,
Obtain the sialic acid (formula IV) with protecting group；
(b) into the ethyl acetate solution of the sialic acid (formula IV) with protecting group, Trimethylsilyl trifluoromethanesulfonate is added dropwise,
40-50 DEG C reaction 5-6 hours；Add water quenching reaction；Stirring, branch vibration layer, washing, concentration ethyl acetate obtain ring to doing
It closes object (formula III)；
(c) metal amino object is added into the organic solvent solution of cyclocomplex (formula III), heating flows back in organic solvent
At a temperature of react 6-8 hours, quenching reaction, concentration is added solvent dissolution, washing, and concentrated solvent is recrystallized, filtered, dry to dry
It is dry, obtain the amino-compound (Formula II) of acetylation protection；
(d) amino-compound (Formula II) for protecting acetylation, is added in suitable quantity of water, and sodium hydroxide solution, room is added dropwise
Temperature is stirred to react, and the pH value for controlling reaction end is 10-11, and addition acid-exchange resin tune PH is 4-5, and condensed water is extremely
It is dry, recrystallisation from isopropanol is added, filters, drying obtains 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate (Formulas I a)；
(e) by 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate, (Formulas I a), is added in suitable quantity of water, and carbonic acid is added
Then sodium is added guanylpyrazole hydrochloride, reacts 6-8 hours at 30-40 DEG C；Part water is fallen in concentration, and isopropanol is added, stirs
It mixes, solid powder, filtering is precipitated, isopropanol washing is dried, zanamivir crude product is obtained, then recrystallize by isopropanol-water,
Filtering, drying, obtains the zanamivir of pharmaceutical grade.
One according to the present invention specific but non-limiting embodiment, wherein in step (a), sialic acid (Formula V) with
Methanol, strong acid ion exchange resin mass ratio be 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；The mass ratio of sialic acid (Formula V) and aceticanhydride is 1:1-3.
One according to the present invention specific but non-limiting embodiment, wherein in step (b), the saliva with protecting group
The mass ratio of liquid acid (formula IV) and ethyl acetate is 1:2-8；Sialic acid (formula IV) with protecting group and trifluoromethanesulfonic acid trimethyl
The mass ratio of estersil is 1:0.4-0.8.
One according to the present invention specific but non-limiting embodiment, wherein in step (c), metal amino object is
At least one of Sodamide, amino calcium or potassamide；The mass ratio of cyclocomplex (formula III) and metal amino object is 1:0.05-
0.5。
One according to the present invention specific but non-limiting embodiment, wherein 2,3- bis- dehydrogenation -4- amino-N- second
(mass ratio of Formulas I a) and sodium carbonate is 1:1-1.5 to acyl neuraminic acid；Bis- dehydrogenation -4- amino of 2,3--N-acetyl-neuraminate (formula
It Ia is) 1:0.5-0.6 with the mass ratio of guanylpyrazole hydrochloride.
The beneficial effects are mainly reflected as follows:
1. the present invention achieve 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
Cyclocomplex (III)-three step of (IIa)-(IIb)-(II) synthesis production line is compared, and synthesis step is greatly shortened, simplifies
Technological operation is made that substantive significant improvement for zanamivir preparation method.
2. the azide such as the costly and hazardous trimethyl azide silicon of cheap metal amino object fictitious hosts of the invention,
Make cyclocomplex (formula III) open loop, the amino-compound (Formula II) of one-step synthesis acetylation protection is not only significantly reduced and is produced into
This, and avoid the danger of the trinitride explosive of raw material trimethyl azide silicon and generation, it is ensured that the peace of production technology
Quan Xing.
3. with eight step of GlaxoSmithKline PLC company synthesis zanamivir finally only less than 20% gross mass yield compared with (press
Calculated according to sialic acid), zanamivir preparation method of the invention greatly improved yield, and gross mass yield is up to 50% or more.
4. zanamivir preparation method of the invention has apparent cost advantage and green syt advantage, production technology is more
Simply, more convenient operation is especially suitable for large-scale industrial production.
Specific embodiment
Provided hereinafter specific embodiments to further illustrate the present invention, but the present invention is not limited only to implementation below
Mode.
The present invention obtains important breakthrough in zanamivir preparation process, does on the basis of ZL96107757.3 patent
Go out substantial improvement, the prior art is straight by three step synthetic routes of cyclocomplex (III)-(IIa)-(IIb)-(II)
It connects and is replaced by (III)-(II) one-step synthesis, specifically obtain acetylation with metal amino object processing cyclocomplex (formula III) step
The amino-compound (Formula II) of protection, reaction equation is as follows:
Wherein, the M in Formula II indicates Na, K or Ca.
The present invention provides a kind of preparation methods of zanamivir (Formulas I), with sialic acid, i.e. N-acetyl-neuraminate (formula
V) sialic acid (formula IV) with protecting group is obtained by the radical protection to hydroxyl and carboxyl for raw material；It carries out being cyclized again anti-
It answers, generates cyclocomplex (formula III)；Cyclocomplex (formula III) is handled with metal amino object, a direct step obtains the ammonia of acetylation protection
Based compound (Formula II)；Hydroxy-protecting agent acetic acid esters is sloughed again, obtains 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate (formula
Ia)；Croak base is finally reacted with guanylpyrazole, obtains zanamivir (Formulas I).Specific synthetic route is as follows:
Wherein, the M in Formula II indicates Na, K or Ca.
Zanamivir preparation method of the invention is described in detail below:
(1) sialic acid (formula IV) of anamorphic zone protecting group
Sialic acid (Formula V) is by the radical protection to hydroxyl and carboxyl, the sialic acid (formula IV) of anamorphic zone protecting group.
By sialic acid (Formula V), methanol, strong acid ion exchange resin is stirred at room temperature 10-20 hours, until reaction solution
In the clear solution of dissolution；Filter out resin, concentration methanol is to dry；Pyridine is added, to dimethylamino naphthyridine (DMAP), ice water is cold
Lower that aceticanhydride is added, it is stirred at room temperature 10-16 hour, concentration pyridine is to doing；It is dissolved with ethyl acetate, is washed with water and washs repeatedly, it is dense
Contracting ethyl acetate obtains the sialic acid (formula IV) with protecting group to doing.The step yield about 98%.
Wherein, the mass ratio of sialic acid (Formula V) and methanol, strong acid ion exchange resin can be 1:8-12:0.01-
0.1。
Sialic acid (Formula V) and pyridine can be 1:8-12:0.01-0.05 to the mass ratio of dimethylamino naphthyridine (DMAP).
The mass ratio of sialic acid (Formula V) and aceticanhydride can be 1:1-3.
(2) cyclocomplex (formula III) is synthesized
Sialic acid (formula IV) with protecting group carries out cyclization, synthesizes cyclocomplex (formula III).
Into the ethyl acetate solution of the sialic acid (formula IV) with protecting group, Trimethylsilyl trifluoromethanesulfonate is added dropwise
(TMSOTS), 40-50 DEG C reaction 5-6 hours；Add water quenching reaction；Stirring 30 minutes or so, branch vibration layer are added water and wash again
It washs primary；Ethyl acetate is concentrated to doing, obtains cyclocomplex (formula III).The step yield about 90%.
Wherein, the mass ratio of the sialic acid with protecting group (formula IV) and ethyl acetate can be 1:2-8.
The mass ratio of sialic acid (formula IV) with protecting group and Trimethylsilyl trifluoromethanesulfonate (TMSOTS) can be 1:
0.4-0.8。
The water of addition is quenched to be advisable with 0.5-1 times of sialic acid (formula IV) quality with protecting group.
(3) amino-compound (Formula II) of synthesis acetylation protection
Cyclocomplex (formula III) is handled with metal amino object, the amino-compound (Formula II) of synthesis acetylation protection.
To the organic solvents such as anhydrous tetrahydro furan or toluene are added in cyclocomplex (formula III), it is slowly added to metal amino object,
Stirring, heating, reacts 6-8 hours under the reflux temperature of organic solvent；Add water quenching reaction；Solvent such as acetic acid is added in concentration
Ethyl ester dissolution is washed with water repeatedly, and concentrated solvent is to dry；It is recrystallized, is filtered with alcohol such as isopropanol etc., drying obtains acetylation
The amino-compound (Formula II) of protection.The step yield about 95%
Wherein, metal amino object is usually at least one of Sodamide, amino calcium or potassamide.Cyclocomplex (formula III)
It can be 1:0.05-0.5 with the mass ratio of metal amino object.
The amount for dissolving the organic solvent of cyclocomplex (formula III) can be 2-10 times of cyclocomplex (formula III) quality.
The water of addition is quenched to be advisable with 0.5-1 times of cyclocomplex (formula III) quality.
The isopropanol of recrystallization is usually 4-6 times of cyclocomplex (formula III) quality.
(4) bis- dehydrogenation -4- amino of 2,3--N-acetyl-neuraminate (Formulas I a) is synthesized
The amino-compound (Formula II) of acetylation protection sloughs hydroxy-protecting agent acetic acid esters, synthesizes 2,3-, bis- dehydrogenation -4- ammonia
Base-N-acetyl-neuraminate (Formulas I a).
The amino-compound (Formula II) that acetylation is protected is added in suitable quantity of water, the hydroxide of concentration about 10wt% is added dropwise
Reaction is stirred at room temperature in sodium solution, and the pH value for controlling reaction end is 10-11；Addition acid-exchange resin tune PH is 4-5；
Recrystallisation from isopropanol is added to doing in condensed water；Filtering, drying, obtains 2,3-, bis- dehydrogenation -4- amino-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) reacts croak base with guanylpyrazole to 2,3- bis- dehydrogenation -4- amino-N-acetyl-neuraminate, synthesizes Zha Na meter
Wei (Formulas I).
By 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate, (Formulas I a) is added in suitable quantity of water, sodium carbonate is added, so
Guanylpyrazole hydrochloride is added afterwards；It is reacted 6-8 hours at 30-40 DEG C；Half water or so is fallen in concentration, and isopropanol is added (about
10 times or so of 2,3- bis- dehydrogenation -4- amino-N-acetyl-neuraminate quality), solid powder is precipitated in stirring；Filtering, isopropanol
Washing, drying obtain zanamivir crude product, then are recrystallized by isopropanol-water, filtered, and drying obtains the Zha Na meter of pharmaceutical grade
Wei (Formulas I).The step yield about 70-80%.
Wherein, (mass ratio of Formulas I a) and sodium carbonate can be 1:1- to 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate
1.5。
(Formulas I a) and the mass ratio of guanylpyrazole hydrochloride can be N-acetyl-neuraminate bis- dehydrogenation -4- amino of 2,3- -
1:0.5-0.6.
The zanamivir of above method preparation, through detecting, product purity is greater than 99.0%, and single contaminant is less than 0.1%, symbol
Close pharmaceutical grade requirement.The gross mass yield of above five step can reach 50% or more.
The present invention is further elaborated combined with specific embodiments below, but the present invention is not limited to following embodiments.
Above and experimental method used in following embodiments is conventional method unless otherwise specified.
Above and the materials, reagents and the like used in the following examples, be commercially available unless otherwise specified or
It is prepared with known conventional method.
Embodiment 1
Synthesize the amino-compound (Formula II) of acetylation protection
Cyclocomplex (formula III) 120g is added 1200g anhydrous tetrahydro furan, is slowly added to 20g potassamide.Stirring, heating,
It is reacted 7 hours under tetrahydrofuran reflux temperature.80g water quenching reaction is added.Concentration is added ethyl acetate dissolution, uses every time
Three times, concentration ethyl acetate is to dry for 300g water washing.It with 550g recrystallisation from isopropanol, filters, drying, obtains acetylation protection
Amino-compound (Formula II) 123g.Yield: 93.1%.
Embodiment 2
(1) sialic acid (formula IV) of anamorphic zone protecting group
Sialic acid (Formula V) 100g, methanol 1000g, strong acid ion exchange resin 5g；It stirs 12 hours at room temperature, reaction
Liquid is in the clear solution of dissolution.HPLC detection, sialic acid normalization method content are 1.2%.Filtering, filtrate are concentrated methanol to doing, obtain
To methyl esters sialic acid.
Pyridine 1000g is added, to dimethylamino naphthyridine (DMAP) 3g, the cooling lower addition aceticanhydride 250g of ice water.It is stirred at room temperature
15 hours.HPLC detection, methyl esters sialic acid normalization method content are 0.3%.Pyridine is concentrated to dry.It is dissolved with 1000g ethyl acetate,
Every time three times with 300g water washing, concentration ethyl acetate is to dry.Obtain sialic acid (formula IV) 169g with protecting group.Yield:
97.9%.
(2) cyclocomplex (formula III) is synthesized
Trimethylsilyl trifluoromethanesulfonate is added dropwise in sialic acid (formula IV) 169g, ethyl acetate 1000g with protecting group
(TMSOTS) 80g, 45 DEG C are reacted 6 hours.85g water quenching reaction is added.500g water is added again in stirring 30 minutes, branch vibration layer
It washed once.Ethyl acetate is concentrated to dry.Obtain cyclocomplex (formula III) 117g.Yield 89.3%.
(3) amino-compound (Formula II) of synthesis acetylation protection
Cyclocomplex (formula III) 117g is added 1170g anhydrous tetrahydro furan, is slowly added to 15g Sodamide.Stirring, heating,
It is reacted 6 hours under tetrahydrofuran reflux temperature.80g water quenching reaction is added.Concentration is added ethyl acetate dissolution, uses every time
Three times, concentration ethyl acetate is to dry for 300g water washing.It with 585g recrystallisation from isopropanol, filters, drying.Obtain acetylation protection
Amino-compound (Formula II) 118g.Yield: 95.2%.
(4) bis- dehydrogenation -4- amino of 2,3--N-acetyl-neuraminate (Formulas I a) is synthesized
Amino-compound (Formula II) 118g of acetylation protection, is added in 1180g water, and it is molten that 10wt% sodium hydroxide is added dropwise
Reaction is stirred at room temperature in liquid, and side border ring detects the pH value of reaction solution, and the pH value for controlling reaction end is 10-11.Be added it is acid from
Sub-exchange resin tune PH is 4-5.710g recrystallisation from isopropanol is added to doing in condensed water.Filtering, drying, obtains 2,3-, bis- dehydrogenation-
4- amino-N-acetyl-neuraminate (Formulas I a) 66g.Yield: 84.5%
(5) zanamivir (Formulas I) is synthesized
(Formulas I a) 66g, is added in 660g water 2,3- bis- dehydrogenation -4- amino-N-acetyl-neuraminate, and sodium carbonate is added
Then guanylpyrazole hydrochloride 36g is added in 66g.It is reacted 7 hours at 35 DEG C.330g water is fallen in concentration, and 660g isopropanol is added,
Solid powder is precipitated in stirring.Filtering, isopropanol washing, drying obtain zanamivir crude product 67g.Pass through isopropanol-water weight again
Crystallization is filtered, and drying obtains zanamivir (Formulas I) 55g of pharmaceutical grade.Yield: 72.8%
HPLC analysis, the zanamivir purity being prepared are greater than 99.2%, and single contaminant is less than 0.1%.According to starting
Raw material sialic acid calculates, and the total mass yield of zanamivir is 55%.
Embodiment 3
(1) sialic acid (formula IV) of anamorphic zone protecting group
In 30L glass reaction kettle, sialic acid (Formula V) 2kg, methanol 20kg, strong acid ion exchange resin 100g is added；
It stirs 10 hours at room temperature, reaction solution is in the clear solution of dissolution.HPLC detection, sialic acid normalization method content are 1.0%.It crosses
Filter, filtrate are transferred to 30L glass reaction kettle, and concentration methanol obtains methyl esters sialic acid to doing.
Pyridine 20kg is added, to dimethylamino naphthyridine (DMAP) 80g, the cooling lower addition aceticanhydride 5kg of ice water.It is stirred at room temperature 15
Hour.HPLC detection, methyl esters sialic acid normalization method content are 0.3%.Pyridine is concentrated to dry.The dissolution of 20kg ethyl acetate is added,
Every time three times with 6L water washing, concentration ethyl acetate is to dry.Obtain sialic acid (formula IV) 3.4kg with protecting group.Yield:
98.6%.
(2) cyclocomplex (formula III) is synthesized
In 30L glass reaction kettle, sialic acid (formula IV) 3.4kg, ethyl acetate 20kg with protecting group is added, is added dropwise three
Fluorine methanesulfonic acid trimethylsilyl group (TMSOTS) 1.6kg, 40 DEG C are reacted 5 hours.1.8kg water quenching reaction is added.Stirring 30 minutes,
Branch vibration layer, 5kg water is added washed once again.Ethyl acetate is concentrated to dry.Obtain cyclocomplex (formula III) 2.4kg.Yield
90.1%.
(3) amino-compound (Formula II) of synthesis acetylation protection
In 30L glass reaction kettle, cyclocomplex (formula III) 2.4kg is added, 20kg anhydrous tetrahydro furan is added, slowly adds
Enter 150g amino calcium.Stirring, heating, reacts 8 hours under tetrahydrofuran reflux temperature.1.7kg water quenching reaction is added.It is dense
The dissolution of 20kg ethyl acetate is added in contracting, and every time three times with 6kg water washing, concentration ethyl acetate is to dry.It is tied again with 10kg isopropanol
Crystalline substance filters, drying.Obtain amino-compound (Formula II) 2.4kg of acetylation protection.Yield: 94.5%.
(4) bis- dehydrogenation -4- amino of 2,3--N-acetyl-neuraminate (Formulas I a) is synthesized
In 30L glass reaction kettle, amino-compound (Formula II) 2.4kg of acetylation protection is added, 20kg water, drop is added
Add 10wt% sodium hydroxide solution, reaction is stirred at room temperature, side border ring detects the pH value of reaction solution, controls the pH value of reaction end
For 10-11.Addition acid-exchange resin tune PH is 4-5.12kg recrystallisation from isopropanol is added to doing in condensed water.Filtering is dried
It is dry, obtain 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate (Formulas I a) 1.4kg.Yield: 86.3%
(5) zanamivir
In 30L glass reaction kettle, 2,3-, bis- dehydrogenation -4- amino-is added, and (Formulas I a) 1.4kg, adds N-acetyl-neuraminate
Enter to 15kg water, sodium carbonate 1.3kg is added, guanylpyrazole hydrochloride 800g is then added.It is reacted 6 hours at 40 DEG C.Concentration
Fall 8kg water, 13kg isopropanol is added, solid powder is precipitated in stirring.It is thick to obtain zanamivir for filtering, isopropanol washing, drying
Product 67g.It is recrystallized, is filtered by isopropanol-water again, drying obtains zanamivir (Formulas I) 1.2kg of pharmaceutical grade.Yield:
74.9%
HPLC analysis, the zanamivir purity being prepared are 99.6%, and single contaminant is less than 0.1%.It is former according to starting
Expect that sialic acid calculates, the total mass yield of zanamivir is 60%.
The above is only specific application examples of the invention, are not limited in any way to protection scope of the present invention.All uses
Equivalent transformation or equivalent replacement and the technical solution formed, all fall within rights protection scope of the present invention.
Claims (10)
1. a kind of preparation method of the amino-compound (Formula II) of zanamivir intermediate acetylization protection, comprising: use metal ammonia
Substratess are reacted with cyclocomplex (formula III), obtain the amino-compound (Formula II) of acetylation protection；Wherein, metal amino object is ammonia
At least one of base sodium, amino calcium or potassamide
Wherein, the M in (Formula II) indicates Na, K or Ca.
2. method as claimed in claim 1, comprising: metal amino object is added into the organic solvent solution of cyclocomplex (formula III), adds
Heat is reacted 6-8 hours, quenching reaction under organic solvent reflux temperature, concentration, solvent dissolution is added, washing, concentrated solvent is extremely
It is dry, it recrystallizes, filters, drying obtains the amino-compound (Formula II) of acetylation protection.
3. such as according to the method for claims 1 or 2, wherein the mass ratio of cyclocomplex (formula III) and metal amino object is 1:0.05-
0.5。
4. a kind of preparation method of zanamivir (Formulas I), comprising: protected with method preparation acetylation any in claim 1-3
The amino-compound (Formula II) that acetylation obtained is protected is sloughed hydroxy-protecting agent acetic acid by the amino-compound (Formula II) of shield
Ester, then reacted with guanylpyrazole, obtain zanamivir (Formulas I)
Wherein, the M in (Formula II) indicates Na, K or Ca.
5. a kind of preparation method of zanamivir (Formulas I), comprising:
(a) sialic acid (Formula V) generates the sialic acid (formula IV) with protecting group by the radical protection to hydroxyl and carboxyl；
(b) sialic acid with protecting group (formula IV) carries out cyclization, generates cyclocomplex (formula III)；
(c) cyclocomplex (formula III) is reacted with metal amino object, generates the amino-compound (Formula II) of acetylation protection, wherein gold
Belonging to amino substance is at least one of Sodamide, amino calcium or potassamide；
Wherein, the M in (Formula II) indicates Na, K or Ca
(d) amino-compound (Formula II) of acetylation protection sloughs hydroxy-protecting agent acetic acid esters, generates 2,3-, bis- dehydrogenation -4- ammonia
Base-N-acetyl-neuraminate (Formulas I a)；
Wherein, the M in (Formula II) indicates Na, K or Ca
(e) (Formulas I a) and guanylpyrazole hydrochloric acid reactant salt, obtain Zha Na meter to 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate
Wei (Formulas I)
6. method as claimed in claim 5, comprising:
(a) by sialic acid (Formula V), methanol, strong acid ion exchange resin is stirred at room temperature 10-20 hours, until reaction solution is in
Clear solution is dissolved, filters out resin, concentration methanol is to dry；Pyridine is added, to dimethylamino naphthyridine, the cooling lower addition of ice water
Aceticanhydride is stirred at room temperature 10-16 hours, and concentration pyridine is to dry；It is dissolved, is washed with ethyl acetate, concentration ethyl acetate is obtained to doing
Sialic acid (formula IV) with protecting group；
(b) into the ethyl acetate solution of the sialic acid (formula IV) with protecting group, Trimethylsilyl trifluoromethanesulfonate is added dropwise,
40-50 DEG C reaction 5-6 hours；Add water quenching reaction；Stirring, branch vibration layer, washing, concentration ethyl acetate obtain cyclization to doing
Object (formula III)；
(c) metal amino object, heating, in organic solvent reflux temperature are added into the organic solvent solution of cyclocomplex (formula III)
Solvent dissolution, washing is added in lower reaction 6-8 hours, quenching reaction, concentration, and concentrated solvent is recrystallized to doing, filtered, drying,
Obtain the amino-compound (Formula II) of acetylation protection；
(d) amino-compound (Formula II) for protecting acetylation, is added in suitable quantity of water, and sodium hydroxide solution is added dropwise, and room temperature is stirred
Reaction is mixed, the pH value for controlling reaction end is 10-11, and addition acid-exchange resin tune pH is 4-5, and condensed water adds to doing
Enter recrystallisation from isopropanol, filter, drying obtains 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate (Formulas I a)；
(e) by 2,3-, bis- dehydrogenation -4- amino-N-acetyl-neuraminate, (Formulas I a), is added in suitable quantity of water, sodium carbonate is added, so
Guanylpyrazole hydrochloride is added afterwards, is reacted 6-8 hours at 30-40 DEG C；Part water is fallen in concentration, and isopropanol is added, and stirs, and is precipitated
Solid powder, filtering, isopropanol washing, drying obtain zanamivir crude product, then are recrystallized by isopropanol-water, filter, dry
It is dry, obtain the zanamivir of pharmaceutical grade.
7. method as claimed in claim 6, wherein in step (a), sialic acid (Formula V) and methanol, strong acid ion exchange resin
Mass ratio is 1:8-12:0.01-0.1；Sialic acid (Formula V) and pyridine are 1:8-12 to the mass ratio of dimethylamino naphthyridine:
0.01-0.05；The mass ratio of sialic acid (Formula V) and aceticanhydride is 1:1-3.
8. method as claimed in claim 6, wherein in step (b), the quality of sialic acid (formula IV) and ethyl acetate with protecting group
Than being 1:2-8；Sialic acid (formula IV) with protecting group and the mass ratio of Trimethylsilyl trifluoromethanesulfonate are 1:0.4-0.8.
9. such as the method for claim 5 or 6, wherein in step (c), cyclocomplex (formula III) and the mass ratio of metal amino object are
1:0.05-0.5.
10. method as claimed in claim 6, wherein 2,3- bis- dehydrogenation -4- amino-N-acetyl-neuraminate (Formulas I a) and sodium carbonate
Mass ratio be 1:1-1.5；Bis- dehydrogenation -4- amino of the 2,3--N-acetyl-neuraminate (matter of Formulas I a) and guanylpyrazole hydrochloride
Measuring ratio is 1:0.5-0.6.
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