A kind of preparation method of La Nina meter Wei monooctyl esterTechnical field
The present invention relates to the method for the neuraminic acid derivatives preparing neuraminic acid enzyme inhibition activity, and relate to synthetic intermediate and their preparation method of neuraminic acid derivatives.In addition, the present invention relates to there is highly purified neuraminic acid derivatives.
Background technology
In numerous viral infection disease, influenza is one of communicable disease that maximum, the pathogenic region of pathogenic number is the widest and lethality rate is the highest.The influenza caused by influenza virus is a kind of respiratory infection diseases.In April, 2009, the Influenza A H1N1 of outburst allowed the whole world shroud under haze especially.As can be seen here, influenza as a kind of viral infectious not only serious threat public health, and give country and society bring heavy economical load.Therefore, the research and development of Tamiflu become the study hotspot of people.
The resistance report of existing anti-influenza virus medicament is in recent years on the increase, and the danger of the global great outburst of novel influenza grows with each passing day.And existing anti-influenza virus medicament exists compliance problem, mostly need repeatedly to take medicine until fully recover.Under this background, for influenza infection disease, seek new therapy approach and scheme, make every effort to release the original intention only needing single-dose can reach therapeutic purpose medicine new drug development staff development this product just.
Long-acting selective neuraminidase (neuramidinase, NA) inhibitor/anti-influenza virus medicament plays an important role in influenza virus reproduction process.La Nina meter Wei monooctyl ester is the long-acting neuraminidase inhibitor of s-generation induction type, be used for the treatment of the infection symptoms caused with flu-prevention virus, in September, 2010 goes on the market in Japan first, also be the first pure domestic anti-influenza virus medicament of Japan, to all effective to the A type of adult, Type B influenza infection disease patient from children, and also effective to oseltamivir drug-resistant viral (A/H1N1).La Nina meter Wei monooctyl ester has the feature not available for existing anti-influenza virus medicament---inhalation, the medicine influenza viruses such as air flue that go directly copy objective, be distributed in these regions and give full play to drug effect, and rest on for a long time these regions be conducive to continue play drug effect; Another feature is single-dose, and compared with existing medicine, only need single-dose namely to demonstrate the equal curative effect of continuous 5d administration with oseltamivir, reach therapeutic purpose, this also becomes the maximum bright spot of this product.The appearance of La Nina meter Wei monooctyl ester, for treatment of influenza from now on provides a new selection scheme.
About the report of La Nina meter Wei monooctyl ester synthetic route a lot (1. Chinese pharmaceutical chemistry magazine, 2012,22 (4): 294-301. in document; 2. drug evaluation research, 2011,34 (2): 144-151.), sum up, mainly contain 2 thinkings.
Route one: using N-acetyl-neuraminate as starting raw material, through over-churning, acidylate, Cheng Huan, deprotection, protection, azide, methylate and hydrolysis etc. 13 steps reaction preparation La Nina meter Wei monooctyl esters, total recovery is that 16%(is shown in Fig. 1).This route is long, and yield is low, uses the explosive reagent such as sodium hydride, cannot use in industrialized production.
Route two ~ tri-: amine (I) and N, N'-bis--tertbutyloxycarbonyl thiocarbamide (II), under mercury chloride and triethylamine effect, condensation reaction occur; Or amine (1) and two-tertbutyloxycarbonyl-guanylpyrazole (III) obtain shielded guanidine derivative (IV) in tetrahydrofuran (THF) (THF) solution.Guanidine derivative (IV) is deacetylated under the effect of sodium methylate obtains compound (V); Meanwhile, guanidine derivative (IV), in the methanol solution of sodium hydroxide or salt of wormwood, obtains carboxylic acid (VI) by hydrolysis reaction.It is the result under diphenyl diazomethane and boron trifluoride ether solution acting in conjunction that acid (VI) changes into corresponding benzhydryl ester (VII).Benzhydryl ester (VII) in the basic conditions subsequently, reacts, the primary hydroxy group of selectively acylating with capryl(yl)chloride (VIII), 9-octanoate (Ⅸ) (see figure 2) obtained.Finally, react with trifluoroacetic acid and compound (Ⅸ), remove N-tertbutyloxycarbonyl and O-diphenyl-methyl, alkalize subsequently, reverse column chromatography obtains target product simultaneously.
Route four ~ five: or amino-5, the 6-dihydropyran derivatives (X) of 4-are obtained by reacting intermediate 4-guanidine radicals dihydropyrane with two-tertbutyloxycarbonyl-guanylpyrazole (III), and the latter is hydrolyzed and obtains carboxylic acid (VI) in the methanol aqueous solution of salt of wormwood.In other route, the preparation of carboxylic acid (VI) is with amino-5, the 6-dihydroxyl pyrans carboxylicesterss (Ⅹ) of sodium hydroxide hydrolysis 4-, and then is obtained by reacting with guanylpyrazole derivative (III).And stirring reaction deprotection obtains laninamivir(Ⅺ in the methanol solution of two-tertbutyloxycarbonyl intermediate (VI) at 80 DEG C), the latter in methanolic HCl solution with 1,1,1-trimethoxy octane optionally acidylate obtain target product.Laninamivir(Ⅺ) also can obtain in the following manner: the unhindered amina (Ⅹ III) that intermediate (X) obtains with sodium hydroxide hydrolysis, unhindered amina (Ⅹ III) is by reacting with pyrazoles-1-amitraz hydrochloride (Ⅹ IV), or it is also passable, 4-amino-5-2,6-dihydropyrane (X) and pyrazoles-1-amitraz hydrochloride (Ⅹ IV) react, and then under the effect of salt of wormwood, are hydrolyzed methyl esters (see figure 2).
From route two ~ five, we can see that reaction scheme is all very long, are substantially greater than 4 step reactions; Reaction conditions is violent, not easily manipulates; And starting material are not easily bought, the synthesis as starting raw material I need have passed through 7 step reactions; The technique multistep reported in document adopts column chromatography purification mode, complicated operation, and the usage quantity of organic solvent increases greatly, causes pollution to environment; In addition, also use the poisonous reagents such as mercury chloride in technological process, do not meet industrial requirement.
Summary of the invention
The object of the present invention is to provide a kind of method preparing La Nina meter Wei monooctyl ester, the method route is simple, cost is low, energy consumption is low, product purity is high and avoid the use of poisonous reagent and explosive reagent.
In order to achieve the above object, the invention provides following technical scheme: proceed step by step in same reactor or in multiple reactor, described reaction process is followed successively by (see Fig. 3):
1) by formula (15) compound zanamivir and methanol mixed, add acid positive resin simultaneously, after reaction, obtain formula (16) compound zanamivir methyl esters;
2) by formula (16) compound in the basic conditions, with dimethyl carbonate production (17) compound;
3) by formula (17) compound in the basic conditions with iodomethane reaction, obtain formula (18) compound;
4) formula (18) compound and alkali are reacted, then use acid positive resin adjust ph to neutral, obtain formula (19) compound;
5) by formula (19) compound in the basic conditions, react with capryl(yl)chloride, obtain target product formula (14) La Nina meter Wei monooctyl ester.
Reaction scheme is:
Wherein step 1) zanamivir formula (15) compound and methanol solution mixing, add acid positive resin, reaction conditions is normal pressure, and temperature is room temperature ~ 70 DEG C, and the reaction times is 10 ~ 72 hours, and preferable reaction temperature is room temperature, and the reaction times is 30 hours; Wherein the weight ratio of zanamivir and methyl alcohol and the positive resin of acidity is: 1.0: 20 ~ 100: 0.3 ~ 1.0; The weight ratio of preferred zanamivir and methyl alcohol and the positive resin of acidity is: 1.0: 50: 0.5; The positive resin of wherein said acidity is selected from Dowex50 (H+) or Bio-Rad (H+); The positive resin of preferred acidic is: Dowex50 (H+).
Wherein step 2) in formula (16) compound added organic solvent mixing, then add the methanol solution of methylcarbonate, sodium methylate respectively, by mixed solution heating reflux reaction 4 ~ 8 hours, preferably 5 hours reaction times; The mol ratio of its Chinese style (16) compound and methylcarbonate and sodium methylate is: 1: 1.1 ~ 5.0: 0.01 ~ 0.1; The mol ratio of preferred formula (16) compound and methylcarbonate and sodium methylate is: 1: 2.5: 0.02; Described temperature of reaction is 50 ~ 100 DEG C, is preferably 80 DEG C; Wherein said organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol etc., preferred toluene.
Wherein in step 3), formula (17) compound is added in organic solvent, stirring 10 ~ 30 minutes under low temperature and under the existence of alkali, preferably 15 minutes; Then 35 ~ 60 hours are reacted with methyl iodide room temperature lucifuge, preferably 45 hours; Described organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol etc., preferred DMF; Described low temperature is-10 ~ 10 DEG C, preferably 0 DEG C; Described alkali is selected from the one such as oxyhydroxide, carbonate, organic or inorganic aminated compounds, Pyrrolidine, piperidines, morpholine, piperazine or its combination, preferred barium hydroxide octahydrate and barium oxide; The mol ratio of its Chinese style (17) compound and alkali is: 1: 3 ~ 10; Wherein compound 17 with the mol ratio of barium hydroxide octahydrate and barium oxide and methyl iodide is: 1: 0.1 ~ 0.5: 3 ~ 10: 10 ~ 20, and preferred molar ratio is 1: 0.2: 4: 15.
Wherein in step 4), formula (18) compound is added in organic solvent, adds basic solution simultaneously, stirred at ambient temperature reaction 10 ~ 30 hours, preferably 24 hours; After completion of the reaction, add acid positive resin adjust ph 7 ~ 9, preferred pH is 8; The mol ratio of formula (18) compound and alkali is: 1: 2 ~ 5, preferred molar ratio 1: 3; Described organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol etc., particular methanol; Described basic solution is selected from the one such as oxyhydroxide, carbonate, organic or inorganic aminated compounds, Pyrrolidine, piperidines, morpholine, piperazine or its combination, preferred sodium hydroxide; The positive resin of described acidity is selected from Dowex50 (H+) or Bio-Rad (H+); The positive resin of preferred acidic is: Dowex50 (H+), now preferable reaction temperature is room temperature.
Wherein step 5) reaction is under protection of inert gas, and at the temperature of-10 ~ 15 DEG C, added in organic solvent by formula (19) compound, then mix with alkali, then add capryl(yl)chloride, temperature rises to room temperature reaction 15 ~ 40 hours, and the preferred reaction time is 24 hours; React complete, add alkali adjust ph to neutral; The mol ratio of its Chinese style (19) compound and alkali and capryl(yl)chloride is: 1: 1.1 ~ 3.0: 1.0 ~ 1.5, preferably 1: 2: 1; Wherein said rare gas element is nitrogen, argon gas; Described alkali is selected from the one such as oxyhydroxide, carbonate, organic or inorganic aminated compounds, Pyrrolidine, piperidines, morpholine, piperazine or its combination, is preferably triethylamine; Described organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol etc., particular methanol.
Positively effect of the present invention is, is raw materials usedly easy to get, and in the process of preparation La Nina meter Wei monooctyl ester, intermediate and end product quality easily control, and product yield is higher, and total recovery is about 50%; Purity is higher, is easy to separation and purification; And the equal recoverable of organic solvent that the present invention is used, reduce costs; Use without special, toxic reagent, be conducive to environmental protection; Atmospheric operation in building-up process, reaction conditions is gentle, and technique is simple and direct, and equipment is simple, and cost is low, is easy to industrialized production.
Improvement for conventional preparation techniques is mainly reflected in:
1) avoid the use of poisonous reagent and explosive reagent, improve the feasibility of test.
In the preparation process of product formula (17) compound, adopt the structure of 2-oxo-1,3-dioxolanes to replace the acetal of document or the structure of cyclic ethers to protect 8, the hydroxyl of 9, avoids the use of the unstable reagent such as Methanesulfonyl chloride;
The synthesis of product formula (18) compound, has done very large change compared with document: adopt methyl iodide as methylating reagent, has avoided the use of the severe toxicity such as methyl-sulfate and sodium hydride and explosive reagent, greatly improve the feasibility of experiment;
2) change purification process, reduce the use of organic solvent, reduce environmental pollution.
The compound related in the present invention's research all adopts the method for recrystallization, instead of the column chromatography for separation of bibliographical information, simple, convenient, quick, reproducible, decrease the pollution to environment while reducing organic solvent usage quantity, be applicable to industrial a large amount of manufacture.
Accompanying drawing explanation
Fig. 1 is using N-acetyl-neuraminate as initial preparation La Nina meter Wei monooctyl ester reacting flow chart.
Fig. 2 is for initial preparation La Nina meter Wei monooctyl ester reacting flow chart with amine and N, N'-bis--tertbutyloxycarbonyl thiocarbamide (II).
Fig. 3 is that the present invention prepares La Nina meter Wei monooctyl ester reacting flow chart.
Embodiment
Now in conjunction with the embodiments, the invention will be further described.In embodiment, various chemical used and reagent are commercially available purchase if no special instructions.
The preparation of embodiment 1 La Nina meter Wei monooctyl ester
The synthesis of formula 16 compound zanamivir methyl esters
In 20L reactor, zanamivir (109.7g, 0.33mol) and 6.9L methanol mixed are obtained suspension.In suspension, add acid positive resin be selected from Dowex50 (H+) (55g), react 30 hours under room temperature; Complete, cross and filter resin, with methanol wash (0.1L × 2), filtrate is concentrated obtains off-white color solid, i.e. compound 16, yield 98.1%.
The synthesis of formula 17 compound
By formula 16 compound (103.8g under room temperature, 0.30mol) mix with toluene (300ml), then add methylcarbonate (63.2ml) respectively, the methanol solution (0.3ml) of sodium methylate, mixed solution is heated to 80 DEG C, back flow reaction 5 hours; React complete, be cooled to 0 DEG C, stir 15 minutes, leave standstill crystallization, filter, toluene (50ml × 2) washs, and obtains faint yellow to yellow solid formula 17 compound, yield 85.4%.
The synthesis of formula 18 compound
Formula 17 compound (111.6g is added in 2L tri-neck reaction flask, 0.30mol) and N, N-diformamide (1080ml) mixes, Ba (OH) 2.8H2O (18.9g is added at 0 DEG C, 0.06mol) with BaO (183.6g, 1.20mol), mix and blend, after 15 minutes, adds methyl iodide (280.3ml).Room temperature lucifuge reacts 45 hours, react complete, with ethyl acetate (1.5L × 2) and 5% salt solution (0.5L), it is extracted, collect organic phase, with anhydrous sodium sulfate drying, be evaporated to 200mL, spend the night at being placed on-10 ~-5 DEG C, crystallization off-white color to faint yellow solid formula 18 compound, productive rate 76.3%.
The synthesis of formula 19 compound
By formula 18 compound (154.5g, 0.40mol) be dissolved in 3L methyl alcohol, then add sodium hydroxide (48g, 1.20mol), at room temperature stir 24 hours, TLC (plate layer chromatography) detection reaction is complete, then adds acid positive resin and is selected from Dowex50 (H+), regulates pH=8, filter, concentrated, obtain white to off-white color solid type 19 compound, productive rate 95.0%.
The synthesis of formula 14 compound
Argon shield borehole cooling is to-5 ~ 5 DEG C, by Formula 19 compound (138.5g, 0.40mol) be added in 5L reactor, add 2L methyl alcohol simultaneously, then triethylamine (111.0ml is added respectively, 0.80mol) with capryl(yl)chloride (60.2g, 0.40mol) mix, mixture at room temperature stirring reaction 24 hours, after, add ethyl acetate (2.5L), add 5% sodium bicarbonate (0.5L × 2) more respectively and saturated aqueous common salt (1.0L) washs organic layer, collect organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, dry, obtain white to off-white color solid type 14 compound, productive rate 84.8%.
The preparation of embodiment 2 La Nina meter Wei monooctyl ester
The synthesis of formula 16 compound
In 20L reactor, zanamivir (36.6g, 0.11mol) and 0.92L methanol mixed are obtained suspension.In suspension, add acid positive resin be selected from Bio-Rad (H+) (11.0g), react 10 hours under room temperature; Complete, cross and filter resin, with methanol wash (30mL × 2), filtrate is concentrated obtains off-white color solid, i.e. formula 16 compound, yield 90.6%.
The synthesis of formula 17 compound
By formula 16 compound (34.6g under room temperature, 0.10mol) mix with tetrahydrofuran (THF) (100ml), then methylcarbonate (9.3ml) is added respectively, the methanol solution (0.06ml) of sodium methylate, mixed solution is heated to 50 DEG C, back flow reaction 4 hours; React complete, be cooled to 0 DEG C, stir 20 minutes, leave standstill crystallization, filter, toluene (15ml × 2) washs, and obtains faint yellow to yellow solid formula 17 compound, yield 73.8%.
The synthesis of formula 18 compound
Formula 17 compound (37.2g is added in 2L tri-neck reaction flask, 0.10mol) mix with methyl-sulphoxide (360ml), add NaOH (12g, 0.30mol) mix and blend at-10 DEG C after 10 minutes, add methyl iodide (62.3ml).Room temperature lucifuge reacts 35 hours, react complete, with ethyl acetate (0.5L × 2) and 5% salt solution (0.15L), it is extracted, collect organic phase, with anhydrous sodium sulfate drying, be evaporated to 60mL, spend the night at being placed on-10 ~-5 DEG C, crystallization off-white color to faint yellow solid formula 18 compound, yield 63.2%.
The synthesis of formula 19 compound
By formula 18 compound (51.5g, 0.13mol) be dissolved in 1L toluene, then add triethylamine (36.1ml, 0.26mol), at room temperature stir 10 hours, TLC (plate layer chromatography) detection reaction is complete, then adds acid positive resin and is selected from Bio-Rad (H+), regulates pH=7, filter, concentrated, obtain white to off-white color solid type 19 compound, productive rate 82.1%.
The synthesis of formula 14 compound
Nitrogen protection borehole cooling is to-10 ~ 0 DEG C, by formula 19 compound (46.2g, 0.13mol) be added in 2L reactor, add 0.67L methyl-sulphoxide simultaneously, then piperidines (14.1ml is added respectively, 0.14mol) with capryl(yl)chloride (19.6g, 0.13mol) mix, mixture at room temperature stirring reaction 15 hours, after, add ethyl acetate (0.8L), add 5% sodium bicarbonate (0.15L × 2) more respectively and saturated aqueous common salt (0.3L) washs organic layer, collect organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, dry, obtain white to off-white color solid type 14 compound, yield 76.5%.
The preparation of embodiment 3 La Nina meter Wei monooctyl ester
The synthesis of formula 16 compound
In 20L reactor, zanamivir (54.8g, 0.16mol) and 6.94L methanol mixed are obtained suspension.In suspension, add acid positive resin be selected from Dowex50 (H+) (54.8g), react 72 hours at 70 DEG C; Complete, cross and filter resin, with methanol wash (50mL × 2), filtrate is concentrated obtains off-white color solid, i.e. Formula 16 compound, yield 94.2%.
The synthesis of formula 17 compound
By formula 16 compound (51.9g under room temperature, 0.15mol) with 1,4-dioxane (150ml) mixes, then methylcarbonate (63.2ml) is added respectively, the methanol solution (0.8ml) of sodium methylate, mixed solution is heated to 100 DEG C, back flow reaction 8 hours; React complete, be cooled to 0 DEG C, stir 15 minutes, leave standstill crystallization, filter, toluene (25ml × 2) washs, and obtains faint yellow to yellow solid formula 17 compound, yield 73.8%.
The synthesis of formula 18 compound
Formula 17 compound (55.8g is added in 2L tri-neck reaction flask, 0.15mol) mix with Isosorbide-5-Nitrae-dioxane (540ml), at 10 DEG C, add piperidines (148.1ml, 1.5mol) mix and blend is after 30 minutes, adds methyl iodide (187ml).Room temperature lucifuge reacts 60 hours, react complete, with ethyl acetate (0.8L × 2) and 5% salt solution (0.25L), it is extracted, collect organic phase, with anhydrous sodium sulfate drying, be evaporated to 100mL, spend the night at being placed on-10 ~-5 DEG C, crystallization off-white color to faint yellow solid formula 18 compound, productive rate 68.3%.
The synthesis of formula 19 compound
By formula 18 compound (77.3g, 0.20mol) be dissolved in 1.5L tetrahydrofuran (THF), then add salt of wormwood (138.0g, 1.0mol), at room temperature stir 30 hours, TLC (plate layer chromatography) detection reaction is complete, then adds acid positive resin and is selected from Dowex50 (H+), regulates pH=9, filter, concentrated, obtain white to off-white color solid type 19 compound, productive rate 88.6%.
The synthesis of formula 14 compound
Argon shield borehole cooling to 5 ~ 15 DEG C, by formula 19 compound (69.3g, 0.20mol) be added in 3L reactor, add 1L toluene simultaneously, then triethylamine (83.3ml is added respectively, 0.6mol) with capryl(yl)chloride (49.7g, 0.3mol) mix, mixture at room temperature stirring reaction 40 hours, after, add ethyl acetate (1.2L), add 5% sodium bicarbonate (0.25L × 2) more respectively and saturated aqueous common salt (0.5L) washs organic layer, collect organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, dry, obtain white to off-white color solid type 14 compound, productive rate 80.1%.