CN1986521A - Synthesis process of peramivir as medicine for antagonizing influenza and bird flu virus - Google Patents
Synthesis process of peramivir as medicine for antagonizing influenza and bird flu virus Download PDFInfo
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Abstract
The present invention relates to medicine compound, and discloses synthesis process of peramivir as medicine for antagonizing influenza and bird flu virus. The present invention synthesizes peramivir with Wins lactam and 2-ethyl butyl aldehyde as main materials and through an eight-step process. The preparation process of the present invention is simple, cheap in material and environment friendly, and has high yield, including single step reaction yield of 80-95 % and total yield up to 52.7 %.
Description
Technical field
The present invention relates to the medical compounds field, specifically, relate to the synthetic method of a kind of anti influenza and avian influenza cytotoxic drug Peramivir.
Background technology
Peramivir, English name is peramivir, chemical name is (±)-t-3-(1`-acetamido-2`-ethyl) butyl-c-4-guanidine radicals-t-2-hydroxycyclopent base-1-carboxylic acid, structure is a kind of cyclopentane derivatives class neuraminidase inhibitor of being developed jointly by U.S. BioCryst Pharmaceuticals company and R.W.Johnson institute of materia medica suc as formula (I).This medicine can effectively suppress duplicating and communication process of various strains of influenza viruses, has advantages such as better tolerance, toxicity be little, is a kind of very promising anti influenza chemotherapeutics.
The synthesis preparation method of current Peramivir mainly contains the patent (International Patent Application PCT/US98126871,17Dec, 1998.WO99/33781,08 July, 1999) of BioCryst Pharmaceuticals company.
The chemical equation of BioCryst Pharmaceuticals house journal method is as follows:
This method is to utilize this lactan of literary composition to be raw material, obtain end product through the reaction that reaches ten multisteps, not only step is long, productive rate low (overall yield less than 30%), and in the catalytic hydrogenation process, use expensive platinum dioxide to make catalyzer, when the preparation aldoxime, used hypertoxic benzene cyanogen, and make solvent with benzene, and with high costs, the environmental requirement height, operation easier is big, is unsuitable for suitability for industrialized production.
Summary of the invention
The objective of the invention is to overcome the problem that exists in the existing Peramivir synthetic method, provide a kind of step simple, with low cost, the Peramivir synthetic method of safety and environmental protection.
To achieve these goals, the present invention adopts following synthetic method:
Concrete steps are as follows:
1. this lactan of literary composition is dissolved in the anhydrous methanol, continue logical exsiccant HCl gas 2 hours then under the room temperature, reheat to 45 ℃ stirring 1 hour.Reacting completely, the back concentrates, crystallization, filtration, the dry white solid that gets.This solid is the hydrochloride of (±)-cis-4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester.
2. with (±)-cis-4-amino cyclopentyl-2-alkene-hydrochloride of 1-carboxylate methyl ester, NaHCO
3, BOC
2The mixture of O is put in the methylene dichloride, and mol ratio is 1: 0.5～2: 1～1.5.Stirring at room 3 hours.There was gas to discharge in reacting.Reaction is finished, and organic layer is washed successively, saturated common salt washing, anhydrous Na
2SO
4Dry.After steaming solvent, get oily matter.With normal hexane: the mixing solutions recrystallization of ethyl acetate=95: 5, white crystal product (±)-uncle's cis-4-fourth oxygen carboxamide basic ring penta-2-alkene-1-carboxylate methyl ester.
Oxammonium hydrochloride salt and salt of wormwood is soluble in water 3., wait no longer include bubble and produce after, slowly drip ethanol (99%) solution of 2-ethyl butyraldehyde under the ice bath.After dropwising, stirred 2 hours under the room temperature.With the frozen water dilution, with ether extraction, organic phase is through washing then, and saturated common salt is washed, anhydrous Na SO
4After the drying, concentrate colorless oil product 2-ethyl-butyraldehyde oxime.
4. with (±)-uncle cis-4-fourth oxygen carboxamide basic ring penta-2-alkene-1-carboxylate methyl ester, 2-ethyl-butyraldehyde oxime, 1: 3.5 in molar ratio～7 put in the methylene dichloride, at ice bath, slowly drip NaOCl (9.4%) solution under the lucifuge condition.Dropwise the back and continue reaction 0.5h, be heated to room temperature reaction 7h then.After reacting completely, washing, water is with twice of dichloromethane extraction.Merge organic phase, washing successively, anhydrous Na
2SO
4Drying, concentrating under reduced pressure gets thick liquid.Again with sherwood oil: the mixed solvent recrystallization of ethyl acetate (90: 10) gets white crystal.
5. above-mentioned product is changed in the hydrogenation bottle, add hydrogenation catalyst (PtO
2Or palladium-gac), concentrated hydrochloric acid and methyl alcohol are depressed mild heat hydrogenation adding.Hydrogenation is finished, and blows N
2Half an hour, product is crossed diatomite, filtrate is removed solvent through underpressure distillation, and vacuum-drying gets colourless or faint yellow solid, is (±)-t-3-the hydrochloride of (1`-amino-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester.
The hydrochloride of (±)-t-3-(1`-amino-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester is dissolved in the methylene dichloride, adds the anhydrous acetic acid acid anhydride, stirring at room 16h.Reaction is finished, and adds entry, tells organic layer, and water with dichloromethane extraction repeatedly merges organic phase, washing successively, saturated common salt washing, anhydrous Na
2SO
4Drying, underpressure distillation is removed solvent and is got white solid product (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester.
6. above-mentioned product is dissolved in the anhydrous diethyl ether, logical exsiccant hydrogen chloride gas 0.5h under the reflux state, stirring at room is 10 hours again, filter whitely or the yellow-white consubstantiality, i.e. the hydrochloride of (±)-t-3-(1`-acetamido-2`-ethyl) butyl-c-4-amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester.
With this intermediate and 1,3-two uncle's fourth oxygen carbonic acyl radical-2-methyl-2-isothioureas, mercury chloride dissolve among the DMF stirring at room 20 hours.With the ethyl acetate dilution, produce white precipitate, filter, discard filter residue, filtrate is through washing, saturated common salt washing, anhydrous sodium sulfate drying, and concentrating under reduced pressure gets yellow sticky solid.With sherwood oil: ethyl acetate=3: 7～1: 1 cross post separate white solid product (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester.
7. with (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl) amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester dissolves in (THF: in mixed solvent ethanol=1: 1), slowly drip the sodium hydroxide solution of 1M again.Stirring at room 3 hours steams solvent, adds the water of a little, transfers to slightly acidic with the hydrochloric acid soln of 1M of ice, again with ethyl acetate extraction.The gained organic phase is through washing, saturated common salt washing, anhydrous sodium sulfate drying, concentrate white solid (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxy-cyclopentane-r-1-carboxylic acid.
8. with above-mentioned product, trifluoroacetic acid, Et
3SiH puts in the methylene dichloride, stirring at room 24 hours, decompression steams solvent, the gained dry-matter is washed with ether, get yellow solid, again through methyl alcohol: the mixed solvent recrystallization of water=1: 1 gets white crystal (±)-t-3-(1`-acetamido-2`-ethyl) butyl-c-4-guanidine radicals-t-2-hydroxycyclopent base-1-carboxylic acid, i.e. Peramivir.
Compared with prior art, the present invention adopts following beneficial effect: the deficiency that the present invention is directed to existing Peramivir synthetic method, in the catalytic hydrogenation process, use cheap palladium charcoal instead and made catalyzer, in preparation aldoxime process, replaced hypertoxic benzene cyanogen and benzene, reached the purpose that reduces production costs, avoids using hypertoxic raw material, reduces pollution with ethanol and salt of wormwood; Synthesis step became for eight steps by existing ten multisteps, had simplified synthesis step; In addition, the reaction conditions gentleness of synthetic method of the present invention, equipment is simple, and operation is easily gone, the productive rate height, one-step reaction reaches 80%～95%, and overall yield can reach 52.7%.
Description of drawings
Fig. 1 is (±)-uncle cis-4-fourth oxygen carboxamide basic ring penta-2-alkene-1-carboxylate methyl ester
1The HNMR spectrogram;
Fig. 2 is the MS spectrogram of (±)-uncle cis-4-fourth oxygen carboxamide basic ring penta-2-alkene-1-carboxylate methyl ester;
Fig. 3 is (±)-uncle 4-fourth oxygen carbonamido-3-(1`-ethyl propyl)-4,5,6, and the 6a-4H-3aH-cyclopentyl be [d] isoxazole-6-carboxylate methyl ester
1The HNMR spectrogram;
Fig. 4 is (±)-uncle 4-fourth oxygen carbonamido-3-(1`-ethyl propyl)-4,5,6,6a-4H-3aH-cyclopentyl [the MS spectrogram of d] isoxazole-6-carboxylate methyl ester;
Fig. 5 is (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester
1The HNMR spectrogram;
Fig. 6 is the MS spectrogram of (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester;
Fig. 7 is (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester
1The HNMR spectrogram;
Fig. 8 is (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] the MS spectrogram of amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester;
Fig. 9 is (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxycyclopent base-r-1-carboxylic acid
1The HNMR spectrogram;
Figure 10 is (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] the MS spectrogram of amino-t-2-hydroxycyclopent base-r-1-carboxylic acid;
Figure 11 is a Peramivir
1The HNMR spectrogram;
Figure 12 is the MS spectrogram of Peramivir;
Embodiment
1. in the band magnetic agitation, reflux condensing tube adds 5 Ke Wensi lactan in the there-necked flask of the 250ml of drying tube, and 50ml methyl alcohol continues logical exsiccant HCl gas 2 hours then under the room temperature, reheat to 45 ℃ stirring 2 hours.Underpressure distillation is removed solvent and is got faint yellow dope, adds the 100ml ether in this dope, and stirring at room 2 hours is separated out white precipitate, filtration, the dry white solid product that gets.This solid promptly is the hydrochloride of (±)-cis-4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester.
Output 7.7 grams, yield: 95.2%
2. with gained hydrochloride 2.05 grams (11.5mmol), NaHCO
30.81 gram (8.1mmol), BOC
2O2.61 restrains (11.9mmol), and methylene dichloride 50ml puts in the round-bottomed flask of 250ml, and stirring at room is 3 hours then.Thin-layer chromatography monitors reaction end.Reaction is finished, and organic layer is told in washing, and water layer merges organic phase with dichloromethane extraction twice, through washing, and saturated common salt washing, anhydrous Na
2SO
4Drying after decompression steams solvent, gets oily matter.With this oily matter normal hexane: the mixing solutions drip washing of ethyl acetate=95: 5, white crystal be (±)-uncle cis-4-fourth oxygen carboxamide basic ring penta-2-alkene-1-carboxylate methyl ester (1).
Output: 2.62 grams, yield: 94.6%
Fusing point: 36 ℃
Ultimate analysis: C
12H
19NO
4M.W.:241.12
Calculated value: C 59.72 H 7.88 N 5.80 O 26.54
Analytical value: C 59.57 H 8.62 N 5.65 O 26.31
This product
1HNMR and MS spectrogram are Fig. 1, Fig. 2.
3. earlier the 3.0 oxammonium hydrochloride salt that restrain are dissolved in the water of 25ml, again to the salt of wormwood that wherein add 4 grams.After no longer including the bubble generation, slowly drip ethanol (99%) the solution 25ml of 2-ethyl butyraldehyde (4 gram) under the ice bath.After dropwising, stirred 1 hour under the room temperature.Be diluted to 500ml with frozen water then, with ether extraction three times, washing again, saturated common salt washing, anhydrous Na SO
4Drying concentrates to such an extent that colorless oil 3 restrains, i.e. 2-ethyl butyraldehyde oximes.
4. with (1) 5.18 gram (0.021mol), 2-ethyl butyraldehyde oxime 7.25 grams (0.063mol) are put in the methylene dichloride of 20.7ml, under ice bath, slowly drip NaOCl (9.4%) 38.6 gram (0.048mol) solution.Dropwise the back and continue to react half an hour, be heated to room temperature reaction then 8 hours.Thin-layer chromatography monitors reaction end.Reaction is finished, and tells organic phase, and water is with twice of ethyl acetate extraction.Merge organic phase, washing, anhydrous Na
2SO
4Drying, concentrating under reduced pressure.With sherwood oil: the mixed solvent recrystallization of ethyl acetate (90: 10), 7.1 gram white crystals, be (±)-uncle's 4-fourth oxygen carbonamido-3-(1`-ethyl propyl)-4,5,6 6a-4H-3aH-cyclopentyl [d] isoxazole-6-carboxylate methyl ester (3).Productive rate: 95.4%
Fusing point: 107～108 ℃
Ultimate analysis: C
18H
30N
2O
5M.W:354.21
Calculated value: C 60.98 H 8.47 N 7.90 O 22.58
Analytical value: C 60.29 H 8.32 N 7.75 O 22.41
This product
1HNMR and MS spectrogram are Fig. 3, Fig. 4.
5. (3) 1 grams (2.8mmol), palladium-charcoal 0.156 gram, methyl alcohol 95.2ml are changed in the hydrogenation bottle, add the concentrated hydrochloric acid of 0.5ml again, in the atmosphere of hydrogen of 100～150psi, 45 ℃ of following vigorous stirring of constant temperature 24 hours are cooled to room temperature, blow N
2Cross diatomite half an hour, concentrates, and vacuum-drying gets colourless or yellowish solid 1.09 grams, is (±)-t-3-the hydrochloride of (1`-amino-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester.
Gained intermediate 1.09 grams (2.78mmol) are dissolved in the methylene dichloride of 80ml, add Et more successively
3NO.38ml, anhydrous acetic acid acid anhydride 0.47ml, stirring at room 16h.Reaction is finished, and adds 20ml water, tells organic layer, and water merges organic phase with methylene dichloride 20ml extraction three times, washing successively, saturated common salt washing, anhydrous Na
2SO
4Drying, solvent is removed in underpressure distillation, gets 1.06 gram white solids, is (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester (5), productive rate: 94.6%.
Fusing point: 119～121 ℃
Ultimate analysis: C
20H
36N
2O
6M.W.:400.26
Calculated value: C 59.96 H 8.99 N 6.99 O 23.98
Analytical value: C 59.67 H 8.72 N 7.05 O 23.81
This product
1HNMR and MS spectrogram are Fig. 5, Fig. 6.
6. have magnetic agitation, in the there-necked flask of the 500ml of reflux condensing tube, adding (5) of 1.5 grams (3.75mmol), the ether of 200ml.Treat complete molten after, continue logical dry HCl gas 15 minutes, stirring at room is after 10 hours, reflux 2 hours.Thin-layer chromatography monitoring reaction terminal point.Reaction is finished, and filters, and gets the i.e. hydrochloride of (±)-t-3-(1`-acetamido-2`-ethyl) butyl-c-4-amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester of white solid.
With gained hydrochloride 1.1 gram (3.26mmol), triethylamine 0.85ml (8.45mmol), 1; 3-two uncle's fourth oxygen carbonic acyl radical-2-methyl-2-isothiourea 0.94 gram (3.26mmol), mercury chloride 0.88 gram (3.26mmol) join among the DMF of 50ml stirring at room 16 hours.Reaction is finished, and with the long-pending ethyl acetate dilution of pentaploid, separates out white precipitate, filters, and filtrate is through washing, saturated common salt washing, anhydrous sodium sulfate drying, concentrate yellow sticky solid.With sherwood oil: ethyl acetate=3: 7～1: 1 cross post separate 1.3 gram white solids, be (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester (6), yield 83%.
Fusing point: 167 ℃
Ultimate analysis: C
26H
46N
4O
8M.W.:542.56
Calculated value: C 57.51 H 8.48 N 10.32 O 23.59
Analytical value: C 57.53 H 8.16 N 10.35 O 23.33
This product
1HNMR and MS spectrogram are Fig. 7, Fig. 8.
7. (6) 0.5 grams (0.9mmol) are dissolved in 13ml (THF: in mixed solvent ethanol=1: 1), slowly drip the sodium hydroxide solution 5ml (5mmmol) of 1M, stirring at room 3 hours, solvent is removed in underpressure distillation, the water that adds 6ml, the hydrochloric acid soln of 1M with ice transfers to slightly acidic, again with ethyl acetate extraction.The gained organic phase is through washing, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure gets 0.45 gram white solid, i.e. (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxycyclopent base-r-1-carboxylic acid (7), productive rate: 95%
Fusing point: 219～220 ℃
Ultimate analysis: C
25H
44N
4O
8M.W:528.32
Calculated value: C 56.78 H 8.33 N 10.60 O 24.23
Analytical value: C 56.67 H 8.12 N 10.55 O 24.31
This product
1HNMR and MS spectrogram are Fig. 9, Figure 10.
8. will (7) 0.30 gram (0.56mmol), trifluoroacetic acid 1.9ml, Et
3SiH0.5ml puts in the methylene dichloride of 32ml, stirring at room 12 hours, and decompression steams solvent, and the gained dry-matter is washed with the ether of 20ml, gets yellow solid 0.17 gram.With this solid product with trichloromethane: the mixing solutions of methyl alcohol=7: 3～1: 1 is crossed silicagel column, the gained crude product is again with methyl alcohol: the mixing solutions recrystallization of water=1: 1, get 0.15 gram white solid, i.e. (±)-t-3-(1`-acetamido-2`-ethyl) butyl-c-4-guanidine radicals-t-2-hydroxycyclopent base-1-carboxylic acid (8) is Peramivir.Productive rate: 82.3%
Fusing point:＞251 ℃
Ultimate analysis: C
15H
28N
4O
4M.W:328.24
Calculated value: C 54.84 H 8.53 N 17.06 O 19.50
Analytical value: C 54.67 H 8.52 N 17.11 O 19.31
This product
1HNMR and MS spectrogram are Figure 11, Figure 12.
Claims (9)
1. the synthetic method of a Peramivir is characterized in that comprising the steps:
(1) this lactan of literary composition is dissolved in the alcoholic solution, esterification by ring opening under hydrochloric acid catalysis makes (±)-the cis-4-amino cyclopentyl-hydrochloride of 2-alkene-1-carboxylate methyl ester;
(2) hydrochloride and the di-t-butyl carbonic ether with (±)-cis-4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester drops in the two-phase system of basic solution and organic solvent composition, the vigorous stirring reaction makes (±)-uncle's cis-4-fourth oxygen carboxamide basic ring penta-2-alkene-1-carboxylate methyl ester;
(3) 2-ethyl butyraldehyde makes 2-ethyl butyraldehyde oxime with the oxammonium hydrochloride reactant salt in alcohol-carbonate system;
(4) (±)-uncle cis-4-fourth oxygen carboxamide basic ring penta-2-alkene-1-carboxylate methyl ester and 2-ethyl butyraldehyde oxime are put in the organic solvent, cycloaddition reaction takes place under base catalysis, make (±)-uncle's 4-fourth oxygen carbonamido-3-(1`-ethyl propyl)-4,5,6,6a-4H-3aH-cyclopentyl [d] isoxazole-6-carboxylate methyl ester;
(5) with (±)-uncle 4-fourth oxygen carbonamido-3-(1`-ethyl propyl)-4,5,6, [d] isoxazole-6-carboxylate methyl ester catalytic hydrogenation in alcoholic solution makes (±)-t-3-the hydrochloride of (1`-amino-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester to the 6a-4H-3aH-cyclopentyl; Again with products therefrom through acetylize, promptly generate intermediate product (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester;
(6) intermediate product (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-fourth oxygen carbonamido-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester in ether, take off BOC protect the hydrochloride of (±)-t-3-(1`-acetamido-2`-ethyl) butyl-c-4-amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester; With products therefrom and 1,3-two uncle's fourth oxygen carbonic acyl radical-2-methyl-2-isothioureas are put in the reaction system of inorganic salt and alkali organic solvent composition, the vigorous stirring reaction makes (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester;
(7) with (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxycyclopent base-r-1-carboxylate methyl ester puts in the reaction system of being made up of alcohol, organic solvent, aqueous sodium hydroxide solution, makes (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxy-cyclopentane-r-1-carboxylic acid;
(8) with (±)-t-3-(1`-acetamido-2`-ethyl) butyl-uncle's c-4-[(fourth oxygen carbonamido-uncle's fourth oxygen carbimide base) methyl] amino-t-2-hydroxy-cyclopentane-r-1-carboxylic acid is dissolved in the inert solvent, takes off BOC and promptly obtain the final product Peramivir under organic acid and organosilane catalysis.
2. according to the described synthetic method of claim 1, it is characterized in that the described alcohol of step (1) is methyl alcohol.
3. according to the described synthetic method of claim 1, it is characterized in that the described alkali of step (2) is NaHCO
3Or Na
2CO
3, described organic solvent is methylene dichloride or hexane.
4. according to the described synthetic method of claim 1, it is characterized in that the described alcohol of step (3) is methyl alcohol or ethanol, described carbonate is Na
2CO
3Or K
2CO
3
5. according to the described synthetic method of claim 1, it is characterized in that the described solvent of step (4) is methylene dichloride, hexane or heptane, described alkali is triethylamine or clorox.
6. according to the described synthetic method of claim 1, it is characterized in that the described alcohol of step (5) is methyl alcohol, described catalyzer is platinum dioxide or palladium-activated carbon, and used acylating agent is a diacetyl oxide.
7. according to the described synthetic method of claim 1, it is characterized in that the described ether of step (6) is ether, described inorganic salt are mercury chloride, and described alkali is triethylamine or quadrol.
8. according to the described synthetic method of claim 1, it is characterized in that the described alcohol of step (7) is ethanol, described organic solvent is a tetrahydrofuran (THF).
9. according to the described synthetic method of claim 1, it is characterized in that the described inert solvent of step (8) is a methylene dichloride, described organic acid is a trifluoroacetic acid, and described organosilane is a triethyl silicane.
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| DK1040094T3 (en) * | 1997-12-17 | 2009-06-02 | Biocryst Pharm Inc | Substituted cyclopentane and cyclopenten compounds useful as neuraminidase inhibitors |
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