CN101538228A - Method for synthesizing medical compound peramivir for resisting influenza viruses and avian influenza viruses - Google Patents
Method for synthesizing medical compound peramivir for resisting influenza viruses and avian influenza viruses Download PDFInfo
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Abstract
The invention provides a method for synthesizing a medical compound peramivir for resisting influenza viruses and avian influenza viruses, which is suitable for industrial production after improvement. The method uses (+/-) 2-azabicyclo[2.2.1]hept-5-alkene-3-ketone as a raw material to synthesize the peramivir through reaction. The method has the advantages of less reaction steps, simple, convenient and safe operation, simple and easily obtained raw material, and low cost. The method has the total yield up to 37.7 percent and is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, particularly, the present invention relates to the improved synthetic method of anti influenza and avian influenza virus medical compounds Peramivir.
Technical background
Peramivir, English name peramivir, chemistry (1S by name, 2S, 3R, 4R, 1 ' S)-(-)-3-[(1 '-acetylaminohydroxyphenylarsonic acid 2 '-ethyl) butyl]-the 4-[[(amino imino) methyl] amino]-2-hydroxy-cyclopentane-1-carboxylic acid, structural formula is as shown in the formula shown in (I).This medicine is by the neural amino acid enzyme inhibitors of a kind of cyclopentane derivatives class of U.S. Biocryst Pharmaceuticals, Inc. exploitation, can effectively suppress duplicating of each parainfluenza virus, has better tolerance, and side effect is little, advantage such as can inject.It is a kind of anti-avian influenza virus medicine that has a extensive future.
Patent documentation relevant with the synthetic method of Peramivir in the prior art comprises that CN1227466, CN1282316, CN1358170A and CN1367776A etc. disclose a plurality of synthetic schemess.Wherein CN1282316 discloses so that chirality 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is raw material, through open loop, amido protecting, Diels-Alder addition, reductive ring open, acetylize, go up the synthetic route of carbonamidine, hydrolysis methyl esters.CN1358170A discloses the open loop and the method for splitting of 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone.CN1367776A discloses Diels-Alder addition, esterification, reductive ring open, acetylize, has gone up the improvement synthetic method of carbonamidine, hydrolysis.
Summary of the invention
Unless otherwise indicated, term used herein " hydrochloric acid methanol " is meant the methanol solution of hydrogenchloride.
Unless otherwise indicated, statement used herein " concentration of hydrochloric acid methanol " is meant that hydrogenchloride accounts for the per-cent of the methanol solution gross weight of hydrogenchloride.
Unless otherwise indicated, statement used herein " the chlorine oxime of 2-ethyl butyraldehyde preparation " is meant the compound with following structural formula:
The objective of the invention is to, the improved synthetic method of medical compounds Peramivir is provided.
At the foregoing invention purpose, the invention provides following technical scheme:
On the one hand, the invention provides a kind of synthetic method of Peramivir, described method comprises: so that 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is raw material, process: open loop step I), amido protecting, Step II) Diels-Alder addition, Step II I) reductive ring open and step IV) acetylize, hydrolysis methyl esters, go up carbonamidine, make Peramivir; Wherein said step I) comprising: (±) 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is dissolved in the methyl alcohol, dripping hydrochloric acid methyl alcohol, open loop adds L tartrate and splits and obtain L tartrate (1S, 4R) 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester.
Preferably, in the synthetic method of the present invention, the hydrogenchloride described in the step (I) in the hydrochloric acid methanol and reactant (±) 2-azabicyclo [2.2.1] heptan-mol ratio of 5-alkene-3-ketone is 1.20: 1-1.35: 1.
Further preferably, in the synthetic method of the present invention, the hydrogenchloride described in the step (I) in the hydrochloric acid methanol and reactant (±) 2-azabicyclo [2.2.1] heptan-mol ratio of 5-alkene-3-ketone is 1.30: 1.
Preferably, in the synthetic method of the present invention, the concentration range of hydrochloric acid methanol is 20-40% in the step (I), is preferably 32%-40% weight.
On the other hand, the invention provides a kind of synthetic method of Peramivir, described method comprises: so that 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is raw material, process: open loop step I), amido protecting, Step II) Diels-Alder addition, Step II I) reductive ring open and step IV) acetylize, hydrolysis methyl esters, go up carbonamidine and make Peramivir; Wherein said Step II) comprising: the chlorine oxime of 2-ethyl butyraldehyde preparation slowly is added dropwise to (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] encircle in penta-2-alkene-1-carboxylic acid (compound IV) solution and carry out the Diels-Alder addition, handle with alkali extraction and acid precipitation afterwards, add the hydrochloric acid methanol esterification and obtain (3aR, 4R, 6S, 6aS)-(+)-4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is [d] isoxazole-6-carboxylate methyl ester also.
Preferably, in the synthetic method of the present invention, Step II) described in described chlorine oxime by 2-ethyl butyraldehyde preparation slowly is added dropwise to (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] encircle in penta-2-alkene-1-carboxylic acid (compound IV) solution and carry out the Diels-Alder addition, wherein, described chlorine oxime is the toluene solution with the preparation of 2-ethyl butyraldehyde, its usage quantity is by the decision of raw material 2-ethyl butyraldehyde charging capacity, and its ratio is mentioned for 12 li at the embodiment of back.2-ethyl butyraldehyde charging capacity is about 3: 1 with the ratio of compound IV amount, and the dropping time is for the add-on of the toluene solution of chlorine oxime (preferably about 4N).The dropping time of described slow dropping was at least 5 hours, was preferably 5-7 hour.
Preferably, in the synthetic method of the present invention, Step II) described in the alkali extraction and acid precipitation employed alkali be aqueous sodium hydroxide solution, employed acid is middle strong acid, comprises formic acid and/or acetate.
Preferably, the pH value of hydrochloric acid methanol is 3-4 in the synthetic method of the present invention, Step II).
On the other hand, the invention provides a kind of synthetic method of Peramivir, comprise the steps: so that 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is raw material, through open loop, amido protecting, Diels-Alder addition, reductive ring open, acetylize, hydrolysis methyl esters, go up carbonamidine and make Peramivir; Wherein said Step II I) comprising: (3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6, also [d] isoxazole-6-carboxylate methyl ester comes reductive ring open with lithium aluminum hydride as reductive agent to 6a-tetrahydrochysene-4H-pentamethylene.
Preferably, in the synthetic method of the present invention, described Step II I) also comprises, obtain (1S with saturated soluble tartrate sodium water solution processing, 2S, 3S, 4R, 1`S)-and 3-[(1`-amino-2`-ethyl) butyl]-4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-2-hydroxy-cyclopentane-1-carboxylate methyl ester.
Below according to the improved most preferred synthetic route of the present invention, set forth technical scheme of the present invention and superiority further.
On the further investigation basis for existing synthetic method, we have invented following synthetic route by a large amount of tests:
At first, for L-tartrate (1S, 4R) 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester (compound III) is synthetic, the quality of this reaction and productive rate depend on the accurate dropping of the amount of hydrogenchloride, and closely related with three aspects of mol ratio of the mode that feeds hydrogenchloride, the concentration that adds hydrogenchloride, adding hydrogenchloride and reactant, the yield and the quality product of reacting had a significant impact.The method of the disclosed logical hydrogen chloride gas of CN1358170, the amount of hydrogenchloride can't accurately be controlled, and forms inhomogeneous reaction with liquid reaction system, and the scale of reaction can not be amplified, and the big more yield of reaction scale is low more, can't realize industrialized production.Adopt the hydrochloric acid methanol of lower concentration in the CN1282316 disclosed method, it is optimum that the mol ratio of reaction does not reach, and causes reaction to be difficult to carry out fully, and the reaction times is very long, the productive rate instability.And we find unexpectedly that by a large amount of tests in the process that adds hydrochloric acid methanol, the concentration of hydrochloric acid methanol is the bigger the better, and is 20-40%, the 32%-40% weight of preferred high density; Too big and too little productive rate and the downgrade of all causing of the mol ratio of hydrogenchloride and reactant, should be between 1.20-1.35 for well, preferred 1.30 the bests.Productive rate and quality are all good under this condition, and the reaction times only needed to finish in 30 minutes, and circulation ratio is fine, is easy to the amplification of scale, are fit to suitability for industrialized production.
Second, for (3aR, 4R, 6S, 6aS)-(+)-4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene also [d] isoxazole-6-carboxylate methyl ester (compound VI) synthetic, prior art is with (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] ring penta-2-alkene-1-carboxylic acid (compound IV) and carry out the Diels-Alder addition with the chlorine oxime of 2-ethyl butyraldehyde preparation, after the sodium hydroxide hydrolysis methyl esters becomes acid, obtain solid product (3aR with the TERTIARY BUTYL AMINE salify, 4R, 6S, 6aS)-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is [d] isoxazole-6-carboxylic acid 2,2-dimethyl ethyl ammonium (compound V) also
Afterwards, with highly toxic product methyl-sulfate and carboxylic esterification, amino with the protection of Boc acid anhydrides once more; obtain product (3aR; 4R, 6S, 6aS)-(+)-4-[[(1; 1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a; 5,6,6a-tetrahydrochysene-4H-pentamethylene also [d] isoxazole-6-carboxylate methyl ester compound VI); one shared two-step reaction has increased and has handled and the cost of operation.The generation (seeing reaction formula I) of side reaction is arranged in the reaction, have by-product compounds VIII to generate, need to adopt TERTIARY BUTYL AMINE to become salt refining,, reduced yield though improved quality; The use of the phenylcarbimide of severe toxicity and benzene etc. proposes higher requirement to safety precaution and liquid waste disposal; In esterification process, be easy to cause the BOC-protecting group partly to take off, need to go up again protecting group.
We find to adopt oxime compound, with suitable drop rate and mol ratio by a large amount of tests unexpectedly, the greatly generation of side reaction in the inhibited reaction, do not need to use TERTIARY BUTYL AMINE to make with extra care and to obtain high-quality product, simplified operation, improved yield.In the process of carrying out esterification, we find that unexpectedly accurately the control pH value is extremely important in the reaction, and the pH value is too low, easily amino Boc protecting group is taken off, and the too high esterification of pH value does not take place again.Therefore adopt hydrochloric acid methanol rather than logical hydrogenchloride; help the amount of reactant and the accurate control of pH value; and under suitable pH value; can make reaction obtain the carboxylate of high yield; and simultaneously the BOC-protecting group is taken off, thus avoided going up again the operation of protecting group, can greatly reduce the operation of aftertreatment by this method; with a synthetic step of the reaction in two steps, and improved yield.Method productive rate after the improvement brings up to 76% by 42%, and mild condition, need not use the reagent and the solvent of severe toxicity, has simplified operation, is fit to suitability for industrialized production.
The 3rd, for (3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6, also [it is the method for catalyzer pressure hydration that the reductive ring open of d] isoxazole-6-carboxylate methyl ester (compound VI), CN1282316 disclose with the platinum dioxide to 6a-tetrahydrochysene-4H-pentamethylene, and equipment and safety precaution are proposed requirements at the higher level, and platinum dioxide is very expensive, and cost is very high.CN1367776A discloses use nickelous chloride/sodium borohydride composition and has improved one's methods as reductive agent, but relating to accurate pH value in the reaction regulates, need specific installation such as highly sensitive pH meter, and measuring process is also very loaded down with trivial details, is not suitable for the production operation of industry; Post-reaction treatment is used toluene in a large number, and needs to repeat adding ammoniacal liquor 3 times, is heated to 80 ℃, is separated again, and complicated operation is loaded down with trivial details, can't continuity operate, and ammoniacal liquor violent volatilization under 80 ℃, cause very big atmospheric pollution, be not suitable for suitability for industrialized production.We find in test is explored unexpectedly by adopting lithium aluminum hydride to substitute nickelous chloride/sodium borohydride as reductive agent, the reaction conditions gentleness, not pH value control accurately, simplified schedule of operation greatly, removed numerous and diverse last handling process from, also improved reaction yield, brought up to 80% by original 70%.
According to an embodiment preferred of the present invention, the concrete improved synthetic method of the present invention is as follows:
1.L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester (compound III)
(±) 2-azabicyclo [2.2.1] heptan-5-alkene-methanol solution of 3-ketone (Compound I I) is added dropwise to the hydrochloric acid methanol (preferred 30%-40% weight) of 20-40% weight under stirring at room, stir while dripping, added with 30 minutes, natural back flow during this time, the hydrogenchloride and the reactant molar ratio 1.10-1.40 that introduce, preferred 1.20-1.35, more preferably 1.30.Stir cooling, add L-tartrate and water, be added dropwise to triethylamine, stir, have a large amount of solids to separate out.Filter washing, drying.Get white solid (compound III), yield 84.9%.
2. (1S, 4R)-(-)-preparation of the preparation (compound IV) of methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] ring penta-2-alkene-1-carboxylic acid
Utilize art methods with tert-Butyl dicarbonate with L-tartrate (1S; 4R) the amido protecting of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester (compound III); get product (1S; 4R)-(-)-methyl-[[(1; 1 dimethyl oxyethyl group) carbonyl] amino] ring penta-2-alkene-1-carboxylic acid (compound IV), yield 90.1%.
3. (3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is the [preparation of d] isoxazole-6-carboxylate methyl ester (compound VI) also
Will (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] ring penta-2-alkene-1-carboxylic acid (compound IV) is dissolved in toluene and triethylamine, and solution is heated to 60～70 ℃.Vigorous stirring also slowly drips the inferior acyl chlorides toluene solution of 2-ethyl butyraldehyde, generates white precipitate, drips the time spent more than 5 hours, preferred 5-7 hour, adds the afterreaction mixture and continues to stir more than 1 hour.Products therefrom with sodium hydroxide hydrolysis after, divide water-yielding stratum, be acidified with acid (strong acid in preferred, as Glacial acetic acid), the low boiling point organic solvent extraction boils off solvent, dissolve with methanol after the drying, add lower concentration acid acidifying, preferred 10% hydrochloric acid methanol, control pH value 3-4, stirring at room is to reacting completely, promptly get product, productive rate 76%.
4. (1S, 2S, 3S, 4R, 1`S)-and 3-[(1`-amino-2`-ethyl) butyl]-4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-2-hydroxy-cyclopentane-1-carboxylate methyl ester (compound VI I)
Add tetrahydrofuran (THF) in the reaction vessel, gradation adds lithium aluminum hydride.Agitation and dropping (3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6, also [tetrahydrofuran solution of d] isoxazole-6-carboxylate methyl ester (compound VI) drips off the back stirring and refluxing to reacting completely to 6a-tetrahydrochysene-4H-pentamethylene.Cooling is poured in the soluble tartrate saturated aqueous solution of sodium.After telling organic layer, the water layer ether extraction merges organic layer and dry.The evaporated under reduced pressure solvent adds the methyl alcohol thermosol, cooling, crystallization.Filter, drying gets white solid (compound VI I), yield 81.1%.
5. the preparation of Peramivir (Compound I)
With (1S; 2S; 3S; 4R; 1`S)-and 3-[(1`-amino-2`-ethyl) butyl]-4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-2-hydroxy-cyclopentane-1-carboxylate methyl ester (compound VI I) adds diacetyl oxide acetylize amino, and carbonic acid tert-butyl ester protecting group and carboxylate methyl ester are fallen in hydrolysis; add that the carbonamidine group gets final product Peramivir (Compound I), productive rate 82% on the hydrochloric acid pyrazoles carbonamidine.
Compared with prior art, the present invention has following obvious advantage:
1. the present invention is so that 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is starting raw material, and reaction obtains product Peramivir (Compound I) through five steps, and synthetic route shortens, the reaction conditions gentleness, and total recovery has brought up to 37.7% by 17.7% of prior art.
2. reduced the generation of side reaction in the reaction by improvement, impurity reduces in the product, has simplified post-processing operation greatly, is fit to large-scale industrial production.
3. avoided methyl-sulfate, phenylcarbimide, the use of hypertoxic heavy-polluted reagent such as ammoniacal liquor and benzene and solvent has significantly reduced the use of aftertreatment organic solvent, meets the requirement that the industrialization energy-conserving and environment-protective reduce discharging.
Description of drawings
Below, describe embodiments of the invention in conjunction with the accompanying drawings in detail, wherein:
Fig. 1 for the method according to this invention obtain (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] ring penta-2-alkene-1-carboxylic acid (compound IV)
1The HNMR spectrogram;
(3aR, 4R, 6S, 6aS)-(+)-4-[[(1,1 dimethyl oxyethyl group) carbonyl that Fig. 2 obtains for the method according to this invention] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene be also [d] isoxazole-6-carboxylate methyl ester (compound VI)
1The HNMR spectrogram;
(1S, 2S, 3S, 4R, 1` S)-3-[(1`-amino-2`-ethyl that Fig. 3 obtains for the method according to this invention) butyl]-4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-2-hydroxy-cyclopentane-1-carboxylate methyl ester (compound VI I)
1The HNMR spectrogram;
Fig. 4 is the method according to this invention synthetic Peramivir
1The HNMR spectrogram;
Fig. 5 is the method according to this invention synthetic Peramivir
13The CNMR spectrogram;
Fig. 6 is the MS spectrogram of the method according to this invention synthetic Peramivir;
Fig. 7 is the infrared spectrum of the method according to this invention synthetic Peramivir.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Be not used in but these embodiment only limit to the present invention is described and limit the scope of the invention.The experimental technique of unreceipted concrete experiment condition in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Embodiment 1
L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester
200g (1.832mol) (±) 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone (Compound I I) joins and is with in the churned mechanically 1L four-hole boiling flask, adds 75ml methyl alcohol.Be added dropwise to the hydrochloric acid methanol 184g (2.015mol) of 40% weight under the stirring at room, the amount of hydrogenchloride is 1.10 than the amount of reactant.Add with 30 minutes, during temperature can rise to reflux temperature.Stirring is cooled to 20-25 ℃, adds L-tartrate 165g (1.10mol), water 100ml.Low-grade fever to 30 ℃ is added dropwise to triethylamine 165ml, and the control rate of addition makes system temperature be no more than 50 ℃.Finish and continue to stir 30 minutes, cooling temperature stirred 1 hour to 20-25 ℃, had a large amount of solids to separate out.Filter 150ml methanol wash filter cake, 40 ℃ of vacuum-dryings.
Get white solid (compound III) 110g, fusing point 167.1-168.0 ℃, specific rotatory power (20 ℃, 1g/100ml methyl alcohol)-38.0 degree.Yield 41.5%.
Embodiment 2
L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester
Press the method for embodiment 1, charging capacity: be added dropwise to the hydrochloric acid methanol 200.5g (2.198mol) of 40% (weight ratio), 200g (1.832mol) Compound I I, ratio 1.20.
Get white solid (compound III) 188g, fusing point 166.7-167.8 ℃, specific rotatory power (20 ℃, 1g/100ml methyl alcohol)-37.6 degree.Yield 70.9%.
Embodiment 3
L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester
Press the method for embodiment 1, charging capacity: be added dropwise to the hydrochloric acid methanol 218g (2.382mol) of 40% (weight ratio), 200g (1.832mol) Compound I I, ratio 1.30.Get white solid (compound III) 225g, fusing point 167.4-168.1 ℃, specific rotatory power (20 ℃, 1g/100ml methyl alcohol)-38.5 degree.Yield 84.9%.
Embodiment 4
L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester
Press the method for embodiment 1, charging capacity: be added dropwise to the hydrochloric acid methanol 225.8g (2.473mol) of 40% (weight ratio), 200g (1.832mol) Compound I I, ratio 1.35.
Get white solid (compound III) 188g, fusing point 165.1-167.5 ℃, specific rotatory power (20 ℃, 1g/100ml methyl alcohol)-24.7 degree.Yield 47.5%.
Embodiment 5
L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester
Press the method for embodiment 1, charging capacity: be added dropwise to the hydrochloric acid methanol 234.0g (2.565mol) of 40% (weight ratio), 200g (1.832mol) Compound I I, ratio 1.40.
Get white solid (compound III) 82g, fusing point 163.7-166.8 ℃, specific rotatory power (20 ℃, 1g/100ml methyl alcohol)-17.3 degree.Yield 30.9%.
Embodiment 6
L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester
The 1L four-hole boiling flask installs mechanical stirring additional, long ventpipe, and prolong adds 300g (2.748mol) (±) 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone (Compound I I), adds 315ml methyl alcohol stirring and dissolving, the record of weighing.In solution, feed hydrogen chloride gas under the stirring at room, get flask after 20 minutes and weigh, until the weightening finish 113.4g (hydrochloric acid weight, 3.105mol).Be cooled to 25 ℃, add L-tartrate 248g (1.65mol), pure water 150ml.Low-grade fever to 30 ℃ is added dropwise to triethylamine 248ml, and the control rate of addition makes system temperature be no more than 50 ℃.Finish and continue to stir 30 minutes, cooling temperature stirred 1 hour to 20-25 ℃, had solid to separate out.Filter 225ml methanol wash filter cake, 40 ℃ of vacuum-dryings.
Get white solid (compound III) 194g, fusing point 167.0-168.2 ℃, specific rotatory power (20 ℃, 1g/100ml methyl alcohol)-38.8 degree.Yield 48.8%.
Embodiment 7
L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester
Press the method for embodiment 6, charging capacity: feed hydrogen chloride gas 173.9g (4.763mol), 400g (3.664mol) Compound I I, ratio 1.30.
Get white solid (compound III) 202g, fusing point 166.7-167.8 ℃, specific rotatory power (20 ℃, 1g/100ml methyl alcohol)-37.9 degree.Yield 38.1%.
Embodiment 8
L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester
Press the method for embodiment 1, charging capacity: be added dropwise to the hydrochloric acid methanol 435g (4.763mol) of 40% (weight ratio), 400g (3.664mol) Compound I I, ratio 1.30.
Get white solid (compound III) 435g, fusing point 167.2-168.0 ℃, specific rotatory power (20 ℃, 1g/100ml methyl alcohol)-38.2 degree.Yield 82.0%.
Embodiment 9
(1S, 4R)-(-)-preparation of methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] ring penta-2-alkene-1-carboxylic acid
(1S, 4R) 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester (compound III) 225g (0.779mol) is dissolved among the methyl alcohol 420ml, adds dimethyl dicarbonate butyl ester 220g (1.01mol), 30～35 ℃ of adding triethylamine 306ml with L tartrate.Finished stirring at room 1 hour.This solution is cooled to 5～10 ℃, adds entry 1020ml, cooling and stirring obtains white precipitate.Mixture stirred 2 hours at 5～10 ℃, filtered.Filter to such an extent that solid water 150ml washs drying.
Get slightly brown white solid 169g, yield 90.1%.mp?51.9～52.4℃，[α]
D 20℃＝-52.0°(C＝1g/dL，H
2O)。
1HNMR(DMSO-d6)：δ1.44(s，9H)，1.71(m，1H)，2.51(m，1H)，3.49(m，1H)，3.61(s，3H)，4.48(br?s，1H)，5.76(m，2H)。Collection of illustrative plates is Fig. 1.
(3aR, 4R, 6S, 6aS)-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is [d] isoxazole-6-carboxylic acid 2, the preparation of 2-dimethyl ethyl ammonium also
Will (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] ring penta-2-alkene-1-carboxylic acid (compound IV) 260g (1.08mol) is dissolved in toluene 1800ml and triethylamine 430ml (3.23mol), this solution is heated to 60～70 ℃.With the 750ml toluene solution that in this solution, added the inferior acyl chlorides 483g of above 2-ethyl butyraldehyde (3.23mol) in 2.5 hours, form white precipitate (chlorination triethyl ammonium), after adding, reaction mixture continues to stir 5 hours at 60～70 ℃.Reaction mixture is cooled to 20～25 ℃, filters and remove precipitation, with toluene 300ml washing leaching cake.Merging filtrate at 20～25 ℃, is handled with the 430ml aqueous solution of sodium hydroxide 66g.This biphasic system stirred 2.5～3.5 hours, with the water-soluble 380ml of 37% hydrochloric acid 180ml (2.15mol), added above system with 30 minutes, was separated, and discarded the sour water phase.At 20～40 ℃, handle organic phase with TERTIARY BUTYL AMINE 140ml (1.26mol).So be settled out yellow solid product.This mixture heating up is refluxed, form suspension, stirred 2.5 hours, be cooled to 20～25 ℃ with 2 hours then, restir 60 minutes at 90～100 ℃.Filter collecting precipitation, with acetone 300ml washing, 50 ℃ of dryings 12 hours.
Get white solid 197g, fusing point 187.5-189.1 ℃, yield 44.2%.
Embodiment 11
(3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is the [preparation of d] isoxazole-6-carboxylate methyl ester also
Compound V 197g (0.477mol) is suspended among the acetone 200ml, add salt of wormwood 3.3g (0.024mol), add the aqueous sodium hydroxide solution 31.8g (0.239mol) of 30wt% then, the 150ml solvent is removed in evaporation, add acetone 150ml again, and then boil off the 150ml solvent.This solution is cooled to 40-50 ℃, in suspension, adds methyl-sulfate 43.4g (0.339mol).The biphasic system that forms stirred 60 minutes at 40-45 ℃, was cooled to 15-20 ℃ then.Add 25% ammoniacal liquor 40ml, reaction mixture stirred 20 minutes, produced crystallization, and 5 ℃ down with the ammoniacal liquor 56ml that added 25% in 40 minutes, filtered, and washed vacuum-drying with 130ml.
Get white solid (compound VI) 162g, fusing point 64.7-66.2 ℃, yield 95.9%.
Embodiment 12
(3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is the [preparation of d] isoxazole-6-carboxylate methyl ester also
Will (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] ring penta-2-alkene-1-carboxylic acid (compound IV) 260g (1.08mol) is dissolved in toluene 1800ml and triethylamine 430ml (3.23mol), this solution is heated to 60～70 ℃.With 5 hours, the slow chlorine oxime that must in this solution, add self-control (pressing disclosed method preparation among the CN 1367776A)
The 750ml toluene solution of 483g (3.23mol) forms white precipitate (chlorination triethyl ammonium), and after adding, reaction mixture continues to stir 3 hours at 60～70 ℃.Reaction mixture is cooled to 20～25 ℃, filters and remove precipitation, with toluene 300ml washing leaching cake.Merging filtrate at 20～25 ℃, is handled with the 430ml aqueous solution of sodium hydroxide 66g.This biphasic system stirred 2.5～3.5 hours.Leave standstill the branch water-yielding stratum.Organic layer extracts at twice with aqueous sodium hydroxide solution 200ml.Combining water layer, frozen water cooling drip glacial acetic acid adjust pH 5-6 down.Ethyl acetate 800ml * 3 extractions.Merge the ester layer, water 1000ml washes 2 times, anhydrous magnesium sulfate drying.The evaporated under reduced pressure solvent gets light yellow oil, adds methyl alcohol 1500ml dissolving, dripping hydrochloric acid methyl alcohol regulator solution pH value 3-4.Stirring at room 8 hours.Drip 25% ammoniacal liquor adjust pH 7.The pressure reducing and steaming solvent gets solids.Filter washing, vacuum-drying.
Get white waxy solid (compound VI) 290g, fusing point 66.7-68.3 ℃, yield 76.0%.
1HNMR(CDCl
3)：δ0.87-0.95(m，6H)，1.44(s，9H)，1.58-1.78(m，4H)，2.0-2.15(m，2H)，2.51(bs，1H)，3.21(d，1H)，3.58(d，1H)，3.76(s，3H)，4.23(bs，1H)，5.21(d，1H)，5.59(bs，1H)。Collection of illustrative plates is Fig. 2.
Embodiment 13
(3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is the [preparation of d] isoxazole-6-carboxylate methyl ester also
Get light yellow oil by embodiment 12 methods, add methyl alcohol, drip 10% hydrochloric acid methanol regulator solution pH value to 5, stirring at room 24 hours is handled the last yellow oil water mixture that gets with embodiment 12 methods, can not get solid product.Thin-layer chromatography shows and above-mentioned light yellow oil is a same substance, and esterification fails to finish.
Embodiment 14
(1S, 2S, 3S, 4R, 1`S)-and 3-[(1`-amino-2`-ethyl) butyl]-4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-preparation of 2-hydroxy-cyclopentane-1-carboxylate methyl ester
With (3aR, 4R, 6S, 6aS)-(+)-4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6, also [d] isoxazole-6-carboxylate methyl ester (compound VI) 70.5g (0.20mol) and Nickel dichloride hexahydrate 50.0g (0.21mol) are dissolved among the methyl alcohol 200ml 6a-tetrahydrochysene-4H-pentamethylene, this green solution is cooled to 0～5 ℃, sodium hydroxide 0.44g (0.01mol) and sodium borohydride 20.0g (0.53mol) are dissolved in methyl alcohol 200ml, it are added in the above reaction mixture, temperature of reaction is remained on 0～10 ℃ simultaneously with 2 hours.After adding sodium borohydride solution, reaction mixture stirred 30 minutes at 0～5 ℃, was warmed to 10～15 ℃ then, added 37% hydrochloric acid 12.0g (0.122mol), the solution that adds Sodium Nitrite 7.0g (0.10mol) and water 35ml then, the speed of adding keep temperature of reaction to be no more than 25 ℃.After adding Sodium Nitrite, with the about 35.7g of 37% hydrochloric acid (0.36mol) regulator solution pH to 6.85.Reaction mixture is 20～25 ℃ of stirrings, dissolves fully until black precipitate and forms green solution.The 70ml aqueous solution that adds ammonium chloride 22.0g (0.41mol).Add 25% ammoniacal liquor 180g (2.64mol) then, until reaching pH9.6.Add the about 2g of 30wt% aqueous sodium hydroxide solution (0.015mol), be adjusted to pH9.87.This mixture spends the night 20～25 ℃ of stirrings.Filter collecting precipitation, with the water 170ml solution washing of 25% ammoniacal liquor 30g, the crude product that obtains wetting.The crude product that this is wet is suspended among the toluene 970ml, and this suspension forms biphasic system 75～80 ℃ of heating 20 minutes.Make to be separated, in organic phase, add 25% ammoniacal liquor 110g.This mixture is heated to 80 ℃ once more, is separated.In organic phase, add 25% ammoniacal liquor 110g once more.This mixture is heated to 80 ℃ once more, is separated.With 1.5 hours organic phase is cooled to 0～5 ℃.Filter and collect product, with toluene 50ml washing.Should wet product 40～50 ℃ of vacuum-dryings.
Output: 52g, fusing point 156.3-157.5 ℃, yield 70%.
Embodiment 15
(1S, 2S, 3S, 4R, 1`S)-and 3-[(1`-amino-2`-ethyl) butyl]-4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-preparation of 2-hydroxy-cyclopentane-1-carboxylate methyl ester
Add the 1100ml tetrahydrofuran (THF) in the 3L round-bottomed flask, gradation adds 30g (0.790mol) lithium aluminum hydride.Be added dropwise to (3aR, 4R, 6S under stirring, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is [the 1000ml tetrahydrofuran solution of d] isoxazole-6-carboxylate methyl ester (compound VI) 185g (0.523mol) also.1.5 hour add back flow reaction 4 hours.Cooling is poured reaction solution in the 2000ml soluble tartrate saturated aqueous solution of sodium into.After telling organic layer, water layer extracts with ether 1000ml * 2, merges the organic layer anhydrous magnesium sulfate drying.The evaporated under reduced pressure solvent adds the methyl alcohol thermosol, cooling, crystallization.Filter drying.
Get white solid (compound VI I) 152g, fusing point 157.1-158.4 ℃, yield 81.1%.
1HNMR(CDCl
3)：δ0.81(m，6H)，1.21-1.57(m，14H)，1.69-1.78(m，1H)，2.02-2.07(m，1H)，2.47-2.56(m，1H)，2.80-2.86(m，lH)，2.92(d，1H)，3.68(s，3H)，4.32-4.43(m，2H)，4.89(d，1H)。Collection of illustrative plates is Fig. 3.
Embodiment 16
(1S, 2S, 3R, 4R, 1`S)-(-)-and 3-[(1`-acetylamino-2`-ethyl) butyl]-the 4-[[(amino imino) methyl] amino]-preparation of 2-hydroxy-cyclopentane-1-carboxylic acid
With (1S, 2S, 3S, 4R, l`S)-and 3-[(1`-amino-2`-ethyl) butyl]-4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-2-hydroxy-cyclopentane-1-carboxylate methyl ester (compound VI I) 140g (0.391mol) is suspended among the toluene 675ml, is cooled under 5 ℃, adds diacetyl oxide 46.5g (0.457mol) in the soup compound that forms.Mixture stirring at room 1 hour is used the 330ml solution washing of yellow soda ash 33g (0.311mol) then.Under 0-5 ℃, in organic phase, add concentrated hydrochloric acid 153.5g (1.56mol).0-10 ℃ was stirred 1 hour, told water, and organic phase water 66ml extraction merges water.0-10 ℃ is added dropwise to 30% aqueous sodium hydroxide solution 239g toward aqueous phase down, keeps temperature to continue to stir 1 hour.0-30 ℃ adds hydrochloric acid pyrazoles carbonamidine 71.5g (0.484mol) toward above-mentioned light yellow muddy aqueous phase down.Suspension stirred 15 minutes.The aqueous sodium hydroxide solution of adding 30% is transferred to 8.4 with the pH value of solution value, obtains clarifying yellow solution.The stirring at room crystallization.Filter, cold water 66ml washes, drying.
Get white solid 106g, fusing point 256.3-257.7 ℃, yield 82.7%
1HNMR(D
2O)：δ0.84(m，3H)，0.89(m，3H)，0.92-1.02(m，2H)，1.40(m，2H)，1.73-1.79(m，1H)，1.92(s，3H)，2.13-2.21(m，1H)，2.45-2.54(m，1H)，2.64-2.59(m，1H)，3.76-3.83(m，1H)，4.28-4.33(m，2H)。Collection of illustrative plates is Fig. 4.
Product
13CNMR spectrogram, MS spectrogram and infrared spectrum are Fig. 5, Fig. 6 and Fig. 7.
Claims (10)
1, a kind of synthetic method of Peramivir, described method comprises: so that 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is raw material, process: open loop step I), amido protecting, Step II) Diels-Alder addition, Step II I) reductive ring open and step IV) acetylize, hydrolysis methyl esters, go up carbonamidine, make Peramivir; It is characterized in that described step I) comprising: (±) 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is dissolved in the methyl alcohol, dripping hydrochloric acid methyl alcohol, open loop adds L tartrate and splits and obtain L tartrate (1S, 4R) 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester.
2, the described synthetic method of claim 1 is characterized in that, the hydrogenchloride described in the step (I) in the hydrochloric acid methanol and reactant (±) 2-azabicyclo [2.2.1] heptan-mol ratio of 5-alkene-3-ketone is 1.20: 1-1.35: 1.
3, the described synthetic method of claim 2 is characterized in that, the hydrogenchloride described in the step (I) in the hydrochloric acid methanol and reactant (±) 2-azabicyclo [2.2.1] heptan-mol ratio of 5-alkene-3-ketone is 1.30: 1.
4, the described synthetic method of claim 1 is characterized in that, the concentration range of hydrochloric acid methanol is a 20-40% weight described in the step (I), is preferably 32%-40% weight.
5, a kind of synthetic method of Peramivir, described method comprises: so that 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is raw material, process: open loop step I), amido protecting, Step II) Diels-Alder addition, Step II I) reductive ring open and step IV) acetylize, hydrolysis methyl esters, go up carbonamidine and make Peramivir; It is characterized in that, described Step II) comprising: the chlorine oxime solution of 2-ethyl butyraldehyde preparation slowly is added dropwise to (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] encircle in penta-2-alkene-1-carboxylic acid (compound IV) solution and carry out the Diels-Alder addition, handle with alkali extraction and acid precipitation afterwards, add the hydrochloric acid methanol esterification and obtain (3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is [d] isoxazole-6-carboxylate methyl ester also.
6, the described synthetic method of claim 5, it is characterized in that, Step II) described in described chlorine oxime by 2-ethyl butyraldehyde preparation slowly is added dropwise to (1S, 4R)-(-)-methyl-[[(1,1 dimethyl oxyethyl group) carbonyl] amino] encircle in penta-2-alkene-1-carboxylic acid (compound IV) solution and carry out the Diels-Alder addition, the dropping time of described slow dropping was at least 5 hours, was preferably 5-7 hour.
7, the described synthetic method of claim 5 is characterized in that Step II) described in the alkali extraction and acid precipitation employed alkali be aqueous sodium hydroxide solution, employed acid is for example formic acid and/or acetate of middle strong acid.
8, the described synthetic method of claim 5 is characterized in that Step II) described in the pH value of hydrochloric acid methanol be 3-4.
9, a kind of synthetic method of Peramivir, comprise the steps: so that 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is raw material, through step I) open loop, amido protecting, Step II) Diels-Alder addition, Step II I) acetylize reductive ring open, step IV), hydrolysis methyl esters, goes up carbonamidine and make Peramivir; It is characterized in that, described Step II I) comprising: (3aR, 4R, 6S, 6aS)-(+)-and 4-[[(1,1 dimethyl oxyethyl group) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6, also [d] isoxazole-6-carboxylate methyl ester comes reductive ring open with lithium aluminum hydride as reductive agent to 6a-tetrahydrochysene-4H-pentamethylene.
10, the described synthetic method of claim 9, it is characterized in that, described Step II I) also comprises, obtain (1S with saturated soluble tartrate sodium water solution processing, 2S, 3S, 4R, 1`S)-and 3-[(1`-amino-2`-ethyl) butyl]-4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-2-hydroxy-cyclopentane-1-carboxylate methyl ester.
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| CN102603577A (en) * | 2011-01-19 | 2012-07-25 | 董慧珍 | Derivatives of anti-influenza and anti-avian influenza medicament and application thereof |
| CN102757365A (en) * | 2011-04-29 | 2012-10-31 | 上海泓博智源医药技术有限公司 | New method for preparing peramivir key intermediate |
| WO2012145932A1 (en) * | 2011-04-29 | 2012-11-01 | Pharmaresources (Shanghai) Co., Ltd. | A novel process for the preparation of peramivir and intermediates thereof |
| CN102796056A (en) * | 2012-08-23 | 2012-11-28 | 湖北丽益医药科技有限公司 | Peramivir intermediate and preparation method for analogue |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20010024743A (en) * | 1997-12-17 | 2001-03-26 | 몽고메리 죤 에이 | Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors |
| IL147243A0 (en) * | 1999-06-28 | 2002-08-14 | Biocryst Pharm Inc | Process for preparing (-)-(1s,4r) n-protected 4-amino-2-cyclopentene-1-carboxylate esters |
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2008
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| CN101538228B (en) | 2012-05-30 |
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