CN102372657B - Synthesis method of anti-influenza and avian influenza virus resistant medicine peramivir - Google Patents
Synthesis method of anti-influenza and avian influenza virus resistant medicine peramivir Download PDFInfo
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Abstract
The invention belongs to the synthesis technical field of organic medicine, and discloses a synthesis method of anti-influenza and avian influenza virus resistant medicine peramivir, which is characterized by adopting (1R, 4S)-2-azabicyclo[2.2.1]hept-5-en-3-one as a raw material and by comprising the following steps: step I: catalyzing, loop-opening and amino protection; step II: 1,3-dipolarcycloaddition; step II: sodium borohydride and nickel chloride hexahydrate reduction and acetylization; and step IV: amino protection removal, and chloroformamidine hydrochloride is adopted as reaction agent to generate guanidyl and hydrolysis methyl ester to prepare peramivir. The sodium borhydride and the nickelous chloride reduction system is used for substituting the expensive platinum dioxide to be used as reducing agent during the hydrogenation reduction process, and the self-produced chloroformamidine hydrochloride is used during the process for feeding the guanidyl reagent, so the cost is reduced, and the operation procedures are simplified. The synthesis method has short reaction routine and moderate reaction condition, is simple and convenient to operate, has low cost, and is suitable for the industrialized production.
Description
Technical field
The invention belongs to organic drug synthesis technical field, specifically, the present invention relates to the synthetic method of a kind of anti influenza and avian influenza cytotoxic drug and influenza virus neuraminidase inhibitor Peramivir.
Background technology
Influenza is called for short influenza, is a kind of acute respiratory disease being caused by influenza virus, has infectivity strong, and velocity of propagation is fast, M & M high.
The structure of influenza virus is in fact also uncomplicated, and it is an Oil globule, and eight sections of RNA chains are equipped with in the inside, and there is much important albumen on ball surface, they as " nail " " nail " on surface, its structural representation is shown in Fig. 1.These " nails " are divided into two classes, and a class is hemagglutinin (HA), and effect is virus infection host cell, and another kind of is neuraminidase (NA), and they are responsible for cutting off host cell, have determined the efficiency of virus disseminating.Therefore, neuraminidase plays a crucial role in the process of influenza virus infection host cell.
The neuraminidase of influenza and avian influenza virus claims again sialidase, to be present in the glucoproteinase on influenza virus surface, can promote newborn influenza virus to discharge from the sialic acid residues of host cell, accelerate other host cell of influenza infection, in viral reproduction process, play a part crucial.Therefore, the brand-new target spot that has been found to be Effect of Anti influenza virus drug provision of influenza neuraminidase.
Peramivir, English name is Peramivir, chemistry (-)-(1S by name, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-guanidine basic ring penta-1-carboxylic acid, structural formula is suc as formula shown in I, it is a kind of Novel cyclopentane derivatives parainfluenza virus neuraminidase (NA) inhibitor of U.S. BioCryst drugmaker exploitation, this medicine can effectively suppress copying and communication process of various strains of influenza viruses, and there is better tolerance, untoward reaction is few and be not prone to the advantages such as resistance.U.S. FDA was promptly ratified this medicine and was used for the treatment of H1N1 type influenza in October, 2009.In January, 2010, Peramivir was gone on the market in Japan.
Formula I
The synthetic method bibliographical information of Peramivir is less, mainly patent application CN1282316A, the CN1227466A of U.S. BioCryst drugmaker, the synthetic method that CN1358170A, CN1367776A etc. disclose Peramivir and important intermediate thereof, wherein CN1282316A, CN1227466A have openly reported the synthetic method as the substituted cyclopentane derivative compound of neuraminidase inhibitor, comprise the report of the synthetic method of Peramivir.CN1358170A has openly reported chiral separation method and the synthetic method of Peramivir intermediate (-)-(1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.CN1367776A has openly reported that take literary composition this lactone and 2-ethyl butyraldehyde is main raw material, through catalysis open loop, amido protecting, 1, and the cycloaddition of 3-dipole, the steps such as hydro-reduction, N-acetylize, deprotection, upper guanidine radicals and hydrolysis methyl esters have been synthesized Peramivir.
The main synthetic route of BioCryst drugmaker Peramivir is as follows:
This synthetic route be take (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone as being raw material, through the synthetic Peramivir of nine steps reactions, route is longer, yield is low.The use of highly toxic benzene in the cycloaddition process and phenyl isocyanate; and the hydrogenation process, the use of more expensive platinum dioxide as catalyst, hydrogen reduction needs in the safe operation of high demand; in the guanidine reagent used in the process of toxic mercury chloride, resulting in environmental pollution, is not suitable for industrial production.
The domestic not yet approval of this medicine listing.The application has studied a kind of synthesis technique of new Peramivir, has reduced production cost, is conducive to industrialization.Anti-avian influenza medicine is current clinical more rare kind.The production of this medicine has good market outlook, and will produce good economic benefit and social benefit.
Summary of the invention
For overcoming the deficiency in existing Peramivir synthetic method, primary and foremost purpose of the present invention be to provide a kind of easy and simple to handle, cost is lower, be more suitable for the anti influenza of suitability for industrialized production and the synthetic method of avian influenza cytotoxic drug Peramivir.
Object of the present invention is achieved through the following technical solutions:
A synthetic method for anti influenza and avian influenza cytotoxic drug Peramivir, the method is that take (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone (being designated as (1)) is raw material, comprises the following steps:
I, catalysis open loop, amido protecting: (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone (1) is dissolved in absolute methanol solution, under hydrogen chloride gas catalysis, react, make (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (being designated as (2)); Then by (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2), protective material and alkali are mixed in normal hexane, after dripping water, react, make (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (being designated as (3));
II, 1,3-dipole cycloaddition: (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) and 2-ethyl butyraldehyde oxime and sodium hypochlorite reaction, obtain (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [d] isoxazole-6-carboxylate methyl ester (being designated as (4));
III, hydro-reduction, N-acetylize: at (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [adds Nickel dichloride hexahydrate and sodium hydroxide in the methanol solution of d] isoxazole-6-carboxylate methyl ester (4), after adding sodium borohydride, reaction makes (1S in batches again, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (being designated as (5));
By (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5) adds in methylene dichloride, then add successively diacetyl oxide and triethylamine, under room temperature, react, obtain (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (being designated as (6));
IV, deaminizating protect, take chlorine amidine as reagent generation guanidine radicals and methyl esters hydrolysis: (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (6) is in anhydrous diethyl ether, under hydrogen chloride gas catalysis, reaction obtains (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride (being designated as (7));
(1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride (7) reacts with hydrochloric acid chloromethane amidine, then under alkaline condition, is hydrolyzed, obtain (-)-(1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-guanidine basic ring penta-1-carboxylic acid, i.e. Peramivir.
The synthetic route of Peramivir of the present invention is as follows:
In the synthetic method of above-mentioned Peramivir, in described step I and step IV, the preparation method of hydrogen chloride gas is as follows: 25～30g sodium-chlor is put in reaction flask, slowly drip 30～40ml vitriol oil, after the gas producing is dried by the vitriol oil, obtain hydrogen chloride gas, hydrogen chloride gas is directly passed in reaction soln and reacted.The massfraction of the described vitriol oil is 98%.
In described step I, (1S, the preparation process of 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2) is specially: by 10～15g (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone (1) is dissolved in the anhydrous methanol that 100～120ml is dry, under room temperature, stir and pass into hydrogen chloride gas 2.5～3h simultaneously, at 45～50 ℃, react 2～3h, after reaction finishes, reaction solution is concentrated into dry, obtain thick liquid, add 100～120ml ice anhydrous diethyl ether, stirring is spent the night, separate out solid, after filtering, use anhydrous diethyl ether washing leaching cake, dry, obtain (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2).
Preferably, described protective material is tert-Butyl dicarbonate, and alkali used is sodium carbonate; Described (1S, the mol ratio of 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2), tert-Butyl dicarbonate and sodium carbonate is 1: (1.2～1.5): (2.5～3), the amount of substance of described normal hexane is (1S, 30～40 times of 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2), can guarantee the carrying out of reaction; Many 10～the 20ml of volume ratio normal hexane of water.
Described (1S, the preparation process of 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) is specially: by (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride joins in normal hexane, then add successively sodium carbonate and tert-Butyl dicarbonate, stir the lower water that drips; Dropwise under rear room temperature and react 8～10h, after reaction bundle, separate organic layer, freezing after, mistake chromatographic column dry through wash, be dried, being concentrated into, obtain (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.Described washing is water and saturated nacl aqueous solution washing successively; Described being dried is with anhydrous sodium sulfate drying 4～6h; The described chromatographic column of crossing is that dry gained material be take to the petrol ether/ethyl acetate of mixing for 8: 1 is by volume moving phase, crosses silica gel chromatographic column.
In the synthetic method of a kind of anti influenza provided by the invention and avian influenza cytotoxic drug Peramivir, 1 of described Step II, in 3-dipole cyclisation addition process, (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) and 2-ethyl butyraldehyde oxime, sodium hypochlorite reaction, obtain molecular formula respectively suc as formula II-1, formula II-2, four kinds of steric isomer compounds shown in formula II-3 and formula II-4, wherein suc as formula the compound (3aR shown in II-1, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4, 5, 6, [d] isoxazole-6-carboxylate methyl ester (being designated as (4)) is primary product to 6a-tetrahydrochysene-3aH-cyclopentyl.
Formula II-1 formula II-2
Formula II-3 formula II-4
In above reaction process, temperature of reaction is lower, and 2-ethyl butyraldehyde oxime generates intermediate nitrile oxide under the effect of clorox, and its structural formula is:
there is the addition of 1,3-dipole-ring with reaction substrate in this material, obtain above four kinds of steric isomer compounds under the condition of controlling temperature.
Described 2-ethyl butyraldehyde oxime is that 2-ethyl butyraldehyde reacts and makes with oxammonium hydrochloride, and reaction scheme is as follows:
The preparation process of described 2-ethyl butyraldehyde oxime is: 9～12g oxammonium hydrochloride and 12～18g sodium carbonate are dissolved in 80～100ml water, reaction is to no longer producing after bubble, at 0～5 ℃, drip the ethanolic soln 60～80ml containing 12～17g2-ethyl butyraldehyde, after dropwising, under room temperature, reaction is spent the night, after reaction finishes, with frozen water, be diluted to 800～1000ml, with merging organic phase after extracted with diethyl ether, wash successively, be dried, be concentrated into the dry rear chromatographic column of crossing, obtain 2-ethyl butyraldehyde oxime.
Described (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4, 5, 6, [the concrete preparation process of d] isoxazole-6-carboxylate methyl ester (4) is 6a-tetrahydrochysene-3aH-cyclopentyl: at-5～10 ℃, to containing (1S, in the dichloromethane solution of 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) and 2-ethyl butyraldehyde oxime, slowly drip chlorine bleach liquor, make reacting liquid temperature be no more than 0～5 ℃, after dripping, at 0～5 ℃, continue reaction 30min～1h, then at room temperature react 18～20h, after reaction finishes, isolate organic layer, through washing, dry, be concentrated into dry, after crossing chromatographic column, be dried, obtain (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4, 5, 6, 6a-tetrahydrochysene-3aH-cyclopentyl [d] isoxazole-6-carboxylate methyl ester (4).The mass content of described chlorine bleach liquor's available chlorine is 10%.
Preferably, described (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) is 1 with the mol ratio of reacting of diethyl butyraldehyde oxime, clorox: (3～3.5): (10～15), the amount of substance of described methylene dichloride is (1S, the material of 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) 25～30 times, can guarantee reaction carrying out.
In the synthetic method of a kind of anti influenza provided by the invention and avian influenza cytotoxic drug Peramivir, in the hydro-reduction of described Step II I, the acetylizad operation of N-, preferably, described (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5, [d] isoxazole-6-carboxylate methyl ester (4) is 1 with the mol ratio of sodium borohydride, Nickel dichloride hexahydrate, sodium hydroxide to 6,6a-tetrahydrochysene-3aH-cyclopentyl: (2～2.5): (1～1.2): 0.05; For guaranteeing that reduction fully, the amount of substance of described Nickel dichloride hexahydrate is at least (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [1 times of d] isoxazole-6-carboxylate methyl ester (4) amount of substance.
Described preparation (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] reaction of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5) is at N
2under protective condition, carry out; describedly slowly add in the process of sodium borohydride in batches; sodium borohydride adds in 10～15min; and control temperature of reaction and be no more than 0～5 ℃; after adding, at 0～-5 ℃ of reaction 2～3h, reaction product obtains (1S, 2S after separation and purification; 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5).
Described separation and purification need to be used Sodium Nitrite and ammonium chloride, the detailed process of separation and purification is: as reactant (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4, 5, 6, 6a-tetrahydrochysene-3aH-cyclopentyl is [when the consumption of d] isoxazole-6-carboxylate methyl ester is 4.9～7.5g, reaction product is concentrated into dry, add Sodium Nitrite 1～2g, ammonium chloride 3～5g and ammoniacal liquor 100～120ml, under room temperature, stir 16～18h, after suction filtration by gained solid drying, obtain (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5).The mass concentration of described ammoniacal liquor is 25～28%.
Described (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] in the preparation process of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (6), (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] consumption of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5) is 2～4.8g, and the consumption of diacetyl oxide is 1.0～2.5ml, and the consumption of triethylamine is 1～2ml; The consumption of described methylene dichloride is 10～60ml.
Described adding after diacetyl oxide, triethylamine, the time of reacting under room temperature is 6～8h, after reaction finishes, reaction solution is concentrated into dry, add a small amount of water to be formulated as solution, after dichloromethane extraction, merge organic phase, then through washing, be dried, be concentrated into after dry, cross chromatographic column, then after dry, obtain (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (6).
In the synthetic method of a kind of anti influenza provided by the invention and avian influenza cytotoxic drug Peramivir; the process of the deprotection of described step IV, upper guanidine radicals and hydrolysis methyl esters specifically comprises deaminizating protection, take chlorine amidine as reagent generation guanidine radicals and the esterolytic reaction process of first; in this step; described hydrochloric acid chloromethane amidine is that the cyanamide aqueous solution reacts and makes at low temperatures with concentrated hydrochloric acid in ether, and reaction scheme is as follows:
The concrete preparation process of hydrochloric acid chloromethane amidine is: the cyanamide aqueous solution 5～10g that is 50% by mass concentration joins in 20～40ml ether, at 0～5 ℃, add concentrated hydrochloric acid 30～50ml, make reacting liquid temperature be no more than 5 ℃, after adding, under room temperature, react 2～3h; After reaction finishes, ether in reaction solution is concentrated into dry, separates out white crystal after freezing, through suction filtration, anhydrous diethyl ether washing and dry, obtain hydrochloric acid chloromethane amidine.Described concentrated hydrochloric acid is that massfraction is 36～38% hydrochloric acid.
Described (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] preparation process of butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride (7) is specially: by (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (6) 4～8.4g are dissolved in the anhydrous diethyl ether that 80～120ml is dry, under room temperature, pass into dry hydrogen chloride gas 1～2h, no longer pass into hydrogen chloride gas, while passing into hydrogen chloride gas, adularescent solid is separated out immediately; Then under room temperature, react 10～12h, reaction finishes rear, suction filtration, use anhydrous diethyl ether washing leaching cake, gained solid, through super-dry, obtains (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride (7).
Then by (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride (7) 1.2～2g and hydrochloric acid chloromethane amidine 1.23～4g be dissolved in N, in dinethylformamide 20～30ml, add triethylamine 1.8～2.3ml, under room temperature, reaction is spent the night, filter, in filtrate, add 10～12ml water and 2N NaOH solution 9～15ml, stirring reaction 6～8h under room temperature, after reaction finishes, steam solvent, add a small amount of water, obtained aqueous solution is through ion exchange resin treatment and collect elutriant, after elutriant is concentrated, obtain solid, water/methanol solvate the recrystallization that is 1: 9 by volume ratio, drying again, obtain (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine basic ring penta-1-carboxylic acid, it is Peramivir.
In the process of described ion exchange resin treatment, storng-acid cation exchange resin used, by aqueous solution loading to resin, water is washed to neutrality by highly acid Zeo-karb, then the ammoniacal liquor wash-out that is 8～10% by mass concentration, collects elutriant, is concentrated into dry; Described being dried as at 40 ℃ of vacuum-drying 4～6h.
Compared with prior art, tool of the present invention has the following advantages and beneficial effect:
1. on the further investigation basis to existing synthetic method, by a large amount of experiments, invented the improvement synthetic route of Peramivir, take (1R, 4S)-2-of this route azabicyclic [2.2.1] heptan-5-alkene-3-ketone is raw material, through 7 step reactions, make Peramivir, total recovery is 36.4%; This synthetic route is shorter, and reaction conditions is gentle, easy and simple to handle, is applicable to suitability for industrialized production.
2 in the hydrogenation process, the use of sodium borohydride and nickel chloride to restore the system to replace the expensive platinum dioxide as a reducing agent, reduces costs, simplifies operation, high security....
3. in the process of upper guanidinated reagent, use homemade hydrochloric acid chloromethane amidine to replace the domestic N without manufacturer production, N-bis-tertbutyloxycarbonyls-S-methyl-isothiourea, avoided the use of poisonous reagent mercury chloride, reduced cost, avoid the generation of heavy metal waste liquid, avoided contaminate environment, be applicable to industrial production.
4. in the present invention, on the purification process of Peramivir, improve to some extent, by test of many times, find to use highly acid Zeo-karb, can purifying Peramivir.
Accompanying drawing explanation
Fig. 1 is the structural representation of influenza virus.
Fig. 2 is the 1H NMR collection of illustrative plates of (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.
Fig. 3 is the 13C NMR collection of illustrative plates of (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.
Fig. 4 is (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [1H NMR collection of illustrative plates of d] isoxazole-6-carboxylate methyl ester.
Fig. 5 is (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [13C NMR collection of illustrative plates of d] isoxazole-6-carboxylate methyl ester.
Fig. 6 is (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] the 1H NMR collection of illustrative plates of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester.
Fig. 7 is (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] the 13C NMR collection of illustrative plates of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester.
Fig. 8 is (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] the 1H NMR collection of illustrative plates of butyl-4-guanidine basic ring penta-1-carboxylic acid.
Fig. 9 is (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] the 13C NMR collection of illustrative plates of butyl-4-guanidine basic ring penta-1-carboxylic acid.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Be below the Preparation Example of Peramivir, comprise following 9 parts:
The preparation of 1, (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride
10g (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is dissolved in the anhydrous methanol that 120ml is dry, under room temperature, stirs and pass into dry hydrogen chloride gas 3h, no longer pass into hydrogen chloride gas; At 50 ℃, react 2h, TLC monitoring.After reaction finishes, reaction solution is concentrated into dry black viscous liquid, the anhydrous diethyl ether to adding 120ml ice in this thick liquid, stirs and spends the night under room temperature, separates out white solid, and suction filtration, uses anhydrous diethyl ether washing leaching cake, obtains white solid; 40 ℃ of vacuum-drying 6h, obtain white solid 15.6g, be (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride; Yield 96%.
Wherein the preparation method of hydrogen chloride gas is as follows: 30g sodium-chlor is dropped in 250ml there-necked flask, under normal temperature, by constant pressure funnel, slowly dripping 40ml massfraction is that 98% the vitriol oil is in sodium-chlor, with rubber plug by bottleneck jam-pack, the hydrogenchloride that reaction is produced passes in the vitriol oil and is dried with conduit, then with conduit, pass in reaction flask and react, the stopping property of whole device is good, and connects suck-back device.
The preparation of 2, (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester
By (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride 5g (28mmol) joins in 60ml hexane solution, then add successively sodium carbonate 8.9g (84mmol), tert-Butyl dicarbonate 7.3g (34mmol), under agitation drip water 80ml; After dropwising, at room temperature react 8h, TLC monitoring.After reaction finishes, separate organic layer, water layer, with ethyl acetate extraction three times, merges organic layer, washes with water successively and saturated nacl aqueous solution is washed, and then uses anhydrous sodium sulfate drying 6h, is concentrated into dry faint yellow oily matter; By this faint yellow oily matter take 8: 1 by volume preparation petrol ether/ethyl acetate solvent be moving phase, cross fast silica gel chromatographic column and obtain colourless oil liquid, after freezing, make white solid 6.4g, be (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester; Fusing point 35.4-36.9; Yield 94%.
The 1H NMR collection of illustrative plates of (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester as shown in Figure 2,
1h NMR (300MHz, CDCl
3) δ 5.74 (m, 2H), 4.95-4.97 (d, 1H), 4.65 (m, 1H), 3.58 (s, 3H), 3.35-3.37 (m, 1H), 2.34-2.38 (ddd, 1H), 1.71-1.77 (ddd, 1H), 1.32 (s, 9H).
The 13C NMR collection of illustrative plates of (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester as shown in Figure 3,
13c NMR (75MHz, CDCl
3) δ 175.06,155.26,134.97,131.21,79.40,55.89,52.27,49.27,34.66,28.52.
3, the preparation of 2-ethyl butyraldehyde oxime
Oxammonium hydrochloride 12g (172mmol), sodium carbonate 18g (170mmol) are dissolved in 100ml water, reaction, to no longer producing after bubble, drips the ethanolic soln 80ml of 2-ethyl butyraldehyde 17g (148mmol), after dropwising at 0 ℃, under room temperature, reaction is spent the night, TLC monitoring.After reaction finishes, with frozen water, be diluted to 1000ml, by extracted with diethyl ether three times, merge organic phase, wash successively, saturated nacl aqueous solution is washed, and anhydrous sodium sulfate drying 6h is concentrated into dry colourless oil liquid; It is moving phase that this colourless oil liquid be take to the petrol ether/ethyl acetate solvent of preparation in 10: 1 by volume, and the quick silica gel chromatographic column of crossing, obtains colourless oil liquid 17.5g, is 2-ethyl butyraldehyde oxime, yield 90%.
4, (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6, [the preparation of d] isoxazole-6-carboxylate methyl ester of 6a-tetrahydrochysene-3aH-cyclopentyl
By (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester 5g (20.7mmol) and 2-ethyl butyraldehyde oxime 7.2g (62.1mmol) join in methylene dichloride 60ml, at-10 ℃, slowly drip clorox (effective chlorine density Cl%=10%) 74ml (207mmol) solution, make reacting liquid temperature be no more than 0～5 ℃, after dropwising, at 5 ℃, continue reaction 1 hour, then at room temperature react 20h, reaction solution becomes green from light green and is becoming light green, TLC monitoring.After reaction finishes, separate organic layer, dichloromethane extraction three times for water layer, merges organic layer, washing successively, and saturated nacl aqueous solution is washed, and anhydrous sodium sulfate drying 6h is concentrated into dry pale yellow oily liquid body; It is moving phase that this pale yellow oily liquid body be take to the petrol ether/ethyl acetate solvent of preparation in 9: 1 by volume, crosses silica gel chromatographic column, obtains white cotton-shaped solid; 40 ℃ of vacuum-drying 6h, obtain white cotton-shaped solid 4.94g, are (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [d] isoxazole-6-carboxylate methyl ester; Fusing point 108.5-110.2, yield 67.6%.
(3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [Fig. 4 is shown in by the 1H NMR collection of illustrative plates of d] isoxazole-6-carboxylate methyl ester,
1h NMR (300MHz, CDCl
3) δ 5.57-5.59 (d, 1H), 5.17-5.20 (d, 1H), 4.19 (m, 1H), 3.73 (s, 3H), 3.54-3.57 (d, 1H), 3.16 (d, 1H), 2.48 (m, 1H), 1.97-2.06 (m, 2H), 1.61-1.63 (m, 4H), 1.41 (s, 9H), 0.83-0.93 (tt, 6H).
(3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [Fig. 5 is shown in by the 13C NMR collection of illustrative plates of d] isoxazole-6-carboxylate methyl ester,
13c NMR (75MHz, CDCl
3) δ 175.18,161.22,155.03,87.11,79.58,63.51,55.65,52.60,52.18,40.55,33.44,28.43,25.70,24.03,11.12,10.84.
5, (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] preparation of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester
By (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5, [d] isoxazole-6-carboxylate methyl ester 4.9g (13.8mmol), Nickel dichloride hexahydrate 3.3g (14mmol) and sodium hydroxide 0.028g (0.69mmol) join in anhydrous methanol 60ml, at N 6,6a-tetrahydrochysene-3aH-cyclopentyl
2under protection and-5 ℃ of conditions; by dry application of sample pipe, slowly add sodium borohydride 1.3g (34.5mmol) in batches; in 10min, add sodium borohydride; make the temperature of reaction must not be over 5 ℃; reaction soln becomes black from green; constantly have gas to emit, after adding, at 0 ℃ of reaction 2h, TLC monitors.After reaction finishes, reaction solution is concentrated into dry atrament, add wherein the ammoniacal liquor 120ml that Sodium Nitrite 1g (14mmol), ammonium chloride 3g (56mmol) and mass concentration are 28%, under room temperature, stir 16h, in solution, there is canescence floss to separate out, solution becomes blue solution, and suction filtration obtains canescence floss; 40 ℃ of vacuum-drying 6h, obtain canescence floss 4.2g, are (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester; Yield 84.8%, is directly used in next step reaction by this canescence floss.
6, (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] preparation of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester
By dry complete (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester 2.7g (7.5mmol) joins in dry methylene dichloride 30ml, adding successively diacetyl oxide 1.4ml (15mmol), triethylamine 1.0ml (7.5mmol), under room temperature, react 6h, TLC monitoring.After reaction finishes, reaction solution is concentrated into dry, adds wherein a small amount of water, with dichloromethane extraction three times, merge organic phase, washing successively, saturated nacl aqueous solution is washed, and anhydrous sodium sulfate drying 6h is concentrated into dry light black liquid; It is moving phase that this light black liquid be take to the sherwood oil/acetone solvent of preparation in 3: 1 by volume, and the quick silica gel chromatographic column of crossing, obtains white solid; 40 ℃ of vacuum-drying 6h, obtain white solid 2.75g, are (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester; Its fusing point is 121.6-123.1; Yield 92%.
(1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] the 1H NMR collection of illustrative plates of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester is shown in Fig. 6,
1h NMR (300MHz, CDCl
3) δ 7.53-7.56 (d, 1H), 4.75-4.78 (d, 1H), 4.24-4.25 (d, 1H), 4.11-4.18 (m, 1H), 4.00-4.06 (m, 1H), 3.72 (s, 3H), 2.81-2.86 (m, 1H), 2.48-2.52 (ddd, 1H), 2.09 (s, 3H), 2.01 (m, 1H), 1.66-1.75 (ddd, 1H), 1.35-1.45 (m, 15H), 0.84-0.89 (t, 3H), 0.78-0.82 (t, 3H).
(1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] the 13C NMR collection of illustrative plates of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester is shown in Fig. 7,
13c NMR (75MHz, CDCl
3) δ 175.62,171.73,156.15,80.19,77.88,52.26,52.19,50.48,49.04,48.19,43.66,33.45,28.51,23.42,22.03,21.42,10.70,10.17.
7, (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] preparation of butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride
By dry complete (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester 8.4g is dissolved in the anhydrous diethyl ether that 120ml is dry, at room temperature pass into dry hydrogen chloride gas 2h, no longer pass into hydrogen chloride gas, pass into hydrogen chloride gas immediately adularescent solid separate out; Vigorous stirring reaction 12h under room temperature, TLC monitoring.Reaction finishes rear, and suction filtration, uses anhydrous diethyl ether washing leaching cake, obtains white solid; 40 ℃ of vacuum-drying 6h, obtain white solid 6.9g, are (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride; Yield 98%.The preparation of hydrogen chloride gas is identical with 1.
8, the preparation of hydrochloric acid chloromethane amidine
50% cyanamide aqueous solution 5g (containing 60mmol cyanamide) is joined in 20ml diethyl ether solution, at 0 ℃, be added dropwise to massfraction and be 38% concentrated hydrochloric acid 30ml (360mmol), make reacting liquid temperature be no more than 5 ℃, after adding, under room temperature, react 2h.Reaction finish after, ether in reaction solution is concentrated into dry, the freezing white crystal of separating out; Pumping rate, uses anhydrous diethyl ether washing leaching cake, obtains white crystal; 40 ℃ of vacuum-drying 6h.Obtain white crystal 5.6g, obtain hydrochloric acid chloromethane amidine; Yield 82%.
9, (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] preparation of butyl-4-guanidine basic ring penta-1-carboxylic acid
By (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride 1.2g (3.6mmol) and hydrochloric acid chloromethane amidine 1.23g (10.8mmol) be dissolved in dry N, in dinethylformamide 20ml, adding triethylamine 2.3ml, under room temperature, reacting and spend the night.Filter, in filtrate, add 10ml water, adding 2N NaOH solution 9ml, under room temperature, stir 6h, after reaction finishes, decompression steams most of solvent, add a small amount of water, to processed good storng-acid cation exchange resin, wash to neutrality this solution loading with water be then 10% by mass concentration ammoniacal liquor wash-out.Collect elutriant, concentrate to obtain white solid.Water/methanol solvate recrystallization by this white solid with preparation in 1: 9 by volume, obtains white solid; 40 ℃ of vacuum-drying 6h, obtain white solid 0.91g, are (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine basic ring penta-1-carboxylic acid; Yield 78%.
(1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] the 1H NMR collection of illustrative plates of butyl-4-guanidine basic ring penta-1-carboxylic acid is shown in Fig. 8,
1h NMR (600MHz, D
2o) δ 4.29-4.31 (m, 2H), 3.76-3.80 (m, 1H), 2.65-2.67 (m, 1H), 2.46-2.51 (ddd, 1H), 2.13-2.16 (m, 1H), 1.90 (s, 3H), 1.72-1.76 (m, 1H), 1.35-1.44 (m, 3H), 0.92-0.97 (m, 2H), 0.86-0.89 (t, 3H), 0.81-0.83 (t, 3H).
(1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] the 13C NMR collection of illustrative plates of butyl-4-guanidine basic ring penta-1-carboxylic acid is shown in Fig. 9,
13c NMR (150MHz, D
2o) δ 181.67,173.70, and 155.63,75.41,55.23,54.12,50.35,49.96,43.43,34.04,22.83,21.92,20.96,12.15,11.30.
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (9)
1. a synthetic method for anti influenza and avian influenza cytotoxic drug Peramivir, is characterized in that comprising the following steps:
I, catalysis open loop, amido protecting: (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is dissolved in after anhydrous methanol, under hydrogen chloride gas catalysis, reacts, make (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride; Then (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride, protective material and alkali are mixed and are added in normal hexane, after dropping water, react make (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester; Described protective material is tert-Butyl dicarbonate;
II, 1,3-dipole cycloaddition: (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester and 2-ethyl butyraldehyde oxime and sodium hypochlorite reaction, make (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [d] isoxazole-6-carboxylate methyl ester;
III, hydro-reduction, N-acetylize: at (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [adds Nickel dichloride hexahydrate and sodium hydroxide in the methanol solution of d] isoxazole-6-carboxylate methyl ester, after adding sodium borohydride again, react in batches, make (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester;
By (1
s, 2
s, 3
r, 4
r)-2-hydroxyl-3-[(1
s)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester adds in methylene dichloride, then add successively diacetyl oxide and triethylamine, and under room temperature, react, make (1
s, 2
s, 3
r, 4
r)-2-hydroxyl-3-[(1
s)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester;
IV, deaminizating protect, take hydrochloric acid chloromethane amidine as reagent generation guanidine radicals and methyl esters hydrolysis: by (1
s, 2
s, 3
r, 4
r)-2-hydroxyl-3-[(1
s)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester 4～8.4g is dissolved in 80～120ml anhydrous diethyl ether, pass into hydrogen chloride gas 1～2h, under room temperature, react 10～12h, reaction finishes rear suction filtration, by solid drying, obtain (1
s, 2
s, 3
r, 4
r)-2-hydroxyl-3-[(1
s)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride;
Then, by (1
s, 2
s, 3
r, 4
r)-2-hydroxyl-3-[(1
s)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride 1.2～2g mixes and adds 20～30ml N with hydrochloric acid chloromethane amidine 1.23～4.0g, in dinethylformamide, add 1.8～2.3ml triethylamine, under room temperature, reaction is spent the night, filter, in filtrate, add 10～12ml water and 2N NaOH solution 9～15ml, stirring at room reaction 6～9h, after finishing, reaction steams solvent, add water wiring solution-forming, elutriant is processed and collected to spent ion exchange resin, and the concentrated solid obtaining of elutriant is dry after recrystallization, obtains (1
s, 2
s, 3
r, 4
r)-2-hydroxyl-3-[(1
s)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine basic ring penta-1-carboxylic acid.
2. synthetic method according to claim 1, it is characterized in that: in described step I and step IV, the preparation method of hydrogen chloride gas is: 25 ~ 30g sodium-chlor is added in reaction flask, drip 30 ~ 40ml vitriol oil, by the gas of generation pass in the vitriol oil dry after, make hydrogen chloride gas, this hydrogen chloride gas is directly passed in reaction soln and reacted; The massfraction of the described vitriol oil is 98%.
3. synthetic method according to claim 1, it is characterized in that: in described step I, (1S, the concrete preparation process of 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride is: by 10 ~ 15g (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is dissolved in 100ml ~ 120ml anhydrous methanol, under agitation condition, pass into hydrogen chloride gas 2.5 ~ 3h, at 45 ~ 50 ℃, react 2h ~ 3h, after reaction finishes, reaction solution is concentrated into dry, obtain thick liquid, add 100 ~ 120ml ice anhydrous diethyl ether, stirring is filtered after spending the night, dry, obtain (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride,
In described step I, (1S, 4R)-4-(tertbutyloxycarbonyl) preparation process of amino-2-cyclopentenyl-1-carboxylate methyl ester is specially: by (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride adds in normal hexane, add successively alkali and protective material, under agitation condition, drip water; Dropwise under rear room temperature and react 8h ~ 10h, after reaction finishes, separate organic layer, freezing after washing, be dried, be concentrated into dry and mistake chromatographic column, obtain (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester; Wherein, described alkali is sodium carbonate; The mol ratio of described (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride and tert-Butyl dicarbonate, sodium carbonate is 1:(1.2 ~ 1.5): (2.5 ~ 3); The amount of substance of described normal hexane is 30 ~ 40 times of amount of substance of (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride, the many 10 ~ 20ml of volume ratio normal hexane of the water dripping in reaction.
4. synthetic method according to claim 1, it is characterized in that: in described step II, the preparation process of 2-ethyl butyraldehyde oxime is: 6 ~ 12g oxammonium hydrochloride and 8 ~ 18g sodium carbonate are dissolved in 80 ~ 100ml water, to not producing after bubble, at 0 ~ 5 ℃, drip the ethanolic soln 70 ~ 80ml containing 6 ~ 17g 2-ethyl butyraldehyde, under room temperature, reaction is spent the night, after reaction finishes, add frozen water to be diluted to 800 ~ 1000ml, with merging organic phase after extracted with diethyl ether, wash successively, be dried, be concentrated into the dry rear chromatographic column of crossing, obtain 2-ethyl butyraldehyde oxime.
5. synthetic method according to claim 1, it is characterized in that: the concrete operations of described step II are: at-5 ~-10 ℃, by (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester and 2-ethyl butyraldehyde oxime are dissolved in methylene dichloride, slowly drip chlorine bleach liquor, make reacting liquid temperature be no more than 0～5 ℃, after dropwising, at 0～-5 ℃, react 30min～1h, then at room temperature react 18～20h, after reaction finishes, separate organic layer, through washing, dry, be concentrated into dry, after crossing chromatographic column, be dried, obtain (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4, 5, 6, 6a-tetrahydrochysene-3aH-cyclopentyl [d] isoxazole-6-carboxylate methyl ester, described chlorine bleach liquor's available chlorine quality percentage composition is 10%,
Wherein, described (1S, 4R)-4-(tertbutyloxycarbonyl) mol ratio of amino-2-cyclopentenyl-1-carboxylate methyl ester and 2-ethyl butyraldehyde oxime, clorox is 1:(3～3.5): (10～15); The amount of substance of described methylene dichloride is (1S, 4R)-4-(tertbutyloxycarbonyl) 25 ~ 30 times of the amount of substance of amino-2-cyclopentenyl-1-carboxylate methyl ester.
6. synthetic method according to claim 1, it is characterized in that: in described step III, (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [mol ratio of d] isoxazole-6-carboxylate methyl ester, sodium borohydride, Nickel dichloride hexahydrate and sodium hydroxide is 1:(2～2.5): (1～1.2): 0.05;
The reaction of described step III is at N
2under protective condition, carry out; In the described process that in batches adds sodium borohydride, sodium borohydride adds in 10～15min, control temperature of reaction and be no more than 5 ℃, after adding, at 0～5 ℃, react 2～3h, reaction product obtains (1S after separation and purification, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester; As reactant (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [when the consumption of d] isoxazole-6-carboxylate methyl ester is 4.9 ~ 7.5 g, being operating as of described separation and purification: reaction product is concentrated into dry, add Sodium Nitrite 1～2g, ammonium chloride 3～5g and ammoniacal liquor 100～120ml, under room temperature, stir 16～18h, after suction filtration, by gained solid drying, obtain (1
s, 2
s, 3
r, 4
r)-2-hydroxyl-3-[(1
s)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester; The mass concentration of described ammoniacal liquor is 25～28%.
7. synthetic method according to claim 1, it is characterized in that: in described step III, (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] in the preparation process of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester, (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-1-amino-2-ethyl] consumption of butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester is 2～4.8g, the consumption of diacetyl oxide is 1.0～2.5ml, the consumption of triethylamine is 1～2ml, and the consumption of methylene dichloride is 10～60ml; The time of reacting under described room temperature is 6～8h; After described reaction finishes, reaction solution is concentrated into dry, adds after water wiring solution-forming with dichloromethane extraction, merge organic phase, then through wash, be dried, be concentrated into dry after mistake chromatographic column, after super-dry, obtain (1
s, 2
s, 3
r, 4
r)-2-hydroxyl-3-[(1
s)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester.
8. synthetic method according to claim 1, it is characterized in that: in described step IV, the preparation process of hydrochloric acid chloromethane amidine is: the cyanamide aqueous solution 5～10g that is 50% by cyanamide mass concentration joins in 20～40ml ether, at 0～5 ℃, adding massfraction is concentrated hydrochloric acid 30～50ml of 36～38%, make reacting liquid temperature be no more than 5 ℃, then in room temperature reaction 2～3h; After reaction finishes, reaction solution is concentrated into dry, freezing rear crystallize out, through suction filtration, with anhydrous diethyl ether washing and dry, obtains hydrochloric acid chloromethane amidine.
9. synthetic method according to claim 1, it is characterized in that: during described spent ion exchange resin is processed, institute's spent ion exchange resin is storng-acid cation exchange resin, by solution loading to resin, with deionized water, storng-acid cation exchange resin is washed with water to neutrality, then the ammoniacal liquor wash-out that is 8～10% by mass concentration, collects elutriant; Described recrystallization is the water/methanol solvate recrystallization with 1:9～5:5 mixes by volume.
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| CN114181117B (en) * | 2020-09-15 | 2023-05-05 | 南京正济医药研究有限公司 | Preparation method of peramivir intermediate |
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| CN115504908A (en) * | 2022-10-25 | 2022-12-23 | 桂林南药股份有限公司 | Preparation method of (1S, 4R) -4-tert-butoxycarbonylamino-cyclopent-2-alkenyl-1-methyl formate |
| CN116425659B (en) * | 2023-03-02 | 2023-11-03 | 浙江康聚药业有限公司 | Method for synthesizing peramivir |
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