CN102372657A - 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 the organic drug synthesis technical field, specifically, the present invention relates to the compound method of a kind of influenza and avian influenza cytotoxic drug and influenza virus neuraminidase inhibitor RWJ 270201.
Background technology
Influenza is called for short influenza, is a kind of acute respiratory disease that is caused by influenza virus, and it is strong to have infectivity, and velocity of propagation is fast, characteristics such as M & M height.
The structure of influenza virus is also uncomplicated in fact, and it is an Oil globule, and eight sections RNA chains are equipped with in the inside, and there are many important protein on the ball surface, and on the surface, its structural representation is seen Fig. 1 as " nail " " nail " for they.These " nails " are divided into two types, and one type is hemagglutinin (HA), and effect is the virus infection host cell, and another kind of is neuraminidase (NA), and they are responsible for cutting off host cell, have determined the efficient of virus disseminating.Therefore, neuraminidase plays a crucial role in the process of influenza virus infection host cell.
The neuraminidase of influenza and bird flu virus is claimed sialidase again; Be 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; Quicken other host cell of influenza infection, in the reproduction process of virus, play a part crucial.Therefore, the research anti-influenza virus medicament that is found to be of influenza neuraminidase provides a brand-new target spot.
RWJ 270201; English name is Peramivir, chemistry (-)-(1S, 2S by name; 3R; 4R)-2-hydroxyl-3-[(1S)-and 1-acetamido-2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid, structural formula is a kind of novel cyclopentane derivatives parainfluenza virus neuraminidase (NA) suppressor factor of U.S. BioCryst drugmaker exploitation suc as formula shown in the I; This medicine can effectively suppress duplicating and communication process of various strains of influenza viruses, and has better tolerance, untoward reaction is few and is not prone to advantages such as resistance.U.S. FDA was promptly ratified this medicine and was used to treat H1N1 type influenza in October, 2009.In January, 2010, RWJ 270201 went on the market in Japan.
Formula I
The compound method bibliographical information of RWJ 270201 is less; Patented claim CN1282316A, CN1227466A, CN1358170A, CN1367776A that mainly is U.S. BioCryst drugmaker etc. discloses the compound method of RWJ 270201 and important intermediate thereof; Wherein CN1282316A, CN1227466A public reported as the compound method of the substituted cyclopentane derivative compound of neuraminidase inhibitor, comprise the report of the compound method of RWJ 270201.The CN1358170A public reported RWJ 270201 midbody (-)-(1S, 4R)-chiral separation method and the compound method of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.The CN1367776A public reported be main raw material with literary composition this lactone and 2-ethyl butyraldehyde, through catalysis open loop, amido protecting, 1, the cycloaddition of 3-dipole, steps such as hydro-reduction, N-acetylize, deprotection, last guanidine radicals and hydrolysis methyl esters have been synthesized RWJ 270201.
The main synthetic route of BioCryst drugmaker RWJ 270201 is following:
This synthetic route be with (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is for being raw material, through the synthetic RWJ 270201 of nine steps reaction, route is longer, yield is low.Use the benzene and the phenyl isocyanate of severe toxicity in the cycloaddition process; And in the hydro-reduction process, use the expensive platinum dioxide of price to make catalyst, need hydrogen reducing, in safety operation, have relatively high expectations; In the process of last guanidine radicals reagent, use hypertoxic mercury chloride, caused environmental pollution, be not suitable for industrialized production.
The domestic not approval listing as yet of this medicine.The application has studied a kind of synthesis technique of new RWJ 270201, has reduced production cost, helps industrialization.The anti-avian influenza medicine is present 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 the existing RWJ 270201 compound 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 influenza of suitability for industrialized production and the compound method of avian influenza cytotoxic drug RWJ 270201.
The object of the invention is realized through following technical proposals:
The compound method of a kind of influenza and avian influenza cytotoxic drug RWJ 270201, this method be with (1R 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone (being designated as (1)) is raw material, may further comprise the steps:
I, catalysis open loop, amido protecting: (1R; 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone (1) is dissolved in the absolute methanol solution; Reaction under hydrogen chloride gas catalysis, make (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (being designated as (2)); Then will (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2), protective material be mixed in the normal hexane with alkali, dropping water afterreaction, make (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (being designated as (3));
II, 1, the cycloaddition of 3-dipole: (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, adds the Peng Qinghuana afterreaction more in batches and make (1S, 2S in the methanol solution of d] isoxazole-6-carboxylate methyl ester (4); 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (being designated as (5));
With (1S, 2S, 3R; 4R)-and 2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5) adds in the methylene dichloride, adds diacetyl oxide and triethylamine more successively, react under the room temperature; Obtain (1S; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (being designated as (6));
The protection of IV, deaminizating, be that reagent generates guanidine radicals and methyl esters hydrolysis: (1S with the chlorine amidine; 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; Reaction obtains (1S under hydrogen chloride gas catalysis; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 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)-and 1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride (7) and the reaction of hydrochloric acid chloromethane amidine, hydrolysis under alkaline condition then obtains (-)-(1S; 2S; 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetamido-2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid, i.e. RWJ 270201.
The synthetic route of RWJ 270201 of the present invention is following:
In the compound method of above-mentioned RWJ 270201; The preparation method of hydrogen chloride gas is following among said step I and the step IV: 25～30g sodium-chlor is put in the reaction flask; Slowly drip 30～40ml vitriol oil; The gas that produces through after the vitriol oil drying, is obtained hydrogen chloride gas, hydrogen chloride gas is directly fed in the reaction soln react.The massfraction of the said vitriol oil is 98%.
Among the said step I, (1S, 4R)-the preparation process of 4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2) is specially: with 10～15g (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone (1) is dissolved in 100～120ml exsiccant anhydrous methanol; Stir under the room temperature and feed hydrogen chloride gas 2.5～3h simultaneously, react 2～3h down at 45～50 ℃, after reaction finishes; Reaction solution is concentrated into dried, thick liquid, add 100～120ml ice anhydrous diethyl ether; Stirred overnight is separated out solid, filters the back and uses the anhydrous diethyl ether washing leaching cake; Drying, promptly get (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2).
Preferably, said protective material is a tert-Butyl dicarbonate, and used alkali is yellow soda ash; Said (1S; 4R)-mol ratio of 4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2), tert-Butyl dicarbonate and yellow soda ash is 1: (1.2～1.5): (2.5～3); The amount of substance of said normal hexane is (1S; 4R)-and 30～40 times of 4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride (2), can guarantee the carrying out that reacts; Many 10～the 20ml of the volume ratio normal hexane of water.
Said (1S; 4R)-the preparation process of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) is specially: with (1S; 4R)-and 4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride joins in the normal hexane, adds yellow soda ash and tert-Butyl dicarbonate then successively, stir to drip water down; Dropwise the back and react 8～10h under the room temperature, behind the reaction bundle, tell organic layer, through washing, dry, be concentrated into dried, cross after the chromatographic column freezingly, obtain (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.Said washing is water and saturated nacl aqueous solution washing successively; Said drying is with anhydrous sodium sulfate drying 4～6h; The said chromatographic column of crossing is to be moving phase with dry gained material with 8: 1 by volume blended petrol ether/ethyl acetate, crosses silica gel chromatographic column.
In the compound method of a kind of influenza provided by the invention and avian influenza cytotoxic drug RWJ 270201,1 of said Step II is in the 3-dipole cycloaddition 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 four kinds of steric isomer compounds shown in II-1, formula II-2, formula II-3 and the formula II-4; Wherein suc as formula the compound shown in the II-1 (3aR, 4R, 6S; 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4; 5,6, [d] isoxazole-6-carboxylate methyl ester (being designated as (4)) is a primary product to 6a-tetrahydrochysene-3aH-cyclopentyl.
Formula II-1 formula II-2
Formula II-3 formula II-4
In the above reaction process; Temperature of reaction is lower; 2-ethyl butyraldehyde oxime generates the midbody nitrile oxide under the effect of Youxiaolin; Its structural formula is:
this material under the condition of controlled temperature, take place 1 with reaction substrate; The cycloaddition of 3-dipole obtains above four kinds of steric isomer compounds.
Said 2-ethyl butyraldehyde oxime is that 2-ethyl butyraldehyde and oxammonium hydrochloride reaction make, and reaction scheme is following:
The preparation process of said 2-ethyl butyraldehyde oxime is: 9～12g oxammonium hydrochloride and 12～18g yellow soda ash are dissolved in 80～100ml water, after reaction extremely no longer produces bubble, drip the ethanolic soln 60～80ml that contains 12～17g2-ethyl butyraldehyde down at 0～5 ℃; After dropwising, reaction is spent the night under the room temperature, after reaction finishes; Be diluted to 800～1000ml with frozen water; With merging organic phase after the extracted with diethyl ether, wash successively, dry, be concentrated into and do the back and cross chromatographic column, obtain 2-ethyl butyraldehyde oxime.
Said (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: under-5～10 ℃, to containing (1S; 4R)-dichloromethane solution of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) and 2-ethyl butyraldehyde oxime in, slowly drip the chlorine bleach liquor, make reacting liquid temperature be no more than 0～5 ℃, drip the back and continue reaction 30min～1h down at 0～5 ℃; At room temperature react 18～20h then, after reaction finishes, isolate organic layer, through washing, dry, be concentrated into dried, cross the chromatographic column after drying; 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 said chlorine bleach liquor's available chlorine is 10%.
Preferably; Said (1S; 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) is 1 with the reaction mol ratio of diethylammonium butyraldehyde oxime, Youxiaolin: (3～3.5): (10～15); The amount of substance of said methylene dichloride be (1S, 4R)-material of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester (3) 25～30 times, can guarantee the carrying out that reacts.
In the compound method of a kind of influenza provided by the invention and avian influenza cytotoxic drug RWJ 270201, in the hydro-reduction of said Step II I, the acetylizad operation of N-, preferably; Said (3aR, 4R, 6S; 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4; 5,6, [d] isoxazole-6-carboxylate methyl ester (4) is 1 with the mol ratio of Peng Qinghuana, Nickel dichloride hexahydrate, sodium hydroxide to 6a-tetrahydrochysene-3aH-cyclopentyl: (2～2.5): (1～1.2): 0.05; For guaranteeing reduction fully, the amount of substance of said 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.
Said preparation (1S, 2S, 3R, 4R)-reaction of 2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5) is at N
2Carry out under the protective condition, saidly slowly add in the process of Peng Qinghuana in batches, Peng Qinghuana adds in 10～15min; And control reaction temperature is no more than 0～5 ℃; Add the back at 0～-5 ℃ of reaction 2～3h, reaction product obtains (1S, 2S through after the separation and purification; 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5).
Said separation and purification need be used Sodium Nitrite and ammonium chloride, and 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 [when the consumption of d] isoxazole-6-carboxylate methyl ester is 4.9～7.5g, is concentrated into reaction product dried, adds Sodium Nitrite 1～2g, ammonium chloride 3～5g and ammoniacal liquor 100～120ml; Stir 16～18h under the room temperature, with the gained solid drying, obtain (1S behind the suction filtration; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (5).The mass concentration of said ammoniacal liquor is 25～28%.
Said (1S, 2S, 3R; 4R)-the preparation process of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (6) in, (1S, 2S; 3R; 4R)-and the consumption of 2-hydroxyl-3-[(1S)-1-amino-2-ethyl] 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 said methylene dichloride is 10～60ml.
Behind said adding diacetyl oxide, the triethylamine, the time of reacting under the room temperature is 6～8h, after reaction finishes; Reaction solution is concentrated into dried, adds less water and be formulated as solution, behind dichloromethane extraction, merge organic phase; Then through washing, dry, be concentrated into and do back mistake chromatographic column, after the drying, obtain (1S again; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester (6).
In the compound method of a kind of influenza provided by the invention and avian influenza cytotoxic drug RWJ 270201; The process of the deprotection of said step IV, last guanidine radicals and hydrolysis methyl esters specifically comprises the deaminizating protection, is the reaction process of reagent generation guanidine radicals and methyl esters hydrolysis with the chlorine amidine; In this step; Said hydrochloric acid chloromethane amidine is that the cyanamide aqueous solution reacts at low temperatures with concentrated hydrochloric acid in ether and makes, and reaction scheme is following:
The concrete preparation process of hydrochloric acid chloromethane amidine is: with mass concentration is that the cyanamide aqueous solution 5～10g of 50% joins in 20～40ml ether; 0～5 ℃ adds concentrated hydrochloric acid 30～50ml down; Make reacting liquid temperature be no more than 5 ℃, after adding, under room temperature, react 2～3h; After reaction finishes, ether in the reaction solution is concentrated into dried, separates out white crystal after freezing,, obtain hydrochloric acid chloromethane amidine through suction filtration, anhydrous diethyl ether washing and dry.Said concentrated hydrochloric acid is that massfraction is 36～38% hydrochloric acid.
Said (1S; 2S, 3R, 4R)-the preparation process of 2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride (7) is specially: with (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 80～120ml exsiccant anhydrous diethyl ether, feed exsiccant hydrogen chloride gas 1～2h under the room temperature; No longer feed hydrogen chloride gas, when feeding hydrogen chloride gas immediately the adularescent solid separate out; Under room temperature, react 10～12h then, after reaction finishes the back, suction filtration; Use the anhydrous diethyl ether washing leaching cake, the gained solid obtains (1S through super-dry; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride (7).
Then will (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; Among dinethylformamide 20～30ml, add triethylamine 1.8～2.3ml, reaction is spent the night under the room temperature, filters; In filtrating, add 10～12ml water and 2N NaOH solution 9～15ml, stirring reaction 6～8h under the room temperature, reaction steams solvent after finishing; Add less water, obtained aqueous solution is through ion exchange resin treatment and collect elutriant, and elutriant obtains solid after concentrating, and the use volume ratio is water/methanol solvate recrystallization of 1: 9; Through dry, obtain (1S, 2S again; 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid, i.e. RWJ 270201.
In the process of said ion exchange resin treatment, used strongly acidic cationic exchange resin, with on the aqueous solution appearance to resin; Water is extremely neutral with highly acid Zeo-karb washing; Using mass concentration then is 8～10% ammoniacal liquor wash-out, collects elutriant, is concentrated into dried; Said drying is at 40 ℃ of vacuum-drying 4～6h.
Compared with prior art, the present invention has following advantage and beneficial effect:
1. on further investigation basis to existing compound method; Through the improvement synthetic route that RWJ 270201 has been invented in a large amount of experiments, this route with (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is raw material; Make RWJ 270201 through the reaction of 7 steps, total recovery is 36.4%; This synthetic route is shorter, and reaction conditions is gentle, and is easy and simple to handle, is fit to suitability for industrialized production.
2. in the hydro-reduction process, use sodium borohydride and nickel chloride restoring system to replace expensive platinum dioxide to make reducing agent, reduced cost, simplified operation, security is higher.
3. in the process of last guanidine radicals reagent; Use homemade hydrochloric acid chloromethane amidine to replace the N of domestic no manufacturer production, N-two tertbutyloxycarbonyls-S-methyl-isothiourea have been avoided the use of poisonous reagent mercury chloride; Reduced cost; Avoid the generation of heavy metal waste liquid, avoided contaminate environment, be fit to the production of industry.
4. on the purification process of RWJ 270201, improve to some extent among the present invention, find to use highly acid Zeo-karb through test of many times, can the purifying RWJ 270201.
Description of drawings
Fig. 1 is the structural representation of influenza virus.
Fig. 2 be (1S, 4R)-the 1H NMR collection of illustrative plates of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.
Fig. 3 be (1S, 4R)-the 13C NMR collection of illustrative plates of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.
Fig. 4 be (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [the 1H NMR collection of illustrative plates of d] isoxazole-6-carboxylate methyl ester.
Fig. 5 be (3aR, 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6,6a-tetrahydrochysene-3aH-cyclopentyl [the 13C NMR collection of illustrative plates of d] isoxazole-6-carboxylate methyl ester.
Fig. 6 be (1S, 2S, 3R, 4R)-the 1H NMR collection of illustrative plates of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester.
Fig. 7 be (1S, 2S, 3R, 4R)-the 13C NMR collection of illustrative plates of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester.
Fig. 8 be (1S, 2S, 3R, 4R)-the 1H NMR collection of illustrative plates of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid.
Fig. 9 be (1S, 2S, 3R, 4R)-the 13C NMR collection of illustrative plates of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid.
Embodiment
Below in conjunction with embodiment and accompanying drawing the present invention is described in further detail, but embodiment of the present invention is not limited thereto.
Below be the preparation embodiment of RWJ 270201, comprise following 9 parts:
1, (1S, 4R)-preparation of 4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride
With 10g (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is dissolved in the 120ml exsiccant anhydrous methanol, under room temperature, stirs and feeds exsiccant hydrogen chloride gas 3h, no longer feeds hydrogen chloride gas; React 2h down at 50 ℃, the TLC monitoring.After reaction finishes, reaction solution is concentrated into dried black viscous liquid, in this thick liquid, adds the anhydrous diethyl ether of 120ml ice, stirred overnight under the room temperature is separated out white solid, and suction filtration use the anhydrous diethyl ether washing leaching cake, gets 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 following: 30g sodium-chlor is dropped in the 250ml there-necked flask; Slowly dripping the 40ml massfraction through constant pressure funnel under the normal temperature is that 98% the vitriol oil is in sodium-chlor;, with the bottleneck jam-pack hydrogenchloride that reacts generation with carrying out drying in the conduit feeding vitriol oil, is fed in the reaction flask with conduit then and reacts with rubber plug; The stopping property of whole device is good, and connects the anti-suck device.
2, (1S, 4R)-preparation of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester
Will (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride 5g (28mmol) joins in the 60ml hexane solution, adds yellow soda ash 8.9g (84mmol), tert-Butyl dicarbonate 7.3g (34mmol) then successively, under agitation drips water 80ml; At room temperature react 8h after dropwising, the TLC monitoring.After reaction finishes, tell organic layer, water layer merges organic layer with ethyl acetate extraction three times, with washing and saturated nacl aqueous solution is washed, uses anhydrous sodium sulfate drying 6h then successively, is concentrated into dried faint yellow oily thing; With this faint yellow oily thing with 8: 1 by volume the preparation the petrol ether/ethyl acetate solvent be moving phase; Cross silica gel chromatographic column fast and get colourless oil liquid; Make white solid 6.4g after freezing, be (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester; Fusing point 35.4-36.9; Yield 94%.
(1S, 4R)-the 1H NMR collection of illustrative plates of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester is 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).
(1S, 4R)-the 13C NMR collection of illustrative plates of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester is 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), yellow soda ash 18g (170mmol) are dissolved in the 100ml water; After reaction extremely no longer produces bubble, at 0 ℃ of ethanolic soln 80ml that drips 2-ethyl butyraldehyde 17g (148mmol) down, after dropwising; Reaction is spent the night under the room temperature, the TLC monitoring.After reaction finishes, be diluted to 1000ml with frozen water, with extracted with diethyl ether three times, the merging organic phase is washed successively, and saturated nacl aqueous solution is washed, and anhydrous sodium sulfate drying 6h is concentrated into dried colourless oil liquid; Is moving phase with this colourless oil liquid with the petrol ether/ethyl acetate solvent of preparation in 10: 1 by volume, the quick silica gel chromatographic column of crossing, colourless oil liquid 17.5g, be 2-ethyl butyraldehyde oxime, yield 90%.
4, (3aR, 4R, 6S, 6aS)-and 4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5,6, [the preparation of d] isoxazole-6-carboxylate methyl ester of 6a-tetrahydrochysene-3aH-cyclopentyl
With (1S; 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester 5g (20.7mmol) and 2-ethyl butyraldehyde oxime 7.2g (62.1mmol) join among the methylene dichloride 60ml, slowly drips Youxiaolin (effective chlorine density Cl%=10%) 74ml (207mmol) solution down at-10 ℃, makes reacting liquid temperature be no more than 0～5 ℃; Dropwise the back and continue reaction 1 hour down at 5 ℃; At room temperature react 20h then, reaction solution becomes green by light green and is becoming light green, the TLC monitoring.After reaction finishes, tell organic layer, water layer merges organic layer with dichloromethane extraction three times, washes successively, and saturated nacl aqueous solution is washed, and anhydrous sodium sulfate drying 6h is concentrated into dried pale yellow oily liquid body; Is moving phase with this pale yellow oily liquid body with the petrol ether/ethyl acetate solvent of preparation in 9: 1 by volume, crosses silica gel chromatographic column, white cotton-shaped solid; 40 ℃ of vacuum-drying 6h get white cotton-shaped solid 4.94g, be (3aR, 4R, 6S, 6aS)-and 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 [the 1H NMR collection of illustrative plates of d] isoxazole-6-carboxylate methyl ester is seen Fig. 4,
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 [the 13C NMR collection of illustrative plates of d] isoxazole-6-carboxylate methyl ester is seen Fig. 5,
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)-preparation of 2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester
With (3aR; 4R, 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4; 5; 6, [d] isoxazole-6-carboxylate methyl ester 4.9g (13.8mmol), Nickel dichloride hexahydrate 3.3g (14mmol) join among the anhydrous methanol 60ml, at N with sodium hydroxide 0.028g (0.69mmol) 6a-tetrahydrochysene-3aH-cyclopentyl
2Under protection and-5 ℃ of conditions, slowly add Peng Qinghuana 1.3g (34.5mmol) in batches, in 10min, add Peng Qinghuana through dry application of sample pipe; Make temperature of reaction surpass 5 ℃, reaction soln becomes black by green, constantly has gas to emit; Add the back in 0 ℃ of reaction 2h, TLC monitoring.After reaction finishes; Reaction solution is concentrated into dried atrament, is 28% ammoniacal liquor 120ml to wherein adding Sodium Nitrite 1g (14mmol), ammonium chloride 3g (56mmol) and mass concentration, under room temperature, stirs 16h; There is the pearl floss to separate out in the solution; Solution becomes blue solution, and suction filtration gets the pearl floss; 40 ℃ of vacuum-drying 6h obtain pearl floss 4.2g, be (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester; Yield 84.8% directly is used for next step reaction with this pearl floss.
6, (1S, 2S, 3R, 4R)-preparation of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester
(the 1S that drying is complete; 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 among the exsiccant methylene dichloride 30ml, adding diacetyl oxide 1.4ml (15mmol), triethylamine 1.0ml (7.5mmol) successively; Under room temperature, react 6h, the TLC monitoring.After reaction finishes, reaction solution is concentrated into dried, to wherein adding a spot of water, with dichloromethane extraction three times, merges organic phase, wash successively, saturated nacl aqueous solution is washed, and anhydrous sodium sulfate drying 6h is concentrated into dried light black liquid; Is moving phase with this light black liquid with the sherwood oil/acetone solvent of preparation in 3: 1 by volume, the quick silica gel chromatographic column of crossing, white solid; 40 ℃ of vacuum-drying 6h obtain white solid 2.75g, be (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 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)-the 1H NMR collection of illustrative plates of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester sees 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), and 1.35-1.45 (m, 15H), 0.84-0.89 (t, 3H), 0.78-0.82 (t, 3H).
(1S, 2S, 3R, 4R)-the 13C NMR collection of illustrative plates of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester sees 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)-preparation of 2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride
(the 1S that drying is complete; 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 120ml exsiccant anhydrous diethyl ether, at room temperature feeds exsiccant hydrogen chloride gas 2h; No longer feed hydrogen chloride gas, feeding hydrogen chloride gas adularescent solid is immediately separated out; Vigorous stirring reaction 12h under room temperature, the TLC monitoring.After reaction finished the back, suction filtration was used the anhydrous diethyl ether washing leaching cake, got white solid; 40 ℃ of vacuum-drying 6h obtain white solid 6.9g, be (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 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 the 60mmol cyanamide) is joined in the 20ml diethyl ether solution, under 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.After reaction finishes, ether in the reaction solution is concentrated into dried, the freezing white crystal of separating out; Take out rate, use the anhydrous diethyl ether washing leaching cake, get white crystal; 40 ℃ of vacuum-drying 6h.Get white crystal 5.6g, promptly get hydrochloric acid chloromethane amidine; Yield 82%.
9, (1S, 2S, 3R, 4R)-preparation of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid
With (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) is dissolved in exsiccant N with hydrochloric acid chloromethane amidine 1.23g (10.8mmol), among the dinethylformamide 20ml; Adding triethylamine 2.3ml, under room temperature, react and spend the night.Filter, in filtrating, add 10ml water, adding 2N NaOH solution 9ml; Stir 6h under the room temperature, after reaction finished, decompression steamed most of solvent; Add a spot of water; With appearance to the strongly acidic cationic exchange resin handled well on this solution, water is washed till neutrality, and using mass concentration then is 10% ammoniacal liquor wash-out.Collect elutriant, concentrate white solid.With the water/methanol solvate recrystallization of this white solid, get white solid with preparation in 1: 9 by volume; 40 ℃ of vacuum-drying 6h obtain white solid 0.91g, be (1S, 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid; Yield 78%.
(1S, 2S, 3R, 4R)-the 1H NMR collection of illustrative plates of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid sees 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), and 0.92-0.97 (m, 2H), 0.86-0.89 (t, 3H), 0.81-0.83 (t, 3H).
(1S, 2S, 3R, 4R)-the 13C NMR collection of illustrative plates of 2-hydroxyl-3-[(1S)-1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid sees 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.
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. the compound method of influenza and avian influenza cytotoxic drug RWJ 270201 is characterized in that may further comprise the steps:
I, catalysis open loop, amido protecting: will (1R, 4S)-after 2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is dissolved in anhydrous methanol, under hydrogen chloride gas catalysis, react, make (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride; Then will (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride, protective material and alkali mixes and add in the normal hexane, drips the water afterreaction, make (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester;
II, 1, the cycloaddition of 3-dipole: (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, adds the Peng Qinghuana afterreaction more in batches, make (1S in the methanol solution of d] isoxazole-6-carboxylate methyl ester; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester;
With (1S, 2S, 3R; 4R)-and 2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester adds in the methylene dichloride, adds diacetyl oxide and triethylamine more successively, react under the room temperature; Make (1S; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester;
The protection of IV, deaminizating, be that reagent generates guanidine radicals and methyl esters hydrolysis: with (1S, 2S, 3R with the chlorine amidine; 4R)-2-hydroxyl-3-[(1S)-and 1-acetamido-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester adding anhydrous diethyl ether; Reaction makes (1S, 2S under hydrogen chloride gas catalysis; 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride;
(1S, 2S, 3R; 4R)-2-hydroxyl-3-[(1S)-and 1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride and the reaction of hydrochloric acid chloromethane amidine, hydrolysis under alkaline condition then makes (-)-(1S; 2S; 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetamido-2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid, i.e. RWJ 270201.
2. compound method according to claim 1; It is characterized in that: the preparation method of hydrogen chloride gas is among said step I and the step IV: 25～30g sodium-chlor is added in the reaction flask; Drip 30～40ml vitriol oil; After drying in the gas feeding vitriol oil that produces, make hydrogen chloride gas, this hydrogen chloride gas is directly fed in the reaction soln react; The massfraction of the said vitriol oil is 98%.
3. compound method according to claim 1 is characterized in that: among the said step I, and (1S; 4R)-the concrete preparation process of 4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride is: with 10～15g (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is dissolved in 100ml～120ml anhydrous methanol, agitation condition feeds hydrogen chloride gas 2.5～3h down; Reaction 2h～3h under 45～50 ℃, reaction is concentrated into reaction solution dried after finishing; Get thick liquid, add 100～120ml ice anhydrous diethyl ether, stirred overnight after-filtration, drying; Obtain (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride;
Among the said step I; (1S, 4R)-the preparation process of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester is specially: will (1S, 4R)-4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride adds in the normal hexane; Add alkali and protective material successively, agitation condition drips water down; Dropwise the back and react 8h～10h under the room temperature, reaction is told organic layer after finishing, through washing, dry, be concentrated into do and freezing after the chromatographic column, obtain (1S, 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester; Wherein, said protective material is a tert-Butyl dicarbonate, and said alkali is yellow soda ash; Said (1S, 4R)-mol ratio of 4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride and tert-Butyl dicarbonate, yellow soda ash is 1: (1.2～1.5): (2.5～3); The amount of substance of said normal hexane be (1S, 4R)-30～40 times of the amount of substance of 4-amino-2-cyclopentenes-1-carboxylate methyl ester hydrochloride, the many 10～20ml of the volume ratio normal hexane of the water that drips in the reaction.
4. compound method according to claim 1 is characterized in that: in the said Step II, the preparation process of 2-ethyl butyraldehyde oxime is: 6～12g oxammonium hydrochloride and 8～18g yellow soda ash are dissolved in 80～100ml water; After not producing bubble; Drip the ethanolic soln 70～80ml that contains 6～17g 2-ethyl butyraldehyde down at 0～5 ℃, reaction is spent the night under the room temperature, after reaction finishes; Add frozen water and be diluted to 800～1000ml; With merging organic phase after the extracted with diethyl ether, wash successively, dry, be concentrated into and do the back and cross chromatographic column, obtain 2-ethyl butyraldehyde oxime.
5. compound method according to claim 1 is characterized in that: the concrete operations of said Step II are: under-5～-10 ℃, with (1S; 4R)-4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester and 2-ethyl butyraldehyde oxime be dissolved in the methylene dichloride, slowly drips the chlorine bleach liquor, makes reacting liquid temperature be no more than 0～5 ℃; Dropwise the back and react 30min～1h down, at room temperature react 18～20h then, after reaction finishes at 0～-5 ℃; Tell organic layer, through washing, dry, be concentrated into dried, cross the chromatographic column after drying, 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; Said chlorine bleach liquor's available chlorine quality percentage composition is 10%;
Wherein, said (1S, 4R)-mol ratio of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester and 2-ethyl butyraldehyde oxime, Youxiaolin is 1: (3～3.5): (10～15); The amount of substance of said methylene dichloride be (1S, 4R)-25～30 times of the amount of substance of 4-(tertbutyloxycarbonyl) amino-2-cyclopentenyl-1-carboxylate methyl ester.
6. compound method according to claim 1 is characterized in that: among the said Step II I, and (3aR; 4R; 6S, 6aS)-4-[(tertbutyloxycarbonyl) amino]-3-(1-ethyl propyl)-4,5; 6, [mol ratio of d] isoxazole-6-carboxylate methyl ester, Peng Qinghuana, Nickel dichloride hexahydrate and sodium hydroxide is 1 to 6a-tetrahydrochysene-3aH-cyclopentyl: (2～2.5): (1～1.2): 0.05;
Said Step II I is reflected at N
2Carry out under the protective condition; In the said process that in batches adds Peng Qinghuana; Peng Qinghuana adds in 10～15min, and control reaction temperature is no more than 0～5 ℃, adds the back at 0～5 ℃ of reaction 2～3h; Reaction product obtains (1S through after the separation and purification; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 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 4.9～7.5g, being operating as of said separation and purification: reaction product is concentrated into dried, adds Sodium Nitrite 1～2g, ammonium chloride 3～5g and ammoniacal liquor 100～120ml; Stir 16～18h under the room temperature, with the gained solid drying, obtain (1S behind the suction filtration; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester; The mass concentration of said ammoniacal liquor is 25～28%.
7. compound method according to claim 1 is characterized in that: among the said Step II I, and (1S; 2S, 3R, 4R)-the preparation process of 2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester in; (1S, 2S, 3R; 4R)-consumption of 2-hydroxyl-3-[(1S)-1-amino-2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester is 2～4.8g; The consumption of diacetyl oxide is 1.0～2.5ml, and the consumption of triethylamine is 1～2ml, and the consumption of methylene dichloride is 10～60ml; The time of reacting under the said room temperature is 6～8h; After said reaction finishes, reaction solution is concentrated into dried, uses dichloromethane extraction after adding the water wiring solution-forming; Merge organic phase, then through washing, dry, be concentrated into after doing chromatographic column, after super-dry; Obtain (1S; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-(tertbutyloxycarbonyl) amino cyclopentyl-1-carboxylate methyl ester.
8. compound method according to claim 1; It is characterized in that: among the said step IV; The preparation process of hydrochloric acid chloromethane amidine is: with the cyanamide mass concentration is that the cyanamide aqueous solution 5～10g of 50% joins in 20～40ml ether; The adding massfraction is concentrated hydrochloric acid 30～50ml of 36～38% under 0～5 ℃, makes reacting liquid temperature be no more than 5 ℃, then in room temperature reaction 2～3h; After reaction finishes, reaction solution is concentrated into dried, separates out crystal after freezing,, obtain hydrochloric acid chloromethane amidine through suction filtration, with anhydrous diethyl ether washing and dry.
9. compound method according to claim 1 is characterized in that: among the said step IV, and (1S; 2S, 3R, 4R)-the concrete preparation process of 2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride is: with (1S; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-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; Feed hydrogen chloride gas 1～2h, react 10～12h under the room temperature, reaction finishes the back suction filtration; With solid drying, obtain (1S, 2S; 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride;
Then, with (1S, 2S, 3R; 4R)-2-hydroxyl-3-[(1S)-1-acetamido-2-ethyl] butyl-4-amino cyclopentyl-1-carboxylate methyl ester hydrochloride 1.2～2g mixes with hydrochloric acid chloromethane amidine 1.23～4.0g and adds 20～30ml N, in the dinethylformamide, adds 1.8～2.3ml triethylamine; Reaction is spent the night under the room temperature, filters, and in filtrating, adds 10～12ml water and 2N NaOH solution 9～15ml; Stirring at room reaction 6～9h, reaction steams solvent after finishing, and adds the water wiring solution-forming; Elutriant is handled and collected to spent ion exchange resin, and the concentrated solid that obtains of elutriant obtains (1S through the recrystallization after drying; 2S, 3R, 4R)-2-hydroxyl-3-[(1S)-and 1-acetylaminohydroxyphenylarsonic acid 2-ethyl] butyl-4-guanidine radicals ring penta-1-carboxylic acid.
10. compound method according to claim 9; It is characterized in that: during said spent ion exchange resin is handled; Institute's spent ion exchange resin is a strongly acidic cationic exchange resin, and appearance on the solution is washed till neutrality with deionized water with the strongly acidic cationic exchange resin water to resin; Using mass concentration then is 8～10% ammoniacal liquor wash-out, collects elutriant; Said recrystallization is with 1: 9 by volume～5: 5 blended water/methanol solvate recrystallizations.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102863359A (en) * | 2012-05-16 | 2013-01-09 | 常州制药厂有限公司 | Synthesis method of anti-flu medicine |
| CN105198827A (en) * | 2015-04-13 | 2015-12-30 | 广州南新制药有限公司 | Synthetic method of peramivir intermediate |
| CN106631904A (en) * | 2017-01-04 | 2017-05-10 | 南京友杰医药科技有限公司 | Method for preparing key intermediate of anti-influenza drug peramivir |
| CN111983074A (en) * | 2020-08-17 | 2020-11-24 | 苏州正济药业有限公司 | Method for determining peramivir intermediate isomer by using high performance liquid chromatography |
| CN112250601A (en) * | 2020-09-08 | 2021-01-22 | 天津应天成科技有限公司 | Method for safely and nontoxic removing nickel ion impurities in peramivir trihydrate intermediate M9 |
| CN113880732A (en) * | 2021-10-12 | 2022-01-04 | 湖南凯铂生物药业有限公司 | Peramivir impurity A and impurity C as well as preparation method and application thereof |
| CN114181117A (en) * | 2020-09-15 | 2022-03-15 | 南京正济医药研究有限公司 | Preparation method of peramivir intermediate |
| CN114853636A (en) * | 2022-05-27 | 2022-08-05 | 温州海鹤药业有限公司 | Preparation method of peramivir intermediate |
| CN115073336A (en) * | 2021-03-15 | 2022-09-20 | 江西中医药大学 | Preparation method of sulfhydryl alanyl amino acid ester salt of peramivir |
| 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 |
| CN116425659A (en) * | 2023-03-02 | 2023-07-14 | 浙江康聚药业有限公司 | Method for synthesizing peramivir |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1367776A (en) * | 1999-06-28 | 2002-09-04 | 生物晶体药品股份有限公司 | Process for preparing substituted cyclopentane derivatives and novel crystalline structures |
| CN1986521A (en) * | 2006-07-03 | 2007-06-27 | 华南农业大学 | Synthesis process of peramivir as medicine for antagonizing influenza and bird flu virus |
-
2011
- 2011-11-14 CN CN201110359706.3A patent/CN102372657B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1367776A (en) * | 1999-06-28 | 2002-09-04 | 生物晶体药品股份有限公司 | Process for preparing substituted cyclopentane derivatives and novel crystalline structures |
| CN1986521A (en) * | 2006-07-03 | 2007-06-27 | 华南农业大学 | Synthesis process of peramivir as medicine for antagonizing influenza and bird flu virus |
Non-Patent Citations (2)
| Title |
|---|
| ROBERT A.MOSS，ET AL: "Stereochemical Dissection of a Carbene Fragmentation Reaction", 《J.AM.CHEM.SOC》, vol. 114, no. 24, 31 December 1992 (1992-12-31), pages 9389 * |
| 陈建新 等: "神经氨酸酶抑制剂帕拉米韦的合成及其抗禽流感病毒药效", 《中国抗生素杂志》, vol. 34, no. 8, 31 August 2009 (2009-08-31) * |
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| CN102863359A (en) * | 2012-05-16 | 2013-01-09 | 常州制药厂有限公司 | Synthesis method of anti-flu medicine |
| CN102863359B (en) * | 2012-05-16 | 2014-05-07 | 常州制药厂有限公司 | Synthesis method of anti-flu medicine |
| CN102796056B (en) * | 2012-08-23 | 2014-12-10 | 湖北丽益医药科技有限公司 | Peramivir intermediate and preparation method for analogue |
| 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 |
| CN105198827A (en) * | 2015-04-13 | 2015-12-30 | 广州南新制药有限公司 | Synthetic method of peramivir intermediate |
| CN106631904A (en) * | 2017-01-04 | 2017-05-10 | 南京友杰医药科技有限公司 | Method for preparing key intermediate of anti-influenza drug peramivir |
| CN106631904B (en) * | 2017-01-04 | 2018-08-14 | 南京友杰医药科技有限公司 | The preparation method of Tamiflu peramivir key intermediate |
| CN111983074B (en) * | 2020-08-17 | 2022-08-05 | 苏州正济药业有限公司 | Method for determining peramivir intermediate isomer by using high performance liquid chromatography |
| CN111983074A (en) * | 2020-08-17 | 2020-11-24 | 苏州正济药业有限公司 | Method for determining peramivir intermediate isomer by using high performance liquid chromatography |
| CN112250601A (en) * | 2020-09-08 | 2021-01-22 | 天津应天成科技有限公司 | Method for safely and nontoxic removing nickel ion impurities in peramivir trihydrate intermediate M9 |
| CN112250601B (en) * | 2020-09-08 | 2022-09-27 | 天津应天成科技有限公司 | Method for safely and nontoxic removing nickel ion impurities in peramivir trihydrate intermediate M9 |
| CN114181117A (en) * | 2020-09-15 | 2022-03-15 | 南京正济医药研究有限公司 | Preparation method of peramivir intermediate |
| 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 |
| CN115073336A (en) * | 2021-03-15 | 2022-09-20 | 江西中医药大学 | Preparation method of sulfhydryl alanyl amino acid ester salt of peramivir |
| CN113880732A (en) * | 2021-10-12 | 2022-01-04 | 湖南凯铂生物药业有限公司 | Peramivir impurity A and impurity C as well as preparation method and application thereof |
| CN114853636A (en) * | 2022-05-27 | 2022-08-05 | 温州海鹤药业有限公司 | Preparation method of peramivir intermediate |
| CN114853636B (en) * | 2022-05-27 | 2024-04-02 | 温州海鹤药业有限公司 | Preparation method of peramivir intermediate |
| 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 |
| CN116425659A (en) * | 2023-03-02 | 2023-07-14 | 浙江康聚药业有限公司 | Method for synthesizing peramivir |
| 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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