CN105859648A - Method for preparing peramivir intermediate - Google Patents
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- CN105859648A CN105859648A CN201610293430.6A CN201610293430A CN105859648A CN 105859648 A CN105859648 A CN 105859648A CN 201610293430 A CN201610293430 A CN 201610293430A CN 105859648 A CN105859648 A CN 105859648A
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Abstract
The invention discloses a method for preparing a peramivir intermediate. The method comprises the steps that 1, in the presence of a compound shown as the formula C and triethylamine, (1S,4R)-(-)-methyl-[[(1,1-dimethyl oxethyl)carbonyl]amidogen]cyclopentene-2-alkene-1-methyl heptine carbonate and 2-ethyl-N-hydroxyl imide chloride are subjected to a contact reaction in THF, after the reaction is finished, a sodium hydroxide water solution is added into reaction liquid, reacting is carried out for 2-3 hours, the pH is adjusted to range from 5 to 7, extraction and concentration are carried out, washing is carried out with cold ethyl alcohol, and (3aR,4R,6S,6aS)-4-[[(1,1-dimethyl oxethyl)carbonyl]amidogen]-3-(1'-ethyl propyl)-3a,5,6,6a-tetralin-4H-cyclopentane[d]-isoxazole-6-carboxylic acid is obtained; 2, the product obtained in the step 1 is dissolved in dichloromethane, then tert-butylamine is added, stirring and reacting are carried out for 2 hours at the temperature of 5 DEG C to 15 DEG C, concentration is carried out, washing is carried out with cold ethyl alcohol, and drying is carried out to obtain the peramivir intermediate. The method for preparing the peramivir intermediate is high in yield, and the reaction time is greatly shortened.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of method preparing Peramivir intermediate.
Background technology
Peramivir (Peramivir), is the another new type nerve propylhomoserin enzyme after both zanamivir and Oseltamivir are researched and developed successfully
(NA) inhibitor parainfluenza virus medicine, this medicine, in listing in 1999, is ground by Biocryst Pharmaceuticals, Inc. of the U.S.
System exploitation, is mainly used in adult and the A type of children and the treatment and prevention of influenza B.
The chemistry entitled (1S, 2S, 3R, 4R, 1 ' S) of Pamela's Wei-(-)-3-[(1 '-acetylaminohydroxyphenylarsonic acid, 2 '-ethyl) butyl]-4-[[(ammonia
Base imino group) methyl] amino]-2-hydroxy-cyclopentane-1-carboxylic acid trihydrate, chemical structural formula is as follows:
From the molecular structure of above-mentioned Peramivir it can be seen that the group that molecule, multiple polarity are different, these groups can be distinguished
Act on the influenza virus multiple avtive spots through aminoacidase molecule, stop virus surface hemagglutinin and infection cell surface sialic
The fracture of the key between acid, it is possible to the activity of strong inhibition NA, thus stop virus from the release of infected cell and penetration cell
Film, reduces cohesion and the diffusion of respiratory tract of virus, and then flu-prevention and alleviation flu-like symptom effectively.
At present, the synthetic method of Peramivir is conducted extensive research by those skilled in the art, such as Military Medical Science Institute
Patent CN101367750B of drug toxicity research institute, forms isoxazolines with 2-ethyl-N-hvdroxv fourth Asia acyl chlorides for initiation material
Ring, then sodium borohydride reduction open loop forms amino and hydroxyl, then carries out acetylating reaction with triazole-carbonamidine and obtains product.
Although the method is compared with the improvement the biggest with other prior aries, but the method causes total receipts owing to step is many, often step productivity is low
Rate the lowest (only about 10%), especially, the annulation productivity of isoxazolines ring only has about 60%, reaction
Time is the longest, has dragged slowly rhythm of production, is unfavorable for large-scale industrial production.
Therefore, this area need badly a kind of reaction time is short and yield is high Peramivir intermediate (3aR, 4R, 6S,
6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-different
The preparation method of azoles-6-carboxylic acid tert-butylamine.
Summary of the invention
It is an object of the invention to overcome existing preparation Peramivir intermediate (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethyl second
Epoxide) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid tert-butylamine
Method product yield is low, the defect of reaction time length, it is provided that a kind of applicable industrial-scale production and yield height, reaction time
The preparation method of short Peramivir intermediate.
The present inventor has been surprisingly found that under study for action, triazole borofluoride is joined (1S, 4R)-(-)-methyl-[[(1,1-
Dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester, 2-ethyl-N-hvdroxv fourth imine acyl chloride reaction in, it is possible to
Greatly promoting the carrying out of this reaction, and this reaction treatment is simple, reaction yield is greatly improved, when also shortening reaction simultaneously
Between.This is owing to the compound triazole borofluoride shown in Formulas I can pass through intermolecular interaction with the alkene double bond in reaction substrate
Power combine, in conjunction with after formed transition state, be especially beneficial the nucleophilic of the atom pair olefinic carbon atoms such as O, thus improve the receipts of reaction
Rate, further, since 2-ethyl-N-hvdroxv fourth imine acyl chloride and inorganic base dissolubility in organic solvent are the best, shown in Formulas I
Compound also act as the effect of phase transfer catalyst, substantially increase the efficiency of reaction.
To achieve these goals, the present invention provides a kind of method preparing Peramivir intermediate, and the method comprises the following steps:
1) in the presence of the compound shown in formula C and triethylamine, by (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino]
Ring amyl-2-alkene-1-carboxylate methyl ester and 2-ethyl-N-hvdroxv fourth imine acyl chloride carry out haptoreaction in THF, after reaction terminates, to instead
Answering the aqueous solution adding NaOH in liquid, react 2～3 hours, regulate pH to 5～7, organic solvent extracts, and concentrates, cold ethanol
Washing, (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetra-
Hydrogen-4H-pentamethylene [d]-isoxazole-6-carboxylic acid；
2) by step 1) (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third of obtaining
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid, in dichloromethane, is subsequently adding tert-butylamine, at 5～15 DEG C
Under the conditions of stirring reaction 2 hours, concentrate, cold ethanol wash, be dried to obtain (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy)
Carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid tert-butylamine；
Under preferable case, step 1) in catalytic process include: by the compound shown in formula C, triethylamine, (1S,
4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester adds in THF, then drip
The THF solution of 2-ethyl-N-hvdroxv fourth imine acyl chloride.
In the present invention, the compound shown in formula C can be prepared according to prior art or be commercially available, relevant existing skill
Art such as J.Am.Chem.Soc.2004,126 14370, Angew.Chem.Int.Ed., 2004,43,6205 etc..
Under preferable case, with the gauge of 2-ethyl-N-hvdroxv fourth imine acyl chloride, dropping 2-ethyl-N-hvdroxv fourth imine acyl chloride
The speed of THF solution is 0.1～0.5g/s.
In the present invention, in order to promote that the Direction of Reaction is carried out to the direction of Peramivir intermediate, under preferable case, (1S,
4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester and 2-ethyl-N-hvdroxv fourth imines
Compound shown in acyl chlorides, formula C, the mol ratio of triethylamine are 1:3～5:0.4～0.7:2.5～5.
Under preferable case, (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester with
Compound shown in 2-ethyl-N-hvdroxv fourth imine acyl chloride formula, formula C, the mol ratio of triethylamine are 1:3.5～4:0.45～0.55:
3～4.
Under preferable case, described catalytic temperature is 35-55 DEG C.In the case of Jin Yibuyouxuan, described catalytic temperature
It it is 40～45 DEG C.
In step 2) in, the amount of described addition tert-butylamine is not particularly limited, as long as making step 1) obtain (3aR,
4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene
[d]-isoxazole-6-carboxylic acid becomes tert-butylamine salt completely, such as, the input amount of described tert-butylamine salt be (1S, 4R)-(-)-methyl-[[(1,
1-dimethylethyloxy) carbonyl] amino] 2～5 times (moles) of ring amyl-2-alkene-1-carboxylate methyl ester.
In the present invention, in reaction, the amount of solvent for use is not particularly limited, can be as required from main separation.The present invention
The room temperature of indication refers to 25 DEG C ± 5 DEG C.The present invention uses cold ethanol to carry out washing the purity that ensure that product, is unlikely to product simultaneously
Too much, cold ethanol can be the ethanol of 0-10 DEG C in loss.
In the present invention, reaction is monitored following the tracks of by the method that this area can be used conventional, such as TLC, LCMS, GCMS
Deng, react complete finger TLC monitor not excess raw material disappeared or in LCMS, GCMS not excess raw material residue less than 2%.
Use preparation Peramivir intermediate (3aR, 4R, 6S, the 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] that the present invention provides
Amino]-3-(1 '-ethyl propyl)-3a, the method for 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid tert-butylamine, operation
Step is simple, and yield is higher, and the reaction time is also greatly shortened.
Other features and advantages of the present invention will be described in detail in detailed description of the invention part subsequently.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.But these embodiments are only limitted to illustrate rather than this
The further restriction of the protection domain of invention.
Embodiment 1
The preparation method of a kind of Peramivir intermediate, comprises the following steps:
1) by (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester 24.1g
(100mmol), the compound shown in formula C and triethylamine join in the flask of THF, then instill 2-ethyl-N-hvdroxv fourth sub-
The THF solution of amine acyl chlorides 40 DEG C carries out haptoreaction 1.5 hours, after reaction terminates, adds the water-soluble of NaOH in reactant liquor
Liquid, reacts 2 hours, regulate pH to 6, organic solvent extract, concentrate, cold ethanol wash, (3aR, 4R, 6S, 6aS)-4-[[(1,
1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid；
With the gauge of 2-ethyl-N-hvdroxv fourth imine acyl chloride, the speed of the THF solution of dropping 2-ethyl-N-hvdroxv fourth imine acyl chloride is
0.4g/s；(1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester and 2-ethyl-N-hydroxyl
Compound shown in base fourth imine acyl chloride, formula C, the mol ratio of triethylamine are 1:3.5:0.55:4.
2) by step 1) (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third of obtaining
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid, in dichloromethane, is subsequently adding tert-butylamine
(250mmol), under the conditions of 5 DEG C stirring reaction 2 hours, concentrate, cold ethanol wash, be dried (3aR, 4R, 6S, 6aS)-4-[[(1,
1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid uncle
Butylamine 37.8g, yield is 91.5%, purity 99.10% (HPLC area normalization method).
Embodiment 2
The preparation method of a kind of Peramivir intermediate, comprises the following steps:
1) by (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester 24.1g
(100mmol), the compound shown in formula C and triethylamine join in the flask of THF, then instill 2-ethyl-N-hvdroxv fourth sub-
The THF solution of amine acyl chlorides 45 DEG C carries out haptoreaction 2 hours, after reaction terminates, adds the aqueous solution of NaOH in reactant liquor,
Reacting 2 hours, regulate pH to 5, organic solvent extracts, and concentrates, and cold ethanol washs, and obtains (3aR, 4R, 6S, 6aS)-4-[[(1,1-
Dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid；With
The gauge of 2-ethyl-N-hvdroxv fourth imine acyl chloride, the speed of the THF solution of dropping 2-ethyl-N-hvdroxv fourth imine acyl chloride is 0.3g/s；
(1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester and 2-ethyl-N-hvdroxv fourth be sub-
Compound shown in amine acyl chlorides, formula C, the mol ratio of triethylamine are 1:3.5:0.45:4.
2) by step 1) (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third of obtaining
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid, in dichloromethane, is subsequently adding tert-butylamine
(250mmol), under the conditions of 10 DEG C stirring reaction 2 hours, concentrate, cold ethanol wash, be dried (3aR, 4R, 6S, 6aS)-4-[[(1,
1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid uncle
Butylamine 37.6g, yield is 90.8%, purity 98.89% (HPLC area normalization method).
Embodiment 3
The preparation method of a kind of Peramivir intermediate, comprises the following steps:
1) by (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester 24.1g
(100mmol), the compound shown in formula C and triethylamine join in the flask of THF, then instill 2-ethyl-N-hvdroxv fourth sub-
The THF solution of amine acyl chlorides 40 DEG C carries out haptoreaction 1.5 hours, after reaction terminates, adds the water-soluble of NaOH in reactant liquor
Liquid, reacts 2 hours, regulate pH to 6, organic solvent extract, concentrate, cold ethanol wash, (3aR, 4R, 6S, 6aS)-4-[[(1,
1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid；
With the gauge of 2-ethyl-N-hvdroxv fourth imine acyl chloride, the speed of the THF solution of dropping 2-ethyl-N-hvdroxv fourth imine acyl chloride is
0.4g/s；(1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester and 2-ethyl-N-hydroxyl
Compound shown in base fourth imine acyl chloride, formula C, the mol ratio of triethylamine are 1:4:0.5:4.
2) by step 1) (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third of obtaining
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid, in dichloromethane, is subsequently adding tert-butylamine
(250mmol), under the conditions of 5 DEG C stirring reaction 2 hours, concentrate, cold ethanol wash, be dried (3aR, 4R, 6S, 6aS)-4-[[(1,
1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid uncle
Butylamine 37.3g, yield is 90.3%, purity 99.20% (HPLC area normalization method).
Embodiment 4
The preparation method of a kind of Peramivir intermediate, comprises the following steps:
1) by (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester 24.1g
(100mmol), the compound shown in formula C and triethylamine join in the flask of THF, then instill 2-ethyl-N-hvdroxv fourth sub-
The THF solution of amine acyl chlorides 55 DEG C carries out haptoreaction 2.5 hours, after reaction terminates, adds the water-soluble of NaOH in reactant liquor
Liquid, reacts 3 hours, regulate pH to 7, organic solvent extract, concentrate, cold ethanol wash, (3aR, 4R, 6S, 6aS)-4-[[(1,
1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid；
With the gauge of 2-ethyl-N-hvdroxv fourth imine acyl chloride, the speed of the THF solution of dropping 2-ethyl-N-hvdroxv fourth imine acyl chloride is
0.1g/s；(1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester and 2-ethyl-N-hydroxyl
Compound shown in base fourth imine acyl chloride, formula C, the mol ratio of triethylamine are 1:5:0.4:2.5.
2) by step 1) (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third of obtaining
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid, in dichloromethane, is subsequently adding tert-butylamine
(250mmol), under the conditions of 15 DEG C stirring reaction 2 hours, concentrate, cold ethanol wash, be dried (3aR, 4R, 6S, 6aS)-4-[[(1,
1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid uncle
Butylamine 36.1g, yield is 87.4%, purity 98.74% (HPLC area normalization method).
Embodiment 5
The preparation method of a kind of Peramivir intermediate, comprises the following steps:
1) by (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester 24.1g
(100mmol), the compound shown in formula C and triethylamine join in the flask of THF, then instill 2-ethyl-N-hvdroxv fourth sub-
The THF solution of amine acyl chlorides 35 DEG C carries out haptoreaction 3 hours, after reaction terminates, adds the aqueous solution of NaOH in reactant liquor,
Reacting 2.5 hours, regulate pH to 7, organic solvent extracts, and concentrates, and cold ethanol washs, and obtains (3aR, 4R, 6S, 6aS)-4-[[(1,1-
Dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid；With
The gauge of 2-ethyl-N-hvdroxv fourth imine acyl chloride, the speed of the THF solution of dropping 2-ethyl-N-hvdroxv fourth imine acyl chloride is 0.2g/s；
(1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylate methyl ester and 2-ethyl-N-hvdroxv fourth be sub-
Compound shown in amine acyl chlorides, formula C, the mol ratio of triethylamine are 1:3:0.7:4.
2) by step 1) (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third of obtaining
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid, in dichloromethane, is subsequently adding tert-butylamine
(250mmol), under the conditions of 10 DEG C stirring reaction 2 hours, concentrate, cold ethanol wash, be dried (3aR, 4R, 6S, 6aS)-4-[[(1,
1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid uncle
Butylamine 35.1g, yield is 84.9%, purity 99.44% (HPLC area normalization method).
Embodiment 6
Such as the preparation method of the Peramivir in embodiment 1, except that, step 1) in, 2-ethyl-N-hvdroxv fourth imines acyl
The rate of addition of chlorine is 1.5g/s, finally obtains (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-second
Base propyl group)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid tert-butylamine 31.9g, yield is 77.2%, purity
99.61% (HPLC area normalization method).
Embodiment 7
Such as the preparation method of the Peramivir in embodiment 1, except that, step 1) in, 2-ethyl-N-hvdroxv fourth imines acyl
Chlorine is disposable addition, finally obtains (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid tert-butylamine 31.8g, yield is 76.9%, purity 98.54%
(HPLC area normalization method).
Comparative example 1
Such as the preparation method of the Peramivir in embodiment 1, except that, do not use the compound shown in Formulas I, haptoreaction
Time is 8 hours, finally obtains (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid tert-butylamine 18.1g, yield is 43.8%, purity 95.47%
(HPLC area normalization method).
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited to the tool in above-mentioned embodiment
Body details, in the technology concept of the present invention, can carry out multiple simple variant to technical scheme, these
Simple variant belongs to protection scope of the present invention.
It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention, in reconcilable feelings
Under condition, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention is to various possible groups
Conjunction mode illustrates the most separately.Additionally, can also be combined between the various different embodiment of the present invention, as long as
It is without prejudice to the thought of the present invention, and it should be considered as content disclosed in this invention equally.
Claims (7)
1. the method preparing Peramivir intermediate, it is characterised in that the method includes:
1) in the presence of the compound shown in formula C and triethylamine, by (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl]
Amino] ring amyl-2-alkene-1-carboxylate methyl ester and 2-ethyl-N-hvdroxv fourth imine acyl chloride carry out haptoreaction in THF, after reaction terminates,
Adding the aqueous solution of NaOH in reactant liquor, react 2～3 hours, regulate pH to 5～7, organic solvent extracts, and concentrates, cold
Ethanol wash, (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,
6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid；
2) by step 1) (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy) carbonyl] amino]-3-(1 '-ethyl third of obtaining
Base)-3a, 5,6,6a-tetrahydrochysenes-4H-pentamethylene [d]-isoxazole-6-carboxylic acid, in dichloromethane, is subsequently adding tert-butylamine, at 5～15 DEG C
Under the conditions of stirring reaction 2 hours, concentrate, cold ethanol wash, be dried to obtain (3aR, 4R, 6S, 6aS)-4-[[(1,1-dimethylethyloxy)
Carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene [d]-isoxazole-6-carboxylic acid tert-butylamine；
Method the most according to claim 1, it is characterised in that step 1) in catalytic process include: by formula C
Shown compound, triethylamine, (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl] amino] ring amyl-2-alkene-1-carboxylic
Acid methyl esters adds in THF, then drips the THF solution of 2-ethyl-N-hvdroxv fourth imine acyl chloride.
Method the most according to claim 2, it is characterised in that with the gauge of 2-ethyl-N-hvdroxv fourth imine acyl chloride, drips
The speed of the THF solution adding 2-ethyl-N-hvdroxv fourth imine acyl chloride is 0.1～0.5g/s.
Method the most according to claim 1, it is characterised in that (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl
Base] amino] ring amyl-2-alkene-1-carboxylate methyl ester and the compound shown in 2-ethyl-N-hvdroxv fourth imine acyl chloride, formula C, triethylamine
Mol ratio is 1:3～5:0.4～0.7:2.5～5.
Method the most according to claim 4, it is characterised in that (1S, 4R)-(-)-methyl-[[(1,1-dimethylethyloxy) carbonyl
Base] amino] ring amyl-2-alkene-1-carboxylate methyl ester and the compound shown in 2-ethyl-N-hvdroxv fourth imine acyl chloride formula, formula C, triethylamine
Mol ratio be 1:3.5～4:0.45～0.55:3～4.
Method the most according to claim 1, it is characterised in that described catalytic temperature is 35-55 DEG C.
Method the most according to claim 6, it is characterised in that described catalytic temperature is 40～45 DEG C.
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| CN102633686A (en) * | 2011-02-09 | 2012-08-15 | 重庆福安药业(集团)股份有限公司 | Preparation method of peramivir |
| CN102757365A (en) * | 2011-04-29 | 2012-10-31 | 上海泓博智源医药技术有限公司 | New method for preparing peramivir key intermediate |
| CN102863359A (en) * | 2012-05-16 | 2013-01-09 | 常州制药厂有限公司 | Synthesis method of anti-flu medicine |
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| CN102633686A (en) * | 2011-02-09 | 2012-08-15 | 重庆福安药业(集团)股份有限公司 | Preparation method of peramivir |
| CN102757365A (en) * | 2011-04-29 | 2012-10-31 | 上海泓博智源医药技术有限公司 | New method for preparing peramivir key intermediate |
| CN102863359A (en) * | 2012-05-16 | 2013-01-09 | 常州制药厂有限公司 | Synthesis method of anti-flu medicine |
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| CN114384193A (en) * | 2020-10-19 | 2022-04-22 | 南京正济医药研究有限公司 | Detection method of peramivir chiral isomer |
| CN114384193B (en) * | 2020-10-19 | 2023-09-29 | 南京正济医药研究有限公司 | Method for detecting chiral isomer of peramivir |
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