Intermediate compounds of tamiflu, methods of preparation and uses thereof
AssigneesShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Lianhe Chemical Technology Co., Ltd., Lianhe Chemical Technology (Taizhou) Co., Ltd
InventorsDawei Ma, Shaolin Zhu, Shouyun Yu, You Wang, Qianghui Zhou
Life of this patent
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Abstract
Chiral amino compounds, methods of preparation and uses thereof. Tamiflu can be obtained from the said compounds. Multi-substituted chiral tetrahydropyrrolyl amine which can be used as intermediate compounds of medicament can also be produced by the said compounds.
Claims16
A chiral amino compound having a structure represented by a formula selected from the group consisting of:
- wherein:
- R1 is an alkyl having 1-10 carbon atoms, an alkoxy having 1-10 carbon atoms, an alkenyl having 2-6 carbon atoms, an alkyl having 1-4 carbon atoms and substituted by R4, an aryl having 5-12 carbon atoms, or an aryl having 5-12 carbon atoms and monosubstituted or multisubstituted by an electron-withdrawing group or electron-donating group;
- R4 is a substituted amino, a hydroxyl, a substituted hydroxyl, an alkylacyloxy having 2-10 carbon atoms, or an alkenyl having 2-6 carbon atoms;
- the substituted amino comprising a substituent selected from the group consisting of:
- t-butoxycarboryl, benzyloxycarbonyl, benzyl, acetyl, trifluoromethyl carbonyl, and phthalyl;
- the phthalyl having a structure represented by formula (a):
- the substituted hydroxyl comprising a substituent selected from the group consisting of:
- benzyl, acetyl, methoxymethyl, t-butyl dimethyl silyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, and 2-tetrahydropyranyl;
- and
- at least one of R2 and R3 is an acyl protecting group.
A method for preparing oseltamivir comprising:
- (1) carrying out a reduction reaction of a nitro group of a compound represented by formula II to prepare a compound represented by formula I;
- and
- (2) preparing oseltamivir by reacting the compound represented by formula I in the presence of an alkali, ammonia gas, and a solvent:
- wherein:
- R5 is an unsubstituted, monosubstituted, or multisubstituted aryl having 6-12 carbon atoms, or an alkyl having 1-6 carbon atoms, the monosubstituted or multisubstituted aryl comprising a substituent selected from the group consisting of:
- a halogen, a nitro, an alkyl having 1-3 carbon atoms, and an alkoxy having 1-3 carbon atoms;
- the compound represented by formula II is prepared by carrying out an addition reaction of a compound represented by formula III as follows:
- and
- the compound represented by formula III is prepared by reacting a chiral amino compound represented by formula IV with ethyl 2-diethoxyphosphinoylacrylate:
A method for preparing an intermediate compound of oseltamivir represented by formula I′, the method comprising preparing the compound represented by formula I′ by carrying out a reaction to remove an ester group and a hydroxyl group from a compound represented by formula II′ in the presence of an inorganic salt, a solvent, and an inert:
- wherein:
- X is an amino protecting group;
- the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, and lithium chloride;
- the solvent is selected from the group consisting of dimethylformamide, xvlene, and dimethylsulfoxide;
- the compound represented by formula II′ is prepared by carrying out an amino protecting reaction of a compound represented by formula III′:
- when X is t-butoxycarbonyl, the amino protecting reaction of the compounds represented by formula III′ and di-tert-butyl dicarbonate ester (Boc2O) in a solvent is carried out to provide the compound represented by formula II′;
- the solvent is one or more selected from the group consisting of dichloromethane, tetrahydrofuran, and acetonitrile;
- an amount of di tert-butyl dicarbonate ester is 1-5 times an amount in moles of the compound represented by formula III′;
- the amino protecting reaction is carried out at a temperature of −20-50° C.;
- the amino protecting reaction is stopped only once the compound represented by formula III′ is completely consumed;
- the compound represented by formula III′ is prepared by carrying out a reduction reaction of a nitro group of a compound represented by formula IV′:
- and
- the compound represented by formula IV′ is prepared by:
- carrying out an isomerization reaction of a compound represented by formula V′ in the presence of an alkali catalyst and a solvent:
- or
- carrying out an intermolecular addition reaction and an intramolecular aldol reaction of a chiral amino compound represented by formula IV and ethyl 2-ethoxy carbonyl acrylate in the presence of an alkali catalyst and a solvent:
Dependencies are inferred from the claim text.