# US 9,040,738 B2 · Intermediate compounds of tamiflu, methods of preparation and uses thereof

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- Number: US 9,040,738 B2
- Document ID: US9040738B2
- Status: Granted
- Kind: B2
- Application number: 14/123,870
- Filed: 2010-12-17
- Published: 2014-08-07
- Granted: 2015-05-26
- Earliest claimed: 2009-12-23
- Assignees: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences; Lianhe Chemical Technology Co., Ltd.; Lianhe Chemical Technology (Taizhou) Co., Ltd
- Applicants: Dawei Ma; Shaolin Zhu; Shouyun Yu; You Wang; Qianghui Zhou
- Inventors: Dawei Ma; Shaolin Zhu; Shouyun Yu; You Wang; Qianghui Zhou
- Web page: https://patentgrep.com/patent/US9040738B2

## CPC

- C07C 319/12: by reactions not involving the formation of mercapto groups
- A61P 31/16: for influenza or rhinoviruses
- C07C 227/14: from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C 227/16: by reactions not involving the amino or carboxyl groups
- C07C 229/66: the carbon skeleton being further substituted by doubly-bound oxygen atoms
- C07C 233/31: with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C 271/18: to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
- C07C 323/61: having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- C07D 207/14: Nitrogen atoms not forming part of a nitro radical
- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07D 213/73: Unsubstituted amino or imino radicals
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07B 2200/07: Optical isomers
- C07C 2601/14: The ring being saturated
- C07C 2601/16: the ring being unsaturated
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The chiral amino compound according to claim 1, wherein R1 is an alkyl having 1-4 carbon atoms; an alkoxy having 1-4 carbon atoms; an alkyl having 1-4 carbon atoms and substituted by R4; a phenyl; or a phenyl monosubstituted, disubstituted, or trisubstituted by an electron-withdrawing group or electron-donating group.

### Claim 3 (depends on 2)

The chiral amino compound according to claim 2, wherein:
the electron-withdrawing group is a halogen, cyano, or nitro; and
the electron-donating group is an alkyl having 1-4 carbon atoms, an alkoxy having 1-4 carbon atoms, an amino, or a hydroxyl.

### Claim 4 (depends on 1)

The chiral amino compound according to claim 1, wherein R1 is an alkyl having 1-10 carbon atoms, 3-pentyloxy, isobutenyl, 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.

### Claim 5 (depends on 1)

The chiral amino compound according to claim 1, wherein the structure is represented by a formula selected from the group consisting of:
and enantiomers thereof,
where:
Boc represents t-butoxycarbonyl;
Bn represents benzyl;
Ac represents acetyl;
Phth represents phthalyl; and
Cbz represents benzyloxycarbonyl.

### Claim 6 (depends on 1)

A method for preparing the chiral amino compound according to claim 1, comprising:
reacting an aldehyde represented by R1CH2CHO and a nitroolefin represented by O2NCHCHNR2R3 for 10 minutes to 48 hours in a solvent at 20 to 30° C. in the presence of a catalyst and an additive;
wherein:
the aldehyde, nitroolefin, catalyst, and additive have a molar ratio of: 1.0-4.0: 1.0-2.0:0.01-0.20:0-0.50;
the additive is one or more selected from the group consisting of acetic acid, chloroacetic acid, bromoacetic acid, sodium acetate, benzoic acid, and substituted benzoic acid; and
the catalyst is:

### Claim 7

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:

### Claim 8 (depends on 7)

The method according to claim 7, wherein:
the reaction of the chiral amino compound represented by formula IV and ethyl 2-diethoxyphosphinoylacrylate is carried out in the presence of an alkali and a solvent;
the solvent is one or more selected from the group consisting of dichloromethane, chloroform, toluene, ethanol, and methanol;
the alkali is inorganic carbonate alkali or organic alkali;
the organic alkali is 1,8-diazabicycloundec-7-ene (DBU);
the inorganic carbonate alkali is cesium carbonate;
an amount of the alkali is 2-10 times an amount in moles of the compound represented by formula IV;
the reaction is stopped only once the chiral amino compound represented by formula IV is completely consumed; and
the reaction is carried out at a temperature of 10-30° C.

### Claim 9

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:

### Claim 10 (depends on 9)

The method according to claim 9, wherein:
the solvent is one or more selected from the group consisting of dichloromethane, tetrahydrofuran, and acetonitrile;
the alkali catalyst is one or more selected from the group consisting of cesium carbonate, sodium carbonate, potassium phosphate, and potassium carbonate;
an amount of the alkali catalyst is 0.1-5 times an amount in moles of the compound represented by formula V′;
the isomerization reaction is carried out at a temperature of −20-60° C.;
the reaction is stopped only once the compound represented by formula V′ is completely consumed;
an amount of the alkali catalyst is 0.1-5 times an amount in moles of the chiral amino compound represented by formula IV;
a molar ratio of the chiral amino compound represented by formula IV and ethyl 2-ethoxy carbonyl acrylate is 0.1-1;
the intermolecular addition reaction and the intramolecular aldol reaction are carried out at a temperature of −20-50° C.; and
the intermolecular addition reaction and the intramolecular aldol reaction are stopped only once the chiral amino compound represented by formula IV is completely consumed.

### Claim 11 (depends on 9)

The method according to claim 9, wherein:
the compound represented by formula V′ is prepared by carrying out an intermolecular addition reaction and an intramolecular aldol reaction of the chiral amino compound represented by formula IV and ethyl 2-ethoxy carbonyl acrylate in the presence of an alkali catalyst and a solvent:

### Claim 12 (depends on 1)

An intermediate compound for preparing oseltamivir having a structure represented by formula III, II, II′, III′, IV′, or V′:
wherein:
R5 is an unsubstituted, monosubstituted, or multi-substituted 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;
R5 is not a tolyl; and
the intermediated compound represented by formula III, II, II′, III′, IV′, or V′ is prepared from the chiral amino compound according to claim 1.

### Claim 13 (depends on 1)

A method for preparing a chiral 3-aminopyrrolidine represented by formula VI or formula VI′, the method comprising carrying out a reduction reaction of a nitro group of the chiral amino compound according to claim 1 and a reductive amination reaction of the chiral amino compound; the chiral amino compound being represented by formula VII or formula VII′:
where:
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.

### Claim 14 (depends on 13)

The method according to claim 13, further comprising:
carrying out the reduction reaction of the nitro group and the reductive amination reaction of the chiral amino compound represented by formula VII or formula VII′ in the presence of a catalyst and hydrogen in a polar solvent; the polar solvent being an alcohol solvent; the catalyst being Pd/C, Pd(OH)2/C, PtO2, or Ranny-Ni; a weight ratio of the chiral amino compound represented by formula VII or formula VII′ to the catalyst being 1:0.001-0.2; a hydrogen pressure being 1×105 Pa to 100×105 Pa; the reaction being stopped only once the chiral amino compound represented by formula VII or formula VII′ is completely consumed; the reduction reaction and the reductive amination reaction being carried out at a temperature of 0° C. to 100° C.; or
first carrying out the reduction reaction of the nitro group of the chiral amino compound represented by formula VII or formula VII′, and then carrying out the reductive amination reaction; the reduction reaction of the nitro group of the chiral amino compound represented by formula VII or formula VII′ being carried out in the presence of a reducing agent selected from the group consisting of Zn/HOAc, Fe powder, and Ranny-Ni/H2 in a solvent;
wherein:
when the reducing agent is Zn/HOAc or Fe powder,
an amount of Zn or Fe powder is 10 to 30 times an amount in moles of the chiral amino compound represented by formula VII or formula VII′;
the solvent is acetic acid or a mixture of acetic acid and water;
the reduction reaction is stopped only once the chiral amino compound represented by formula VII or formula VII′ is completely consumed; and
the reduction reaction is carried out at a temperature of 0° C. to 100° C.;
when the reducing agent is Ranny-Ni/H2,
a weight ratio of the chiral amino compound represented by formula VII or formula VII′ to Ranny-Ni is 1:0.001-0.2;
a hydrogen pressure is 1×105 Pa to 100×105 Pa;
the solvent is an alcohol solvent;
the reduction reaction is stopped only once the chiral amino compound represented by formula VII or formula VII′ is completely consumed; and
the reduction reaction is carried out at a temperature of 0° C. to 100° C.;
the reductive amination reaction is carried out on substances obtained by the reduction reaction in the presence of a reducing agent in a solvent;
the solvent is one or more selected from the group consisting of dichloromethane, tetrahydrofuran, and 1,2-dichloromethane;
the reducing agent is sodium borohydride, sodium cyanoborohydride, acetic acid sodium borohydride, borane/pyridine, sodium borohydride/magnesium perchlorate, zinc borohydride/zinc chloride, or sodium triacetoxyborohydride;
an amount of the reducing agent is 1 to 4 times an amount in moles of the chiral amino compound represented by formula VII or formula VII′;
the reductive amination reaction is stopped only once the substances prepared by the reduction reaction are completely consumed; and
the reductive amination reaction is carried out at a temperature of 0° C. to 30° C.

### Claim 15 (depends on 1)

The chiral amino compound according to claim 1, wherein the acyl protecting group is selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, acetyl, trifluoromethyl carbonyl, and phthalyl.

### Claim 16 (depends on 1)

The chiral amino compound according to claim 1, wherein one of R2 and R3 is hydrogen or benzyl.