# US 9,518,014 B2 · Process for synthesis of ezetimibe and intermediates used in said process

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- Number: US 9,518,014 B2
- Document ID: US9518014B2
- Status: Granted
- Kind: B2
- Application number: 14/415,891
- Filed: 2013-01-29
- Published: 2015-06-18
- Granted: 2016-12-13
- Earliest claimed: 2012-07-20
- Assignees: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Applicants: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Inventors: Kuiling Ding; Xiaoming Wang; Zheng Wang
- Web page: https://patentgrep.com/patent/US9518014B2

## CPC

- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07C 67/08: by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
- C07C 67/31: by introduction of functional groups containing oxygen only in singly bound form
- C07C 67/343: by increase in the number of carbon atoms
- C07C 68/00: Preparation of esters of carbonic or haloformic acids
- C07C 69/734: Ethers
- C07C 69/96: Esters of carbonic or haloformic acids
- C07C 227/16: by reactions not involving the amino or carboxyl groups
- C07C 227/18: by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C 227/32: by stereospecific synthesis
- C07C 229/30: the carbon skeleton being acyclic and unsaturated
- C07C 229/34: the carbon skeleton containing six-membered aromatic rings
- C07D 205/08: with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07F 9/5045: {Complexes or chelates of phosphines with metallic compounds or metals}
- C07F 15/0033: {Iridium compounds}
- C07C 2601/16: the ring being unsaturated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

A process for the production of ezetimibe and intermediates used in said process are disclosed. A kind of Morita-Baylis-Hillman adduct can be altered to chiral carboxylic acid derivatives of β-arylamino α-methylene with high activity and selectivity by means of ally lamination reaction, and the above carboxylic acid derivatives of β-arylamino α-methylene can be altered to the chiral intermediates of ezetimibe by means of simple conversion and further synthesized into the chiral drug ezetimibe. The synthesis route introduces chirality through the use of a chiral catalysis method, thereby avoiding the use of the chiral auxiliary oxazolidinone; and the route is economical and eco-friendly.

## Claims

### Claim 1

A compound of formula I,
wherein P is a hydrogen, an acetyl, a propionyl, a t-butyloxycarbonyl, a benzyl, a carbobenzoxy, a trityl, a trimethylsilyl, a tert-butyldimethylsilyl, a tert-butyldiphenylsilyl or a diphenylmethylsilyl;
R1 is selected from the group consisting of: a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl and an adamantyl;
X is H or CO2R2; and
R2 is selected from the group consisting of: a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl and an adamantyl.

### Claim 2 (depends on 1)

The compound of formula I of claim 1, wherein the compound of formula I is a compound of formula 4, or an enantiomer thereof,

### Claim 3 (depends on 1)

The compound of formula I of claim 1, wherein the compound of formula I is a compound of formula 5, or an enantiomer thereof,

### Claim 4

A preparation method for a compound of formula I,
wherein the method comprises the following steps:
(a) subjecting a compound of formula 1 and p-fluoro aniline to an allyl amination reaction in the presence of a base to prepare a compound of formula 2;
(b) subjecting the compound of formula 2 and a compound of formula 3 to an addition reaction under the action of a base to prepare the compound of formula I having a structure shown in formula 4A;
and optionally,
(c) removing an ester group at the β position of ketone carbonyl from the compound of formula I having a structure shown in formula 4A to form the compound of formula I having a structure shown in formula 5A,
wherein P is a hydrogen, an acetyl, a propionyl, a t-butyloxycarbonyl, a benzyl, a carbobenzoxy, a trityl, a trimethylsilyl, a tert-butyldimethylsilyl, a tert-butyldiphenylsilyl or diphenylmethylsilyl;
X is H or CO2R2;
R1 and R2 are independently selected from the group consisting of: a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl and an adamantyl; and
LG is selected from the group consisting of an acetyl, a t-butyloxycarbonyl, a methoxycarbonyl, and a di(ethoxy)phosphinyl.

### Claim 5 (depends on 4)

The method of claim 4, wherein a complex formed from a phosphine ligand and a transition metal catalyst precursor is used as a catalyst in step (a),
wherein the phosphine ligand is
or a racemate thereof, wherein R3, R4, R5, R6, R7 and R8 are independently selected from the group consisting of a hydrogen, a halogen, and a substituted or unsubstituted group selected from the group consisting of: a C1-C10 alkyl, a C1-C4 alkoxy, a C3-C30 cycloalkyl and an aryl;
R9 and R10 are independently selected from the group consisting of a C3 -C30 cycloalkyl, a C1-C10 alkyl, a 2-furyl and an aryl;
X is CH2, NH, NCH3, O or S;
n=an integer of 0-4;
said substitution refers to being substituted by a substituent which is selected from the group consisting of: a halogen, a C1-6 alkyl, a C1-6 haloalkyl and a C1-6 alkoxy;
said transition metal catalyst precursor is a palladium catalyst precursor, and the palladium catalyst precursor is at least one selected from the group consisting of: Pd(OAc)2, PdCl2, Pd2(dba)3, Pd2(dba)3.CHCl3, Pd(dba)2, [Pd(C3H5)Cl]2, Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(CH3CN)Cl2.

### Claim 6 (depends on 4)

The method of claim 4, wherein the base in step (a) is at least one selected from the group consisting of: potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropylethylamine, N,O-bis(trimethylsilyl)acetamide, and tetra-n-butylammonium difluorotriphenylsilicate; and/or
the base in step (b) is at least one selected from the group consisting of: 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, triethylamine, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium ethoxide, and sodium methoxide.

### Claim 7

A preparation method for a compound of formula 6A, wherein the method includes the step of subjecting the compound of formula I to a cyclization reaction under the action of a base to form the compound of formula 6A,
wherein P is a hydrogen, an acetyl, a propionyl, a t-butyloxycarbonyl, a benzyl, a carbobenzoxy, a trityl, a trimethylsilyl, a tert-butyldimethylsilyl or a diphenylmethylsilyl;
R1 is a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl or an adamantyl; and
X is H.

### Claim 8

A preparation method for Ezetimibe, which is a compound of formula 8, wherein the method includes the following steps:
(i) subjecting a compound of formula 5 to a cyclization reaction under the action of a base to form a compound of formula 6;
(ii) subjecting the compound of formula 6 to an asymmetric reduction reaction at the position of ketone carbonyl in an organic solvent to obtain a compound of formula 7; and
(iii) removing a protecting group from the compound of formula 7 to obtain Ezetimibe, the compound of formula 8,
wherein P is a hydrogen, an acetyl, a propionyl, a t-butyloxycarbonyl, a benzyl, a carbobenzoxy, a trityl, a trimethylsilyl, a tert-butyldimethylsilyl or a diphenylmethylsilyl; and
R1 is a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl or an adamantyl.

### Claim 9 (depends on 8)

The preparation method of claim 8, wherein the organic solvent is at least one selected from the group consisting of benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, methanol, ethanol, N,N-dimethyl formamide and dimethyl sulfoxide.

### Claim 10 (depends on 8)

The preparation method of claim 8, wherein the base is at least one selected from the group consisting of: bis(hexamethyldisilylamine) tin, lithium Hexamethyldisilazide, lithium diisopropylamide, butyllithium, tert-butyllithium, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, and isopropylmagnesium bromide.

### Claim 11 (depends on 4)

The method of claim 4, wherein the compound of formula 1 is prepared by a method including the following steps:
(1) subjecting a compound of formula A and a compound of formula B to a Morita-Baylis-Hillman reaction to prepare a compound of formula C; and
(2) protecting a hydroxyl on the compound of formula C to obtain the compound of formula 1,
wherein P is a hydrogen, an acetyl, a propionyl, a t-butyloxycarbonyl, a benzyl, a carbobenzoxy, a trityl, a trimethylsilyl, a tert-butyldimethylsilyl, or diphenylmethylsilyl;
R1 is a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl or an adamantyl; and
LG is an acetyl, a t-butyloxycarbonyl, a methoxycarbonyl, or a di(ethoxy)phosphinyl.

### Claim 12 (depends on 7)

The preparation method of claim 7, wherein the base is at least one selected from the group consisting of: bis(hexamethyldisilylamine) tin, lithium Hexamethyldisilazide, lithium diisopropylamide, butyllithium, tert-butyllithium, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, and isopropylmagnesium bromide.