# US 10,246,430 B2 · Methods for producing Beraprost and its derivatives

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,246,430 B2
- Document ID: US10246430B2
- Status: Granted
- Kind: B2
- Application number: 15/971,132
- Filed: 2018-05-04
- Published: 2018-09-20
- Granted: 2019-04-02
- Earliest claimed: 2014-05-20
- Assignees: Lung Biotechnology PBC
- Applicants: Lung Biotechnology PBC
- Inventors: Hitesh Batra; Sudersan M. Tuladhar; Sri Harsha Tummala; Raju Penmasta; David A. Walsh
- Web page: https://patentgrep.com/patent/US10246430B2

## CPC

- C07D 307/93: condensed with a ring other than six-membered
- C07C 67/00: Preparation of carboxylic acid esters
- C07C 67/307: by introduction of halogen; by substitution of halogen atoms by other halogen atoms
- C07C 69/65: of unsaturated acids
- C07C 233/20: having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
- C07C 2601/10: the ring being unsaturated
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention is directed to methods for preparing Beraprost and novel synthetic intermediates for Beraprost.

## Claims

### Claim 1

A method of preparing a compound represented by the structural Formula (I):
and salts thereof; comprising:
(a) reacting a substituted halophenol with 6-oxabicyclo[3.1.0]hex-2-ene in presence of a palladium catalyst to form an ether compound represented by structural Formula (III):
(b) acetylating the ether compound of Formula (III) to form a compound of Formula (IV)
(c) allylating the compound of Formula (IV) with allyltributylstannane in presence of AIBN to form the allylation product (V)
(d) subjecting the terminal alkene compound of Formula (V) to intermolecular allylic acetoxylation to form a compound of Formula (VI)
(e) subjecting the compound of Formula (VI) to dihydroxylation to form a compound of Formula (VII)
(f) subjecting the dihydroxy compound (VII) to oxidation to form an aldehyde compound of Formula (VIII)
(g) reducing the aldehyde compound of Formula (VIII) and removing the acetyl group to provide the diol compound of Formula (IX); and
(h) converting the diol of Formula (IX) to a protected aldehyde of Formula (VIIIA); and
(i) reacting the protected aldehyde of Formula (VIIIA) with a phosphonate of Formula (X) to obtain a compound of Formula (I)
wherein:
X is F, Cl, Br or I;
R1 is an alkyl, cycloalkyl or TBDMS;
R2 is independently H or an alcohol protecting group;
R3 is a straight or branched alkyl group having 1-4 carbon atoms; and
R6 is an alcohol protecting group.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is methyl or ethyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein the palladium catalyst is PdCl2(PPh3)2.

### Claim 4 (depends on 1)

The method of claim 1, wherein the allylation reaction is carried out in the presence of an allylating reagent.

### Claim 5 (depends on 1)

The method of claim 1, wherein the allylic acetoxylation reaction is carried out in the presence of acetic acid and PdCl2 catalyst.

### Claim 6 (depends on 1)

The method of claim 1, wherein the catalytic dihydroxylation is carried out in the presence of N-methylmorpholine N-oxide (NMO) oxidant and a catalytic amount of OsO4.

### Claim 7 (depends on 1)

The method of claim 1, wherein the dihydroxy compound (VII) is oxidized in the presence of a periodate compound.

### Claim 8 (depends on 1)

The method of claim 1, wherein the transition metal catalyst is a hydride of ruthenium, iridium, cobalt, rhodium, osmium, platinum, nickel, iron, or combinations thereof or a carbonyl hydride complex of ruthenium, iridium, cobalt, rhodium, osmium, platinum, nickel, iron, or combinations thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the transition metal catalyst is a ruthenium hydride complex.

### Claim 10 (depends on 1)

The method of claim 1, wherein the transition metal catalyst carbonylchlorohydridotris(triphenylphosphine)ruthenium(II).