Process for the production of beraprost and its salts

• US 20040209945A1
• Filed: 04/01/2004
• Published: 10/21/2004
• Est. Priority Date: 07/30/2001
• Status: Active Grant

• Current Assignee: Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Zrt.
• Original Assignee: Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Zrt.
• Inventors: Szabo, Tibor, Bodi, Jozsef, Baloghnekardos, Zsusanna, Szevfrenyi, Zoltan, Dalmadi, Gyuia
• Granted Patent: US 7,005,527 B2
• Time in Patent Office: Days
• US Class Current: 514/468
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a new process for the preparation of beraprost of formula (I) using new intermediates.

Claims

1. A process for the preparation of the compound of formula (I) and its salts, especially its sodium salt, characterized in that, a compound of the general formula (VII)—

wherein R² means a straight or branched alkyl group containing 1-4 carbon atoms—

is reacted with a compound of the general formula (VIII)—

wherein R¹ means a methyl or an ethyl group, X stands for chlorine or bromine or iodine atom,

CF₃SO₂—

O-group, azido-, cyano-, or

2. The process according to claim 1, characterized in that, a compound of the general formula (VIII)—

wherein R¹ stands for ethyl and X is chlorine, bromine or iodine atom, cyano-, azido-, CF₃—

SO₂—

O—

or

3. The process according to claim 1, characterized in that, a compound of the general formula (VI) is oxidized into a compound of the general formula (V) by using a mixture of dimethyl sulfoxide, oxalyl chloride and triethylamine.

4. The process according to claim 1, characterized in that, an aldehyde of the general formula (V) and a phosphonate of the general formula (IX) are reacted under circumstances of Wittig-Horner-Emmon'"'"'s reaction.

5. The process according to claim 1, characterized in that, the protecting group of the hydroxyl group at position 11 in case of a compound of the general formula (IV) is splitted off in the acidic medium.

6. The process according to claim 1, characterized in that, the reduction of a compound of the general formula (III) is carried out by diisobutylaluminium-2,6-di-tert.butyl-4-methylphenoxide.

7. The process according to claim 1, characterized in that, a compound of the general formula (II) is hydrolized in basic medium.

8. The process according to claim 1, characterized in that, the acid of the formula (I) is transformed into its sodium salt and that salt is isolated.

9. The compounds of the general formula (VI)—

wherein the meanings of R¹ and R² are as defined in claim 1.

11. The compounds of the general formula (V)—

wherein the meanings of R¹ and R² are as defined in claim 1.

13. The compounds of the general formula (IV)—

wherein the meanings of R¹ and R² are as defined in claim 1.

10. A compound of the general formula (VI)—

wherein R¹ stands for ethyl group and R² stands for methyl group.

12. A compound of the general formula (V)—

wherein R¹ stands for ethyl group and R² stands for methyl group.

14. A compound of the general formula (IV)—

wherein R¹ stands for ethyl group and R² stands for methyl group.