Process of producing 5,6,7-trinor-4,8-inter-m-phenylene PGI2 derivatives

• US 5,202,447 A
• Filed: 01/02/1991
• Issued: 04/13/1993
• Est. Priority Date: 02/27/1989
• Status: Expired due to Term

• Current Assignee: Toray Industries Incorporated
• Original Assignee: Toray Industries Incorporated
• Inventors: Nagase, Hiroshi, Kawai, Koji, Wakita, Hisanori, Hosono, Yutaka, Ohno, Kiyotaka, Yoshiwara, Hideo
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US07/601,783
• Time in Patent Office: 832 Days
• Field of Search: 549/458
• US Class Current: 549/458
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07C 2601/10 the ring being unsaturated
• CPC Class Codes: C07C 43/247 containing halogen
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered

Abstract

The present invention provides a process for preparing 5,6,7-trinor-4,8-inter-m-phenylene PGI₂ derivative [VII] using 3a,8b-cis-dihydro-3H-5,7-dibromocyclopenta[b]benzofuran (1) as a starting material, as well as compounds of the formulae (8) and (11) which are intermediates for the preparation of the compound of the formula (1). ##STR1##

Claims

1. A process of preparing 5,6,7-trinor-4,8-inter-m-phenylene PGI₂ derivatives of the formula (VII) ##STR28## (wherein R₂ represents methyl or ethyl;

R₃ and R₄ represent hydrogen or methyl) comprising the steps of;

reacting 3,5-cis-dibromocyclopentene of the formula ##STR29## with potassium salt of an o-halophenol to form 3,5-cis-bis(2-halophenoxy)cyclopentene of the formula 6 ##STR30## (wherein X represents chlorine, bromine or iodine);

treating said compound of the formula 6 with magnesium metal to convert to a Grignard reagent;

cyclizing said Grignard reagent in the presence of a metal catalyst to form a cyclopentabenzofuran of the formula 7;

##STR31## brominating said compound of the formula 7 to form a tetrabromide of the formula 8;

##STR32## reductively removing the bromine of the 5-membered ring moiety of said compound of the formula 8 to form 3a,8b-cis-dihydro-3H-5,7-dibromocyclopenta[b]benzofuran of the formula 1 ##STR33## converting said compound by Prins reaction and hydrolysis to a diol of the formula 2;

##STR34## reacting said compound of the formula 2 with a Grignard reagent so as to carry out metal-halogen exchange;

reacting the resulting product with methyl 3-formyl propionate;

subjecting the resulting product to hydrogenolysis to give a diol ester of the formula 3;

##STR35## subjecting said compound of the formula 3 to protection of the primary hydroxyl group, esterification of the secondary hydroxyl group and removal of the protective group of primary hydroxyl group so as to convert said compound of the formula 3 to a compound of the formula (I);

##STR36## (wherein R₁ represents acetyl, p-toluoyl, o-toluoyl, benzoyl m-toluoyl, p-t-butylbenzoyl, p-phenylbenzoyl, 3,5-dinitrobenzoyl, N-phenylcarbamoyl, α

-naphthoyl, β

-naphtholyl or p-nitrobenzoyl);

converting said compound of the formula (I) to a compound of the formula (III) ##STR37## (wherein R₁, R₂ and R₃ represent the same meanings as mentioned above) by oxidizing said compound of the formula (I) and reacting the resulting product with a compound of the formula (II) in the presence of a strong base;

##STR38## (wherein R₂ and R₄ represent the same meanings as mentioned above)

reducing said compound of the formula (III) with a reducing agent to form a compound of the formula (IV);

##STR39## (wherein R₁, R₂ and R₄ represent the same meanings as mentioned above) and

solvolyzing or hydrolyzing said compound of the formula (IV) to form said compound of the formula (VII).

2. A process for preparing 3a,8b-cis-dihydro-3H-cyclopenta[b]benzofuran of the formula 7:

##STR40## comprising the steps of;

converting a 3,5-cis-bis(2-halophenoxy)cyclopentene derivative of the formula 6;

##STR41## (wherein X represents Cl, Br or I) to a Grignard reagent using magnesium metal; and

cyclizing the resulting product in the presence of a metal catalyst.

3. A process for preparing 3a,8b-cis-dihydro-3H-5,7-dibromocyclopenta[b]benzofuran of the formula 1 ##STR42## characterized by comprising the step of reductively debrominating a tetrabromocyclopenta[b]benzofuran derivative of the formula 8:

##STR43## with sodium thiosulfate, sodium sulfide or zinc.

4. A tetrabromocyclopenta[b]benzofuran derivative of the formula 8 ##STR44##

5. A process for preparing the tetrabromocyclopenta[b]benzofuran derivative of claim 4, characterized by comprising the step of brominating 3a,8b-cis-dihydro-3H-cyclopenta[b]benzofuran of the formula 7:

##STR45##

6. A process for preparing a compound of the formula (I):

##STR46## (wherein R₁ represents the same meaning as mentioned above) characterized by comprising the steps of;

forming 3,5-cis-bis(2-halophenoxy)cyclopentene of the formula 6;

##STR47## (wherein X represents chlorine, bromine or iodine) by reacting 3,5-cis-dibromocyclopentene of the formula 5;

##STR48## with potassium salt of o-halophenol;

converting said compound of the formula 6 with magnesium metal to a Grignard reagent;

cyclizing the resulting product in the presence of a metal catalyst to form cyclopentabenzofuran of the formula 7;

##STR49## brominating said compound of the formula 7 to form a tetrabromide of the formula 8;

##STR50## reductively removing the bromines on the 5-membered ring moiety of said compound of the formula 8 to form 3,a,8b-cis-dihydro-3H,5,7-dibromocyclopenta[b]benzofuran of the formula 1;

##STR51## subjecting said compound of the formula 1 to Prins reaction and hydrolysis to convert the same to a diol of the formula 2;

##STR52## treating said compound of the formula 2 with a Grignard reagent so as to carry out metal-halogen exchange;

reacting the resulting product with methyl 3-formyl propionate;

subjecting the resulting product to hydrogenolysis to give a diol ester of the formula 3;

##STR53## and subjecting said compound of the formula 3 to protection of the primary hydroxyl group, esterification of the secondary hydroxyl group and deprotection of the primary hydroxyl group so as to convert said compound of the formula 3 to said compound of the formula [I].