Title:
PRODUCTION OF HALOPYRIDYL-AZABICYCLOHEPTANE DERIVATIVE AND INTERMEDIATE THEREFOR
Document Type and Number:
Japanese Patent JP3446899
Kind Code:
B2
Abstract:
PURPOSE: To obtain the subject compound useful as a nonopioid-based analgesic agent by deprotecting a halopyridyl-N-protected azabicycloheptane derivative.
CONSTITUTION: A sulfonyl-N-protected azabicycloheptene derivative expressed by formula I (R1 is formyl a lower aliphatic acyl, vinyl, lower alkoxycarbonyl, etc.; R3 is methyl, ethyl, phenyl or toluyl) is reacted with sodium amalgam to provide an N-protected azabicycloheptene derivative expressed by formula II, which is then reacted with a halogenated pyridine in the presence of a palladic salt to afford a pyridyl-N-protected azabicycloheptane derivative expressed by formula III. The resultant compound is subsequently oxidized with aqueous hydrogen peroxide, a peracid or an organic peroxide to provide an N-oxyhalopyridyl-N-protected azabicycloheptane derivative expressed by formula IV, which is further reacted with a halogenating agent to afford a halopyridyl-N-protected azabicycloheptane derivative expressed by formula V (R2 is halogen). The obtained compound is subsequently deprotected to provide the objective compound expressed by formula VI (X- is anion).
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Inventors:
Kouzou Akasaka
Sadaharu Kimura
Masahiro Yonaga
Yoshimasa Machida
Sadaharu Kimura
Masahiro Yonaga
Yoshimasa Machida
Application Number:
JP17850093A
Publication Date:
September 16, 2003
Filing Date:
June 28, 1993
Export Citation:
Assignee:
Eisai Co., Ltd.
International Classes:
A61K31/44; A61P25/04; A61P29/00; C07D487/08; (IPC1-7): C07D487/08
Domestic Patent References:
| JP8511768A |
Other References:
Ｈａｎｓ−Ｊｏｓｅｆ Ａｌｔｅｎｂａｃｈ，ｅｔ ａｌ．，Ｓｙｎｔｈｅｓｅｓ ａｎｄ ｐｈｏｔｏｅｌｅｃｔｒｏｎ ｓｐｅｃｔａ ｏｆ ７−ａｚａｎｏｒｂｏｒｎａｄｉｅｎｅ ａｎｄ ｒｅｌａｔｅｄ ｃｏｍｐｏｕｎｄｓ，ａｎ ａｎａｌｙｓｉｓ ｗｉｔｈ ｆｒａ，Ｃｈｅｍ．Ｂｅｒ．，Ｖｏｌ．１２４，ｐ．７９１−８０１，１９９１
Ｒｏｂｅｒｔ Ｒ．Ｆｒａｓｅｒ，ｅｔ ａｌ．，Ｓｙｎｔｈｅｓｉｓ ｏｆ ７−ａｚａｂｉｃｙｃｌｏ［２．２．１］ｈｅｐｔａｎｅ，ｅｘｏ−２−ｃｈｌｏｒｏ−７−ａｚａｂｉｃｙｃｌｏ［２．２．１．］ｈｅｐｔａｎｅ，ａｎｄ ｄｅｒｉｖａｔｉｖｅｓ，Ｃａｎ．Ｊ．Ｃｈｅｍ．，Ｖｏｌ．４８，ｐ．２０６５−２０７４，１９７０
Ｓｔｅｐｈｅｎ Ｆ．Ｎｅｌｓｅｎ，ｅｔ ａｌ．，Ｔｈｅ ｎｉｔｒｏｇｅｎ ｉｎｖｅｎｓｉｏｎ ｂａｒｒｉｅｒ ｏｆ ７−ｍｅｔｈｙｌ−７−ａｚａｂｉｃｙｃｌｏ［２．２．１］ｈｅｐｔａｎｅ ａｎｄ ｔｈｅ ”ｂｉｃｙｃｌｉｃ ｅｆｆｅｃｔ”，Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，Ｖｏｌ．１１１，ｐ．１７７６−１７８１，１９８９
Ｔｈｏｍａｓ Ｆ．Ｓｐａｎｄｅ，ｅｔ ａｌ．，Ｅｐｉｂａｔｉｄｉｎｅ：Ａ ｎｏｖｅｌ（ｃｈｌｏｒｏｐｙｒｉｄｙｌ）ａｚａｂｉｃｙｃｌｏｈｅｐｔａｎｅ ｗｉｔｈ ｐｏｔｅｎｔ ａｎａｌｇｅｓｉｃ ａｃｔｉｖｉｔｙ ｆｒｏｍ ａｎ Ｅｃｕａｄｏ，Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，Ｖｏｌ．１１４，ｐ．３４７５−３４７８，１９９２
Ｒｏｂｅｒｔ Ｒ．Ｆｒａｓｅｒ，ｅｔ ａｌ．，Ｓｙｎｔｈｅｓｉｓ ｏｆ ７−ａｚａｂｉｃｙｃｌｏ［２．２．１］ｈｅｐｔａｎｅ，ｅｘｏ−２−ｃｈｌｏｒｏ−７−ａｚａｂｉｃｙｃｌｏ［２．２．１．］ｈｅｐｔａｎｅ，ａｎｄ ｄｅｒｉｖａｔｉｖｅｓ，Ｃａｎ．Ｊ．Ｃｈｅｍ．，Ｖｏｌ．４８，ｐ．２０６５−２０７４，１９７０
Ｓｔｅｐｈｅｎ Ｆ．Ｎｅｌｓｅｎ，ｅｔ ａｌ．，Ｔｈｅ ｎｉｔｒｏｇｅｎ ｉｎｖｅｎｓｉｏｎ ｂａｒｒｉｅｒ ｏｆ ７−ｍｅｔｈｙｌ−７−ａｚａｂｉｃｙｃｌｏ［２．２．１］ｈｅｐｔａｎｅ ａｎｄ ｔｈｅ ”ｂｉｃｙｃｌｉｃ ｅｆｆｅｃｔ”，Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，Ｖｏｌ．１１１，ｐ．１７７６−１７８１，１９８９
Ｔｈｏｍａｓ Ｆ．Ｓｐａｎｄｅ，ｅｔ ａｌ．，Ｅｐｉｂａｔｉｄｉｎｅ：Ａ ｎｏｖｅｌ（ｃｈｌｏｒｏｐｙｒｉｄｙｌ）ａｚａｂｉｃｙｃｌｏｈｅｐｔａｎｅ ｗｉｔｈ ｐｏｔｅｎｔ ａｎａｌｇｅｓｉｃ ａｃｔｉｖｉｔｙ ｆｒｏｍ ａｎ Ｅｃｕａｄｏ，Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，Ｖｏｌ．１１４，ｐ．３４７５−３４７８，１９９２