申请人：Barrett G. M. Anthony
公开号：US20050038256A1
公开（公告）日：2005-02-17
A method of stereoselectively making an aminocyclohexyl ether comprises, for example, reacting
to form the aminocyclohexyl ether having the formula
respectively,
wherein independently at each occurrence, R
1
and R
2
are independently hydrogen, C
1
-C
8
alkyl, C
3
-C
8
alkoxyalkyl, C
1
-C
8
hydroxyalkyl, or C
7
-C
12
aralkyl; or
R
1
and R
2
are independently C
3
-C
8
alkoxyalkyl, C
1
-C
8
hydroxyalkyl, and C
7
-C
12
aralkyl; or R
1
and R
2
, when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (I):
wherein the ring of formula (I) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently carbon, nitrogen, oxygen, or sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from the group consisting of hydrogen, hydroxy, C
1
-C
3
hydroxyalkyl, oxo, C
2
-C
4
acyl, C
1
-C
3
alkyl, C
2
-C
4
alkylcarboxy, C
1
-C
3
alkoxy, and C
1
-C
20
alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two oxygen and/or sulfur heteroatoms; or any two adjacent additional carbon ring atoms may be fused to a C
3
-C
8
carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C
2
-C
4
acyl, C
2
-C
4
hydroxyalkyl and C
3
-C
8
alkoxyalkyl; or
R
1
and R
2
, when taken together with the nitrogen atom to which they are directly attached in formula (I), may form a bicyclic ring system selected from the group consisting of 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, and 3-azabicyclo[3.2.0]heptan-3-yl; and
wherein R
3
, R
4
and R
5
are independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, cyano, sulfamyl, trifluoromethyl, C
2
-C
7
alkanoyloxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
2
-C
7
alkoxycarbonyl, C
1
-C
6
thioalkyl, aryl or N(R
6
,R
7
) where R
6
and R
7
are independently hydrogen, acetyl, methanesulfonyl or C
1
-C
6
alkyl; or R
3
, R
4
and R
5
are independently hydrogen, hydroxy or C
1
-C
6
alkoxy; with the proviso that R
3
, R
4
and R
5
cannot all be hydrogen; and wherein O-J is a leaving group. Methods of making intermediates are also disclosed.
一种立体选择性制备氨基环己醚的方法，例如，反应生成具有以下式子的氨基环己醚，其中在每个出现的位置上，独立的R1和R2分别为氢、C1-C8烷基、C3-C8烷氧基烷基、C1-C8羟基烷基或C7-C12芳基烷基；或者独立的R1和R2为C3-C8烷氧基烷基、C1-C8羟基烷基和C7-C12芳基烷基；或者R1和R2与它们直接连接的氮原子一起形成由以下式子表示的环：其中式子（I）的环由氮原子形成，以及三到九个独立的环原子，包括碳、氮、氧或硫；任意相邻的两个环原子可以通过单键或双键连接在一起，任何一个或多个额外的碳环原子可以被氢、羟基、C1-C3羟基烷基、氧代、C2-C4酰基、C1-C3烷基、C2-C4烷基羧基、C1-C3烷氧基或C1-C20烷酰氧基中的一个或两个取代，或者被取代以形成一个螺五元或六元杂环环，其中包含一个或两个氧和/或硫杂原子；任意相邻的两个额外碳环原子可以融合到一个C3-C8碳环中，任何一个或多个额外的氮环原子可以被氢、C1-C6烷基、C2-C4酰基、C2-C4羟基烷基和C3-C8烷氧基烷基中的一个或多个取代；或者R1和R2与它们直接连接的氮原子一起形成从以下组中选择的双环系统：3-氮杂双环[3.2.2]壬烷-3-基、2-氮杂双环[2.2.2]辛烷-2-基、3-氮杂双环[3.1.0]己烷-3-基和3-氮杂双环[3.2.0]庚烷-3-基；其中R3、R4和R5独立地为溴、氯、氟、羧基、氢、羟基、羟甲基、甲磺酰胺基、硝基、氰基、磺酰胺基、三氟甲基、C2-C7烷酰氧基、C1-C6烷基、C1-C6烷氧基、C2-C7烷氧羰基、C1-C6硫代烷基、芳基或N（R6，R7），其中R6和R7独立地为氢、乙酰、甲磺酰或C1-C6烷基；或者R3、R4和R5独立地为氢、羟基或C1-C6烷氧基；但是R3、R4和R5不能都为氢；O-J是一个离去基团。还公开了制备中间体的方法。
