CN101125833A - Optically active bisoxazoline compounds, process for production of the same and use thereof - Google Patents

Optically active bisoxazoline compounds, process for production of the same and use thereof Download PDF

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CN101125833A
CN101125833A CNA2007101529332A CN200710152933A CN101125833A CN 101125833 A CN101125833 A CN 101125833A CN A2007101529332 A CNA2007101529332 A CN A2007101529332A CN 200710152933 A CN200710152933 A CN 200710152933A CN 101125833 A CN101125833 A CN 101125833A
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naphthyl
methyl
opticity
amino
compound
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板垣诚
增本胜久
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

Optically active bisoxazoline compounds represented by the general formula (1), a process for producing the compounds, and a process for producing cyclopropanecarboxylic esters by using the same: wherein R<1> and R<2> are the same and each represents C1-6 alkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted phenyl or R<1> and R<2> are bonded each other together with the carbon atom of oxazoline ring to which they are bonded to form a ring; R<3> is substituted or unsubstituted naphthyl; R<4> and R<5> are the same and each represent hydrogen or C1-6 alkyl, or R<4> and R<5> are bonded each other together with the carbon atom to which they are bonded to form a cycloalkyl ring having 3 to 6 carbon atoms; and * represents an asymmetric center.

Description

Opticity two  isoxazoline compounds, Preparation Method And The Use
The application is that international filing date is that application number that international patent application that February 4, international application no in 2004 are PCT/JP2004/001133 enters China is 200480009360.2, denomination of invention is divided an application for the application for a patent for invention of " opticity two  isoxazoline compounds, Preparation Method And The Use ".
Technical field
The present invention relates to opticity two  isoxazoline compounds, Preparation Method And The Use.
Technical background
Make part with opticity two  isoxazoline compounds, the method for preparing the opticity cyclopropane compound with prochiral olefin is considered to asymmetric reaction (JP 11-171874 A for example, Tetrahedron Letter., 32,7373 (1991)), the opticity cyclopropane compound is the synthetic intermediate compound of extremely important agricultural chemicals such as synthetic pyrethroid insecticides, medicine etc., and its representative example is (+)-2,2-dimethyl-3-(2-methyl isophthalic acid-propenyl) cyclopropane-carboxylic acid.The non-enantiomer selectivity of these methods (trans-isomer(ide)/cis-isomeride ratio) is relative with enantio-selectivity good.But consider from industrial point of view, need further to improve the yield of the opticity cyclopropane compound that needs.
Summary of the invention
According to the present invention, the industrial asymmetric catalyst that contains opticity two  isoxazoline compounds and copper compound by use can obtain obtaining optically active compounds as the two  isoxazoline compounds of the opticity with naphthyl of asymmetric synthesis catalyst component and with high yield easily.
Promptly the invention provides the opticity two  isoxazoline compounds of a kind of following formula (1) representative:
Figure A20071015293300061
R wherein 1And R 2Identical, and represent C separately 1-6Alkyl, replacement or unsubstituted aralkyl or replacement or unsubstituted phenyl, or R 1And R 2The  oxazoline ring carbon atom that is connected to each other, connects with them forms ring; R 3Representative replaces or unsubstituted naphthyl (preferred 1-naphthyl or 2-naphthyl); R 4And R 5Identical, and represent hydrogen atom or C separately 1-6Alkyl, or R 4And R 5The carbon atom that is connected to each other, connects with them forms the cycloalkyl ring with 3-6 carbon atom; And * represents asymmetric center; The Preparation method and use of this compounds.
Implement best mode of the present invention
At first illustrate the opticity two  isoxazoline compounds (hereinafter referred opticity two  isoxazoline compounds (1)) by formula (1) representative, it is a new compound.
R 1And R 2The C of representative 1-6Examples of alkyl comprises straight or branched alkyl such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-pentyl and n-hexyl, R 1And R 2The cycloalkyl ring that the ring that the  oxazoline ring carbon atom that is connected to each other, connects with them forms can have 3-7 carbon atom is an example.The cycloalkyl ring example comprises cyclopropane ring, tetramethylene ring, pentamethylene ring, cyclohexane ring and suberane ring.
R 1And R 2The replacement or the unsubstituted phenyl example of representative comprise unsubstituted phenyl; C 1-6The phenyl that alkyl replaces is 3-aminomethyl phenyl and 4-aminomethyl phenyl for example; C 1-6Phenyl such as 2-p-methoxy-phenyl, 3-p-methoxy-phenyl and 4-p-methoxy-phenyl that alkoxyl group (for example methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy and hexyloxy) replaces.
In replacement or unsubstituted aralkyl, the C that has for example above replacement or unsubstituted aryl to replace 1-6Alkyl.The example comprises benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 1-naphthyl methyl and 2-naphthyl methyl.
In the formula of representing opticity two  isoxazoline compounds (1), R 3The replacement of representative or unsubstituted naphthyl also have for example by at least one C except unsubstituted 1-naphthyl or 2-naphthyl 1-6Alkyl or C 1-61-naphthyl or 2-naphthyl that alkoxyl group replaces.C 1-6Alkyl or C 1-6The alkoxyl group example comprises uses R 1Or R 2Those that substituting group exemplifies.Specifically, for example 4-fluoro-1-naphthyl, 2-methyl isophthalic acid-naphthyl, 4-methyl isophthalic acid-naphthyl, 2-methoxyl group-1-naphthyl, 2-oxyethyl group-1-naphthyl, 4-methoxyl group-1-naphthyl, 2 are arranged, 4-dimethoxy-1-naphthyl, 2-naphthyl, 7-methyl-2-naphthyl, 1-n-propyl-2-naphthyl, 6-methoxyl group-2-naphthyl and 3,8-dimethoxy-2-naphthyl.Preferred 1-naphthyl and 2-naphthyl wherein.
R 4And R 5The C of representative 1-6Examples of alkyl comprises C 1-3Alkyl is methyl, ethyl, n-propyl and sec.-propyl and butyl, amyl group and hexyl for example.As R 4And R 5The ring that the  oxazoline ring carbon atom that is connected to each other, connects with them forms, the cycloalkyl ring that can have 3-6 carbon atom is an example.The cycloalkyl ring example comprises cyclopropane ring, tetramethylene ring, pentamethylene ring and cyclohexane ring.Preferred R 4And R 5Represent hydrogen atom, C 1-3Alkyl or R 4And R 5The cycloalkyl ring with 3-6 carbon atom that the  oxazoline ring carbon atom that is connected to each other, connects with them forms, more preferably they represent C 1-3Alkyl.
In two  isoxazoline compounds of formula (1) representative, two unsymmetrical carbons by the * representative are arranged, it is preferred that to use wherein two unsymmetrical carbons all be (S) or (R) compound of configuration.
The specific examples of these class opticity two  isoxazoline compounds (1) comprising:
1) two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] methane,
2) two [2-[(4S)-(1-naphthyl)-5,5-diethyl  azoles quinoline]] methane,
3) two [2-[(4S)-(1-naphthyl)-5,5-two-n-propyl  azoles quinoline]] methane,
4) two [2-[(4S)-(1-naphthyl)-5,5-di-n-butyl  azoles quinoline]] methane,
5) two [2-[(4S)-(1-naphthyl)-5,5-diisobutyl  azoles quinoline]] methane,
6) two [2-[(4S)-(1-naphthyl)-5,5-two-n-pentyl  azoles quinoline]] methane,
7) two [2-[(4S)-(1-naphthyl)-5,5-two-n-hexyl  azoles quinoline]] methane,
8) two [2-[(4S)-(1-naphthyl)-5,5-dibenzyl  azoles quinoline]] methane,
9) two [2-[(4S)-(1-naphthyl)-5,5-two (2-methyl-benzyl)  azoles quinoline]] methane,
10) two [2-[(4S)-(1-naphthyl)-5,5-two (3-methyl-benzyl)  azoles quinoline]] methane,
11) two [2-[(4S)-(1-naphthyl)-5,5-two (4-methyl-benzyl)  azoles quinoline]] methane,
12) two [2-[(4S)-(1-naphthyl)-5,5-two (2-methoxy-benzyl)  azoles quinoline]] methane,
13) two [2-[(4S)-(1-naphthyl)-5,5-two (3-methoxy-benzyl)  azoles quinoline]] methane,
14) two [2-[(4S)-(1-naphthyl)-5,5-two (4-methoxy-benzyl)  azoles quinoline]] methane,
15) two [2-[(4S)-(1-naphthyl)-5,5-two (1-naphthyl methyl)  azoles quinoline]] methane,
16) two [2-[(4S)-(1-naphthyl)-5,5-two (2-naphthyl methyl)  azoles quinoline]] methane,
17) two [2-[(4S)-(1-naphthyl)-5,5-phenylbenzene  azoles quinoline]] methane,
18) two [2-[(4S)-(1-naphthyl)-5,5-two (3-aminomethyl phenyl)  azoles quinoline]] methane,
19) two [2-[(4S)-(1-naphthyl)-5,5-two (4-aminomethyl phenyl)  azoles quinoline]] methane,
20) two [2-[(4S)-(1-naphthyl)-5,5-two (2-p-methoxy-phenyl)  azoles quinoline]] methane,
21) two [2-[(4S)-(1-naphthyl)-5,5-two (3-p-methoxy-phenyl)  azoles quinoline]] methane,
22) two [2-[(4S)-(1-naphthyl)-5,5-two (4-p-methoxy-phenyl)  azoles quinoline]] methane,
23) two [2-[spiral shell (4S)-(1-naphthyl)  azoles quinoline-5,1 '-cyclopropane]]] methane,
24) two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 tetramethylene]]] methane,
25) two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-pentamethylene]]] methane,
26) two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-hexanaphthene]]] methane,
27) two [the 2-[spiral shell [(4S)-and methyl  azoles quinoline-5,1 '-suberane]]] methane,
28) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] propane,
29) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-diethyl  azoles quinoline]] propane,
30) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two-n-propyl  azoles quinoline]] propane,
31) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-di-n-butyl  azoles quinoline]] propane,
32) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-diisobutyl  azoles quinoline]] propane,
33) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two-n-pentyl  azoles quinoline]] propane,
34) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two-n-hexyl  azoles quinoline]] propane,
35) 2,2-[2-two [2-(4S)-(1-naphthyl)-5,5-dibenzyl  azoles quinoline]] propane,
36) 2,2-[2-two [2-two (4S)-(1-naphthyl)-5,5-two (2-methyl-benzyl)  azoles quinoline]] propane,
37) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methyl-benzyl)  azoles quinoline]] propane,
38) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methyl-benzyl)  azoles quinoline]] propane,
39) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methoxy-benzyl)  azoles quinoline]] propane,
40) 2,2-two [(4S)-and (1-naphthyl)-5,5-two (3-methoxy-benzyl)  azoles quinoline]] propane,
41) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methoxy-benzyl)  azoles quinoline]] propane,
42) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (1-naphthyl methyl)  azoles quinoline]] propane,
43) 2,2-two [(4S)-and (1-naphthyl)-5,5-two (2-naphthyl methyl)  azoles quinoline]] propane,
44) 2,2-two [(4S)-and (1-naphthyl)-5,5-phenylbenzene  azoles quinoline]] propane,
45) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (3-aminomethyl phenyl)  azoles quinoline]] propane,
46) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (4-aminomethyl phenyl)  azoles quinoline]] propane,
47) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (2-p-methoxy-phenyl)  azoles quinoline]] propane,
48) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (3-p-methoxy-phenyl)  azoles quinoline]] propane,
49) 2,2-two [2-[(4S)-(1-naphthyl)-5,5-two (4-p-methoxy-phenyl)  azoles quinoline]] propane,
50) 2,2-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-cyclopropane]]] propane,
51) 2,2-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-tetramethylene]]] propane,
52) 2,2-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-pentamethylene]]] propane,
53) 2,2-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-hexanaphthene]]] propane,
54) 2,2-two [the 2-[spiral shell [(4S)-and methyl  azoles quinoline-5,1 '-suberane]]] propane,
55) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] pentane,
56) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-diethyl  azoles quinoline]] pentane,
57) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two-n-propyl-2- azoles quinoline]] pentane,
58) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-di-n-butyl  azoles quinoline]] pentane,
59) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-diisobutyl  azoles quinoline]] pentane,
60) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two-n-pentyl  azoles quinoline]] pentane,
61) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two-n-hexyl  azoles quinoline]] pentane,
62) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-dibenzyl  azoles quinoline]] pentane,
63) 3,3-two [2-two [(4S)-and (1-naphthyl)-5,5-two (2-methyl-benzyl)  azoles quinoline]] pentane,
64) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methyl-benzyl)  azoles quinoline]] pentane,
65) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methyl-benzyl)  azoles quinoline]] pentane,
66) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methoxy-benzyl)  azoles quinoline]] pentane,
67) 3,3-two [(4S)-and (1-naphthyl)-5,5-two (3-methoxy-benzyl)  azoles quinoline]] pentane,
68) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methoxy-benzyl)  azoles quinoline]] pentane,
69) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (1-naphthyl methyl)  azoles quinoline]] pentane,
70) 3,3-[2-two [(4S)-and (1-naphthyl)-5,5-two (2-naphthyl methyl)  azoles quinoline]] pentane,
71) 3,3-[2-two [(4S)-and (1-naphthyl)-5,5-phenylbenzene  azoles quinoline]] pentane,
72) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (3-aminomethyl phenyl)  azoles quinoline]] pentane,
73) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (4-aminomethyl phenyl)  azoles quinoline]] pentane,
74) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (2-p-methoxy-phenyl)  azoles quinoline]] pentane,
75) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (3-p-methoxy-phenyl)  azoles quinoline]] pentane,
76) 3,3-two [2-[(4S)-(1-naphthyl)-5,5-two (4-p-methoxy-phenyl)  azoles quinoline]] pentane,
77) 3,3-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-cyclopropane]]] pentane,
78) 3,3-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-tetramethylene]]] pentane,
79) 3,3-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-pentamethylene]]] pentane,
80) 3,3-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-hexanaphthene]]] pentane,
81) 3,3-two [the 2-[spiral shell [(4S)-and methyl  azoles quinoline-5,1 '-suberane]]] pentane,
82) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] heptane,
83) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-diethyl-2- azoles quinoline]] heptane,
84) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two-n-propyl  azoles quinoline]] heptane,
85) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-di-n-butyl  azoles quinoline]] heptane,
86) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-diisobutyl  azoles quinoline]] heptane,
87) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two-n-pentyl  azoles quinoline]] heptane,
88) 4,4-[2-two [2-[(4S)-(1-naphthyl)-5,5-two-n-hexyl  azoles quinoline]] heptane,
89) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-dibenzyl  azoles quinoline]] heptane,
90) 4,4-two [2-two [(4S)-and (1-naphthyl)-5,5-two (2-methyl-benzyl)  azoles quinoline]] heptane,
91) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methyl-benzyl)  azoles quinoline]] heptane,
92) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methyl-benzyl)  azoles quinoline]] heptane,
93) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methoxy-benzyl)  azoles quinoline]] heptane,
94) 4,4-[2-two [(4S)-and (1-naphthyl)-5,5-two (3-methoxy-benzyl)  azoles quinoline]] heptane,
95) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methoxy-benzyl)  azoles quinoline]] heptane,
96) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (1-naphthyl methyl)  azoles quinoline]] heptane,
97) 4,4-[2-two [(4S)-and (1-naphthyl)-5,5-two (2-naphthyl methyl)  azoles quinoline]] heptane,
98) 4,4-two [(4S)-and (1-naphthyl)-5,5-phenylbenzene  azoles quinoline]] heptane,
99) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (3-aminomethyl phenyl)  azoles quinoline]] heptane,
100) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (4-aminomethyl phenyl)  azoles quinoline]] heptane,
101) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (2-p-methoxy-phenyl)  azoles quinoline]] heptane,
102) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (3-p-methoxy-phenyl)  azoles quinoline]] heptane,
103) 4,4-two [2-[(4S)-(1-naphthyl)-5,5-two (4-p-methoxy-phenyl)  azoles quinoline]] heptane,
104) 4,4-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-cyclopropane]]] heptane,
105) 4,4-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-tetramethylene]]] heptane,
106) 4,4-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-pentamethylene]]] heptane,
107) 4,4-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-hexanaphthene]]] heptane,
108) 4,4-two [the 2-[spiral shell [(4S)-and methyl  azoles quinoline-5,1 '-suberane]]] heptane,
109) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] cyclopropane,
110) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-diethyl  azoles quinoline]] cyclopropane,
111) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-propyl-2- azoles quinoline]] cyclopropane,
112) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-di-n-butyl  azoles quinoline]] cyclopropane,
113) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-diisobutyl  azoles quinoline]] cyclopropane,
114) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-pentyl  azoles quinoline]] cyclopropane,
115) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-hexyl  azoles quinoline]] cyclopropane,
116) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dibenzyl  azoles quinoline]] cyclopropane,
117) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methyl-benzyl)  azoles quinoline]] cyclopropane,
118) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methyl-benzyl)  azoles quinoline]] cyclopropane,
119) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methyl-benzyl)  azoles quinoline]] cyclopropane,
120) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methoxy-benzyl)  azoles quinoline]] cyclopropane,
121) 1,1-two [(4S)-and (1-naphthyl)-5,5-two (3-methoxy-benzyl)  azoles quinoline]] cyclopropane,
122) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methoxy-benzyl)  azoles quinoline]] cyclopropane,
123) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (1-naphthyl methyl)  azoles quinoline]] cyclopropane,
124) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-naphthyl methyl)  azoles quinoline]] cyclopropane,
125) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-phenylbenzene  azoles quinoline]] cyclopropane,
126) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-aminomethyl phenyl)  azoles quinoline]] cyclopropane,
127) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-aminomethyl phenyl)  azoles quinoline]] cyclopropane,
128) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-p-methoxy-phenyl)  azoles quinoline]] cyclopropane,
129) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-p-methoxy-phenyl)  azoles quinoline]] cyclopropane,
130) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-p-methoxy-phenyl)  azoles quinoline]] cyclopropane,
131) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-cyclopropane]]] cyclopropane,
132) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-pentamethylene]]] cyclopropane,
133) 1,1-two [the 2-[spiral shell [(4S)-and methyl  azoles quinoline-5,1 '-suberane]]] cyclopropane,
134) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] tetramethylene,
135) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-diethyl  azoles quinoline]] tetramethylene,
136) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-propyl-2- azoles quinoline]] tetramethylene,
137) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-di-n-butyl  azoles quinoline]] tetramethylene,
138) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-diisobutyl  azoles quinoline]] tetramethylene,
139) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-pentyl  azoles quinoline]] tetramethylene,
140) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-hexyl  azoles quinoline]] tetramethylene,
141) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dibenzyl  azoles quinoline]] tetramethylene,
142) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methyl-benzyl)  azoles quinoline]] tetramethylene,
143) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methyl-benzyl)  azoles quinoline]] tetramethylene,
144) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methyl-benzyl)  azoles quinoline]] tetramethylene,
145) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methoxy-benzyl)  azoles quinoline]] tetramethylene,
146) 1,1-two [(4S)-and (1-naphthyl)-5,5-two (3-methoxy-benzyl)  azoles quinoline]] tetramethylene,
147) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methoxy-benzyl)  azoles quinoline]] tetramethylene,
148) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (1-naphthyl methyl)  azoles quinoline]] tetramethylene,
149) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-naphthyl methyl)  azoles quinoline]] tetramethylene,
150) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-phenylbenzene  azoles quinoline]] tetramethylene,
151) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-aminomethyl phenyl)  azoles quinoline]] tetramethylene,
152) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-aminomethyl phenyl)  azoles quinoline]] tetramethylene,
153) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-p-methoxy-phenyl)  azoles quinoline]] tetramethylene,
154) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-p-methoxy-phenyl)  azoles quinoline]] tetramethylene,
155) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-p-methoxy-phenyl)  azoles quinoline]] tetramethylene,
156) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-cyclopropane]]] tetramethylene,
157) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-tetramethylene]]] tetramethylene,
158) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-pentamethylene]]] tetramethylene,
159) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-hexanaphthene]]] tetramethylene,
160) 1,1-two [the 2-[spiral shell [(4S)-and methyl  azoles quinoline-5,1 '-suberane]]] tetramethylene,
161) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] pentamethylene,
162) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-diethyl  azoles quinoline]] pentamethylene,
163) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-propyl  azoles quinoline]] pentamethylene,
164) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-di-n-butyl  azoles quinoline]] pentamethylene,
165) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-diisobutyl  azoles quinoline]] pentamethylene,
166) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-pentyl  azoles quinoline]] pentamethylene,
167) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-hexyl  azoles quinoline]] pentamethylene,
168) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dibenzyl  azoles quinoline]] pentamethylene,
169) 1,1-two [2-two [(4S)-and (1-naphthyl)-5,5-two (2-methyl-benzyl)  azoles quinoline]] pentamethylene,
170) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methyl-benzyl)  azoles quinoline]] pentamethylene,
171) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methyl-benzyl)  azoles quinoline]] pentamethylene,
172) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methoxy-benzyl)  azoles quinoline]] pentamethylene,
173) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methoxy-benzyl)  azoles quinoline]] pentamethylene,
174) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methoxy-benzyl)  azoles quinoline]] pentamethylene,
175) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (1-naphthyl methyl)  azoles quinoline]] pentamethylene,
176) 1,1-two [(4S)-and (1-naphthyl)-5,5-two (2-naphthyl methyl)  azoles quinoline]] pentamethylene,
177) 1,1-two [(4S)-and (1-naphthyl)-5,5-phenylbenzene  azoles quinoline]] pentamethylene,
178) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-aminomethyl phenyl)  azoles quinoline]] pentamethylene,
179) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-aminomethyl phenyl)  azoles quinoline]] pentane,
180) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-p-methoxy-phenyl)  azoles quinoline]] pentamethylene,
181) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-p-methoxy-phenyl)  azoles quinoline]] pentamethylene,
182) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-p-methoxy-phenyl)  azoles quinoline]] pentamethylene,
183) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-cyclopropane]]] pentamethylene,
184) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-tetramethylene]]] pentamethylene,
185) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-pentamethylene]]] pentamethylene,
186) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-hexanaphthene]]] pentamethylene,
187) 1,1-two [the 2-[spiral shell [(4S)-and methyl  azoles quinoline-5,1 '-suberane]]] pentamethylene,
188) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] hexanaphthene,
189) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-diethyl  azoles quinoline]] hexanaphthene,
190) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-propyl  azoles quinoline]] hexanaphthene,
191) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-di-n-butyl  azoles quinoline]] hexanaphthene,
192) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-diisobutyl  azoles quinoline]] hexanaphthene,
193) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-pentyl  azoles quinoline]] hexanaphthene,
194) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two-n-hexyl  azoles quinoline]] hexanaphthene,
195) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dibenzyl  azoles quinoline]] hexanaphthene,
196) 1,1-two [2-two [(4S)-and (1-naphthyl)-5,5-two (2-methyl-benzyl)  azoles quinoline]] hexanaphthene,
197) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methyl-benzyl)  azoles quinoline]] hexanaphthene,
198) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methyl-benzyl)  azoles quinoline]] hexanaphthene,
199) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-methoxy-benzyl)  azoles quinoline]] hexanaphthene,
200) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-methoxy-benzyl)  azoles quinoline]] hexanaphthene,
201) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-methoxy-benzyl)  azoles quinoline]] hexanaphthene,
202) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (1-naphthyl methyl)  azoles quinoline]] hexanaphthene,
203) 1,1-two [(4S)-and (1-naphthyl)-5,5-two (2-naphthyl methyl)  azoles quinoline]] hexanaphthene,
204) 1,1-two [(4S)-and (1-naphthyl)-5,5-phenylbenzene  azoles quinoline]] hexanaphthene,
205) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-aminomethyl phenyl)  azoles quinoline]] hexanaphthene,
206) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-aminomethyl phenyl)  azoles quinoline]] hexane,
207) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (2-p-methoxy-phenyl)  azoles quinoline]] hexanaphthene,
208) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (3-p-methoxy-phenyl)  azoles quinoline]] hexanaphthene,
209) 1,1-two [2-[(4S)-(1-naphthyl)-5,5-two (4-p-methoxy-phenyl)  azoles quinoline]] hexanaphthene,
210) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-cyclopropane]]] hexanaphthene,
211) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-tetramethylene]]] hexanaphthene,
212) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-pentamethylene]]] hexanaphthene,
213) 1,1-two [2-[spiral shell [(4S)-(1-naphthyl)  azoles quinoline-5,1 '-hexanaphthene]]] hexanaphthene,
214) 1,1-two [the 2-[spiral shell [(4S)-and methyl  azoles quinoline-5,1 '-suberane]]] hexanaphthene; Wherein these compounds of being replaced by the 2-naphthyl of 4 1-naphthyl for example two [2-[(4S)-(2-naphthyl)-5,5-dimethyl  azoles quinoline]] methane; Wherein (4S) configuration of 4 become (4R) these compounds for example two [2-[(4R)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] methane and two [2-[(4R)-(2-naphthyl)-5,5-dimethyl  azoles quinoline]] methane.
Opticity two  isoxazoline compounds (1) can prepare by opticity diamide compound and the Lewis acid-respons that makes following formula (2) representative:
R wherein 1, R 2, R 3, R 4, R 5The same with the * definition, it is new compound (a hereinafter referred opticity diamide compound (2)).
Opticity diamide compound (2) example comprises:
1) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] the third-1, the 3-diamide,
2) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-ethyl-butyl] the third-1, the 3-diamide,
3) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-propyl amyl group] the third-1, the 3-diamide,
4) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-normal-butyl hexyl] the third-1, the 3-diamide,
5) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-isobutyl--4-methyl amyl] the third-1, the 3-diamide,
6) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-pentyl heptyl] the third-1, the 3-diamide,
7) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-hexyl octyl group] the third-1, the 3-diamide,
8) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-benzyl-3-phenyl propyl] the third-1, the 3-diamide,
9) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl) propyl group] the third-1, the 3-diamide,
10) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl) propyl group] the third-1, the 3-diamide,
11) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl) propyl group] the third-1, the 3-diamide,
12) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl) propyl group] the third-1, the 3-diamide,
13) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl) propyl group] the third-1, the 3-diamide,
14) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl) propyl group] the third-1, the 3-diamide,
15) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(1-naphthyl methyl)-3-(1-naphthyl) propyl group] the third-1, the 3-diamide,
16) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-naphthyl methyl)-3-(2-naphthyl) propyl group] the third-1, the 3-diamide,
17) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2, the 2-diphenyl-ethyl] the third-1, the 3-diamide,
18) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-aminomethyl phenyl) ethyl] the third-1, the 3-diamide,
19) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (4-aminomethyl phenyl) ethyl] the third-1, the 3-diamide,
20) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (2-p-methoxy-phenyl) ethyl] the third-1, the 3-diamide,
21) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-p-methoxy-phenyl) ethyl] the third-1, the 3-diamide,
22) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclopropyl) methyl] the third-1, the 3-diamide,
23) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclobutyl) methyl] the third-1, the 3-diamide,
24) N, N '-two [(1S)-(1-naphthyl) (1-hydroxycyclopent base) methyl] the third-1, the 3-diamide,
25) N, N '-two [(1S)-(1-naphthyl) (1-hydroxy-cyclohexyl) methyl] the third-1, the 3-diamide,
26) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl suberyl) methyl] the third-1, the 3-diamide,
27) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
28) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-ethyl-butyl]-2,2-dimethyl propylene-1, the 3-diamide,
29) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-propyl amyl group]-2,2-dimethyl propylene-1, the 3-diamide,
30) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-normal-butyl hexyl]-2,2-dimethyl propylene-1, the 3-diamide,
31) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-isobutyl--4-methyl amyl]-2,2-dimethyl propylene-1, the 3-diamide,
32) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-pentyl heptyl]-2,2-dimethyl propylene-1, the 3-diamide,
33) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-hexyl octyl group]-2,2-dimethyl propylene-1, the 3-diamide,
34) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-benzyl-3-phenyl propyl]-2,2-dimethyl propylene-1, the 3-diamide,
35) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl) propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
36) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl) propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
37) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl) propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
38) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl) propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
39) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl) propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
40) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl) propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
41) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(1-naphthyl methyl)-3-(1-naphthyl) propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
42) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-naphthyl methyl)-3-(2-naphthyl) propyl group]-2,2-dimethyl propylene-1, the 3-diamide,
43) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2, the 2-diphenyl-ethyl]-2,2-dimethyl propylene-1, the 3-diamide,
44) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-aminomethyl phenyl) ethyl)-2,2-dimethyl propylene-1, the 3-diamide,
45) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (4-aminomethyl phenyl) ethyl)-2,2-dimethyl propylene-1, the 3-diamide,
46) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (2-p-methoxy-phenyl) ethyl)-2,2-dimethyl propylene-1, the 3-diamide,
47) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-p-methoxy-phenyl) ethyl)-2,2-dimethyl propylene-1, the 3-diamide,
48) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclopropyl) methyl]-2,2-dimethyl propylene-1, the 3-diamide,
49) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclobutyl) methyl]-2,2-dimethyl propylene-1, the 3-diamide,
50) N, N '-two [(1S)-(1-naphthyl) (1-hydroxycyclopent base) methyl]-2,2-dimethyl propylene-1, the 3-diamide,
51) N, N '-two [(1S)-(1-naphthyl) (1-hydroxy-cyclohexyl) methyl]-2,2-dimethyl propylene-1, the 3-diamide,
52) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl suberyl) methyl]-2,2-dimethyl propylene-1, the 3-diamide,
53) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-diethyl the third-1, the 3-diamide,
54) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-ethyl-butyl]-2,2-diethyl the third-1, the 3-diamide,
55) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-propyl amyl group]-2,2-diethyl the third-1, the 3-diamide,
56) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-normal-butyl hexyl]-2,2-diethyl the third-1, the 3-diamide,
57) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-isobutyl--4-methyl amyl]-2,2-diethyl the third-1, the 3-diamide,
58) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-pentyl heptyl]-2,2-diethyl the third-1, the 3-diamide,
59) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-hexyl octyl group]-2,2-diethyl the third-1, the 3-diamide,
60) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-benzyl-3-phenyl propyl]-2,2-diethyl the third-1, the 3-diamide,
61) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl) propyl group]-2,2-diethyl the third-1, the 3-diamide,
62) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl) propyl group]-2,2-diethyl the third-1, the 3-diamide,
63) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl) propyl group]-2,2-diethyl the third-1, the 3-diamide,
64) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl) propyl group]-2,2-diethyl the third-1, the 3-diamide,
65) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl) propyl group]-2,2-diethyl the third-1, the 3-diamide,
66) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl) propyl group]-2,2-diethyl the third-1, the 3-diamide,
67) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(1-naphthyl methyl)-3-(1-naphthyl) propyl group]-2,2-diethyl the third-1, the 3-diamide,
68) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-naphthyl methyl)-3-(2-naphthyl) propyl group]-2,2-diethyl the third-1, the 3-diamide,
69) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2, the 2-diphenyl-ethyl]-2,2-diethyl the third-1, the 3-diamide,
70) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-aminomethyl phenyl) ethyl]-2,2-diethyl the third-1, the 3-diamide,
71) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (4-aminomethyl phenyl) ethyl]-2,2-diethyl the third-1, the 3-diamide,
72) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (2-p-methoxy-phenyl) ethyl]-2,2-diethyl the third-1, the 3-diamide,
73) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-p-methoxy-phenyl) ethyl]-2,2-diethyl the third-1, the 3-diamide,
74) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclopropyl) methyl]-2,2-diethyl the third-1, the 3-diamide,
75) N, N '-two [(1S)-(1-naphthyl) (1-hydroxycyclopent base) methyl]-2,2-diethyl the third-1, the 3-diamide,
76) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl suberyl) methyl]-2,2-diethyl the third-1, the 3-diamide,
77) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
78) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-ethyl-butyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
79) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-propyl amyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
80) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-normal-butyl hexyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
81) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-isobutyl--4-methyl amyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
82) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-pentyl heptyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
83) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-hexyl octyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
84) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-benzyl-3-phenyl propyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
85) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl) propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
86) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl) propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
87) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl) propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
88) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl) propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
89) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl) propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
90) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl) propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
91) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(1-naphthyl methyl)-3-(1-naphthyl) propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
92) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-naphthyl methyl)-3-(2-naphthyl) propyl group]-2,2-two (n-propyl) the third-1, the 3-diamide,
93) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2, the 2-diphenyl-ethyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
94) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-aminomethyl phenyl) ethyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
95) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (4-aminomethyl phenyl) ethyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
96) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (2-p-methoxy-phenyl) ethyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
97) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-p-methoxy-phenyl) ethyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
98) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclopropyl) methyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
99) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclobutyl) methyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
100) N, N '-two [(1 S)-(1-naphthyl) (1-hydroxycyclopent base) methyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
101) N, N '-two [(1S)-(1-naphthyl) (1-hydroxy-cyclohexyl) methyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
102) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl suberyl) methyl]-2,2-two (n-propyl) the third-1, the 3-diamide,
103) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] cyclopropane-1, the 1-diformamide,
104) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-ethyl-butyl] cyclopropane-1, the 1-diformamide,
105) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-propyl amyl group] cyclopropane-1, the 1-diformamide,
106) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-normal-butyl hexyl] cyclopropane-1, the 1-diformamide,
107) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-isobutyl--4-methyl amyl] cyclopropane-1, the 1-diformamide,
108) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-pentyl heptyl] cyclopropane-1, the 1-diformamide,
109) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-hexyl octyl group] cyclopropane-1, the 1-diformamide,
110) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-benzyl-3-phenyl propyl] cyclopropane-1, the 1-diformamide,
111) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl) propyl group] cyclopropane-1, the 1-diformamide,
112) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl) propyl group] cyclopropane-1, the 1-diformamide,
113) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl) propyl group] cyclopropane-1, the 1-diformamide,
114) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl) propyl group] cyclopropane-1, the 1-diformamide,
115) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl) propyl group] cyclopropane-1, the 1-diformamide,
116) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl) propyl group] cyclopropane-1, the 1-diformamide,
117) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(1-naphthyl methyl)-3-(1-naphthyl) propyl group] cyclopropane-1, the 1-diformamide,
118) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-naphthyl methyl)-3-(2-naphthyl) propyl group] cyclopropane-1, the 1-diformamide,
119) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2, the 2-diphenyl-ethyl] cyclopropane-1, the 1-diformamide,
120) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-aminomethyl phenyl) ethyl] cyclopropane-1, the 1-diformamide,
121) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (4-aminomethyl phenyl) ethyl] cyclopropane-1, the 1-diformamide,
122) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (2-p-methoxy-phenyl) ethyl] cyclopropane-1, the 1-diformamide,
123) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-p-methoxy-phenyl) ethyl] cyclopropane-1, the 1-diformamide,
124) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclopropyl) methyl] cyclopropane-1, the 1-diformamide,
125) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclobutyl) methyl] cyclopropane-1, the 1-diformamide,
126) N, N '-two [(1S)-(1-naphthyl) (1-hydroxycyclopent base) methyl] cyclopropane-1, the 1-diformamide,
127) N, N '-two [(1S)-(1-naphthyl) (1-hydroxy-cyclohexyl) methyl] cyclopropane-1, the 1-diformamide,
128) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl suberyl) methyl] cyclopropane-1, the 1-diformamide,
129) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] tetramethylene-1, the 1-diformamide,
130) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-ethyl-butyl] tetramethylene-1, the 1-diformamide,
131) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-propyl amyl group] tetramethylene-1, the 1-diformamide,
132) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-normal-butyl hexyl] tetramethylene-1, the 1-diformamide,
133) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-isobutyl--4-methyl amyl] tetramethylene-1, the 1-diformamide,
134) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-pentyl heptyl] tetramethylene-1, the 1-diformamide,
135) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-hexyl octyl group] tetramethylene-1, the 1-diformamide,
136) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-benzyl-3-phenyl propyl] tetramethylene-1, the 1-diformamide,
137) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl) propyl group] tetramethylene-1, the 1-diformamide,
138) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl) propyl group] tetramethylene-1, the 1-diformamide,
139) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl) propyl group] tetramethylene-1, the 1-diformamide,
140) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl) propyl group] tetramethylene-1, the 1-diformamide,
141) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl) propyl group] tetramethylene-1, the 1-diformamide,
142) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl) propyl group] tetramethylene-1, the 1-diformamide,
143) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(1-naphthyl methyl)-3-(1-naphthyl) propyl group] tetramethylene-1, the 1-diformamide,
144) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-naphthyl methyl)-3-(2-naphthyl) propyl group] tetramethylene-1, the 1-diformamide,
145) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2, the 2-diphenyl-ethyl] tetramethylene-1, the 1-diformamide,
146) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-aminomethyl phenyl) ethyl] tetramethylene-1, the 1-diformamide,
147) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (4-aminomethyl phenyl) ethyl] tetramethylene-1, the 1-diformamide,
148) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (2-p-methoxy-phenyl) ethyl] tetramethylene-1, the 1-diformamide,
149) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-p-methoxy-phenyl) ethyl] tetramethylene-1, the 1-diformamide,
150) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclopropyl) methyl] tetramethylene-1, the 1-diformamide,
151) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclobutyl) methyl] tetramethylene-1, the 1-diformamide,
152) N, N '-two [(1S)-(1-naphthyl) (1-hydroxycyclopent base) methyl] tetramethylene-1, the 1-diformamide,
153) N, N '-two [(1S)-(1-naphthyl) (1-hydroxy-cyclohexyl) methyl] tetramethylene-1, the 1-diformamide,
154) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl suberyl) methyl] tetramethylene-1, the 1-diformamide,
155) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] pentamethylene-1, the 1-diformamide,
156) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-ethyl-butyl] pentamethylene-1, the 1-diformamide,
157) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-propyl amyl group] pentamethylene-1, the 1-diformamide,
158) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-normal-butyl hexyl] pentamethylene-1, the 1-diformamide,
159) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-isobutyl--4-methyl amyl] pentamethylene-1, the 1-diformamide,
160) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-pentyl heptyl] pentamethylene-1, the 1-diformamide,
161) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-hexyl octyl group] pentamethylene-1, the 1-diformamide,
162) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-benzyl-3-phenyl propyl] pentamethylene-1, the 1-diformamide,
163) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl) propyl group] pentamethylene-1, the 1-diformamide,
164) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl) propyl group] pentamethylene-1, the 1-diformamide,
165) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl) propyl group] pentamethylene-1, the 1-diformamide,
166) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl) propyl group] pentamethylene-1, the 1-diformamide,
167) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl) propyl group] pentamethylene-1, the 1-diformamide,
168) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl) propyl group] pentamethylene-1, the 1-diformamide,
169) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(1-naphthyl methyl)-3-(1-naphthyl) propyl group] pentamethylene-1, the 1-diformamide,
170) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-naphthyl methyl)-3-(2-naphthyl) propyl group] pentamethylene-1, the 1-diformamide,
171) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2, the 2-diphenyl-ethyl] pentamethylene-1, the 1-diformamide,
172) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-aminomethyl phenyl) ethyl] pentamethylene-1, the 1-diformamide,
173) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (4-aminomethyl phenyl) ethyl] pentamethylene-1, the 1-diformamide,
174) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (2-p-methoxy-phenyl) ethyl] pentamethylene-1, the 1-diformamide,
175) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-p-methoxy-phenyl) ethyl] pentamethylene-1, the 1-diformamide,
176) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclopropyl) methyl] pentamethylene-1, the 1-diformamide,
177) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclobutyl) methyl] pentamethylene-1, the 1-diformamide,
178) N, N '-two [(1S)-(1-naphthyl) (1-hydroxycyclopent base) methyl] pentamethylene-1, the 1-diformamide,
179) N, N '-two [(1S)-(1-naphthyl) (1-hydroxy-cyclohexyl) methyl] pentamethylene-1, the 1-diformamide,
180) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl suberyl) methyl] pentamethylene-1, the 1-diformamide,
181) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] hexanaphthene-1, the 1-diformamide,
182) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-ethyl-butyl] hexanaphthene-1, the 1-diformamide,
183) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-propyl amyl group] hexanaphthene-1, the 1-diformamide,
184) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-normal-butyl hexyl] hexanaphthene-1, the 1-diformamide,
185) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-isobutyl--4-methyl amyl] hexanaphthene-1, the 1-diformamide,
186) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-pentyl heptyl] hexanaphthene-1, the 1-diformamide,
187) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-n-hexyl octyl group] hexanaphthene-1, the 1-diformamide,
188) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-benzyl-3-phenyl propyl] hexanaphthene-1, the 1-diformamide,
189) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl) propyl group] hexanaphthene-1, the 1-diformamide,
190) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl) propyl group] hexanaphthene-1, the 1-diformamide,
191) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl) propyl group] hexanaphthene-1, the 1-diformamide,
192) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl) propyl group] hexanaphthene-1, the 1-diformamide,
193) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl) propyl group] hexanaphthene-1, the 1-diformamide,
194) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl) propyl group] hexanaphthene-1, the 1-diformamide,
195) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(1-naphthyl methyl)-3-(1-naphthyl) propyl group] hexanaphthene-1, the 1-diformamide,
196) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2-(2-naphthyl methyl)-3-(2-naphthyl) propyl group] hexanaphthene-1, the 1-diformamide,
197) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2, the 2-diphenyl-ethyl] hexanaphthene-1, the 1-diformamide,
198) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-aminomethyl phenyl) ethyl] hexanaphthene-1, the 1-diformamide,
199) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (4-aminomethyl phenyl) ethyl] hexanaphthene-1, the 1-diformamide,
200) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (2-p-methoxy-phenyl) ethyl] hexanaphthene-1, the 1-diformamide,
201) N, N '-two [(1S)-and (1-naphthyl)-2-hydroxyl-2,2-two (3-p-methoxy-phenyl) ethyl] hexanaphthene-1, the 1-diformamide,
202) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclopropyl) methyl] hexanaphthene-1, the 1-diformamide,
203) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl cyclobutyl) methyl] hexanaphthene-1, the 1-diformamide,
204) N, N '-two [(1S)-(1-naphthyl) (1-hydroxycyclopent base) methyl] hexanaphthene-1, the 1-diformamide,
205) N, N '-two [(1S)-(1-naphthyl) (1-hydroxy-cyclohexyl) methyl] hexanaphthene-1, the 1-diformamide,
206) N, N '-two [(1S)-(1-naphthyl) (1-hydroxyl suberyl) methyl] hexanaphthene-1,1-diformamide;
And these compounds of wherein being replaced by the 2-naphthyl with 1 1-naphthyl of amide nitrogen atom linking group; Wherein configuration (1S) becomes these compounds of (1R).
Usually use aprotic acid as Lewis acid, the example comprises for example titanium tetraisopropylate of tetrol titanium; Halogenated titanium is titanium chloride for example; Tetrol aluminium is four aluminum isopropylates for example; Aluminum halide is aluminum chloride, ethylaluminium dichloride and diethylaluminum chloride for example; Trialkylaluminium is trimethyl aluminium and triethyl aluminum for example; Tin halides is dichloride tin methide and tin chloride for example; Zinc halide is zinc chloride for example; Alkoxyl group zinc is diisopropoxy zinc for example; Zirconium halide is zirconium chloride for example; The halogenation hafnium is hafnium chloride for example.These Lewis acid can be used separately, or form that can mixture uses its two or more.With respect to 1mol opticity diamide compound (2), use the amount of Lewis acid to be about 0.001-5mol, preferably about 0.01-1mol usually.
By making opticity diamide compound (2) and Lewis acid-respons can obtain opticity two  isoxazoline compounds (1), this method can be carried out in the presence of solvent usually.Solvent is not particularly limited, as long as it is an inert solvent in this reaction, the example comprises aromatic solvent for example toluene and dimethylbenzene; Aliphatic hydrocarbon solvent is heptane and octane for example; Halogenated hydrocarbon solvent is chlorobenzene, methylene dichloride and ethylene dichloride for example.They can use separately or use with form of mixtures.Use the amount of solvent to be not particularly limited, with respect to 1 part of (weight) opticity diamide compound (2), it uses about 2-200 part (weight) usually.
Make the temperature of reaction of Lewis acid-respons be about 50-250 ℃ usually, preferably about 60-180 ℃.Time to reaction has no particular limits, and finds opticity diamide compound (2) but termination reaction when disappearing, or by ordinary method for example analysis such as gas-chromatography, high performance liquid chromatography reaction process come the stopped reaction process.
After reaction is finished, concentrate the gained reaction mixture, obtain opticity two  isoxazoline compounds (1).Though can be directly with opticity two  isoxazoline compounds (1) the preparation asymmetric copper complex described below that obtains thus, preferably it for example uses behind the purifying such as column chromatography, recrystallization by conventional purification process.In addition, can separate opticity two  isoxazoline compounds (1) by the following method: for example sodium bicarbonate aqueous solution is mixed with reaction mixture and alkali aqueous solution, then if desired, removes by filter insoluble substance, carries out extraction treatment, concentrates the organic layer that obtains.
By making the opticity amino alcohol of following formula (3) representative:
Figure A20071015293300311
R wherein 1, R 2, R 3With * definition the same (hereinafter referred opticity amino alcohol (3)), the propanedioic acid compound of representing with following formula (4) reacts:
Figure A20071015293300321
R wherein 4And R 5Define the samely, Z representation alkoxy or halogen atom (hereinafter referred propanedioic acid compound (4)) can obtain opticity diamide compound (2).
Opticity amino alcohol (3) example comprises:
1) (R)-1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol,
2) (R)-1-amino-1-(1-naphthyl)-2-ethyl-2-butanols,
3) (R)-1-amino-1-(1-naphthyl)-2-n-propyl-2-amylalcohol,
4) (R)-1-amino-1-(1-naphthyl)-2-normal-butyl-2-hexanol,
5) (R)-1-amino-1-(1-naphthyl)-2-isobutyl--4-methyl-2-amylalcohol,
6) (R)-1-amino-1-(1-naphthyl)-2-n-pentyl-2-enanthol,
7) (R)-1-amino-1-(1-naphthyl)-2-n-hexyl-sec-n-octyl alcohol,
8) (R)-1-amino-1-(1-naphthyl)-2-benzyl-3-phenyl-2-propyl alcohol,
9) (R)-1-amino-1-(1-naphthyl)-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl)-2-propyl alcohol,
10) (R)-1-amino-1-(1-naphthyl)-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl)-2-propyl alcohol,
11) (R)-1-amino-1-(1-naphthyl)-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl)-2-propyl alcohol,
12) (R)-1-amino-1-(1-naphthyl)-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl)-2-propyl alcohol,
13) (R)-1-amino-1-(1-naphthyl)-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl)-2-propyl alcohol,
14) (R)-1-amino-1-(1-naphthyl)-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl)-2-propyl alcohol,
15) (R)-1-amino-1-(1-naphthyl)-2-(1-naphthyl methyl)-3-(1-naphthyl)-2-propyl alcohol,
16) (R)-1-amino-1-(1-naphthyl)-2-(2-naphthyl methyl)-3-(2-naphthyl)-2-propyl alcohol,
17) (R)-2-amino-2-(1-naphthyl)-methyl-diphenyl-carbinol,
18) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (3-aminomethyl phenyl) ethanol,
19) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (4-aminomethyl phenyl) ethanol,
20) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (2-p-methoxy-phenyl) ethanol,
21) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (3-p-methoxy-phenyl) ethanol,
22) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (4-p-methoxy-phenyl) ethanol,
23) 1-[(R)-and amino-(1-naphthyl) methyl] the ring propyl alcohol,
24) 1-[(R)-and amino-(1-naphthyl) methyl] cyclobutanol,
25) 1-[(R)-and amino-(1-naphthyl) methyl] cyclopentanol,
26) 1-[(R)-and amino-(1-naphthyl) methyl] hexalin,
27) 1-[(R)-and amino-(1-naphthyl) methyl] suberyl alcohol,
28) (R)-1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol,
29) (R)-1-amino-1-(2-naphthyl)-2-ethyl-2-butanols,
30) (R)-1-amino-1-(2-naphthyl)-2-n-propyl-2-amylalcohol,
31) (R)-1-amino-1-(2-naphthyl)-2-normal-butyl-2-hexanol,
32) (R)-1-amino-1-(2-naphthyl)-2-isobutyl--4-methyl-2-amylalcohol,
33) (R)-1-amino-1-(2-naphthyl)-2-n-pentyl-2-enanthol,
34) (R)-1-amino-1-(2-naphthyl)-2-n-hexyl-sec-n-octyl alcohol,
35) (R)-1-amino-1-(2-naphthyl)-2-benzyl-3-phenyl-2-propyl alcohol,
36) (R)-1-amino-1-(2-naphthyl)-2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl)-2-propyl alcohol,
37) (R)-1-amino-1-(2-naphthyl)-2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl)-2-propyl alcohol,
38) (R)-1-amino-1-(2-naphthyl)-2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl)-2-propyl alcohol,
39) (R)-1-amino-1-(2-naphthyl)-2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl)-2-propyl alcohol,
40) (R)-1-amino-1-(2-naphthyl)-2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl)-2-propyl alcohol,
41) (R)-1-amino-1-(2-naphthyl)-2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl)-2-propyl alcohol,
42) (R)-1-amino-1-(2-naphthyl)-2-(1-naphthyl methyl)-3-(1-naphthyl)-2-propyl alcohol,
43) (R)-1-amino-1-(2-naphthyl)-2-(2-naphthyl methyl)-3-(2-naphthyl)-2-propyl alcohol,
44) (R)-2-amino-2-(2-naphthyl)-methyl-diphenyl-carbinol,
45) (R)-and 2-amino-2-(2-naphthyl)-1,1-two (3-aminomethyl phenyl) ethanol,
46) (R)-and 2-amino-2-(2-naphthyl)-1,1-two (4-aminomethyl phenyl) ethanol,
47) (R)-and 2-amino-2-(2-naphthyl)-1,1-two (2-p-methoxy-phenyl) ethanol,
48) (R)-and 2-amino-2-(2-naphthyl)-1,1-two (3-p-methoxy-phenyl) ethanol,
49) (R)-and 2-amino-2-(2-naphthyl)-1,1-two (4-p-methoxy-phenyl) ethanol,
50) 1-[(R)-and amino-(2-naphthyl) methyl] the ring propyl alcohol,
51) 1-[(R)-and amino-(2-naphthyl) methyl] cyclobutanol,
52) 1-[(R)-and amino-(2-naphthyl) methyl] cyclopentanol,
53) 1-[(R)-and amino-(2-naphthyl) methyl] hexalin,
54) 1-[(R)-and amino-(2-naphthyl) methyl] suberyl alcohol;
And wherein configuration (R) becomes these compounds of (S).This class opticity amino alcohol (3) can be for example hydrochloride, vitriol and an acetate of acid salt.
By optical resolution amino alcohol compound described below, or make corresponding optical amino-acid ester and corresponding Ge Shi (Grignard) reagent react, can prepare opticity amino alcohol (3).Can obtain the optical amino-acid ester by the esterification optical amino-acid, the method that optical amino-acid can be described by Tetrahedron55 (1999) 11295-11308, obtain by currently known methods or method described below.In addition if desired, the amino available suitable blocking group protection of optical amino-acid ester behind the Yu Geshi reagent react, can make it slough protection.
In propanedioic acid compound (4) formula, Z representation alkoxy or halogen atom.The alkoxyl group example comprises the alkoxyl group with 1-6 carbon atom, for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, pentyloxy and hexyloxy.The halogen atom example comprises chlorine and bromine atoms.
Propanedioic acid compound (4) example comprises diester malonate, for example dimethyl malonate, diethyl malonate, dimethyl malonic acid dimethyl ester, diethyl malonic acid dimethyl ester, two (n-propyl) dimethyl malonate, 1,1-vinaconic acid dimethyl ester, 1,1-tetramethylene dioctyl phthalate dimethyl ester, 1,1-pentamethylene dioctyl phthalate dimethyl ester and 1, the 1-dimethyl hexahydrophthalate; With malonyl-halogen for example malonyl chloride, dimethyl propylene diacid chloride, diethyl malonyl chloride, two (n-propyl) malonyl chloride, 1, propylidene chloride 1 dimethyl chloride, 1,1-tetramethylene dimethyl chloride, 1,1-pentamethylene dimethyl chloride, 1,1-hexanaphthene dimethyl chloride and malonyl bromide.
With respect to 1mol opticity amino alcohol (3), the usage quantity of propanedioic acid compound (4) is generally about 0.3-2mol, preferably about 0.5-1mol.
The reaction of opticity amino alcohol (3) and propanedioic acid compound (4) in the presence of solvent, is undertaken by mixing and the two being in contact with one another usually.Used solvent is not particularly limited, as long as it is inert solvent in reaction, the example comprise with above relevant opticity diamide compound (2) and Lewis acid-respons in exemplify the same solvent of solvent phase.
Z is the situation of the diester malonate of alkoxyl group using wherein when propanedioic acid compound (4), and temperature of reaction is generally about 50-250 ℃, preferably about 60-180 ℃.In this situation, reaction can for example be carried out in the presence of the lithium compound at catalyzer.The lithium compound example comprises lithium alkoxide for example lithium methoxide and lithium ethoxide; Lithium halide is lithium chloride and lithium hydroxide for example.Catalyst consumption is not particularly limited, and with respect to 1mol diamide compound (2), it typically is about 0.0005-0.5mol.
Use wherein at propanedioic acid compound (4) that Z is the situation of the malonyl-halogen of halogen atom, temperature of reaction is generally-30 ℃ to 100 ℃ approximately, preferred-10 ℃ to 50 ℃ approximately.In this situation for capturing by-product hydrogen halide, preferred reaction alkali for example triethylamine in the presence of carry out.
Opticity amino alcohol (3) obtains opticity diamide compound (2) with the reaction of propanedioic acid compound (4), can carry out extraction treatment by water being added reaction mixture, concentrates the organic layer that obtains subsequently, separates opticity diamide compound (2).In addition, can make the reaction mixture that contains opticity diamide compound (2) that obtains thus contact preparation opticity two  isoxazoline compounds (1) with above-mentioned Lewis acid.
The method of the opticity cyclopropane compound (hereinafter referred opticity cyclopropane compound (7)) that will illustrate preparation following formula (7) representative is below described then:
Figure A20071015293300351
R wherein 6, R 7, R 8And R 9Identical or different, and independent hydrogen atom, optional alkyl, optional thiazolinyl, replacement or unsubstituted aryl or the aralkyl that is replaced by halogen atom that is replaced by halogen atom represented, condition is to work as R 6And R 8When identical, R 6And R 7Differ from one another; R 10Representative has the alkyl of 1-6 carbon atom,
By making the prochiral olefin (hereinafter referred alkene (5)) of formula (5) representative:
Figure A20071015293300361
R wherein 6, R 7, R 8And R 9Define the same, and the diazo acid ester (hereinafter referred diazo acid ester (6)) of formula (6) representative:
N 2CHCO 2R 10 (6)
R wherein 10Define the samely, in the presence of with the new asymmetric copper complex of opticity two  isoxazoline compounds (1) of the present invention preparation and copper compound, react.
Opticity two  isoxazoline compounds (1) have two unsymmetrical carbons as mentioned above, usually use wherein two unsymmetrical carbons to be (S) configuration or (R) this compound of configuration.In the asymmetric catalysis synthesis that uses optically active compounds to carry out as catalyzer or catalyst component, optically active compounds is on demand selected them suitably.
Can unit price or cupric compound as the copper compound illustration, specific examples comprises that trifluoromethanesulfonic acid is cuprous, copper trifluoromethanesulfcomposite, cuprous acetate, venus crystals, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride and phosphofluoric acid tetrem nitrile copper (I), and wherein preferred trifluoromethanesulfonic acid is cuprous.Copper compound can use separately, or uses its two or more with form of mixtures.
With respect to the 1mol copper compound, the usage quantity of opticity two  isoxazoline compounds (1) is generally about 0.8-5mol, preferably about 0.9-2mol.
Usually in the presence of solvent, opticity two  isoxazoline compounds (1) and copper compound are in contact with one another to prepare new asymmetric copper complex.Examples of solvents comprises halohydrocarbon for example methylene dichloride, ethylene dichloride, chloroform and tetracol phenixin; With aromatic hydrocarbons for example benzene, toluene and dimethylbenzene.When alkene (5) was liquid, alkene (5) also can be used as solvent and uses.With respect to the copper compound of 1 part (weight), the usage quantity of solvent is generally about 10-500 part (weight).
Usually at the rare gas element asymmetric copper complex of preparation under argon gas or the nitrogen atmosphere for example, preparation temperature is generally about 0-100 ℃.
By being contacted with each other, opticity two  isoxazoline compounds (1) and copper compound can prepare asymmetric copper complex, from reaction mixture, separate the asymmetric copper complex of preparation thus, being used for the reaction of alkene (5) and diazo acid ester (6), or can use without the form of separating with reaction mixture.
In alkene (5) formula, the optional examples of alkyl that is replaced by halogen atom comprises C 1-6Alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl and hexyl for example; These alkyl that replaced by halogen atom with wherein one or more hydrogen atoms are chloro methyl, fluoro methyl, trifluoromethyl and chloro ethyl for example.The optional thiazolinyl example that is replaced by halogen atom comprises C 2-6Thiazolinyl is vinyl, 1-propenyl, 2-propenyl, 2-methyl isophthalic acid-propenyl, 1-butylene base, crotyl, 3-butenyl, pentenyl and 2-hexenyl for example; And these thiazolinyls of being replaced by halogen atom of wherein one or more hydrogen atoms 1-chloro-2-propenyl for example.
Replace or unsubstituted aryl example comprises unsubstituted aryl (phenyl or naphthyl) and the aryl that is replaced by alkyl or alkoxyl group, for example phenyl, 1-naphthyl, 2-naphthyl, 2-aminomethyl phenyl, 4-aminomethyl phenyl and 3-p-methoxy-phenyl replace or unsubstituted aralkyl example comprises the alkyl that is replaced by above replacement or unsubstituted aryl.Specific examples comprises benzyl, 2-methyl-benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 1-naphthyl methyl and 2-naphthyl methyl.
Alkene (5) example comprises propylene, 1-butylene, iso-butylene, the 1-amylene, the 1-hexene, the 1-octene, 4-chloro-1-butylene, the 2-amylene, the 2-heptene, the 2-methyl-2-butene, 2,5-dimethyl-2, the 4-hexadiene, 2-chloro-5-methyl-2, the 4-hexadiene, 2-fluoro-5-methyl-2, the 4-hexadiene, 1,1,1-three fluoro-5-methyl-2, the 4-hexadiene, 2-methoxycarbonyl-5-methyl-2, the 4-hexadiene, 1,1-two fluoro-4-methyl isophthalic acids, the 3-pentadiene, 1,1-two chloro-4-methyl isophthalic acids, 3-pentadiene (pantadiene), 1,1-two bromo-4-methyl isophthalic acids, the 3-pentadiene, 1-chloro-1-fluoro-4-methyl isophthalic acid, the 3-pentadiene, 1-fluoro-1-bromo-4-methyl isophthalic acid, the 3-pentadiene, 2-methyl-2, the 4-hexadiene, 1-fluoro-1,1-two fluoro-4-methyl-2-amylenes, 1,1,1-three chloro-4-methyl-3-amylenes, 1,1,1-three bromo-4-methyl-3-amylenes, 2,3-dimethyl-2-amylene, 2-methyl-3-phenyl-2-butylene, 2-bromo-2,5-dimethyl-4-hexene, 2-chloro-2,5-dimethyl-4-hexene and 2,5-dimethyl-6-chloro-2,4-hexadiene.
In diazo acid ester (6) formula, for example have with the above-mentioned identical group of those groups that exemplifies as C 1-6Alkyl, diazo acid ester (6) example comprises ethyl diazoacetate, diazo acetic acid N2 n-propyl ester, diazo acetic acid N2 isopropyl esters, diazo acetic acid N2 n-butyl, diazo acetic acid N2 isobutyl, diazo acetic acid N2 tertiary butyl ester, diazo acetic acid N2 amyl group ester and diazo acetic acid N2 polyhexamethylene.
Asymmetric copper complex formazan consumption with respect to diazo acid ester (6), is generally about 0.0001-0.05mol in copper metal (copper mol number), preferred 0.0005-0.01mol.
With respect to 1mol diazo acid ester (6), the consumption of alkene (5) is generally about 1mol or more, preferred 1.2mol or more.Do not have the concrete upper limit, when alkene (5) was liquid, it also can be used as a large amount of excessive uses of solvent.
Usually by making three kinds of compositions: asymmetric copper complex, alkene (5), diazo acid ester (6) are in contact with one another, and make them mix the reaction of carrying out alkene (5) and diazo acid ester (6), and mixed order is not particularly limited.Usually diazo acid ester (6) is added in the mixture of asymmetric copper complex and alkene (5).Reaction is carried out in the presence of solvent usually, and examples of solvents comprises halogenated hydrocarbon solvent for example methylene dichloride, ethylene dichloride, chloroform and tetrachloromethane; Aliphatic hydrocrbon is hexane, heptane and hexanaphthene for example; Aromatic hydrocarbons is benzene, toluene and dimethylbenzene for example; And ester ethyl acetate for example.They can use separately or use with the form of mixed solvent.Although usage quantity is not particularly limited, consider the characteristic of volumetric efficiency and reaction mixture, with respect to 1 part of diazo acid ester (6) (weight), this consumption is generally about 2-30 part (weight), preferred 5-20 part (weight).Solvent can be earlier and alkene (5), diazo acid ester (6) and/or asymmetric copper complex mixed.Perhaps as mentioned above, when alkene (5) was liquid, also available alkene (5) was made solvent.
The reaction of alkene (5) and diazo acid ester (6) is for example carried out under argon gas or the nitrogen at rare gas element usually.Because water has disadvantageous effect to reaction, preferably be suppressed at the water yield that exists in the reactive system and carry out this reaction, for example react, or use and pass through the alkene (5) or the solvent of processed in advance by in reactive system, existing under the dewatering agent.
Temperature of reaction is generally-50 ℃ to 150 ℃ approximately, preferred-20 ℃ to 80 ℃.
After reaction is finished, can separate opticity cyclopropane compound (7) by for example concentrated reaction mixture.Can be further by conventional purification process for example distill, the opticity cyclopropane compound (7) of purifies and separates such as column chromatography.
Opticity cyclopropane compound (7) example comprises:
1) opticity 2-methyl cyclopropane methyl-formiate,
2) opticity 2,2-dinethyl cyclopropane carboxylic acid methyl esters,
3) opticity 2,2-dimethyl-3-(2-methyl isophthalic acid-propenyl) cyclopropane-carboxylic acid methyl esters,
4) opticity 2,2-dimethyl-3-(2,2-two chloro-1-vinyl) cyclopropane-carboxylic acid methyl esters,
5) opticity 2,2-dimethyl-3-(2,2,2-three chloroethyls) cyclopropane-carboxylic acid methyl esters,
6) opticity 2,2-dimethyl-3-(2,2, the 2-three bromomethyl) cyclopropane-carboxylic acid methyl esters,
7) opticity 2,2-dimethyl-3-(2,2-two bromo-1-vinyl) cyclopropane-carboxylic acid methyl esters,
8) opticity 2,2-dimethyl-3-(2,2-two fluoro-1-vinyl) cyclopropane-carboxylic acid methyl esters,
9) opticity 2,2-dimethyl-3-(2-fluoro-2-chloro-1-vinyl) cyclopropane-carboxylic acid methyl esters,
10) opticity 2,2-dimethyl-3-(2-fluoro-2-bromo-1-vinyl) cyclopropane-carboxylic acid methyl esters,
11) opticity 2,2-dimethyl-3-(2-chloro-1-propenyl) cyclopropane-carboxylic acid methyl esters,
12) opticity 2,2-dimethyl-3-(2-chloro-1-propenyl) cyclopropane-carboxylic acid methyl esters,
13) opticity 2,2-dimethyl-3-(2-chloro-2,2,2-trifluoromethyl vinyl) cyclopropane-carboxylic acid methyl esters,
14) opticity 2,2-dimethyl-3-(2-methoxycarbonyl-1-propenyl) cyclopropane-carboxylic acid methyl esters,
15) opticity 2,2-dimethyl-3-(2-chloro-2-methyl) propyl group cyclopropane-carboxylic acid methyl esters,
16) opticity 2,2-dimethyl-3-(2-bromo-2-methyl) propyl group cyclopropane-carboxylic acid methyl esters and
17) opticity 2,2-dimethyl-3-(1-propenyl) propyl group cyclopropane-carboxylic acid methyl esters;
And the compound partly replaced by ethyl, n-propyl, sec.-propyl, isobutyl-and tertiary butyl ester of wherein above methyl esters part.
By known method for hydrolysis hydrolysis, opticity cyclopropane compound (7) can be converted into wherein R 10Opticity cyclopropane-carboxylic acid for hydrogen atom.
The opticity amino alcohol of formula (3) representative comprises the opticity amino alcohol of following formula (30) representative:
Figure A20071015293300401
R wherein 31, R 32, R 33And R 34Identical or different, and independent hydrogen atom, the C of representing 1-6Alkyl or C 1-6Alkoxyl group; R 35Represent C 1-6Alkyl, replacement or unsubstituted phenyl or replacement or unsubstituted aralkyl, or two R 35The carbon atom that connects with them forms ring; * represent unsymmetrical carbon (hereinafter referred opticity amino alcohol (30)).Below describe and to illustrate this compounds.
In formula (30), by R 31To R 35The C of representative 1-6Examples of alkyl comprises straight or branched alkyl for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group and n-hexyl.By R 31To R 34The C of representative 1-6The alkoxyl group example comprises straight or branched alkoxyl group for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, pentyloxy and positive hexyloxy.
By R 35The replacement or the unsubstituted phenyl of representative have for example unsubstituted phenyl; Have for example by the above C that exemplifies with the phenyl that replaces 1-6The phenyl that alkyl replaces, for example 3-aminomethyl phenyl and 4-aminomethyl phenyl, and by more than the C that exemplifies 1-6The phenyl that alkoxyl group replaces, for example 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl.Replace or unsubstituted aralkyl for example has the replacement that exemplified more than for example by aryl or the C of unsubstituted phenyl and naphthyl substituted 1-6Alkyl.Its specific examples comprises benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 1-naphthyl methyl and 2-naphthyl methyl.
In addition, at two R 35The carbon atom that connects with them forms in the situation of ring, and the specific examples of ring comprises the ring with 3-7 carbon atom, for example cyclopropane ring, pentamethylene ring, cyclohexyl ring and suberane ring.
Opticity amino alcohol (30) example comprises:
1) (R)-1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol;
2) (R)-1-amino-1-(4-fluoro-1-naphthyl)-2-methyl-2-propyl alcohol;
3) (R)-1-amino-1-(2-methyl isophthalic acid-naphthyl)-2-methyl-2-propyl alcohol;
4) (R)-1-amino-1-(4-methyl isophthalic acid-naphthyl)-2-methyl-2-propyl alcohol;
5) (R)-1-amino-1-(2-methoxyl group-1-naphthyl)-2-methyl-2-propyl alcohol;
6) (R)-1-amino-1-(2-oxyethyl group-1-naphthyl)-2-methyl-2-propyl alcohol;
7) (R)-1-amino-1-(4-methoxyl group-1-naphthyl)-2-methyl-2-propyl alcohol;
8) (R)-1-amino-1-(2,4-dimethoxy-1-naphthyl)-2-methyl-2-propyl alcohol;
9) (R)-1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol;
10) (R)-1-amino-1-(7-methyl-2-naphthyl)-2-methyl-2-propyl alcohol;
11) (R)-1-amino-1-(1-n-propyl-2-naphthyl)-2-methyl-2-propyl alcohol;
12) (R)-1-amino-1-(6-methoxyl group-2-naphthyl)-2-methyl-2-propyl alcohol;
And 13) (R)-1-amino-1-(3,8-dimethoxy-2-naphthyl)-2-methyl-2-propyl alcohol; Wherein 2-methyl-2-propyl alcohol is partly by these compounds of following alcohol replacement:
1) 2-ethyl-2-butanols,
2) 2-n-propyl-2-amylalcohol,
3) 2-normal-butyl-2-hexanol,
4) 2-isobutyl--4-methyl-2-amylalcohol,
5) 2-n-pentyl-2-enanthol,
6) 2-benzyl-3-phenyl-2-propyl alcohol,
7) 2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl)-2-propyl alcohol,
8) 2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl)-2-propyl alcohol,
9) 2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl)-2-propyl alcohol,
10) 2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl)-2-propyl alcohol,
11) 2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl)-2-propyl alcohol,
12) 2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl)-2-propyl alcohol,
13) 2-(1-naphthyl methyl)-3-(1-naphthyl)-2-propyl alcohol and
14) 2-(2-naphthyl methyl)-3-(2-naphthyl)-2-propyl alcohol.
In addition, the example also comprises:
1) (R)-2-amino-2-(1-naphthyl)-methyl-diphenyl-carbinol,
2) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (3-aminomethyl phenyl) ethanol,
3) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (4-aminomethyl phenyl) ethanol,
4) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (2-p-methoxy-phenyl) ethanol,
5) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (3-p-methoxy-phenyl) ethanol,
6) (R)-and 2-amino-2-(1-naphthyl)-1,1-two (4-p-methoxy-phenyl) ethanol,
7) 1-[(R)-and amino-(1-naphthyl) methyl] the ring propyl alcohol,
8) 1-[(R)-amino-(1-naphthyl) methyl] cyclopentanol and
9) 1-[(R)-and amino-(1-naphthyl) methyl] suberyl alcohol;
And wherein be connected to the amino carbon atom that is connected on these compounds of being replaced by following group of 1-naphthyl: 4-fluoro-1-naphthyl, 2-methyl isophthalic acid-naphthyl, 4-methyl isophthalic acid-naphthyl, 2-methoxyl group-1-naphthyl, 2-oxyethyl group-1-naphthyl, 4-methoxyl group-1-naphthyl, 2,4-dimethoxy-1-naphthyl, 2-naphthyl, 7-methyl-2-naphthyl, 1-n-propyl-2-naphthyl, 6-methoxyl group-2-naphthyl and 3,8-dimethoxy-2-naphthyl.
In addition, also exemplify wherein these compounds that (R) configuration becomes (S) configuration.
Can prepare opticity amino alcohol (30) by naphthyl alcohol with opticity N-formyl radical phenylalanine optical resolution following formula (40) representative:
Figure A20071015293300421
R wherein 31, R 32, R 33, R 34And R 35Define the same (hereinafter referred naphthyl alcohol (40)).
Amino alcohol (40) example comprises:
1) 1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol,
2) 1-amino-1-(4-fluoro-1-naphthyl)-2-methyl-2-propyl alcohol,
3) 1-amino-1-(2-methyl isophthalic acid-naphthyl)-2-methyl-2-propyl alcohol,
4) 1-amino-1-(4-methyl isophthalic acid-naphthyl)-2-methyl-2-propyl alcohol,
5) 1-amino-1-(2-methoxyl group-1-naphthyl)-2-methyl-2-propyl alcohol,
6) 1-amino-1-(2-oxyethyl group-1-naphthyl)-2-methyl-2-propyl alcohol,
7) 1-amino-1-(4-methoxyl group-1-naphthyl)-2-methyl-2-propyl alcohol,
8) 1-amino-1-(2,4-dimethoxy-1-naphthyl)-2-methyl-2-propyl alcohol,
9) 1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol,
10) 1-amino-1-(7-methyl-2-naphthyl)-2-methyl-2-propyl alcohol,
11) 1-amino-1-(1-n-propyl-2-naphthyl)-2-methyl-2-propyl alcohol,
12) 1-amino-1-(6-methoxyl group-2-naphthyl)-2-methyl-2-propyl alcohol and
13) 1-amino-1-(3,8-dimethoxy-1-naphthyl)-2-methyl-2-propyl alcohol;
And these compounds that wherein the 2-methyl-2-propyl alcohol part is replaced by following alcohol:
1) 2-ethyl-2-butanols,
2) 2-n-propyl-2-amylalcohol,
3) 2-normal-butyl-2-hexanol,
4) 2-isobutyl--4-methyl-2-amylalcohol,
5) 2-n-pentyl-2-enanthol,
6) 2-benzyl-3-phenyl-2-propyl alcohol,
7) 2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl)-2-propyl alcohol,
8) 2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl)-2-propyl alcohol,
9) 2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl)-2-propyl alcohol,
10) 2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl)-2-propyl alcohol,
11) 2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl)-2-propyl alcohol,
12) 2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl)-2-propyl alcohol,
13) 2-(1-naphthyl methyl)-3-(1-naphthyl)-2-propyl alcohol and
14) 2-(2-naphthyl methyl)-3-(2-naphthyl)-2-propyl alcohol.
The example also comprises:
1) 2-amino-2-(1-naphthyl)-methyl-diphenyl-carbinol,
2) 2-amino-2-(1-naphthyl)-1,1-two (3-aminomethyl phenyl) ethanol,
3) 2-amino-2-(1-naphthyl)-1,1-two (4-aminomethyl phenyl) ethanol,
4) 2-amino-2-(1-naphthyl)-1,1-two (2-p-methoxy-phenyl) ethanol,
5) 2-amino-2-(1-naphthyl)-1,1-two (3-p-methoxy-phenyl) ethanol,
6) 2-amino-2-(1-naphthyl)-1,1-two (4-p-methoxy-phenyl) ethanol,
7) 1-[(amino)-(1-naphthyl) methyl] the ring propyl alcohol,
8) 1-[(amino)-(1-naphthyl) methyl] cyclopentanol and
9) 1-[(amino)-(1-naphthyl) methyl] suberyl alcohol;
And wherein be connected to the amino carbon atom that is connected on these compounds of being replaced by following group of 1-naphthyl:
1) 4-fluoro-1-naphthyl,
2) 2-methyl isophthalic acid-naphthyl,
3) 4-methyl isophthalic acid-naphthyl,
4) 2-methoxyl group-1-naphthyl,
5) 2-oxyethyl group-1-naphthyl,
6) 4-methoxyl group-1-naphthyl,
7) 2,4-dimethoxy-1-naphthyl,
8) 2-naphthyl,
9) 7-methyl-2-naphthyl,
10) 1-n-propyl-2-naphthyl,
11) 6-methoxyl group-2-naphthyl and
12) 3,8-dimethoxy-2-naphthyl.
Usually can use amino alcohol (40) racemic modification, but the low optical purity mixture of optical isomers that also can use wherein a kind of optically active isomer to Duo relatively than other optically active isomer.
Opticity N-formyl radical phenylalanine has R isomer and two kinds of optically active isomers of S isomer, can select them suitably by opticity amino alcohol as required.With respect to 1mol amino alcohol (40), consumption is generally 0.1-1mol.
Usually by both mix the reaction of carrying out amino alcohol (40) and opticity N-formyl radical phenylalanine in solvent with them, mixed order is not particularly limited.Preferably opticity N-formyl radical phenylalanine is added and be dissolved in amino alcohol (40) solution of solvent.Can be continuously or intermittent type add opticity N-formyl radical phenylalanine.In addition, can directly or with the solution form that is dissolved in solvent use opticity N-formyl radical phenylalanine.
Examples of solvents comprises aromatic solvent for example toluene, dimethylbenzene and toluene(mono)chloride; Ether solvents is ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane and glycol dimethyl ether for example; Alcoholic solvent is methyl alcohol, ethanol and Virahol for example; Ester solvent is ethyl acetate for example; The nitrile solvent is acetonitrile for example; And water.Can use them separately or with the form of mixed solvent.In these solvents, preferred ether solvents, alcoholic solvent and with the mixed solvent of water.The consumption of solvent is generally 0.5-100 part (weight) with respect to 1 part of amino alcohol (40) (weight), preferred 1-50 part (weight).Solvent can add before amino alcohol or opticity N-formyl radical phenylalanine.
Temperature of reaction is generally 0 ℃ of reflux temperature to reaction mixture.
After reaction is finished, form the diastereoisomeric salt (hereinafter referred diastereoisomeric salt) of opticity amino alcohol (30) and opticity N-formyl radical phenylalanine, common a kind of diastereoisomeric salt partly precipitated is in reactant.Can directly separate this precipitation, and preferably more substantial diastereoisomeric salt precipitation be separated out by cooling or concentration response thing.According to condition, diastereoisomeric salt is dissolved in reactant fully, can cool off or the concentration response thing in this situation, crystallization separates diastereoisomeric salt.Can easily separate a kind of diastereoisomeric salt precipitation by conventional filtration.Can handle by for example recrystallization and be further purified isolating diastereoisomeric salt.
The diastereoisomeric salt example that obtains thus comprises:
1) diastereoisomeric salt of opticity 1-amino-(1-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
2) diastereoisomeric salt of opticity 1-amino-1-(4-fluoro-1-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
3) diastereoisomeric salt of opticity 1-amino-1-(2-methyl isophthalic acid-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
4) diastereoisomeric salt of opticity 1-amino-1-(4-methyl isophthalic acid-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
5) diastereoisomeric salt of opticity 1-amino-1-(2-methoxyl group-1-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
6) diastereoisomeric salt of opticity 1-amino-1-(2-oxyethyl group-1-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
7) diastereoisomeric salt of opticity 1-amino-1-(4-methoxyl group-1-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
8) diastereoisomeric salt of opticity 1-amino-1-(2,4-dimethoxy-1-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
9) diastereoisomeric salt of opticity 1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
10) diastereoisomeric salt of opticity 1-amino-1-(7-methyl-2-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
11) diastereoisomeric salt of opticity 1-amino-1-(1-n-propyl-2-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
12) diastereoisomeric salt of opticity 1-amino-1-(6-methoxyl group-2-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine,
13) diastereoisomeric salt of opticity 1-amino-1-(3,8-dimethoxy-2-naphthyl)-2-methyl-2-propyl alcohol and opticity N-formyl radical phenylalanine;
And these diastereoisomeric salts that wherein the 2-methyl-2-propyl alcohol part is replaced by following alcohol:
1) 2-ethyl-2-butanols,
2) 2-n-propyl-2-amylalcohol,
3) 2-normal-butyl-2-hexanol,
4) 2-isobutyl--4-methyl-2-amylalcohol,
5) 2-n-pentyl-2-enanthol,
6) 2-benzyl-3-phenyl-2-propyl alcohol,
7) 2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl)-2-propyl alcohol,
8) 2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl)-2-propyl alcohol,
9) 2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl)-2-propyl alcohol,
10) 2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl)-2-propyl alcohol,
11) 2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl)-2-propyl alcohol,
12) 2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl)-2-propyl alcohol,
13) 2-(1-naphthyl methyl)-3-(1-naphthyl)-2-propyl alcohol and
14) 2-(2-naphthyl methyl)-3-(2-naphthyl)-2-propyl alcohol.
The example also comprises:
1) diastereoisomeric salt of opticity 2-amino-2-(1-naphthyl)-methyl-diphenyl-carbinol and opticity N-formyl radical phenylalanine;
2) opticity 2-amino-2-(1-naphthyl)-1, the diastereoisomeric salt of 1-two (3-aminomethyl phenyl) ethanol and opticity N-formyl radical phenylalanine;
3) opticity 2-amino-2-(1-naphthyl)-1, the diastereoisomeric salt of 1-two (4-aminomethyl phenyl) ethanol and opticity N-formyl radical phenylalanine;
4) opticity 2-amino-2-(1-naphthyl)-1, the diastereoisomeric salt of 1-two (2-p-methoxy-phenyl) ethanol and opticity N-formyl radical phenylalanine;
5) opticity 2-amino-2-(1-naphthyl)-1, the diastereoisomeric salt of 1-two (3-p-methoxy-phenyl) ethanol and opticity N-formyl radical phenylalanine;
6) opticity 2-amino-2-(1-naphthyl)-1, the diastereoisomeric salt of 1-two (4-p-methoxy-phenyl) ethanol and opticity N-formyl radical phenylalanine;
7) opticity 1-[(amino)-(1-naphthyl) methyl] diastereoisomeric salt of ring propyl alcohol and opticity N-formyl radical phenylalanine;
8) opticity 1-[(amino)-(1-naphthyl) methyl] diastereoisomeric salt of cyclopentanol and opticity N-formyl radical phenylalanine; With
9) opticity 1-[(amino)-(1-naphthyl) methyl] diastereoisomeric salt of suberyl alcohol and opticity N-formyl radical phenylalanine;
And wherein be connected to constitute more than exemplify these compounds that the 1-naphthyl on the carbon atom that the amino of the opticity naphthyl alcohol of each diastereoisomeric salt is connected is replaced by following group: 4-fluoro-1-naphthyl, 2-methyl isophthalic acid-naphthyl, 4-methyl isophthalic acid-naphthyl, 2-methoxyl group-1-naphthyl, 2-oxyethyl group-1-naphthyl, 4-methoxyl group-1-naphthyl, 2,4-dimethoxy-1-naphthyl, 2-naphthyl, 7-methyl-2-naphthyl, 1-n-propyl-2-naphthyl, 6-methoxyl group-2-naphthyl and 3,8-dimethoxy-2-naphthyl.
Can be directly or be converted into opticity amino alcohol (30) by washing, recrystallization etc., the diastereoisomeric salt that easily will obtain thus behind the alkaline purification purifying subsequently.
Usually can be by carrying out alkaline purification with diastereoisomeric salt and alkali are mixed, mix temperature is generally 0-100 ℃.Used alkali example comprises alkali metal hydroxide for example potassium hydroxide and sodium hydroxide, uses its aqueous solution usually.When using alkali aqueous solution, the concentration of alkali is generally 1-50% (weight), preferred 3-20% (weight).With respect to the 1mol diastereoisomeric salt, the consumption of alkali is generally about 1-5mol.
When making diastereoisomeric salt through alkaline purification, usually from the alkaline purification thing with oil reservoir or solid precipitation isolated in form opticity amino alcohol (30), can directly separate opticity amino alcohol (30), or extract by water-insoluble organic solvents is added in the alkaline purification thing, and the separable opticity amino alcohol of the organic solvent that obtains organic layer (30) is removed in distillation.The water-insoluble organic solvents example comprises ether solvents for example ether and methyl tertiary butyl ether; Ester solvent is ethyl acetate for example; Aromatic solvent is toluene, dimethylbenzene and chlorobenzene for example; Halogenated hydrocarbon solvent is methylene dichloride and chloroform for example, and with respect to 1 part of (weight) diastereoisomeric salt that uses, its consumption is generally 0.5-50 part (weight).Can before with the alkaline purification diastereoisomeric salt, add water-insoluble organic solvents.
By with sour pre-treatment diastereoisomeric salt, then through the also separable opticity amino alcohol of alkaline purification (30).When with sour pre-treatment diastereoisomeric salt, discharge opticity N-formyl radical phenylalanine.Then, preferably will carry out alkaline purification after the opticity N-formyl radical phenylalanine separation that discharge.
Usually by carrying out acid treatment with diastereoisomeric salt and aqueous acid are mixed, mix temperature is generally 0-100 ℃.Employed acid has for example aqueous solution of hydrochloric acid, sulfuric acid and phosphoric acid of mineral acid usually, and concentration is generally 1-50% (weight), preferred 5-40% (weight).With respect to the 1mol diastereoisomeric salt, the consumption of acid is generally 1-5mol, preferred 1-2mol.
The separation method of the opticity N-formyl radical phenylalanine that discharges for example have by water-insoluble organic solvents is added wherein diastereoisomeric salt in the pretreated material of peracid with its method of extraction.Water-insoluble organic solvents has solvent for example same as described above, and its consumption is generally 0.5-20 part (weight) in the consumption of 1 part of (weight) diastereoisomeric salt.Both made when it to add before with the acid treatment diastereoisomeric salt, water-insoluble organic solvents can not have problems yet.
When the opticity N-of some or all releases formyl radical phenylalanine precipitates in the acid treatment thing, also can direct filtration or further this material of cooled and filtered if desired, separate the opticity N-formyl radical phenylalanine that discharges.
In the alkaline purification of after acid treatment, carrying out, use for example aqueous solution of potassium hydroxide and sodium hydroxide of alkali metal hydroxide, the concentration of solution is generally 1-50% (weight), preferred 5-20% (weight).The consumption of alkali can make the pH of object being treated become 10 or higher, and treatment temp is generally 0-100 ℃.
When carrying out the alkaline purification diastereoisomeric salt after with sour pre-treatment, in the alkaline purification thing, separate opticity amino alcohol (30) oil reservoir or precipitated solid usually, can directly separate oil reservoir or solid.Perhaps, by water-insoluble organic solvents being added the alkaline purification thing extracting, and the organic solvent in the organic layer that obtains, separable opticity amino alcohol (30) are removed in distillation.Water-insoluble organic solvents for example has and described identical solvent, and with respect to 1 part of (weight) diastereoisomeric salt that is used to handle, its consumption is generally 0.5-50 part (weight).Before alkaline purification, can add water-insoluble organic solvents earlier.
Can reclaim used opticity N-formyl radical phenylalanine easily, the opticity N-formyl radical phenylalanine of recovery can re-use in the reaction of amino alcohol (40) and opticity N-formyl radical phenylalanine.When without sour pre-treatment during with the alkaline purification diastereoisomeric salt, opticity N-formyl radical phenylalanine can reclaim by reclaim back gained handled thing with acid treatment opticity amino alcohol (30).When after sour pre-treatment, using the alkaline purification diastereoisomeric salt; some or all opticity N-formyl radical phenylalanines precipitate in the acid treatment thing that obtains by acid treatment usually; direct filtration or further if desired this material of cooled and filtered reclaim opticity N-formyl radical phenylalanine.Perhaps, water-insoluble organic solvents added in the acid treatment thing extract, and organic solvent is removed in distillation from the organic layer that obtains, and reclaims opticity N-formyl radical phenylalanine.Water-insoluble organic solvents has solvent for example same as described above.Before acid treatment, can add water-insoluble organic solvents.
Can prepare amino alcohol (40) by the method that relates to following steps (A) to (D).
That is, (A) make wherein R 31, R 32, R 33And R 34Define the naphthyl glycine compound (hereinafter referred naphthyl glycine compound (41)) of the same formula (41) representative:
Figure A20071015293300501
With chlorizating agent and R wherein 9Represent C 1-6Alcohol (hereinafter referred alcohol (the 42)) reaction of the formula of alkyl (42) representative:
R 9OH (42)
Obtain the amino acid ester hydrochloride (hereinafter referred amino acid ester hydrochloride (43)) of formula (43) representative:
Figure A20071015293300502
R wherein 31, R 32, R 33, R 34And R 9Describe the same;
(B) in the presence of tertiary amine, make the compound reaction of the amino acid ester hydrochloride (43) that obtains in the above step (A) and formula (44) representative:
(C nF 2n+1CO) 2O (44)
Wherein n represents 1,2 or 3 (hereinafter referred compound (44)), or with compound (hereinafter referred compound (the 45)) reaction of formula (45) representative:
C nF 2n+1COX (45)
Wherein n describes the same; X represents chlorine atom, bromine atoms or iodine atom,
Obtain the compound (hereinafter referred compound (46)) of formula (46) representative:
R wherein 31, R 32, R 33, R 34, R 9Describe the same with n;
(C) make compound (hereinafter referred compound (the 47)) reaction of the compound (46) that obtains in the above step (B) and formula (47) representative:
R 35MgX’ (47)
R wherein 35Represent C 1-6Alkyl, replacement or unsubstituted aralkyl or replacement or unsubstituted phenyl; X ' represents halogen atom, or with compound (hereinafter referred compound (the 48)) reaction of formula (48) representative:
X’-Mg-R 35’-Mg-X’ (48)
R wherein 35' represent C 2-6Alkylidene group, X ' definition is the same, obtains the compound (hereinafter referred compound (49)) of formula (49) representative:
Figure A20071015293300511
R wherein 31, R 32, R 33, R 34, R 35The same with the n definition; And
(D) make compound (49) and the alkali reaction that obtains in the above step (C), obtain naphthyl alcohol (40).
At first will illustrate step (A).Step (A) is by making naphthyl glycine compound (41) obtain the step of amino acid ester hydrochloride (5) with chlorination reaction in the presence of alcohol (42).
Naphthyl glycine compound (3) example comprises:
1) 1-naphthyl glycine;
2) 2-methyl isophthalic acid-naphthyl glycine;
3) 4-methyl isophthalic acid-naphthyl glycine;
4) 2-methoxyl group-1-naphthyl glycine;
5) 2-oxyethyl group-1-naphthyl glycine;
6) 4-methoxyl group-1-naphthyl glycine;
7) 2,4-dimethoxy-1-naphthyl glycine;
8) 2-naphthyl glycine;
9) 7-methyl-2-naphthyl glycine;
10) 1-n-propyl-2-naphthyl glycine;
11) 6-methoxyl group-2-naphthyl glycine; With
12) 3,8-dimethoxy-2-naphthyl glycine.
Naphthyl glycine compound (3) can be bought and obtain, maybe can be by making for example sodium cyanide reaction of naphthyl aldehyde and volatile salt and cyano compound, then with alkali for example the potassium hydroxide treatment reaction product prepare (Experimental Chemistry for example, the 4th edition, the 22nd volume, the 195th page, Chemical Society of Japan).
The chlorizating agent example comprises the thionyl chloride photoreactive gas, and with respect to 1mol naphthyl glycine compound (41), consumption is generally 1mol or more, preferred 1.1mol or more.Do not have the concrete upper limit, but when consumption is too big, may cause economic inferior position.So 2 times of mol amounts or following feasible.
In alcohol (42) formula, R 6Represent C 1-6Alkyl, the example comprise group same as described above.Alcohol (42) example comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, amylalcohol and hexanol.
With respect to 1mol naphthyl glycine compound (41), the consumption of alcohol (42) is generally 1mol or more, and does not have the concrete upper limit.Alcohol also can be used as a large amount of excessive uses of solvent.
Usually by three kinds of reactants being mixed the reaction of carrying out naphthyl glycine compound (41) and chlorizating agent and alcohol (42), order by merging is not particularly limited.In addition, reaction is carried out in solvent usually, and examples of solvents comprises aliphatic hydrocarbon solvent for example hexane and heptane; Aromatic solvent is toluene, dimethylbenzene and chlorobenzene for example; Halogenated hydrocarbon solvent is methylene dichloride and chloroform for example; Ether solvents is ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane and glycol dimethyl ether for example; Ester solvent is ethyl acetate for example; The nitrile solvent is acetonitrile for example.They can use separately or use with the form of mixed solvent.As mentioned above, alcohol (42) also can be used as the solvent use.The consumption of solvent can reaction stirred be advisable.Usually, with respect to 1 part of (weight) naphthyl glycine compound (41), its consumption is 1 part (weight) or more, and does not have the concrete upper limit.
Temperature of reaction is generally 0 ℃ of reflux temperature to reaction mixture, preferred 10-60 ℃.
After reaction is finished, make reaction mixture through concentration or precipitation process, amino acid separation ester hydrochloride (43).Sometimes, the amino acid ester hydrochloride (43) of some or all formation precipitates in reaction mixture, in this case, and direct filtration reaction mixture or through partial concentration, cooled and filtered if desired, amino acid separation ester hydrochloride (43).Although isolating amino acid ester hydrochloride (43) can be directly used in next step (B), but it is because it contains unreacted alcohol (42) or chlorizating agent sometimes, so preferred with being used for next step (B) after for example above ether solvents washing of the solvent that does not dissolve amino-acid ester salt hydrochlorate (43).
Amino acid ester hydrochloride (43) example that obtains thus comprises:
1) 1-naphthyl glycine methyl ester hydrochloride;
2) 2-methyl isophthalic acid-naphthyl glycine methyl ester hydrochloride;
3) 4-methyl isophthalic acid-naphthyl glycine methyl ester hydrochloride;
4) 2-methoxyl group-1-naphthyl glycine methyl ester hydrochloride;
5) 2-oxyethyl group-1-naphthyl glycine methyl ester hydrochloride;
6) 4-methoxyl group-1-naphthyl glycine methyl ester hydrochloride;
7) 2,4-dimethoxy-1-naphthyl glycine methyl ester hydrochloride;
8) 2-naphthyl glycine methyl ester hydrochloride;
9) 7-methyl-2-naphthyl glycine methyl ester hydrochloride;
10) 1-n-propyl-2-naphthyl glycine methyl ester hydrochloride;
11) 6-methoxyl group-2-naphthyl glycine methyl ester hydrochloride;
12) 3,8-dimethoxy-2-naphthyl glycine methyl ester hydrochloride;
And the compound replaced by following ester respectively of these methyl esters wherein: ethyl ester, n-propyl ester, isopropyl esters, n-butyl, isobutyl and sec-butyl ester.
To illustrate step (B) then.Step (B) is by making the amino acid ester hydrochloride (43) that obtains in above-mentioned steps (A) obtain the step of compound (46) with compound (44) or compound (45) reaction in the presence of tertiary amine.
In compound (44) formula, n represents 1,2 or 3.Compound (6) example comprises trifluoroacetic anhydride, 2,2,3,3,3-PFPA, 2,2,3,3,4,4,4-heptafluorobutyric anhydride.In compound (45) formula, X represents chlorine, bromine or iodine atom, and compound (45) example comprises trifluoroacetyl chloride, 2,2,3,3,3-five fluorine propionyl chlorides, 2,2,3,3,4,4,4-seven fluorine butyryl chlorides.As for compound (44) and (45), for example can use the commercial compound.
With respect to 1mol amino acid ester hydrochloride (43), the consumption of compound (44) or compound (45) is generally 0.8-2mol, preferred 1-1.5mol.
The tertiary amine example comprises triethylamine, three n-propyl amine, tri-n-butyl amine, diisopropylethylamine, N, accelerine, N, N-Diethyl Aniline, pyridine and 4-(N, N-dimethylamino) pyridine.With respect to 1mol amino acid ester hydrochloride (43), its consumption is generally 1.5-3mol, preferred 1.8-2.5mol.
Usually, by two kinds of reactants being mixed the reaction of carrying out amino acid ester hydrochloride (43) and compound (44) or compound (45), mixed order is not particularly limited.Reaction is carried out in solvent usually, and examples of solvents comprises above-mentioned aliphatic hydrocarbon solvent, aromatic solvent, halogenated hydrocarbon solvent, ether solvents, ester solvent, nitrile solvent.They can use separately or use with the form of mixed solvent.Its consumption can be advisable by stirred reaction mixture.Usually, with respect to 1 part of (weight) amino acid ester hydrochloride (43), its consumption is 1 part (weight) or more.
Temperature of reaction is generally 0 ℃ or lower, preferred-20 ℃ to-50 ℃.
After reaction is finished, reaction mixture and water is mixed, then if desired, add water-insoluble organic solvents and carry out extraction treatment, concentrate the organic layer that obtains, separating compound (46).Isolated compound (46) can be directly or is used for next step (C) by conventional purification process after for example recrystallization or column chromatography are further purified.
Compound (46) example comprises:
1) N-(trifluoroacetyl group)-1-naphthyl glycine methyl ester;
2) N-(trifluoroacetyl group)-2-methyl isophthalic acid-naphthyl glycine methyl ester;
3) N-(trifluoroacetyl group)-4-methyl isophthalic acid-naphthyl glycine methyl ester;
4) N-(trifluoroacetyl group)-2-methoxyl group-1-naphthyl glycine methyl ester;
5) N-(trifluoroacetyl group)-2-oxyethyl group-1-naphthyl glycine methyl ester;
6) N-(trifluoroacetyl group)-4-methoxyl group-1-naphthyl glycine methyl ester;
7) N-(trifluoroacetyl group)-2,4-dimethoxy-1-naphthyl glycine methyl ester;
8) N-(trifluoroacetyl group)-2-naphthyl glycine methyl ester;
9) N-(trifluoroacetyl group)-7-methyl-2-naphthyl glycine methyl ester;
10) N-(trifluoroacetyl group)-1-n-propyl-2-naphthyl glycine methyl ester;
11) N-(trifluoroacetyl group)-6-methoxyl group-2-naphthyl glycine methyl ester;
12) N-(trifluoroacetyl group)-3,8-dimethoxy-2-naphthyl glycine methyl ester;
The compound that the methyl esters that exemplifies is wherein replaced by following ester respectively: ethyl ester, n-propyl ester, isopropyl esters, n-butyl, isobutyl and sec-butyl ester; And wherein the substituting group trifluoroacetyl group on the above amino that exemplifies compound by 2,2,3,3,3-five fluorine propionyls and 2,2,3,3,4,4, the compound that 4-seven fluorine butyryl radicalies are replaced.
To illustrate step (C) then.Step (C) is by making the compound (46) that obtains in above-mentioned steps (B) react the step that obtains compound (49) with compound (47) or compound (48).
In compound (48) formula, R 35' represent C 2-6Alkylidene group, the example comprise ethylene, 1,3-cyclopropyl, 1,4-cyclobutyl, 1,5-cyclopentyl and 1,6-cyclohexyl.
Compound (47) or compound (48) example comprise methyl chlorination (or bromination) magnesium, ethyl chlorination (or bromination) magnesium, n-propyl chlorination (or bromination) magnesium, normal-butyl chlorination (or bromination) magnesium, isobutyl-chlorination (or bromination) magnesium, n-pentyl chlorination (or bromination) magnesium, n-hexyl chlorination (or bromination) magnesium, benzyl chlorination (or bromination) magnesium, 2-methyl-benzyl chlorination (or bromination) magnesium, 4-methyl-benzyl chlorination (or bromination) magnesium, 2-methoxy-benzyl chlorination (or bromination) magnesium, 3-methoxy-benzyl chlorination (or bromination) magnesium, 4-methoxy-benzyl chlorination (or bromination) magnesium, 1-naphthyl methyl chlorination (or bromination) magnesium, 2-naphthyl methyl chlorination (or bromination) magnesium, phenyl chlorination (or bromination) magnesium, 3-aminomethyl phenyl chlorination (or bromination) magnesium, 4-aminomethyl phenyl chlorination (or bromination) magnesium, 2-p-methoxy-phenyl chlorination (or bromination) magnesium, 3-p-methoxy-phenyl chlorination (or bromination) magnesium, 4-p-methoxy-phenyl chlorination (or bromination) magnesium, 1,2-ethylidene chlorination (or bromination) two magnesium, 1,4-cyclobutyl chlorination (or bromination) two magnesium and 1,6-cyclohexyl chlorination (or bromination) two magnesium.Can use commercially available compound (47) or compound (48), maybe can by make corresponding halogenated compound and MAGNESIUM METAL prepared in reaction they.
With respect to the compound (46) of 1mol, the consumption when using compound (47) is generally 2-3mol, preferred 2.1-2.7mol.With respect to the compound (46) of 1mol, the consumption when using compound (48) is generally 1-1.5mol, preferred 1.1-1.4mol.
Usually, by two kinds of reactants are mixed in solvent, carry out the reaction of compound (46) and compound (47) or compound (48), mixed order is not particularly limited.Examples of solvents comprises for example ether of above-mentioned ether solvents, and with respect to 1 part of (weight) compound (46), its consumption is generally 1-50 part (weight), preferred 3-20 part (weight).If desired, can for example toluene be mixed with above-mentioned aromatic solvent.
Temperature of reaction is generally-20 ℃ of reflux temperatures to reaction mixture, preferred-10 ℃ to 30 ℃.
After reaction was finished, for example the aqueous solution of hydrochloric acid, sulfuric acid or phosphoric acid was mixed with reaction mixture and mineral acid, carries out extraction treatment, the concentrated organic layer that obtains, separating compound (49).Isolated compound (49) can be directly or is used for next step (D) by conventional purification process after for example recrystallization or column chromatography are further purified.
The compound that obtains thus (49) example comprises:
1) 1-(trifluoroacetamido)-(1-naphthyl)-2-methyl-2-propyl alcohol,
2) 1-(trifluoroacetamido)-1-(4-fluoro-1-naphthyl)-2-methyl-2-propyl alcohol,
3) 1-(trifluoroacetamido)-1-(2-methyl isophthalic acid-naphthyl)-2-methyl-2-propyl alcohol,
4) 1-(trifluoroacetamido)-1-(4-methyl isophthalic acid-naphthyl)-2-methyl-2-propyl alcohol,
5) 1-(trifluoroacetamido)-1-(2-methoxyl group-1-naphthyl)-2-methyl-2-propyl alcohol,
6) 1-(trifluoroacetamido)-1-(2-oxyethyl group-1-naphthyl)-2-methyl-2-propyl alcohol,
7) 1-(trifluoroacetamido)-1-(4-methoxyl group-1-naphthyl)-2-methyl-2-propyl alcohol,
8) 1-(trifluoroacetamido)-1-(2,4-dimethoxy-1-naphthyl)-2-methyl-2-propyl alcohol,
9) 1-(trifluoroacetamido)-1-(2-naphthyl)-2-methyl-2-propyl alcohol,
10) 1-(trifluoroacetamido)-1-(7-methyl-2-naphthyl)-2-methyl-2-propyl alcohol,
11) 1-(trifluoroacetamido)-1-(1-n-propyl-2-naphthyl)-2-methyl-2-propyl alcohol,
12) 1-(trifluoroacetamido)-1-(6-methoxyl group-2-naphthyl)-2-methyl-2-propyl alcohol,
13) 1-(trifluoroacetamido)-1-(3,8-dimethoxy-2-naphthyl)-2-methyl-2-propyl alcohol;
And the compound that the 2-methyl-2-propyl alcohol part is replaced by following alcohol that exemplifies compound wherein: 2-ethyl-2-butanols, 2-n-propyl-2-amylalcohol, 2-normal-butyl-2-hexanol, 2-isobutyl--4-methyl-2-amylalcohol, 2-n-pentyl-2-enanthol, 2-benzyl-3-phenyl-2-propyl alcohol, 2-(3-methyl-benzyl)-3-(3-aminomethyl phenyl)-2-propyl alcohol, 2-(2-methyl-benzyl)-3-(2-aminomethyl phenyl)-2-propyl alcohol, 2-(4-methyl-benzyl)-3-(4-aminomethyl phenyl)-2-propyl alcohol, 2-(2-methoxy-benzyl)-3-(2-p-methoxy-phenyl)-2-propyl alcohol, 2-(3-methoxy-benzyl)-3-(3-p-methoxy-phenyl)-2-propyl alcohol, 2-(4-methoxy-benzyl)-3-(4-p-methoxy-phenyl)-2-propyl alcohol, 2-(1-naphthyl methyl)-3-(1-naphthyl)-2-propyl alcohol, 2-(2-naphthyl methyl)-3-(2-naphthyl)-2-propyl alcohol; And the trifluoroacetamido that exemplifies compound wherein is by 2,2,3,3,3-five fluorine propionamido and 2,2,3,3,4,4, the compound that 4-seven fluorine butyrylaminos are replaced.
In addition, the example also comprises:
1) 2-(trifluoroacetamido)-2-(1-naphthyl)-methyl-diphenyl-carbinol;
2) 2-(trifluoroacetamido)-2-(1-naphthyl)-1,1-two (3-aminomethyl phenyl) ethanol;
3) 2-(trifluoroacetamido)-2-(1-naphthyl)-1,1-two (4-aminomethyl phenyl) ethanol;
4) 2-(trifluoroacetamido)-2-(1-naphthyl)-1,1-two (2-p-methoxy-phenyl) ethanol;
5) 2-(trifluoroacetamido)-2-(1-naphthyl)-1,1-two (3-p-methoxy-phenyl) ethanol;
6) 2-(trifluoroacetamido)-2-(1-naphthyl)-1,1-two (4-p-methoxy-phenyl) ethanol;
7) methyl 1-[(trifluoroacetamido)-(1-naphthyl)] the ring propyl alcohol;
8) methyl 1-[(trifluoroacetamido)-(1-naphthyl)] cyclopentanol;
9) methyl 1-[(trifluoroacetamido)-(1-naphthyl)] suberyl alcohol;
And wherein be connected to more than exemplify the compound that the 1-naphthyl on the carbon atom that trifluoroacetamido is connected in the compound is replaced by following group: 4-fluoro-1-naphthyl, 2-methyl isophthalic acid-naphthyl, 4-methyl isophthalic acid-naphthyl, 2-methoxyl group-1-naphthyl, 2-oxyethyl group-1-naphthyl, 4-methoxyl group-1-naphthyl, 2,4-dimethoxy-1-naphthyl, 2-naphthyl, 7-methyl-2-naphthyl, 1-n-propyl-2-naphthyl, 6-methoxyl group-2-naphthyl and 3,8-dimethoxy-2-naphthyl.
At last, will illustrate the step that obtains amino alcohol (40) with alkali reaction by making the compound (49) that obtains in the above-mentioned steps (C).
The alkali example comprises alkali metal hydroxide for example sodium hydroxide and potassium hydroxide; Alkaline earth metal hydroxides is calcium hydroxide and hydrated barta for example, uses its aqueous solution usually.With respect to the compound (49) of 1mol, the consumption of alkali is generally 1-3mol, preferred 1.2-2.5mol.Usually compound (49) and being reflected in the solvent of alkali are carried out, and examples of solvents comprises the mixed solvent of above-mentioned alcoholic solvent, water and water and alcoholic solvent.With respect to 1 part of (weight) compound (49), its consumption is generally 2-30 part (weight), preferred 3-15 part (weight).
Temperature of reaction is generally 0 ℃ of reflux temperature to reaction mixture, preferred 10 ℃ to 60 ℃.
After reaction was finished, for example concentrated reaction mixture with the mixed extraction treatment of carrying out of water-insoluble organic solvents, concentrated the organic layer that obtains then, separates amino alcohol (40).The water-insoluble organic solvents example comprises and above-mentioned those identical solvents.Isolating amino alcohol (40) can for example recrystallization or column chromatography be further purified by conventional purification process.
Industrial usability
By using asymmetric copper complex by new opticity two  isoxazoline compounds of the present invention and copper compound preparation, can prepare opticity cyclopropane compound by high yield with excellent non-enantiomer selectivity and enantio-selectivity, therefore consider that from the angle of industry the present invention more has superiority.
Embodiment
To further illustrate in greater detail the present invention by embodiment.The invention is not restricted to these embodiment.
Embodiment 1
Under nitrogen atmosphere, by mixing and stirring 5 hours down for 130 ℃ at internal temperature, make 1.2g (S)-1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol, 0.37g dimethyl malonate and the reaction of 70ml dimethylbenzene, obtain containing N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] the third-1, the reaction mixture of 3-diamide.79mg titanium tetraisopropylate (Titanium tetraisopropoxide) is added in the reaction mixture, reaction is finished by stirring down for 130 ℃ at internal temperature.After reaction was finished, concentrated reaction mixture, spissated resistates be by column chromatography (neutral alumina, chloroform) purifying, obtain two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] methane white powder 0.7g (yield: 54%).
Two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] methane 1H-NMR data (δ: ppm, CDCl 3Solvent, the TMS standard) 0.84 (s, 6H), 1.82 (s, 6H), 3.69 (s, 2H), 5.81 (s, 2H), 7.43-7.59 (m, 8H), 7.75-7.95 (m, 6H)
Embodiment 2
Except replacing 1.2g (S)-1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol with 1.2g (S)-1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol, according to embodiment 1 described identical method, obtain 0.79g two [2-[(4S)-(2-naphthyl)-5,5-dimethyl  azoles quinoline]] methane (yield: 61%), be pale yellow powder.
Two [2-[(4S)-(2-naphthyl)-5,5-dimethyl  azoles quinoline]] methane 1H-NMR data (δ: ppm, CDCl 3Solvent, the TMS standard) 0.92 (s, 6H), 1.69 (s, 6H), 3.63 (s, 2H), 5.10 (s, 2H), 7.40-7.48 (m, 6H), 7.70-7.83 (m, 8H)
Embodiment 3
Under nitrogen atmosphere, 2g (S)-1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol, 1.1g triethylamine (anhydrous) and 17ml methylene dichloride (anhydrous) is mixed, be cooled to internal temperature-10 ℃ then.In 3 minutes,, make the mixture that obtains be warming up to room temperature to wherein dripping 0.8g dimethyl propylene diacid chloride (Dimethylmalonicacid dichloride).Stir the mixture reaction is finished.After reaction is finished, to wherein adding 20ml saturated aqueous ammonium chloride, layering.The organic layer that obtains concentrates with 25ml water washing 3 times.Spissated resistates obtains 2.5gN at 40 ℃ of following drying under reduced pressure of internal temperature, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-dimethyl propylene-1,3-diamide (yield: 100%).
N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-dimethyl propylene-1, the 3-diamide 1H-NMR data (δ: ppm, CD 3The OD solvent, the TMS standard) 0.90 (s, 6H), 1.36 (s, 6H), 1.46 (s, 6H), 4.85 (s, 4H), 5.47 (s, 2H), 7.13 (t, J=9.0Hz, 2H), 7.33-7.35 (m, 2H), 7.45-7.52 (m, 4H), 7.70 (d, J=9.0Hz, 2H), 7.83-7.86 (m, 2H), 8.29 (d, J=9.0Hz, 2H)
With the 1.8g N that obtains thus, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-dimethyl propylene-1,3-diamide and 90ml dimethylbenzene are mixed, stir 1 hour down for 130 ℃ at internal temperature.In mixture, add the 97mg titanium tetraisopropylate then, under uniform temp, stirred the mixture 48 hours, reaction is finished.After reaction is finished, concentrated reaction mixture, spissated resistates is by column chromatography (neutral alumina, hexane/ethyl acetate=10/1 (volume ratio)) purifying, obtain 1.4g 2,2-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] propane white powder (yield: 83%).
2,2-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] propane 1H-NMR data (δ: ppm, CDCl 3Solvent, the TMS standard) 0.81 (s, 6H), 1.78 (s, 6H), 1.81 (s, 6H), 5.85 (s, 2H), 7.39-7.55 (m, 8H), 7.75 (d, J=9.0Hz, 2H), 7.87 (d, J=9.0Hz, 2H), 7.94 (d, J=9.0Hz, 2H)
Embodiment 4
Under nitrogen atmosphere, 1.5g (S)-1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol, 0.84g triethylamine (anhydrous) and 13ml methylene dichloride (anhydrous) is mixed, be cooled to internal temperature-10 ℃ then.In 3 minutes, to wherein dripping 0.6g dimethyl propylene diacid chloride.Make the mixture that obtains be warming up to room temperature.Stir the mixture reaction is finished.After reaction is finished, to wherein adding 20ml saturated aqueous ammonium chloride, layering.The organic layer that obtains concentrates with 25ml water washing 3 times.Spissated resistates obtains 1.8gN at 40 ℃ of following drying under reduced pressure of internal temperature, N '-two [(1S)-and (2-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-dimethyl propylene-1,3-diamide (yield: 100%).
N, N '-two [(1S)-and (2-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-dimethyl propylene-1, the 3-diamide 1H-NMR data (δ: ppm, CD 3The OD solvent, the TMS standard) 1.00 (s, 6H), 1.30 (s, 6H), 1.50 (s, 6H), 4.86 (s, 4H), 4.87 (s, 2H), 7.27-7.45 (m, 8H), 7.66-8.06 (m, 6H)
With the 1.8g N that obtains thus, N '-two [(1S)-and (2-naphthyl)-2-hydroxy-2-methyl propyl group]-2,2-dimethyl propylene-1,3-diamide and 90ml dimethylbenzene are mixed, stir 1 hour down for 130 ℃ at internal temperature.In reaction mixture, add the 97mg titanium tetraisopropylate then, under uniform temp, stirred the mixture 48 hours, reaction is finished.After reaction is finished, concentrated reaction mixture, spissated resistates is by column chromatography (neutral alumina, hexane/ethyl acetate=5/1 (volume ratio)) purifying, obtain 1.3g 2,2-two [2-[(4S)-(2-naphthyl)-5,5-dimethyl  azoles quinoline]] propane white powder (yield: 77%).
2,2-two [2-[(4S)-(2-naphthyl)-5,5-dimethyl  azoles quinoline]] propane 1H-NMR data (δ: ppm, CDCl 3Solvent, the TMS standard) 0.90 (s, 6H), 1.66 (s, 6H), 1.76 (s, 6H), 5.05 (s, 2H), 7.34-7.46 (m, 6H), 7.66-8.05 (m, 8H)
Embodiment 5
Under nitrogen atmosphere, 1.5g (S)-1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol, 0.84g triethylamine (anhydrous) and 13ml methylene dichloride (anhydrous) is mixed, be cooled to internal temperature-10 ℃ then.In 3 minutes, to wherein dripping 0.58g 1,1-cyclopropane dimethyl chloride makes the mixture that obtains be warming up to room temperature.Stir the mixture reaction is finished.After reaction is finished, to wherein adding 20ml saturated aqueous ammonium chloride, layering.The organic layer that obtains concentrates with 25ml water washing 3 times.Spissated resistates obtains 1.9g N at 40 ℃ of following drying under reduced pressure of internal temperature, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] cyclopropane-1,1-diformamide (yield: 100%).
N, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] cyclopropane-1, the 1-diformamide 1H-NMR data (δ: ppm, CD 3The OD solvent, the TMS standard) 0.97 (s, 6H), 1.0-1.08 (m, 2H), 1.32-1.35 (m, 2H), 1.35 (s, 6H), 4.87 (s, 4H), 5.86 (s, 2H), 7.32-7.54 (m, 8H), 7.76 (d, J=9.0Hz, 2H), 7.85 (d, J=9.0Hz, 2H), 8.31 (d, J=9.0Hz, 2H)
With the 1.83g N that obtains thus, N '-two [(1S)-and (1-naphthyl)-2-hydroxy-2-methyl propyl group] cyclopropane-1,1-diformamide and 100ml dimethylbenzene are mixed, stir 1 hour down for 130 ℃ at internal temperature, add the 99mg titanium tetraisopropylate then in reaction mixture.Under uniform temp, stirred the mixture 40 hours, reaction is finished.After reaction is finished, concentrated reaction mixture, spissated resistates is by column chromatography (silica gel, hexane/ethyl acetate=4/1 (volume ratio)) purifying, obtain 1.23g 1,1-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] cyclopropane buff powder (yield: 72%).
1,1-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] cyclopropane 1H-NMR data (δ: ppm, CDCl 3Solvent, the TMS standard) 0.83 (s, 6H), 1.53-1.61 (m, 2H), 1.69-1.75 (m, 2H), 1.77 (s, 6H), 5.76 (s, 2H), 7.46-7.54 (m, 8H), 7.78 (d, J=9.0Hz, 2H), 7.86-7.94 (m, 4H)
Embodiment 6
In the 50ml Schlenk pipe that feeds nitrogen, add in the white suspension that contains the cuprous and 5ml ethylene dichloride of 18mg trifluoromethanesulfonic acid that 27mg embodiment 3 obtains 2,2-two [2-[(4S)-(1-naphthyl)-5,5-dimethyl  azoles quinoline]] propane, at room temperature stirred the gained mixture 10 minutes, preparation contains the blue look homogeneous phase solution of asymmetric copper complex.Then to wherein adding 7.8g 2,5-dimethyl-2, the 4-hexadiene transfers to 40 ℃ with internal temperature.In 2 hours, to wherein dripping the 1.1g ethyl diazoacetate, the mixture that stirring obtains under uniform temp 30 minutes is finished reaction.By the gas chromatographic analysis reaction mixture, find to generate 2,2-dimethyl-3-(2-methyl isophthalic acid-propenyl) cyclopropane-carboxylic acid ethyl ester, yield 93% (in ethyl diazoacetate), trans-isomer(ide)/cis-isomeride ratio=69/31.And, by liquid-phase chromatographic analysis optical purity, find that the optical purity of trans-isomer(ide) is 82% enantiomeric excess (e.e), the optical purity of cis-isomeride is 8% enantiomeric excess.In this relation, trans-isomer(ide) represents that 2-methyl isophthalic acid-propenyl of 1 ester group and 3 is in the compound of offside each other about the cyclopropane ring plane, cis-isomeride represents that 2-methyl isophthalic acid-propenyl of 1 ester group and 3 is positioned at the compound (hereinafter, following examples are identical) of homonymy.
Embodiment 7
Except replacing the 1.1g ethyl diazoacetate with 1.4g diazo acetic acid N2 tertiary butyl ester, according to embodiment 6 described identical methods, obtain 2,2-dimethyl-3-(2-methyl isophthalic acid-propenyl) cyclopropane-carboxylic acid tertiary butyl ester, yield: 92% (in the diazo acetic acid N2 tertiary butyl ester).Trans-isomer(ide)/cis-isomeride ratio=87/13.Concentrated reaction mixture, concentration residue 1g part of obtaining.To wherein adding 0.1ml trifluoroacetic acid and 5ml toluene, by under 100 ℃ of internal temperatures, stir the gained mixture reaction is finished, obtain 2,2-dimethyl-3-(2-methyl isophthalic acid-propenyl) cyclopropane-carboxylic acid.Make obtain 2,2-dimethyl-3-(2-methyl isophthalic acid-propenyl) cyclopropane-carboxylic acid and 1-menthol (menthol) reaction, 1-menthyl ester by the gas chromatographic analysis generation, the optical purity of finding trans-isomer(ide) is 95% enantiomeric excess, and the optical purity of cis-isomeride is 69% enantiomeric excess.
EXPERIMENTAL EXAMPLE 1
In the 50ml Schlenk pipe that feeds nitrogen, in the white suspension that contains the cuprous and ethylene dichloride 5ml of 18mg trifluoromethanesulfonic acid, add 22mg 2,2-two [2-[(4S)-1-naphthyl  azoles quinoline]] propane, at room temperature stirred 10 minutes, prepare asymmetric copper complex formazan blue look homogeneous phase solution.Then, to wherein adding 7.8g 2,5-dimethyl-2,4-hexadiene, internal temperature is transferred to 40 ℃, in 2 hours, to wherein dripping 1.4g diazo acetic acid N2 tertiary butyl ester, the mixture that restir obtains under uniform temp made reaction finish in 30 minutes, obtain 2,2-dimethyl-3-(2-methyl isophthalic acid-propenyl) cyclopropane-carboxylic acid tertiary butyl ester, yield 89% (in the diazo acetic acid N2 tertiary butyl ester), trans-isomer(ide)/cis-isomeride ratio=81/19.The optical purity of trans-isomer(ide) is 86% enantiomeric excess, and the optical purity of cis-isomeride is 60% enantiomeric excess.
Embodiment 8
23.3g 1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol is dissolved in the 410ml Virahol, solution is heated to internal temperature 60-70 ℃.The 410ml aqueous isopropanol that in gained solution, adds 8.4g N-formyl radical-L-phenylalanine.Then, the mixture placement is spent the night the opticity diastereoisomeric salt precipitation of filtering separation 1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol and N-formyl radical-L-phenylalanine.Filtering diastereoisomeric salt obtains diastereoisomeric salt with the washing of 50ml cold isopropanol.This diastereoisomeric salt and 750ml Virahol and 40ml water is mixed once more, and heating gained mixture is to reflux temperature, with the dissolving diastereoisomeric salt.Then gained solution is cooled to room temperature, filtering separation diastereoisomeric salt precipitation.Filtering diastereoisomeric salt obtains 14.2g diastereoisomeric salt white crystals with the washing of 50ml cold isopropanol.
The fusing point of diastereoisomeric salt is 186-188 ℃.Ultimate analysis value: C:69.8%, H:7.0%, N:6.7% (theoretical value C:70.6%, H:6.9%, N:6.9%).
60ml aqueous sodium hydroxide solution (1mol/L), 80ml water and 300ml chloroform are added in the 13.8g diastereoisomeric salt that obtains.At room temperature carry out extraction treatment, separate organic layer and water layer.The organic layer that obtains washes with water, concentrates, and obtains 5.6g (S)-1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol (yield: 24%).Optical purity: S isomer ratio=99.95%.
(S)-analytical results of 1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol:
[α] D (c0.5, CH 3OH)+60.4 °: fusing point 86-87 ℃:
1H-NMR collection of illustrative plates (300MHz, CDCl 3, the TMS standard) and δ (ppm); 1.07 (3H, s), 1.29 (3H, s), 1.50-2.16 (2H, br), 2.16-3.22 (1H, br), 4.83 (1H, s), 7.46-8.19 (7H, m) ultimate analysis value: C:77.8%, H:7.9%, N:6.4% (theoretical value C:78.1%, H:8.0%, N:6.5%).
Embodiment 9
24.0g 1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol is dissolved in the 410ml Virahol, gained solution is heated to 40 ℃ of internal temperatures.The 410ml aqueous isopropanol that in gained solution, adds 8.3g N-formyl radical-L-phenylalanine.Then mixture is placed and spent the night, the opticity diastereoisomeric salt precipitation of filtering separation 1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol and N-formyl radical-L-phenylalanine.Filtering diastereoisomeric salt obtains diastereoisomeric salt with the washing of 50ml cold isopropanol.This diastereoisomeric salt and 750ml Virahol and 40ml water is mixed once more, with the gained mixture heating up to reflux temperature, with the dissolving diastereoisomeric salt.Then, gained solution is cooled to room temperature, filtering separation diastereoisomeric salt precipitation.Filtering diastereoisomeric salt obtains 12.4g diastereoisomeric salt white crystals with the washing of 50ml cold isopropanol.
The fusing point of diastereoisomeric salt is 193-195 ℃.Ultimate analysis value: C:70.4%, H:6.9%, N:6.8% (theoretical value C:70.6%, H:6.9%, N:6.9%).
35ml aqueous sodium hydroxide solution (1mol/L), 100ml water and 300ml chloroform are added in the 11.9g diastereoisomeric salt that obtains.At room temperature carry out extraction treatment, separate organic layer and water layer.The organic layer that obtains washes with water, concentrates, and obtains 6.2g (S)-1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol (yield: 26%).Optical purity: S isomer ratio=99.89%.(S)-analytical results of 1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol:
(c 0.5, CH for [α] D 3OH)+14.1 °: fusing point 77-78 ℃:
1H-NMR collection of illustrative plates (300MHz, CDCl 3, the TMS standard) and δ (ppm); 1.09 (3H, s), 1.26 (3H, s), 1.47-2.35 (2H, br), 2.35-3.20 (1H, br), 3.97 (1H, s), 7.44-7.83 (7H, m)
Ultimate analysis value: C:78.0%, H:8.0%, N:6.4% (theoretical value C:78.1%, H:8.0%, N:6.5%.
Embodiment 10
Under 35 ℃ of internal temperatures, in 1 hour, in the mixture of 50.3g 1-naphthyl glycine (racemic isomer) and 200ml methyl alcohol (anhydrous), drip the 33ml thionyl chloride, stirring the mixture under uniform temp then made reaction finish in 3 hours.Concentrated reaction mixture, the concentration residue and the 200ml ether that obtain is mixed.The crystallization of filtering separation generation then is with the washing of 50ml ether.Under 50 ℃ of internal temperatures, the isolating after filtration crystallization of drying under reduced pressure, obtain 61.9g reddish brown 1-naphthyl glycine methyl ester hydrochloride (yield: 98%).
Internal temperature-40 ℃ to-50 ℃ under, in the mixture of above 61.9g 1-naphthyl glycine methyl ester hydrochloride that obtains and 390ml methylene dichloride, drip the 72ml triethylamine, then under-45 ℃ to-50 ℃, in 1 hour, again to wherein dripping the 38ml trifluoroacetic anhydride.Under uniform temp, this mixture of restir made reaction finish in 1 hour, made reaction mixture be warming up to 0 ℃ then.In this reaction mixture, add the mixture of 280ml cold water and 10ml concentrated hydrochloric acid, carry out extraction treatment with the 1100ml methylene dichloride.The organic layer that obtains 280ml cold water washing.The organic layer that obtains concentrates then through anhydrous sodium sulfate drying, the filtering for crystallizing precipitation.After cold washed with dichloromethane, crystallization obtains 51.7g white N-(trifluoroacetyl group)-1-naphthyl glycine methyl ester (yield: 68%) at 60 ℃ of following drying under reduced pressure of internal temperature.
The fusing point of N-(trifluoroacetyl group)-1-naphthyl glycine methyl ester: 183-184 ℃.
1H-NMR collection of illustrative plates (300MHz, CDCl 3, the TMS standard) and δ (ppm); 3.76 (3H, s), 6.31 (1H, d), 7.30-7.40 (1H, br), 7.46-8.10 (7H, m)
To be cooled to internal temperature 0-5 ℃ by the solution that adding 360ml tetrahydrofuran (THF) (anhydrous) in the tetrahydrofuran solution 180ml of methyl-magnesium-bromide (3mol/L) obtains; then under uniform temp, in 30 minutes, to wherein dripping the mixture that contains above 33.7g N-(trifluoroacetyl group)-1-naphthyl glycine methyl ester that obtains and 170ml tetrahydrofuran (THF) (anhydrous).Make the gained mixture be warming up to room temperature, under uniform temp, stir then to make in 2.5 hours to react and finish.In the mixture of 900g ice and 200ml concentrated hydrochloric acid, add this reaction mixture, keep 5 ℃ of internal temperatures or lower simultaneously, carry out extraction treatment with the 800ml cold toluene.The water layer that obtains extracts with the 800ml cold toluene.Organic layer that obtains and the organic layer that had before obtained are merged, then this mixture 400ml cold water washing.The organic layer that obtains is through anhydrous sodium sulfate drying, concentrates then, and drying under reduced pressure concentration residue at room temperature obtains that 36.0g is light yellow, thickness oily 1-(trifluoroacetamido)-1-(1-naphthyl)-2-methyl-2-propyl alcohol.
1-(trifluoroacetamido)-1-(1-naphthyl)-2-methyl-2-propyl alcohol 1H-NMR collection of illustrative plates (300MHz, CDCl 3, the TMS standard) and δ (ppm); 0.98 (3H, s), 1.47 (3H, s), 5.83 (1H, d) 7.46-7.89 (7H, m), 8.18 (1H, d)
180ml Virahol and 180ml ethanol are added in 36.0g 1-(trifluoroacetamido)-1-(1-the naphthyl)-2-methyl-2-propyl alcohol that obtains, at room temperature, in 30 minutes, to the 63g potassium hydroxide aqueous solution that wherein drips 22% (weight).The internal temperature of mixture is risen to 50 ℃, and under uniform temp, stirring the mixture made reaction finish in 2 hours then.Concentrated reaction mixture is added to 500ml chloroform and 180ml water in the concentration residue that obtains, to carry out extraction treatment.The organic layer that obtains 100ml water washing through anhydrous sodium sulfate drying, concentrates the organic layer that obtains then.Under 30 ℃ of internal temperatures, the concentration residue that drying under reduced pressure obtains obtains that 28.0g is brown, thickness oily 1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol.
1-amino-1-(1-naphthyl)-2-methyl-2-propyl alcohol 1H-NMR collection of illustrative plates (300MHz, CDCl 3, the TMS standard) and δ (ppm); 1.07 (3H, s), 1.29 (3H, s), 1.48-2.94 (3H, br) 4.83 (1H, s) 7.4 6-8.19 (7H, m)
Embodiment 11
Under 35 ℃ of internal temperatures, in 1 hour, in the mixture of 50.3g 2-naphthyl glycine (racemic modification) and 200ml methyl alcohol (anhydrous), drip the 33ml thionyl chloride, stirring the mixture under uniform temp then made reaction finish in 3 hours.Concentrated reaction mixture, the concentration residue and the 200ml ether that obtain is mixed.The crystallization of filtered and recycled generation then is with the washing of 50ml ether.Under 50 ℃ of internal temperatures, the crystallization that drying under reduced pressure reclaims after filtration obtains 59.0g white 2-naphthyl glycine methyl ester hydrochloride (yield: 94%).
After the cooling of the mixture of above 59.0g 2-naphthyl glycine methyl ester hydrochloride that obtains and 1180ml methylene dichloride, internal temperature-35 ℃ to-38 ℃ under, in this mixture, drip the 69ml triethylamine.Internal temperature-40 ℃ to-42 ℃ under, in 70 minutes, again to wherein dripping the 38ml trifluoroacetic anhydride.Under uniform temp, the restir mixture made reaction finish in 1 hour, made reaction mixture be warming up to 0 ℃ then.In this reaction mixture, add the mixture of 280ml cold water and 4ml concentrated hydrochloric acid, carry out extraction treatment with the 500ml methylene dichloride.The organic layer that obtains 280ml cold water washing.The organic layer that obtains concentrates then through anhydrous sodium sulfate drying, the filtering for crystallizing precipitation.After cold methylene dichloride/normal hexane=1/1 (volume ratio) washing, crystallization obtains 55.5g white N-(trifluoroacetyl group)-2-naphthyl glycine methyl ester (yield: 76%) at 60 ℃ of following drying under reduced pressure of internal temperature.
N-(trifluoroacetyl group)-2-naphthyl glycine methyl ester 1H-NMR collection of illustrative plates (300MHz, CDCl 3, the TMS standard)
δ(ppm)；3.77(3H，s)，5.72(1H，d)，7.41-7.88(8H，m)
To be cooled to internal temperature 0-5 ℃ by the solution that adding 390ml tetrahydrofuran (THF) (anhydrous) in the tetrahydrofuran solution 200ml of methyl-magnesium-bromide (3mol/L) obtains; under uniform temp, in 30 minutes, to wherein dripping the mixture that contains above 37.0g N-(trifluoroacetyl group)-2-naphthyl glycine methyl ester that obtains and 190ml tetrahydrofuran (THF) (anhydrous).Make the gained mixture be warming up to room temperature, under uniform temp, stir then to make in 2.5 hours to react and finish.Reaction mixture is added in the mixture of 900g ice and 220ml concentrated hydrochloric acid, keep 5 ℃ of internal temperatures or lower simultaneously, carry out extraction treatment with the 800ml cold toluene then.The water layer that obtains extracts with the 800ml cold toluene.Organic layer that obtains and the organic layer that had before obtained are merged, use the 400ml cold water washing then.The organic layer that obtains concentrates then through anhydrous sodium sulfate drying, and concentration residue obtains 36.0g 1-(trifluoroacetamido)-1-(2-naphthyl)-2-methyl-2-propyl alcohol light yellow solid at 35 ℃ of following drying under reduced pressure of internal temperature.
1-(trifluoroacetamido)-1-(2-naphthyl)-2-methyl-2-propyl alcohol 1H-NMR collection of illustrative plates (300MHz, CDCl 3, the TMS standard) and δ (ppm); 1.09 (3H, s), 1.42 (3H, s), 4.95 (1H, d) 7.43-7.85 (8H, m)
In 36.0g 1-(trifluoroacetamido)-1-(2-the naphthyl)-2-methyl-2-propyl alcohol that obtains, add 170ml Virahol and 170ml ethanol, then at room temperature, in 30 minutes, to the 56g potassium hydroxide aqueous solution that wherein drips 22% (weight).Then, the internal temperature of mixture is risen to 50 ℃, under uniform temp, stirring the mixture made reaction finish in 2 hours.Concentrated reaction mixture is added to 320ml chloroform and 160ml water in the concentration residue that obtains, and carries out extraction treatment.The organic layer that obtains 80ml water washing through anhydrous sodium sulfate drying, concentrates the organic layer that obtains then.Under 30 ℃ of internal temperatures, the concentration residue that drying under reduced pressure obtains obtains 24.3g 1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol brown solid (yield: 97%).。
1-amino-1-(2-naphthyl)-2-methyl-2-propyl alcohol 1H-NMR collection of illustrative plates (300MHz, CDCl 3, the TMS standard) and δ (ppm); 1.08 (3H, s), 1.26 (3H, s), 1.46-3.05 (3H, br) 3.96 (1H, s) 7.42-7.84 (7H, m).

Claims (6)

1. the method for the opticity diamide compound of a preparation formula (2) representative:
Figure A2007101529330002C1
R wherein 1And R 2Identical, and represent C separately 1-6Alkyl, replacement or unsubstituted aralkyl or replacement or unsubstituted phenyl, or R 1And R 2The  oxazoline ring carbon atom that is connected to each other, connects with them forms ring; R 3Representative replaces or unsubstituted naphthyl; R 4And R 5Identical, and represent hydrogen atom or C separately 1-6Alkyl, or R 4And R 5The carbon atom that is connected to each other, connects with them forms the cycloalkyl ring with 3-6 carbon atom; And * represents asymmetric center, and described method comprises makes wherein R 1, R 2, R 3Opticity amino alcohol with formula (3) representative of * definition cotype (2):
Figure A2007101529330002C2
Propanedioic acid compound reaction with formula (4) representative:
Figure A2007101529330002C3
R wherein 4And R 5Definition cotype (2); And Z representation alkoxy or halogen atom.
2. the opticity amino alcohol of a formula (30) representative:
Figure A2007101529330002C4
R wherein 31, R 32, R 33And R 34Identical or different, and independent hydrogen atom, the C of representing 1-6Alkyl or C 1-6Alkoxyl group; R 35Represent C 1-6Alkyl, replacement or unsubstituted phenyl or replacement or unsubstituted aralkyl, or two R that are connected to identical carbon atoms 35Be connected to form ring with this carbon atom; And * represents unsymmetrical carbon.
3. method for preparing opticity naphthyl alcohol, described method comprise the amino alcohol that makes formula (40) representative:
Figure A2007101529330003C1
R wherein 31, R 32, R 33And R 34Identical or different, and independent hydrogen atom, the C of representing 1-6Alkyl or C 1-6Alkoxyl group; R 35Represent C 1-6Alkyl, replacement or unsubstituted phenyl or replacement or unsubstituted aralkyl, or two R that are connected to identical carbon atoms 5Be connected to form ring with this carbon atom,
In solvent, react the diastereoisomeric salt of the pure and mild opticity N-formyl radical of the opticity naphthyl phenylalanine of the formula that forms (30) representative with opticity N-formyl radical phenylalanine:
Figure A2007101529330003C2
R wherein 31, R 32, R 33, R 34And R 35Describe the samely, and * represents unsymmetrical carbon,
A kind of diastereoisomeric salt is separated with another kind of diastereoisomeric salt, use the isolating diastereoisomeric salt of alkaline purification then.
4. the opticity amino alcohol of the formula of claim 3 (30) representative and the diastereoisomeric salt of opticity N-formyl radical phenylalanine.
5. the method for the amino alcohol of a preparation formula (40) representative:
Figure A2007101529330004C1
R wherein 31, R 32, R 33And R 34Identical or different, and independent hydrogen atom, the C of representing 1-6Alkyl or C 1-6Alkoxyl group; R 35Represent C 1-6Alkyl, replacement or unsubstituted phenyl or replacement or unsubstituted aralkyl, or two R that are connected to identical carbon atoms 35Be connected to form ring with this carbon atom,
Said method comprising the steps of (A) to (D):
(A) the naphthyl glycine compound that formula (41) is represented:
Figure A2007101529330004C2
R wherein 31, R 32, R 33And R 34Identical or different, and independent hydrogen atom, the C of representing 1-6Alkyl or C 1-6Alkoxyl group,
Wherein R with chlorizating agent and formula (42) representative 9Represent C 1-6The alcohol reaction of alkyl:
R 9OH (42)
Obtain the amino acid ester hydrochloride of formula (43) representative:
Figure A2007101529330004C3
R wherein 31, R 32, R 33, R 34And R 9Describe the same,
(B) in the presence of tertiary amine, the compound reaction of amino acid ester hydrochloride that the formula (43) that above step (A) is obtained is represented and formula (44) representative:
(C nF 2n+1CO) 2O (44)
Wherein n represents 1,2 or 3,
Or with the compound reaction of formula (45) representative:
C nF 2n+1COX (45)
Wherein n describes the same; And X represents chlorine atom, bromine atoms or iodine atom, obtains the compound of formula (46) representative:
Figure A2007101529330005C1
R wherein 31, R 32, R 33, R 34, R 9With n describe the same,
(C) make the compound reaction of compound (46) that above step (B) obtains and formula (47) representative:
R 35MgX’ (47)
R wherein 35Represent C 1-6Alkyl, replacement or unsubstituted aralkyl or replacement or unsubstituted phenyl; And X ' represents halogen atom,
Or with the compound reaction of formula (48) representative:
X’-Mg-R 35’-Mg-X’ (48)
R wherein 35' represent C 2-6Alkylidene group, and X ' definition is the same,
Obtain the compound of formula (49) representative:
Figure A2007101529330005C2
R wherein 31, R 32, R 33, R 34, R 35With n definition the same and
(D) compound (49) and the alkali reaction that above step (C) is obtained.
6. the compound of the formula of claim 5 (49) representative.
CNA2007101529332A 2003-02-07 2004-02-04 Optically active bisoxazoline compounds, process for production of the same and use thereof Pending CN101125833A (en)

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