Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2180000
Specification
Amino-Acid Amide Derivatives, Method for Producing the Same, and
Agricultural or Horticultural Fungicides
Field of the Invention
The present invention relates to novel amino-acid amide
derivatives as well as to agricultural or horticultural fungicides
containing the same as active ingredients.
Background Art
Heretofore, it is known that the amino-acid amide derivatives
such as N2-tert-butoxycarbonyl-Nl-(2-phenoxyethyl)-D- alaninamide and
N2-tent-butoxycarbonyl-Nl-(2-phenylthioethyl)-D- alaninamide (Japanese
Patent Application, First Publication, No. Sho 62-89696} are
intern~cdiates for medicines; however, the utility of the amino-acid
amide derivatives are not known. In addition, it is known that the
amigo-acid amide derivatives such as N-(tert-butoxycarbonyl)-L-valine-
1-(4-mcthylphenyl)ethylamide (Japanese Patent Application, First
Publication, No. Hei 3-5451), N2-(4-chlorophenoxycarbonyl)-Nl-[1-(4-
chlorophenyl)ethyl)-L-valinamide (Japanese Patent Application, First
Publication ,No. Hei 3-153657), and the like are useful for biocides.
However, the fungicidal activities of fungicides may become
degraded because of the emergence of resistant fungi after repeated uses
of the fungicides. For this reason, as well as because of environmental
problems, it is desired to provide a novel fungicide which can
efficiently control harmful fungi even at a low concentration.
Disclosure of the Invention
In order to develop a fungicide possessing fungicidal activity
superior to that of known fungicides, the present inventors have
synthesized various amino-acid amide derivatives and have carried out
extensive research in connection with their effects on the biological
activities of fungi. As a result, we have found that the compounds
according to the present invention, possessing a substituted or non-
substituted phenoxy group, a substihited or non-substituted benzyloxy
2
group, a substituted or non-substituted alkoxy group, and the like, as a
terminal group, exhibit a broad spectrum of anti-fungal activity
especially against cucumber downy mildew, grape downy mildew, and
tomato late blight in small amounts, while at the same time do not
hinder desirable plant growth.
According to an aspect of the present invention, there is provided
( 1 ) an amino-acid amide derivative represented by the formula
Z2 H O R3 Rs R~
-
R Z CNHC- CNHC- (C)m- Z (C)n- Q
2 ~4 ~ 6
R R R R
wherein R1 represents
(a) a lower alkyl group (optionally having at least one same or
different substituent selected from the group consisting of a halogen
atom, an alkoxy group, and a cyano group),
(b) a lower alkenyl group,
(c) a lower alkynyl group,
(d) a cycloalkyl group (optionally having at least one substituent
selected from the group consisting of methyl group and a halogen
atom),
(e) a cycloalkylalkyl group,
(f) a cycloalkenyl group,
(g) a cyclic ether group,
(h) a phenyl group (optionally having at least one same or
different substituent selected from the group consisting of
a halogen atom,
a lower alkyl group which may be substituted with a same
or different halogen atom,
a lower alkoxy group which may be substituted with a same
or different halogen atom,
a cyano group, and
a nitro group),
218UUUfl
(i) an aralkyl group (optionally having at least one same or
different substituent selected from the group consisting of a methyl
group, a cyano group, and a nitro group), or
(j) a heterocyclic group,
R2 represents a lower alkyl group, a lower alkenyl group, a
cycloalkyl group, or a phenyl group (optionally having at least one
substituent of halogen atom),
R3 represents a hydrogen atom or a lower alkyl group,
R4 represents a hydrogen atom, a lower alkyl group, or a cyano
group,
R5, R~, and R~ independently represent a hydrogen atom or a
lower alkyl group,
Rg represents a hydrogen atom, a lower alkyl group, an aralkyl
group, a phenyl group, an alkoxycarbonyl group, or a cyano group,
Z1 and Z2 independently represent an oxygen atom or a sulfur
atom,
Z3 represents
an oxygen atom,
a sulfur atom,
a group N-R 1 ~ (wherein R 1 ~ represents a hydrogen atom,
a methyl group, an acetyl group, a benzoyl group, a methoxycarbonyl
group, or a methoxymethyl group),
a sulfinyl group,
a sulfonyl group,
a group -C(O)O-,
a group CONR 11 (wherein R 11 represents a hydrogen atom or a
1 ower alkyl group),
Q represents
(a) a phenyl group [optionally having at least one same or
different substituent selected from the group consisting of
a halogen atom,
21~OOU0
a lower alkyl group which may be substituted with at least
one same or different halogen atom,
a lower alkoxy group which may be substituted with a same
or different halogen atom,
a cyano group,
a nitro group,
a lower alkoxycarbonyl group,
a methylsulfonyl group,
a methylsulfinyl group,
a methylthio group which may be substituted with a
halogen atom,
a dimethylamino group,
a phenylsulfonyl group,
an acyl group, and
a phenyl group],
(b) a cyclic ether group,
(c) a heterocyclic group (optionally having a substituent selected
from the group consisting of a halogen atom, an alkyl group, a
trifluoromethyl group, and a nitro group), or
(d) a condensed heterocyclic group optionally having a
substituent selected from the group consisting of a halogen atom and a
nitro group,
m represents an integer from 0 to 2, and
n represents 0 or 1,
(2) a process for preparing an amino-acid amide derivative
represented by the formula:
Z2 H O R3 Rs R~
R1- Z~CNHC- CNHC- (C)m- Z3 - (C)n- Q
2 ~4 ~ 6
R R R R
wherein Rl, R2, R3, R4, R5, R6, R~, Rg, Zl, Z2, Z3, Q, m, and
n have the same meanings as defined in (1),
2180000
comprising the step of: reacting an amino acid derivative or the amino
acid derivative with an activated carboxyl group, represented by the
formula:
Z2 H O
R - Z CNHC - COH
R2
with an amine represented by the formula:
R3 Rs R~
NH2C -- (C)m -- Z3 - (C)n- Q
Ra R6 R8
in the presence of a catalyst and /or a base as required,
(3) a process for preparing an amino-acid amide derivative
represented by the formula:
Z2 H O Rs Rs R~
R' - Z~CNHC- CNHC- (C)m - Z3 - (C)n- Q
2 ~4 6
R R R R
wherein R1, R2, R3, R4, R5, R6, R~, Rg, Z1, Z2, Z3, Q, m, and
n .have the same meanings as defined in ( 1 ),
comprising the step of: reacting a compound represented by the
formul a:
Z2
R'- ZI- C- Y
6 2180000
Y represents a halogen atom, a 4,6-dimethylpyrimidinylthio group,
Ph
'C= NO -
an R10C(O)O- group, or a NC/ group,
(wherein Ph represents a phenyl group),
with an amine represented by the formula:
H O R3 Rs R~
II ~ I I
NH2C- CNHC- (C)m - Z3 - (C)n- Q
I
2 ~4 ~ 6
R R R R
or an inorganic acid salt of the same such as hydrochloride or an
organic acid salt of the same such as tosylate, and
(4) an agricultural or horticultural fungicide which includes an
effective amount of an amino-acid amide derivative as recited in (1).
The terms employed in the present invention are defined as
follows.
The term "lower alkyl group" is used herein to mean a straight or
branched alkyl group possessing 1 to 6 carbon atoms including, but not
limited to, a methyl group, ethyl group, propyl group, isopropyl group,
butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl
group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl
group, 2,2-dimethylpropyl group, 1,1-dimethylpropyl group, 1-
cthylpropyl group, hexyl group, or the like.
The term "halogen atom" is used herein to mean a fluorine atom,
chlorine atom, bromine atom, or iodine atom.
The term "lower alkenyl group" is used herein to mean a straight
or branched alkenyl group possessing 2 to 6 carbon atoms and
including, but not limited to, a vinyl group, 1-propenyl group, 2-
propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group,
3-butenyl group, 1-methyl-1-propenyl group, 2-methylpropenyl group,
1-ethylvinyl group, or the like.
x'180000
The term "lower alkynyl group" is used herein to mean a straight
or branched alkynyl group possessing 2 to 6 carbon atoms and
including, for example, an ethynyl group, propynyl group, butynyl
group, I -methyl-2-propynyl group, or the like.
The term "cycloalkyl group" is used herein to mean a cycloalkyl
group possessing 3 to 8 carbon atoms and including, but not limited to,
a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl
group, cycloheptyl group, or the like.
The term "cycloalkenyl group" is used herein to mean a
cycloalkenyl group possessing 4 to 8 carbon atoms and including, for
example, a cyclobutenyl group, cyclopentenyl group, cyclohexenyl
group, cycloheptenyl group, or the like.
The term "aralkyl group" is used herein to mean an aralkyl group
possessing 7 to 8 carbon atoms and including, but not limited to, a
benzyl group, phenethyl group, or the like.
The term "cyclic ether group" is used herein to mean a cyclic
ether group possessing 2 to 6 carbon atoms and including, for example,
an oxiranyl group, oxetanyl group, tetrahydrofuranyl group,
tetrahydropyranyl group, or the like.
The term "heterocyclic group" is used herein to mean a 5-
membered or 6-membered ring including one or two hetero atoms
consisting of a nitrogen atom, an oxygen atom, and a sulfur atom and
including, for example, a pyridinyl group, a pyrimidinyl group, a furyl
group, a thienyl group, or the like.
The term "condensed heterocyclic group" is used herein to mean
a bicyclic compound consisting of S-membered and/or 6-membered
rings including one or two hetero atoms of a nitrogen atom, an oxygen
atom, and a sulfur atom and including, but not limited to, a
benzofuranyl group, a benzothienyl group, a quinolinyl group, or the
like.
The preferred compounds of the present invention are
represented by formula [I], wherein R1 represents a straight or
branched alkyl group possessing 2 to 6 carbon atoms, a straight or
branched alkenyl group possessing 3 carbon atoms, a cycloalkyl group
possessing 5 to 6 carbon atoms, or an optionally substituted phenyl
2180000
group; R2 represents an ethyl group, a propyl group, an isopropyl
group, or a sec-butyl group; R3 represents a hydrogen atom or a
methyl group; R4 represents a hydrogen atom or a methyl group; RS
represents a hydrogen atom or a methyl group; R6 represents a
hydrogen atom or a methyl group; Q represents an optionally
substituted phenyl group; m represents an integer of 0 or 1; n
represents 0; Z1, Z2, and Z3 represent an oxygen atom or a sulfur
atom; and the amino acid is an L-isomer.
The compounds represented by formula [I] according to the
present invention can exist in stereoisomers by virtue of the presence of
two or more chiral centers in a molecule. The present invention relates
to all such stereoisomers, including diastereomers, enantiomers, and
mixtures thereof, which can be separated by appropriate methods.
Next, representative examples of the compounds represented by
Formula [I] according to the present invention are listed in Tables 1
13. However, it should be understood that the invention is not limited
to these compounds. Compound Numbers given in the Tables will be
referred to in the subsequent description.
Ln Tables 1 to 12, Compound Nos. 108, 433, 456, 459 ~ 462, 464,
467, 470, 471, 472, and 475 possess D,L-configurational amino acid
moieties; Compound No. 109 possesses a D-configurational amino acid
moiety; and tte compounds other than the compounds described above
possess L-configurational amino acid moieties. In Compound Nos. 233
238 and 425 ~ 427, the acid moieties of the amino-acid amide
derivatives are (2S)-butyric acids.
Compound Nos. 33, 345, and 346; Compound Nos. 107, 116, and
117; Compound Nos. 135, 395, and 396; Compound Nos. 228, 414, and
415; and Compound Nos. 452, 453, and 454 are mixtures of
diastereomers, and are also individual diastereomers.
In addition, Compound Nos. 26 and 27; Compound Nos. 45 and
356; Compound Nos. 335 and 336; Compound Nos. 397 and 401; and
Compound Nos. 409 and 410 are mixtures of diastereomers, and are
also one of the individual diastereomers.
Compound No. 108 is a mixture of four isomers and Compound
No. 433 is a mixture of two isomers.
9 ~i8~04~'
Compound Nos. 483 ~ 501, 504, 505, 510 ~ S 18, 521, and 522
form a part of L-Val-DL-Ala; Compound Nos. 502, 503, 508, 509,
519, and 525 form a part of L-Val-D-Ala; Compound No. 520 forms a
part ol' L-Val-L-Ala; Compound Nos. 506 and 523 form a part of L-
Ile-D-Ala; Compound No. 526 forms a part of L-Val-Gly; and
COml7c)Llild NOS. 507 and 524 form a part of (2S)-butylyl-D-Ala.
In the tables of the present specification, the expressions "C3H7-
i", "C4H9-t", "C4H9-s", and "C4H9-i" are used to indicate an isopropyl
group, a tent-butyl group, a sec-butyl group, and an isobutyl group,
respect i vely.
'~' 2180000
ZZ O
Rl-Zl-C-NH-CH-C-NH-CH-CH2Z3-A
I 1
CH CH3
R9 / \CH3
COm- Melting
No.nd R1 R9 Zl Z2 Z3 A Point
Index ~
D p~ ci~e
1 C4H9-t CH3 O O O ~ / 88-92
Ct
2 C4H9-t CH3 O O O - 98-100
CI
3 C4H9-t CH3 O O O - 1.5051
4 C4H9-t CH3 O O O ~ / CI 97-98
CH3
C4H9-t CH3 O O O '- 77-80
CH3
6 C4H9-t CH3 O O O \ / 1.5051
C4H9-t CH3 O O O ~ / CH3 99-101
OCH3
g C4H9-t CH3 O O O ~ / 86-89
OCH3
g C4H9-t CH3 O O O - 1.4899
IO C4H9-t CH3 O O O ~ / OCH3 86-89
II 2180000
Table 1 (continued)
Melting
COm- Point
pound R1 R9 ZI Z2 Z3 A (°~) or
Reflactive
No.
(nD20)
CN
11 C4H9-t CH3 O O O '.'
\ /
CN
I2 C4H9-t CH3 O O O - 83-87
13 C4H9-t CH3 O O O \ / CN 53-56
N02
I4 C4H9-t CH3 O O O - 1.5081
\ /
N02
15 C4H9-t CH3 O O O - 112-114
\ /
16 C4H9-t CH3 O O O \ / N02 105-I07
F
I7 C4H9-t CH3 O O O -' 95-97
\ /
F
Ig C4H9-t CH3 O O O - 89-92
\ /
19 C4H9-t CH3 O O O \ / F 85-89
C1
20 C4H9-t CH3 O O O \ / 99-100
CI
CI
21 C4H9-t CH3 O O O ~ / CI 102-104
12 2 ~ 800
Table 1 (continued)
Melting
Point
Com-
pound R1 R9 Z1 Z2 Z3 A R~eftactive
Index
(nD20)
OCH3
22 C4H9-t CH3 O O O \ / 87-91
OCH3
OCH3
23 C4H9-t CH3 O O O \ / OCH3 88-90
C1
24 C4H9-t CH3 O O O - Cl 98-103
\ /
C1
25 C4H9-t CH3 O O O \ / C1 120-125
Cl
CH3
26 C4H9-t CH3 O O O '- Cl I08-lI0
\ /
CH3
27 C4H9-t CH3 O O O - Cl 143-146
\ /
2g C4H9-t CH3 O O O \ / CF3 I15-117
29 C4H9-t CH3 O O O \ / OCF3 94-98
30 C3H7-i CH3 O O O \ /
C1
31 C3H7-i CH3 O O O '-
\ /
C1
32 C3H7-i CH3 O O O -
\ /
,~ 2180000
Table 1 (continued)
- Melting
pound R1 R9 Z1 Z2 Z3 Point (°C)
A o
Rctlactivc
No.
Iadcx (np20~
33 C3H~-i CH3 O O O \ / Cl 149-152
CH3
34 C3H~-i CH3 O O O -
\ /
CH3
35 C3H7-i CH3 O O O -
\ /
36 C3H~-i CH3 O O O \ / CH3
OCH3
37 C3H~-i CH3 0 O O --
\ /
OCH3
3g C3H~-i CH3 0 O O -
\ /
39 C3H~-i CH3 O O O \ / OCH3
CN
40 C3H~-i CH3 O O O '-
\ /
CN
41 C3H~-i CH3 O O O
\ /
42 C3H~-i CH3 O O O \ / CN 149-152
N02
43 C3H~-i CH3 O O O
\ /
NOz
q.4 C3H2-i CH3 O O O -
\ /
14 2180000
Table 1 (continued)
Melting
COm- Point (°C)
pound R1 R9 Z1 Z2 Z3 p or
Reflactive
No.
Index (nD20)
45 C3H7-i CH3 O O O \ / N02 not
determined
F
q~ C3H~-i CH3 O O O
\ /
F
4~ C3H~-i CH3 O O O
\ /
48 C3H~-i CH3 O O O \ / F
C1
49 ~HS CH3 O O O
\ /
Cl
50 ~HS CH3 O O O
\ /
51 ~HS CH3 O O O \ / C1
CN
52 ~HS CHg O O O
\ /
CN
53 ~HS CH3 O O O
\ /
54 ~HS CH3 O O O \ / CN 112-115
N02
55 ~HS CH3 O O O
\ /
N02
56 CZHS CH3 O O O -'-
\ /
'S 2180000
Table 1 (continued)
Melting
COm- Point (°C)
p or
pound R1 R9 Z1 Z2 Z3
Reflactive
No.
Index (nD20)
57 C2H5 CH3 O O O ~ / NOZ
Sg C4H9-s CH3 O O O ~ . / Cl
59 C4H9-s CH3 O O O ~ / CH3
60 C4H9-s CH3 O O O ~ / OCH3
61 C4Hg-s CH3 O O O ~ / F
62 C4H9-s CH3 O O O ~ / Br
63 C4H9-s CH3 O O O ~ / CN I40-143
C4H9-s CH3 O O O ~ / N02
65 C4H9-s CH3 O O O ~ / CF3
66 C4H9-s CH3 O O O ~ / OCF3
C1
67 C4H9-s CH3 O O O
C1
68 C4H9-s CH3 O O O
- C=CH2 Cl
69 ~ CH3 O O O
CH3
C1
- C=CH2
70 CH CH3 O O O
3
t6 2180000
Table 1 (continued)
Melting
Com- Point (°C)
pound R1 R9 Z1 Z2 Z3 A or
N o . Reflactive
Index (np20)
- C=CH2
71 CH CH3 O O O ~ / CI
3
N02
- C=CHZ
72 CH CH3 O O O -
3
NOZ
- C=CH2
73 CH CH3 O O O -
3 ~ /
- C=CH2
74 CH CH3 O O O ~ / N02
3
CN
- C=CH2
75 CH CH3 O O O
3 \ /
CN
- C=CH2
76 CH CH3 O O O ~ /
3
- C=CH2
77 CH CH3 O O O ~ / CN 82-86
3
- C=CHZ
78 CH CH3 O O O \ / CF3
3
- C=CH2
79 CH CH3 O O O \ / OCF3
3
Cl
80 ---~ CH3 O O O
\ /
Ct
81 -~ CH3 O O O -
\ /
82 --~ CH3 O O O \ / Ct
I7 2
Table 1 (continued)
Melting
Point
Com-
pound RI R9 ZI Z2 Z3
ReQactive
No.
(ndcx
(n~20)
N02
83 --~ CH3 O O O
\ /
N02
84 --~ CH3 O O O
\ /
85 ~--~ CH3 O O O \ / NO,
CN
86 ~ CH3 O O O
\ /
CN
g7 ~ CH3 O O O
\ /
gg ~ CH3 O O O \ / CN 145-148
CI
89 ~ CH3 O O O
\ /
CI
90 -~ CH3 O O O
\ /
91 --O CH3 O O O \ / CI
N02
92 -O CH3 O O O
\ /
N02
93 --O CH3 O O O
\ /
94 --O CH3 O O O \ / NO2
2180000
18
Table 1 (continued)
Melting
Point
Com- (°c)
pound RI R9 ZI Z2 Z3 A or
Reftactive
No.
Index
(nD20)
CN
95 -O CH3 O O O
\ /
CN
96 -O CH3 O O O
\ /
97 --O CH3 O O O \ / CN I58-162
98 \ / CH3 O O O \ / I23-126
_ CI
99 \ / CH3 O O O
\ /
_ CI
100 \ / CH3 O O O
\ /
101 \ / CH3 O O O \ / CI 165=170
_ N02
102 \ / CH3 O O O
\ /
_ N02
103 \ / CH3 O O O
\ /
104 \ / CH3 O O O \ / N02 166-169
_ CN
105 \ / CH3 O O O
\ /
CN
I06 \ / CH3 O O O
\ /
19 2180000
Table 1 (continued)
Melting
COm- Point (°C)
pound R 1 R9 Zl Z2 Z3 A or
Rellactive
No.
Index (nD~)
107 \ / CH3 O O O \ / CN 142-146
I08 \ / CH3 O O O \ / CN 158-162
109 \ / CH3 O O O \ / , CN 128-133
_ F
I10 \ / CH3 O O O
\ /
_ F
111 \ / CH3 O O O
\ /
112 \ / CH3 O O O \ / F 137-142
113 \ / CH3 O O O ~ / Br
114 \ / Cl-I3 O O O \ / CF3 15I-I55
I15 \ / CH3 O O O \ / OCF3 144-147
II6 \ / CH3 O O O \ / CN 145-147
I I7 \ / CH3 O O O \ / CN 166-170
C1 C1
I18 CH3 O O O
\ / \ /
C1 ~ C1
119 CH3 O O O -
\ / \ /
C1 _
120 CH3 O O O \ / CI
\ /
20
Table I (continued)
Melting
Com- R1 R9 ZI Z2 Z3 A Point
pound (C)
No. or
ReHactive
Index
(nD~)
Cl N02
I21 CH3 O O O
\ / \ /
CI NOZ
122 - CH3 O O O '-
\ / \ /
C1 _
123 CH3 O O O \ / NOz
\ /
CI _
124 CH3 O O O \ / CN 137-142
\ /
C1 _
125 CH3 O O O \ / F
\ /
C1 _
126 CH3 O O O \ / Br
\ /
C1 _
I27 CH3 O O O \ / C1
\
C1 _
128 CH3 O O O \ / N02
\ /
C1 _
129 CH3 O O O \ / CN 114-117
\ /
CI _
I30 CH3 O O O \ /
\ /
C1 _
I31 CH3 O O O \ / Br
\
~18Q~~)~
21
Table 1 (continued)
Melting
pound R1 R9 Zl Z2 Z3 A Qoint
N~ (C)
~ Rctlactivc
Index
(np20
CI
132 CH3 O O O \ / CF3
\ /
133 \ / C1 CH3 O O O \ / C1
I34 \ / CI CH3 O O O \ / N02 133-138
135 \ ~ CI CH3 O O O \ ~ CN I56-160
136 , \ / CI CH3 O O O \ / F
I37 \ / Cl CH3 O O O \ / Br
_ O
I38 \ / CH3 O O O C-OCH
\ / 3
_ O
139 \ / CH3 O O O ~ ~ C-OCZHS
O
140 ~ / CH3 O O O II
\ / ~ -CH3
O
_ O
141 \ / CH3 O O O S-CH
\ / 3
142 ~ / CH3 O O O ~ ~ S-CH3
I43 \.-: / CH3 O O O \ / S-CF3
144 ~ / CH3 O O O \ / N(CH3)z
2~.8~Q~~
22
Table 1 (continued)
Com- Mating
pound R1 R9 Z1 Z2 Z3 A ooint (°C)
N 0 . Rcflacti vc
Index (np24
O
I45 \ / CH3 O O O \ / SI \ /
If
O
_ O
14b \ / CH3 O O O C-CH
\ / 3
_ O
147 \ / CH3 O O O C
\ / \ /
148 \ ~ CH3 O O O ~ / \ /
149 \ / CH3 O O O \ / CZHs
150 \ / CH3 O O O \ / C3H~-i
151 \ / CH3 O O O . \ / OCH3
~3 _
152 CH3 O O O \ / C1
\ /
CH3
153 CH3 O O O \ / NOZ
\ /
CH3 _
14b-150
I54 CH3 O O O \ / CN
\ /
CH3 _
155 CH3 O O O \ / Cl
\ /
CH3 _
156 CH3 O O O \ / N02
\ /
~1800Q~
23
Table 1 (continued)
C0ln- Melting
pound R1 R9 Z1 Z2 Z3 A ooint
(C)
N0. Reflactive
Index
(np20
CH3
157 CH3 O O O \ / CN 97-100
\ /
158 \ / CH3 CH3 O O O \ / C(
159 ~ / CH3 CH3 O O 0 \ / NOZ
160 \ / CH3 CH3 O O O \ ~ CN 152-155
OCH3 _
161 ~ CH3 O O O \ / CI
\ /
OCH3 _
I62 CH3 O O O \ / N02
\ /
OCH3
163 CH3 O O O \ / CN I37-140
\ /
OCH3 _
164 CH3 O O O \ / Cl
\ /
OCH3 _
165 CH3 O O O \ / N02
\ /
OCH3 _
166 CH3 O O O \ / CN 134-137
\ /
167 \ / OCH3 CH3 O O O \ / C1
168 \ ~ OCH3 CH3 O O 0 \ / N02
24
Table 1 (continued)
Melting ,
Point.
ound (°C) or
P R1 R9 ZI Z2 Z3 ~' ttetlactive
No.
(~D20)
169 \ / OCH3 CH3 O O O \ / CN 139-145
C1 _
170 CH3 O O O \ / CI
C1
C1 _
I71 CH3 O O O \ / N02
\ / C1
C1 _
172 CH3 O O O \ / CN
,\ ~ C1
OCH3
173 ~H CH3 O O O \ / CI
3
~H3
174 OCH CH3 O O O \ / N02
\ / 3
OCH3
I75, OCH CH3 O O O \ / CN
3
-N
I76 \ ~ CH3 O O O \ . / CI
-N
177 ~ ~ CH3 O O O \ / NOZ
-N
I78 \ / CH3 O O O I\ / CN
179 --~ ~ CH3 O O O \ / CI
180 -O CH3 O O O \ / NOZ
18I ~ CH3 O O O \ ~ CN
~I80~~~
Table 1 (continued)
Melting
Com- Point
R1 R9 ZI Z2 Z3 A (C) or
pound Reflective
No.
(nD20)
182 C~ CH3 O O O ~ ~ NOz
3
0
183 ~ CH3 O O O ~ ~ Cl
184 CH2CH2C1 CH3 O O O ~ ~ CN 170-i75
I85 CH2C1 CH3 O O O ~ ~ NOZ
I86 CH(CI)CH3 CH3 O O O ~ ~ CN
lg7 CH2CF3 CH3 O O O ~ ~ CN
lgg CH2-C=CH CH3 O O O ~ ~ NOZ
189 CH2CH20CH3 CH3 O O O ~ ~ Cl
I90 CH2CH20CH3 CH3 O O O ~ ~ N02
~
19I CH2CH20CH3 CH3 O O O ~ ~ CN
192 -CHZ ~ ~ CH3 O O O ~ ~ NOZ
193 -CHZ ~ ~ CH3 O O O ~ ~ CN I25-128
194 -CHz ~ / CH3 O O O ~ ~ CI
~3
195 -CHI ~ / CH3 O O O ~ ~ CN 98-101
CH3
I96 -~z ~ / NCz CH3 O O O ~ ~ Cl
~184~Q~
26
Table 1 (continued)
Melting
Com-
RI R9 ZI Z2 Z3 p, Point
pound (C) or
Reflactive
No.
(nD20)
197 C4H9-t CH3 O O O ~ / CH2CI
I98 C4H9-t CH3 O O O ~ / OCHFz
I99 C3H7-i CH3 O O O ~ / CH2CI
200 C3H7-i CH3 O O O ~ / OCHFz
201 ' ~ / CH3 O O O ~ / CH2CI
202 ~ ~ CH3 O O O ~ / OCHF2
203 ~ / CH3 S O O ~ / CI 111-I13
204 ~ / CH3 S O O ~ / NOz 149-I52
205. ~ / CH3 S O O ~ / CN 146-149
206 ~ / CH3 O S O ~ / CI
207 ~ / CH3 O S O ~ / NOz
208 ~ / CH3 O S O ~ / CN
209 ~ / CH3 S S O
210 ~~ / CH3 S S O ~ ~ NOz
211 CH3 not
/ S S O ~ ~ CN deteni~ined
212 ~ ~ CH3 O O S ~ ~ 140-144
~~.80~00
27
Table 1 (continued)
Melting
pound RI R9 ZI Z2 Z3 A Point
(~) or
No. Reflactive
(np20)
213 ~ ~ CH3 O O S ~ / Cl 136-140
214 ~ ~ CH3 O O S ~ ~ NOZ 123-I26
215 ~ ~ CH3 O O S ~ ~ CN I 44-146
216 C4H9-t CH3 O O S ~ ~ 74-78
217 C4H9-t CH3 O O S ~ / N02 I09-1
I2
218 C4H9-~ CH3 0 0 S ~ ~ CN
219 C3H~-i CH3 O O S ~ ~ 122-I26
220 C3H7-i CH3 O O S ~ ~ CN 165-I69
221 C3H7-i CH3 O O NH ~ ~ CI 158-I60
222 C4H9-t CH3 O O NCH3 ~ ~ N02
223 ~ ~ CH3 O O NCOCH3 ~ ~ CN
224 ~ ~ CH3 O O NCO ~ ~ ~ ~ CI
225 , ~ CH3 O O NC02CH3 ~ ~ CN
~
226 C4H9-t C2H5 O O O ~ ~ CI I01-104
227 C4Hg-t C2H5 O O O ~ / N02 128-I30
228 C4H9-t C2H5 O 0 O ~ ~ CN 100-106
218~1~~0
28
Table 1 (continued)
Melting
_ Point (°C)
or
p om R1 R9 Zl Z2 Z3 A
ound Rellactive
No. Index (nD~)
229 C4H9-t ~HS O O O \ / F
230 \ / ~HS O O O \ / C1 149-154
231 \ / ~HS O O O \ / NOz 152-154
232 \ / ~HS O O O \ / CN 108-112
233 C4H9-t H O O O \ / Cl 1.5081
234 C4H9-t H O O O \ / NOz
not
235 C4H9-t H O O O \ / CN
236 \ ~ H O O O \ / C1 125-130
237. \ / H O O O \ / NOz
238 \ / H O O O \ / CN 43-46
239 C4H9-t CH3 O O O -CHz \ /
C1
240 C4H9-t CH3 O O O
-CHz \ /
C1
241 C4H9-t CH3 O O O
-CHz \ /
242 C4H9-t CH3 O O O -CHz \ / CI
243 C4H9-t CH3 O O O -CHz \ / CH3
2180000
29
Table 1 (continued)
Melting
Com- Point (°C)
pound RI R9 Z1 Z2 Z3 p or
Reflactive
No.
Index (nD~)
2~ C4H9-t CH3 O O O -CH2 \ / N02
245 C4H9-t CH3 O O O -CHZ \ / CN
2~ C3H7-i CH3 O O O -CH2 \ / Cl I04-109
247 C3H7-i CH3 O O O -CH2 \ / NOZ
248 C3H7-i CH3 O O O -CH2 \ / CN
249 \ / CH3 O O O -CH2 \ / CI
250 \ / CH3 O O O -CH2 \ / N02
25I \ ~ CH3 O O O -CH2 \ / CN
_ C1
252 \ / CH3 O O O -CH2 C1
253 \ / CI CH3 O O O -CHZ \ / NO,
254 C3H7-i CH3 O .O O -CH \ /
CH3
255 ~ C3H7-i CH3 O O O -CH \ / CI
CH3
256 \ / CH3 O O O -CH \ / Cl
CH
3
CH3
257 C3H7-i CH3 O O O -C \ /
CH3
2180000
Table 1 (continued)
Melting
Com- Point (°C)
pound R1 R9 Z1 Z2 Z3 A or
No . Rellactive
Index (np20)
CH3 _
258 C3H~-i CH3 O O O -C \ / CI
CH3
_ CH3
259 \ / CH3 O O O -C \ /
CH3
260 C4H9-t CH3 O O NH -CH \ /
CH3
CH3
26I C4H9-t CH3 O O NH -C \ /
CH3
262 C3H~-i CH3 O O NH ~H \ /
CH3
CH3
263 C3H~-i CH3 O O NH -C \ /
CH3
264 \ / CH3 O O NH -CH \ /
CH
3
_ CH3 _
265_ \ / CH3 O O NH -C \ /
CH3
N
266 C4H9-t CH3 O O O \ /
CI
267 C4H9-t CH3 O O O -N
\ /
-N
268 C3H7-i CH3 O O O \ /
CI
269 C3H7-i CH3 O O O -'N
\ /
31
Table 1 (continued)
Melting
Com- Point (°C)
pound R1 R9 Z1 Z2 Z3 p or
N o . ReHactive
Index (np~)
-N
270 C3H7-i CH3 O O O \ /
CI
\. /
27I \ / CH3 O O O N
_ CI
272 \ / CH3 O O O -N
\ /
_ -N
273 \ / CH3 O O O \ /
CI
_ N02
274 \ / CH3 O O O -N
\ /
N-
275 \ / CH3 O O O --w ~ 60-65
N
276 C4H9-t CH3 O O O --GO
277 C3H7-i CH3 O O p ~O
D
278~ \ / CH3 O O O
_N
279 C4H9-t CH3 O O O -CHZ \ /
280 C4H9-t CH3 O O O -CHz \ ~N
N
281 C3H7-i CH3 O O O -CH2 \
282 C3H7-i CH3 O O O -CH2 \ ~N
N
283 \ / CH3 O O O -CHZ \ /
32 21 X0000
Table 1 (continued)
. Melting
COtn- R1 R9 Z1 Z2 Z3 Point
pound p (C)
or
N0. Reflactive
Index
(np20)
284 ~ ~ CH3 O O O -CH2 ~ N
285 C3H7-i CH3 O O O -CHZ- I I
O
286 C3H7-i CH3 O O S -CH2- I I
O
287 ~ / CH3 O O O -CH2- I I
O
288 ~ / CH3 O O S -CH2- I I
S
289 ~ / CH3 O O NH -CH2- I I
O
I I
290 C3H7-i CH3 O O NH -CH
O
CN
( I
29I C3H7-i CH3 O O NH -CH
CN
292 ~ / CH3 O O NH -CH I O I
CN
293 ~ / CH3 O O NH -CH ~ S (
CN
C1
294 C3H~-i CH3 O O O -CH
I I i
Z
O
CI
295 C3H2-i CH3 O O O -CH
CH3
296 C3H~-i CH3 O O O -CH
O
CN
33 2 ~ 8000
Table 1 (continued)
Melting
COm- Point (°C)
pound R1 R9 Zl Z2 Z3 p or
N o . Reflactive
Index (nD20) -
297 C3H7-i CH3 O O NH -CH I S (
CN
\ C1
298 ~ ~ CH3 O O O -CHZ ( I
O
\ CI
299 ~ ~ CH3 O O O -CH 101 i
CH3
300 ~ ~ ~ CH3 O O O -CH 101 i
CN
301 ~ ~ CH3 O O NH -CH I S I i
CN
\ C(
302 ~ ~ CH3 O O NH -CH ( O I i
CH3
_ \ NOz
303 ~ ~ CH3 O O NH -CH ~ O I i
CH3
w
304 C3H7-i CH3 O O NH -CH
CH3
305 C3H7-i CH3 O O NH -CH
CH3 S
~ F
3~ C3H7-i CH3 O O NH -CH
CH3
Cl
307 C3H7-i CH3 O O NH -CH ~ S
CH3
34 2180000
Table 1 (continued)
Melting
Com- point (~C)
pound R1 R9 Z1 Z2 Z3 A or
N o . Reflactive
Index (np20~
CH w
308 C3H~-i CH3 O O NH -C 3 I S I
CH3
309 C3H~-i CH3 O O O \ /
\ N
310 C3H~-i CH3 O O O \ /
N' /
311 \ / CH3 O O NCH20CH3 \ / CN
312 \ / CH3 O O SO \ / CN
3I3 \ / CH3 O O S02 \ ~ CN
-CH~
314 \ / CH3 O O N H ~ \ //
COOCH3
\ /
315 C3H~-i CH3 O O NH -CH
\ /
-CH
316 C3H~-i CH3 O O O
CH2 \ /
35 2180000
Table 1 (continued)
Melting
Com- R1 R9 Zl Z2 Z3 p Point
pound (C)
N o or
. Reflactive
Index
(nD20)
3I7 -CHZ ~ / CH3 O O O ~ ~ Cl
CN
318 -CHz ~ / CH3 O O O ~ ~ CN
CN
319 ~ ~ CN CH3 O O O ~ ~ Ci
320 ~ ~ CN CH3 O O O ~ ~ NOZ
321 ~ ~ CN CH3 O O O ~ ~ CN
322 ~ ~ CF3 CH3 O O O ~ ~ N02
323 ~ ~ CF3 CH3 O O O ~ ~ CN IIS-117
324 ~ ~ OCF3 CH3 O O O ~ ~ CI
325 ~ ~ OCF3 CH3 O O O ~ ~ N02
326 ~ ~ OCF3 CH3 O O O ~ ~ CN 127-129
327 C4H9-t CH3 O O O ~ ~ S-CH3 93-96
O
328 C4H9-t CH3 O O O ~ / S_CH 48-51
3
O
329 C H -t CH
4 9 3 O O O ~ / i-CH3 122-125
O
36 2 ~ ~~~00
Table 1 (continued)
Melting
Com- R1 R9 Zl Z2 Z3 ,4 Poinc
pound (C)
N o
. ReHactive
Indeic
(nD~)
F
330 C4Hg-t CH3 O O S
\ / 74-77
F
331 C4Hg-t CH3 O O S 1.5164
\ /
OCH3
332 C4Hg-t CH3 O O S - 1.5319
\ /
333 C4Hg-t CH3 O O S \ / OCH3 1.5361
334 C4Hg-t CH3 O O NH \ / I02-I04
335 C4Hg-t CH3 O O S \ / CI 80-84
336 C4Hg-t CH3 0 O S \ / CI I33-137
CI
337 C4Hg-t CH3 0 O S 1.5360
\ /
CI
338 C4Hg-t CH3 O O S 1.5361
\ /
CH3
339 C4Hg-t CH3 O 0 S - 1.5274
\ /
CH3
3~ C4Hg-t CH3 O O S - 1.S24S
\ /
34I C4Hg-t CH3 O O S \ / CH3 1.5269
37 2180000
Table 1 (continued)
Melting
d RI 9 Z 2 3 A Peoint
N o (C)
. Rellactive
Index
(nD20)
342 C4H9-t CH3 O O S \ / F
66-69
N02
343 C4H9-t CH3 O O O \ / 71-74
OCH3
OCH3
3q.4 C4H9-t CH3 O O S 1.5312
\ /
345 C3H7-i CH3 O O O \ / C1 I61-163
3~ C3H7-i CH3 O O O \ / CI I67-171
C1
347 C3H7-i CH3 O O O \ / CI I66-172
CI
F
348 C3H7-i CH3 O O S '- 121-123
F
349 C3H7-i CH3 O O S 125-I29
\ /
OCH3
350 C3H7-i CH3 O O S 103-106
\ /
35i C3H7-i CH3 O O S \ / OCH3 122-I25
352 C3H7-i CH3 O O S \ / NOZ I55-I58
2180000
38
Table 1 (continued)
Melting
Vim- R1 R9 Zl Z2 Z3 A Point
pound (C)
No. or
Reflactive
Index
(nD20)
353 C3H7-i CH3 O O NH \ / 130-134
354 C3H7-i CH3 O 0 SO ~ / F lI9-123
355 C3H7-i CH3 O 0 S02 \ / F IS 1-153
356 C3H7-i CH3 0 O O ~ / NOZ i77-180
CN
357 C3H7-i CH3 O O S 137-I40
\ /
358 C3H7-i CH3 O O NCH3 \ / 145-148
359 C3H7-i CH3 O O NH \ / F 155-I56
360 ~H7-i CH3 O O NCH3 \ / F I41-143
C1
361 C3H7-i CH3 O O NH - 85-90
\ /
C1
362 C3H7-i CH3 O O NH 143-145
\ /
363 C3H7-i CH3 O O NCH \ / CI 65-67
3
3~ C3H7-i CH3 O O NH \ / Br 146-149
365 C3H7-i CH3 O O S \ / CI 115-118
CI
366 C3H7-i CH3 O O S 124-I27
\ /
2180000
39
Table 1 (continued)
Melting
Cotn- R1 R9 Zl Z2 Z3 A Point
pound (C)
Na. or
RefIactive
Index
(np20)
CH3
367 C3H7-i CH3 O O S II9-121
\ /
368 C3H7-i CH3 O O S \ / CH3 I07-110
369 C3H7-i CH3 O O S \ / F 111-115
OCH3
370 C3H7-i CH3 O O S - I09-1I2
\ /
371 C4H9-i CH3 O O O \ / CN 125-I30
372 C5H11 CH3 O O O \ / CN 109-III
373 C6H I3 CH3 O O O \ ~ CN I07-1
IO
-CH-C3H~
C
374 CH H3 O O O \ / CN 122-125
3
375 C3H7-i CH3 O O NCOCH3 \ / F 56-60
~O
376 -~~' C H3 O O O \ / CN 181-184
377 --CO CH3 O O O \ / CN 201-204
37g ~CH3 CH3 O O O \ / CN 111-lI6
~
J
. _
379 CH3 CH3 O O O CN 14I-I42
\ /
40 2180000
Table 1 (continued)
Melting
Com- R1 R9 Z1 Z2 Z3 A Point
pound (C)
No. RefIactive
Index
(np20)
~3
380 CH3 O O O ~ ~ CN 133-136
381 CHZ-C-CH CH3 O O O ~ ~ CN 148-151
CH3 _
382 CH O O O CN 16I-164
3 \ /
-CH-CHZOCH3
CH CN
383 C 3 O O O ~ ~ I02-I07
H
3
CI
384 ~ ~ CH3 O O O \ / C1 I59-162
CI
385 ~ ~ CH3 O O NH ~ ~ I30-134
386 ~ ~ CH3 O O S \ ~ F 127-130
CN
387 \ / CH3 O O S - 108-110
\ /
388 ~ ~ CH3 O O NH \ / C~ I54-156
389 . ~ ~ CH3 O O NCH3 \ / 125-130
41 2180000
Table 1 (continued)
Melting
Com- A Point
R1 R9 Zl Z2 Z3 (C) or
pound Reflactive
No.
(nD20)
390 \ / CH3 O O NH \ / F 147-149
391 ~ / CH3 O O NCH3 \ / F 64-70
_ CI
392 \ ~ CH3 O O NH 117-119
\ /
393 ~ ~ CH3 O O NH \ / Br I56-160
394 \ / Br CH3 O O O \ / CN I56-162
395 \ / Cl CH3 O O O \ / CN 137-140
396 \ ~ Cl CH3 O O O \ ~ CN 174-179
397 \ ~ F CH3 O O O \ ~ CN I53-156
398 \ ~ N02 CH3 O O O \ / CN 130-134
399 \ / F CH3 O O O \ ~ NOz IS6-161
NO2 _
400 CH3 O O O \ ~ CN I25-129
401 \ ~ F CH3 O O O ~ / CN ISS-IS8
CH3 _
402 CH CH3 O O O \ ~ CN 141-144
3
X180000
42
Table 1 (continued)
Melting
_ Point
R1 R9 Zl Z2 Z3 A (C) or
pound Reflactive
No . Index
(np20)
CH3
403 CH CH3 O O O CN 1S3-1S4
3 \ ~
F _
404 CH3 O O O \ ~ CN 144-148
F
F _
40S CH3 O O O CN 129-I33
' / F \ ~
Cl
406 _ CH3 O O NH 60-62
\ ~
N-
407 C4H9-t CH3 O O O \ ~ C1 90-93
CH3 _
408 CH3 O O O CN 129-130
\ ~ Cl \ ~
N
409 C4H9-t CH3 O O O \ ~ 111-112
N
4I0 C4H9-t CH3 O O O \ ~ I29-131
CH3
411 \ ~ CH3 CH3 O O O \ ~ CN 163-I64
CH3
N
412 C3H7-i CH3 O O O \ ~ Cl 118-I20
N
413 \ ~ CH3 O O O \ ~ Cl 123-124
414 C4H9-t C2HS O O O \ ~ CN 122-12S
41S C4H9-t C2H5 O O O \ / CN 13S-137
43
Table 1 (continued)
Melting
Com- RI R9 Zl Z2 Z3 A Point
pound (~) or
N o Reflactive
. Index
(np20)
416 C3H7-i C2H5 O O S ~ ~ F 8S-86
417 C3H7-i CZHS O O O ~ ~ CN 14S-148
4I8 -CH2 ~ ~ ~HS O O O ~ ~ CN 139-141
419 ~ ~ ~HS O O S ~ ~ CN lOS-107
420 ~ ~ ~HS O O S ~ ~ F 130-133
421 ~ ~ ~HS O O NH ~ ~ F 137-139
422 ~ ~ ~HS O O NCH3 ~ ~ F S3-S6
423 ~ ~ CI ~HS O O O ~ ~ CN 1S9-163
424 ~ ~ F C2HS O O O ~ ~ CN 1S0-1S3
42S ~H7-i H O O O ~ ~ CN 118-121
426 -CH2 ~ ~ H O O O ~ / CN 127-132
427 ~ ~ CI H O O O ~ ~ CN 141-14S
428 C3H7-i CH3 O O O ~ N 217-220
429 ~ ~ CH3 O O O ~ ~N 65-68
44 2180000
Table 1 (continued)
Melting
Com-
R1 R9 Zl Z2 Z3 p' Point
No nd (C) or
Rellactive
Index
(n~20)
430 ~H7-i CH3 S O O ~ / CN 161-163
431 C2H5 CH3 S O O ~ / CN I52-154
432 ~H5 CH3 S O O ~ / N02 164-166
433 ~ ~ CH3 O O O ~ / CN 118-120
434 ~ / CH3 O O NCOCH3 ~ / F
435 C3H7-i CH3 O O NC02CH3 ~ / Cl
436 C3H7-i CH3 O O NCO ~ ~ ~ / Cl 71-73
437 C3H7-i CH3 O O NCH20CH3 ~ / Cl
C1
438 ~ ~ C1 CH3 O O O ~ ~ CN
C1
CH3 _
439 Cl CH3 O O O ~ / CN 135-138
440 -CHZCH2 ~, CH3 O O O ~ / CN I I 2-
/ I 14
~1 C3H7-i CH3 O O NH ~ ~ CN
45 2180000
Table 2
ZZ O
Rt-ZI-C-NH-CH-C-NH-CH-CH2-CH2-Z3-A
I
CH CH3
R9 / ~CH3
Melting
COm- Point
Rl R9 Zl Z2 Z3 A (C)
No nd or
Reflactive
Index
(nD20)
442 ~ / CH3 O O O ~ / Cl
~3 C4H9-t CH3 O O 0 ~ / CI
4~ C3H~-i CH3 O O O ~ / Cl
_ OCH3
445 -CHZ ~ / CI-~3CH3 O O O ~ / OCH3
_ OCH3
-CH2 ~ / CH3 O O O ~ / OCH3
OCH3
C3H~-i CH3 O O O ~ / OCH3
q.4g, ~ / CH3 O O O ~ / CN
C4H9-t CH3 O O O ~ / CN
450 C3H~-i CH3 O O O ~ / CN
46 2180000
Table 3
O O
R1-O-C-NH-CH-C-NH-CH-CH2-O-Q
R2 CH3
Melting
Com- Point
(C) or
N R1 R2 ~
nd
o Index (np20)
4SI \ / OCHF2 C3H7 \ / CN 117-119
4S2 C4Hg-t C3H7 \ / CN 78-80
4S3 , C4H9-t C3H7 \ / CN lOS-I07
4S4 C4H9-t C3H7 \ / CN 93-95
4SS C4H9-t C4H9-1 \ / CN not determined
4S6 C4H9-t ~ \ / CN 140-142
4S7 C4H9-t C4H9-t \ / CN 68-71
4S8 C4H9-t \ / \ / CN 61-64
4S9 C4H9-t \ / CI \ / CN 124-126
- C=CH2
C4H9 t CH \ / CN 1.5132
3
- C=CHz
461 C4H9-t CH \ / CN 107-109
3
462 C3H7-i -~ \ / CN 155-158
463 C3H7-i \ / \ / CN 149-151
47 2180000
Table 3 (continued)
Melting Point
Com- RI R2 Q (C) or
pound Reflactive
No. Index-(nD2o)
4(~ C3H7-i \ / CI \ / CN 158-161
465 \ / C3H7 \ / CN 88-9I
\ / C4H9-i \ / CN 43-47
467 CN 153-156
\ / \ /
468 \ / C4H9 t \ / CN 75-78
469 \ / \ / \ / CN 68-71
470 \ / \ / CI \ / CN I52-I55
471 \ / C1 ~ \ / CN 141-145
472 -CHZ \ / \ / CN 170-174
473 -CH2 \ / C4H9-t \ / CN 46-49
474 -CH2 \ / \ / \ / CN 155-157
475 -CH2 \ / \ / Cl \ / CN 128-129
CH3
476 -C-CN C3H7-i ~ / CN 127-129
CH3
~~ - 2 j $oooo
Table 3 (continued)
Com-
Melting
pound R1 R2 ~ Point
(C) or
No. Rdex(np2o)
C1 _
477 ~H7-i ~ / CN 152-154
N-
478 C4H9-t C3H7-i ~ / CF3 100-103
N-
479 C4H9-t C3H7-i
105-I06
Cl
N =~
' N
480 C4H9-t C3H7-i ~ 109-112
CI CzHs
N =~
N
481 C3H7-i C3H7-i ~ 173-175
CI C2H5
482 -CH2--( ) C3H7-i ~ / CN 128-129
49 2 ~ 8U000
Table 4
O O
R1-O-C-NH-CH-C-NH-CH-Z3-A
R2 Ra
Com-
R1 R2 R4 Z3 A Melting
pound Point
NO. Re(1)active
Index (np20~
483 C4H9-t C-3H7-i CH3 'OC' \ / C( 82-87
_N
484 C4H9-t C-3H7-i CH3 C-N \ / OCH3 156-159
485 C4H9-t C3H7-i CH3 ~ N \ / CH3 145-149
486 C4H9-t C3H7-i CH3 ~C. \ / CN 96-100
_N
487 C4H9-t C3H7-i CH3 ~ \ / 157-158
-N
Cl
488 C4H9-t C3H7-i CH3 ~-N 83-86
\ /
O
489 C4H9-t C3H7-i CH3 -CH2 \ / C1 144-146
C _N
490 C4H9-t C3H7-i CH3 O C \ / CI 7 0-73
H3
1
C1
491 C4Hg-t C3H7-i CH3 ~ - 140-143
N
_ \ /
492 C3H7-i C3H7-i CH3 ~-N \ / Cl 179-182
493 C3H7-i C3H7-i CH3 ~ \ / OCH3 25I-255
N
-
494 C3H7-i C3H7-i CH3 ~_N \ / CH3 219-222
2180000-
Table 4 (continued)
CoIIl- Melting
RI R2 R4 Z3 A Point
pound (C) or
No. Ron~ti~~
Index
(np~)
495 C3H~-i C3H7-i CH3 ~ N ~ / CN 88-92
496 ~H7-i C3H7-i CH3 O H
N \ / 211-212
C-
Cl
497 ~H7-i C3H7-i CH3 OC. - 2I0-213
-N \ /
498 C3H7-i C3H7-i CH3 ~-N -CHZ \ / CI 200-203
O C
3
499 C3H7 C3H7-i CH3 N ' / CI 68-72
i =
Cl
Sp0 C3H7-i C3H7-i CH3 ~ N - 205-210
\ /
CN
SOI C3H7-i C3H7-i CH3 ~ 113-lI5
N
- \ /
502 C3H7-i C3H7-i CH3 ~ N \ / CN I84-186
O
503 C3H7-i C3H7-i CH3 ' \ / CN 73-75
C' _N
504- C3H7-i C3H7-i CH3 COO \ / CI 184-185
505 C3H7-i C3H7-i CH3 Cpp \ / 151-153
506 C3H7-i C4H9-s CH3 O-N \ / CN 197-198
O
507 C3H7-i ClHS CH3 ' \ / CN 84-87
C' -N
508 C4H9-s C3H7-i CH3 ~_N \ / CN 165-167
2180000
51
Table 4 (continued)
COIn- Melting
R1 R2 R4 Z3 A Point
pound (C) or
R
fl
ti
ve
NO. e
ec
tndex
(np~)
O H -' CN I97-199
S09 --~ C3H7-i CH3 C_,N \ /
S 10 \ / C3H7-i CH3 ~-N \ / CI 20I-204
S 11 \ / C3H~-i CH3 ~-N \ / OCH3 2I9-221
S 12 \ / C3H7-i CH3 OC \ / CH3 24S-2S0
N
S13 \ / C3H7-i CH3 ~-N \ / CN 22S-230
S 14 \ / C3H7-i CH3 'OC' \ / I99-202
N
CI
SIS ~ / C3H7-i CH3 O H 194-197
C-N \ /
S16 \ / C3H7-i CH3 ~-N -CH2 \ / C1 173-17S
517 \ / i CH3 O C \ / CI 6 9-71
C3H7 - H3
1
CN
SI8 \ / C3H7-i CH3 ~ N 149-iS3
\ /
S19 \ / C3H7-i CH3 ~ N \ / CN 1S8-161
S20 \ / C3H7-i CH3 ~ \ / CN 202-203
N
-
S21 \ / C3H7-i CH3 Cpp \ / CI 168-i70
S22 \ / C3H7-i CH3 Cpp \ / 17S-I78
2180000
52
Table 4 (continued)
CO Melting
In- RI R2 R4 Z3 A Poin(
(C7 or
pound Rettacci~e
No.
Index
(nD20~
523 ~ / C4H9-S CH3 O N ~ / CN I57-I59
524 ~ / C2H5 CH3 'OC' ~ / CN 156-158
N
Cl C3H7-i ~CH3 ~ N ~ / CN 182-184
526 C-3H7-i C3H7-i H O H CN 181-185
C-N
53 2180000
Table 5
Z2 O
Rl-ZI-C-NH-CH-C-NH-CHZ-CH2-Z3-A
I
CH
CH~ 'CH3
Melting
Point
(°C) or
pound R1 Zl Z2 Z3 A Refractive
No.
Index
(nD20)
527 C4Hg-t O O O \ / 158-160
528 C4Hg-t O O O ~ / Cl
529 C4Hg-t O O O ~ / N02
530 C4Hg-t O O O \ / CN
531 C4Hg-t O O O ~ / F
532 C3H7-i O O O ~ / NOz
533 C3H7-i O O O \ / CN
534 C3H7-1 O O O \ / CF3
_ C1
535 \ / O O O
\ /
_ C1
536 \ / O O O
\ /
537 \ / O O O \ / CI
_ NO2
538 \ / O O O
\ /
54 2180000
Table 5 (continued)
Meltiag
Com- Point
pound R1 Zl Z2 Z3 A (°C) or
No. Reflactive
Index
(nD20)
N02
539 \ / O O O
\ /
540 \ / O O O \ / N02
_ CN
54I \ / O O O
\ /
_ CN
542 \ / O O O
\ /
543 \ / . O O O \ / CN
544 \ / S O O \ / CN
545 \ / O S O \ / CN
54b \ / S S O \ / CN
547 \ / O O S \ /
548 \ / O O S \ / CI
549 \ / O O S \ / N02
550 ~ / O O S ~ ~ CN
551 C4H9-t O O S \ / 75-77
218000
Table 5 (continued)
Melting
Com- RI Zl Z2 Z3 A Point
pound (C) or
No. Reflective
Index (np~)
552 C4H9-t O O S \ / N02
553 C4H9-t O O S \ / CN
Cl _
554 O O O \ / C1
\ /
C1 _
555 O O O ~ / N02
C1 _
556 O O O \ / CN
\ /
CI _
557 O O O \ / CI
\ /
C1 _
558 O O O \ / N02
\ /
CI _
559 O O O \ / CN
\ /
560 \ / CI O O O \ / CI
561 \ / CI O O O ~ / NOz
562 \ / Cl O O O \ / CN
563 \ / ~H3 O O O \ / CI
56 2 ~ 8000
Table 5 (continued)
Melting Point
Com- (°C) or
pound R1 Zl Z2 Z3 A Reflactive
N0. Index (np~)
564 -CH2 \ / O O O \ / CN
565 -CH2 \ / CH3 O O O \ / CN
_ OCH3
566 -CH2 \ / CH3 O O O \ / OCH3
567 \ / N02 O O O \ / CN
C1
568 ~H7-I O O O \ / C1
Cl
CH3
569 C3H7-i
O O O \ / CH3
CH3
Cl
5'70 \ / O O O \ / CI
Cl
CH3
571 \ / O O O \ / CHI
CH3
572 C3H7-i O O NH \ /
C1
573 C3H7-' O O NH
\ /
57 2180000
Table 5 (continued)
Melting
Com- R1 Z1 Z2 Z3 A Point
pound (C) or
NO. Rellactive
Index (np~)
CI
574 ~H7-i O O NH '-
\ /
57S C3H7-i O O NH \ / CI
S76 C3H7-i O O NCH3 \ / C(
S77 C3H7-t O p NCH3 \ / N02
S78 C3H7-i O O NCH3 \ / CN
S79 \ / O O NH \ ~ CI
S80 \ / O O NH \ / CN
S81 \ / O O NCH3 \ / N02
S82 \ / O O NCH3 \ / CN
S83 C3H7-' O O S \ /
S84 C3H7-t O O S \ / Cl
S8S C3H7-t O O S \ / NOZ
S86 C3H7-i O O S \ / CN
S87 C3H7-t O O O -CH \ / Cl
CH3
5g 2180000
Table 5 (continued)
Melting Point
po nd R1 Zl Z2 Z3 A Refl~active
No. ~X. ~nD20~
588 ~ / O O O -CH ~ ~/ Cl
CH
3
Cl
589 C3H~-i O O O -N
-N
590 C3H~-i O O O
CI
_ -N
591 ~ / O O O
Cl
592 C3H7-i O O O -CH2- ~
O
-CH ~
593 C3H~-i O O O O
CN
594 C3H~-I O O O -CH ~ S
CN
595 ~ / O O O -CH2- ~
O
596 ~ / O O O -CH ~
CN
N
597 C3H7-t O O O -CH2 ~ /
598 C3H7-~ O O O -CH2 ~ rI
599 ~ / O O O -CH2 ~ N
59
Table 5 (continued)
Melting
Point
COm- (C) or
pound R1 Zl Z2 Z3 A Reflactive
N0. Index
(np20)
CI
600 C3H7-i O O O I
-CH
2
O
60I C3H7-1 O O O -CH2 I S
60 2180000
Table 6
Z2 O
Rt-Zt-C-NH-CH-C-NH-CH-CH-Z3-A
[ [ I
CH CH3 CH3
CH~ \CH3
Melting Point
pound R1 Zl Z2 Z3 A (°C) or Rellactive
Index (np20)
No.
602 C4Hg-t O O O \ / not determined
C1
603 C4H9-t O O O -
\ /
C1
604 C4Hg-t O O O '-
\ /
605 C4H9-t O O O ~ / C1 1.4784
606 C4Hg-t O O O \ / N02 1.5109
607 C4Hg-t O O O \ / CN not determined
608 C3H7-i O O O \ / Cl
609 C3H7-i O O O \ / NOZ
610 C3H7-i O O O \ / CN
611 \ ~ O O O \ /
612 \ / O O O \ / C1
613 \ ~ O O O \ ~ NOZ
614 \ / O O O \ / CN
6I 2180000
Table 6 (continued)
COm- Melting Point
pound R1 Zl Z2 Z3 A (°C) or Reflactive
No. Index (np~)
6I5 ~ ~ S O O \ / ~Cl
6I6 ~ / S O O \ / CN
6I7 ~ / O S O \ / CI
618 ~ / O S O \ / CN
619 ~ ~ S S O ~ ~ C(
620 ~ ~ ~ S S O ~ ~ CN
621 C3H7-i O O S \ ~ CI
622 C3H7-i O O S \ / CN
623 ~ / O O S \ / CI
624 ~ / O O S \ ./ N02
625 \ / O O S \ / CN
CI _
626 O O O \ / NOZ
\ /
CI _
627 O O O \ / CN
\ /
CI
628 - O O O \ / N02
\ /
62 2180000
Table 6 (continued)
Com- Melting Point
pound Rl Zl Z2 Z3 A (°C) or Re oactive
Index (nD )
No.
Cl _
629 O O O ~ / CN
\ /
630 \ / Cl O O O \ / N02
631 \ / Cl O O O \ / CN
632 -CH2 \ / O O O \ / CN
_ OCH3
633 -CH2 \ / CH3 O O O 4CH3
\ /
634 C H -i O O O - ~H \ / CI
3 7
CH3
635 O O O ~H \ / CI
\ / CH
3
-N
636 C3H7-i O O O \ /
CI
_ -N
637 \ / O O O \ /
CI
N
638 C3H7-i O O O -CH2 \ /
639 C3H7-i O O O -CH2 \ iN
63 2180000
Table 7
O O
Rl-O-C-NH-CH-C-NH-CH-CHZ-Z3-A
I I
CH CN
CH~ \CH3
C0111- Melting Point
pound R1 Z3 A (°C) or Reflacti~e
NO. Index (nD20)
C4H9 t O \ /
641 C4H9't O \ / CI
642 C4H9-t O \ / CN
643 C3H~-i O \ / Cl 153-155
644 C3H~ 1 O \ / NO2
645 C3H~'I O \ / CN
_ CI
64b \ / O
\ /
_ C1
647 \ / O
\ /
648 ~ / O ~ / CI 157-160
649 ~ / O \ / N02
650 \ / O \ / CN
CI _
651 O \ / CI
\ /
64 ~ ~ 8000
Table 7 (continued)
COm- Melting Point
pound RI Z3 A Inde ~~ D ~~ctive
No.
C1 _
652 O \ / CN
\ /
CI _
653 O \ / NOZ
\ /
CI _
654 O \ ~ CN
\ /
655 \ / CI O \ ~ NOZ
656 \ / CI O \ / CN
657 -CH2 \ ~ O \ / CI
658 -CH2 ~ / O \ / CN
659 -CH2 ~ / CH3 O ~ / N02
660 -CH2 \ / CH3 O \ / CN
661 \ / S \ /
662 \ / S \ / CI
663 \ / S \ / CN
_ -N
664 \ / O \ /
CI
665 \ / O -CHZ \ rI
65 2180000
Table 8
O O CH3
R1-O-C-NH-CH-C-NH-C-CH2-Z3-A
i I
CH CH3
CH~ ~CH3
C0I11- Melting Point
pound R1 Z3 A (°C) or Reflacci~e
N0. Index (np20)
666 C4H9-t O \ /
CI
667 C4H9-t O --
\ /
CI
668 C4H9-t O -
\ /
669 C4H9-t O \ / CI
670 C3H7-' O \ / CI
67I C3H7-1 O \ / N02
672 C3H7-i O \ / CN 1.5111
_ C1
673 \ / O
\ /
_ Cl
674 \ / O
\ /
675 \ / O \ / Cl
676 \ / O \ / NOZ
677 \ / O \ / CN
66 2 ~ g~~~0
Table 8 (continued)
C0m- Melting Point
R1 Z3 A (C) or Reflaccive
No Index (np20~
nd
67g \ / CI O \ / C1
679 \ / C1 O \ / NOZ
680 \ ~ Cl O \ / CN
681 \ / CH3 O \ / Cl
682 \ ~ CH3 O \ ~ NO2
683 \ / CH3 O \ / CN
684 \ / OCH3 O \ / CI
685 \ / OCH3 O \ / F
686 \ / OCH3 O \ / NOZ
687 \ / OCH3 O \ / CN
688 -CH2 \ / O \ / NOZ
689 -CHZ \ / O \ / CN
690 -CH2 \ / N02 O \ / Cl
691 -CH2 \ / N02 O \ ~ CN
6~ 2180000
Table 8 (continued)
COm- Melting Point
R1 Z3 (C) or Reflective
d
No Index (nD20)
n
692 \ / - S \ / CI
693 \ / S \ / N02
694 \ . / S \ / CN
695 C3H7-1 O -CH2 \ /
696 C3H~-i O -CH2 \ ~ Cl
697 \ / O CH2 \ /
698 \ / ~ -CH2 \ / CI
68 2180000
Table 9
O O
II II
R1-O-C-NH- i H-C-NH- j H-CH2-Z3-A
CH C2H5
CH~ \CH3
C0I11- Melting Point
poucld R1 Z3 A (°C) o~ Reflacti~e
NO. Index (np20)
699 C4H9-t O \ /
C1
700 C4H9-t O -
\ /
C1
701 C4H9-t O -
\ /
702 C4H9-t O \ / C1
703 C3H7-1 O \ / Cl
704 C3H7-I O \ / NOz
705 C3H7-i O \ / CN
706 \ / O \ / C1
707 \ / O \ / NOz
7pg ~ / O \ / CN 128-130
709 ~ / Cl O ~ / Cl
710 \ / Cl O \ / NOz
711 ~ / Cl O \ / CN
69 2180000
Table 9 (continued)
Melting Point
Com- 1 3 A (°C) or Reflactive
pound R Z Index (nD20)
No.
7I2 C'-3H7-t O -CH2 \ /
713 C3H7-1 O -CH2 \ / Cl
714 C3H7-i O CH \ /
CH3
715 \ / O -CH2 \ / CI
O - iH \ / CI
716 \ /
CH3
-N
717 C3H7-t O \ /
CI
718 C3H7-i O -CH2 ~ N
_ -N
719 \ / O
C1
720 \ / O -CH2 \ N
721 C3H7-t S \ / CI
722 C31i7-' S \ / NO2
723 C3H7-1 S \ / CN
724 \ / S \ / Cl
725 \ / S \ / N02
726 \ / S \ / CN
70 2180000
Table 10
O O
R1-O-C-NH-CH-C-NH-CH-CH2-Z3-A
I I
CH C3H~
CH~ \CH3
COITl- Melting Point
pound R1 Z3 A (C) or Reflactive
NO. Index (np20)
727 C4H9-t O \ / Cl
728 C4H9-t O \ / N02
729 C4H9-~ O \ / CN
730 C3H7-i O \ / Cl
731 C3H7-1 O \ / N02
732 C3H7-i O \ / CN
733 \ / O \ / CI
734 \ / O \ / N02
735 \ / O \ / CN
736 C3H7-i S \ / Cl
737 C3H7-1 S \ / CN
738 \ / S \ / CN
2180000
Table 11
O O
II I(
RI-O-C-NH- i H-C-NH-CH2-CH2-CHZ-Z3-A
CH
CH~ \CH3
COm- Melting Point
pound R1 Z3 A (°C) or Reflactive
Index (np20~
No.
OCH3
739 -CH2 \ / CH3 O \ / OCH3
740 C3H7-' O \ / NO2
741 C3H7-i O \ / CN 1 SO-151
742 \ / O \ / C1
743 \ / O \ / NOZ
744 \ / O \ / CN
745 C3H7-1 S \ / CN
74b \ / S \ / CN
747 C3H7-t O -CH2 \ / Cl
-N
748 C3H7-~ O \ /
C1
749 C3H7-i O -CH2 \ N
2180000
72
Table 12
O O RS
R1-O-C-NH-CH-C-NH-CH-C-O-A
CH R4 R6
CH~ 'CH3
Melting
Com- Point
R1 R4 R5 R6 A (C) or
pound Reflactive
No.
(np20)
not
750 \ / H H CH3 \ / CN determined
75i C4H9-t H H CH3 \ / CN 46-50
752 C3H7-t H H CH3 \ / CN
753 \ / H H CH3 \ / N02
754 C4H9-t H H CH3 \ / N02
755 C3H7-' H H CH3 \ / N02
756 \ / H H CH3 \ / CI
757 C4H9-t H H CH3 \ / Ct
758 C3H7-t H H CH3 \ / Cl
759 \ / H CH3 CH3 \ / CN
760 C4H9-t H CH3 CH3 \ / CN
761 C3H7-t H CH3 CH3 \ / CN
2180000
73
Table 12 (continued)
Melting
Com- Point
R 1 R4 RS R6 A (C) or
pound Reflactive
r10. Index
(nD20)
762 \ ~ H CH3 CH3 \ / NOz
763 C4H9-t H CH3 CH3 \ / N02
764 C3H7-i H CH3 CH3 \ / NOz
76S \ / H CH3 CH3 ~ / CI
766 C4H9-t H CH3 CH3 \ / CI
767 C3H7-i H CH3 CH3 \ / Cl
768 \ / C3H7-i H H \ / CN 1S0-1S2
769 C4H9-t C3H7-i H H \ / CN
770 C3H7-i C3H7-i H H \ / CN 1S4-1S7
77I \ / C3H7-1 H H \ / NOz
772 C4H9-t C3H7-i H H \ / NO,
773 C3H7-i C3H7-i H H \ / NOZ
774 \ / C3H7-I H H \ / Cl
77S C4H9-t C3H7-i H H \ / Cl
776 C3H7-i C3H7-i H H \ / Cl
74 2180000
Table 13
O H O CH3
Rl-O-C-NH-C -C-NH-C-CH2- O -A
S I
CH CH3
CH~ \CH3
Optically
CpIT1- Melting Point
pound R1 Formenc A (°C) or Reflactive
NO. of Ck Index (nD20)
F _
777 L \ / CN 115-116
\ / F
778 pL \ / CN
\ /
F
779 / \ L \ / CN 146-147
F
7g0 / \ DL \ / CN
781 F \ / L \ / CN 130-131
782 F \ / DL \ / CN 164-165
F F _
783 \ ~ I. \ / CN
F F
784 \ / DL \ / CN
F
78S F \ / L \ / CN 114-116
F _
786 F \ / DL \ / CN
F
787 F \ / L \ / CN
F
788 F \ / DL \ / CN
2180000
Next, synthesis processes of the compounds represented by
Formula [I] according to the present invention will be explained.
Preparation Process A
Z' H O R~ RS R~
II ~ II ~ ~ I
R~- Z~CNHC- COH + NI-I2C- (C)m- Z3 - (C)n- Q
R2 R4 R6 Rg
[_IX] LX]
Z2 H O R3 R5 R~
II ~ II ~ ~ I
R' - Z1CNHC- CNHC- (C)m - Z3 - (C)n- Q
I
2 ~4 I 6
R R R R
wherein Rl, R2, R3, R4, R5, R6, R~, Rg, Zl, Z2, Z3, Q, m, and
n have the sale meanings as defined above.
The compounds represented by Formula [I] according to the
present invention can be prepared by reacting an amino acid derivative
represented by Formula [IX] or the amino acid derivative possessing the
activated carboxyl group, with an amine represented by Formula [X] in
the presence of a base and/or a catalyst, if necessary.
In the present reaction, as the amino acid derivative represented
by Formula [IX] with the activated carboxyl group, there can be
mentioned, for example, an acid halide such as an acid chloride, an acid
anhydride derived from the two molecules of the amino acid derivatives
represented by Formula [IX], a mixed acid anhydride derived from the
a1111I10 aCld derivative represented by Formula [IX] and other acid or an
O-alkyl carbonic acid, and an activated ester such as p-nitrophenyl ester,
2-tetrahydropyranyl ester, and 2-pyridyl ester and the like.
2180000
It is possible to perform the present reaction using a condensing
agent such as N, N'-dicyclohexylcarbodiimide, carbonyldiimidazole, 2-
chloro-1,3-dimethylimidazolium chloride, or the like.
The present reaction can be carried out in a conventional solvent:
this solvent can be any solvent that does not hinder the reaction; for
example, hydrocarbons such as pentane, hexane, heptane, cyclohexane,
petroleum ether, ligroin, benzene, toluene, xylene and the like;
halogenated hydrocarbons such as dichloromethane, dichloroethane,
chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene and
the like; ethers such as diethyl ether, diisopropyl ether, ethylene glycol
dimethyl ether, tetrahydrofuran, dioxane and the like; ketones such as
acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl
ketone and the like; esters such as methyl acetate, ethyl acetate, and the
like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like;
aprotic polar solvents such as dimethylsulfoxide, dimethylformamide,
sulfolane and the like; and mixed solvents combining solvents selected
from the aforementioned.
The base can be any type of base generally used in this type of
reaction. For example, there can be mentioned hydroxides of alkaline
metals such as sodium hydroxide, potassium hydroxide and the like;
hydroxides of alkaline earth metals such as calcium hydroxide and the
like; carbonates of alkaline metals such as sodium carbonate, potassium
carbonate and the like; bicarbonates of alkaline metals such as sodium
bicarbonate, potassium bicarbonate and the like; organic bases such as
triethylamine, trimethylamine, dimethylaniline, pyridine, N-
methylmorpholine, N-methylpiperidine, 1,5-diazabicyclo [4.3.0) non-5-
ene (DBN), 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), and the like;
and pre-ferably tertiary amines such as triethylamine, pyridine, N-
methylpiperidine and the like.
As the catalyst, there can be mentioned 4-dimethylaminopyridine,
1-hydroxybenzotriazole, dimethylformamide and the like.
The present reaction is carried out at a temperature of -75°C to
100°C, preferably -60°C to 40°C. The reaction time is
preferably 1 to
20 hours.
Furthermore, compounds represented by Formula [IX] as the
starting material can be synthesized, for example by reacting Id-valine
2180000
with di(tert-butyl) Bicarbonate in the presence of sodium bicarbonate to
afford N-tent-butoxycarbonyl-L-valine, or by reacting D,L-valine with
carbobenzoxy chloride in the presence of sodium bicarbonate to afford
N-benzyloxycarbonyl-DL-valine (see Methoden der Organischen
Clterrtie, Vol. 15, No. 2, page 2 seq.; Georg Thiem.e Verlag Stuttgart:
1974; Cherttisrry of the Arnino Acids, vol. 2, page 891; John Wiley &
Sorts, N. Y. ( 1964); and Journnl of the American Chemical Society, Vol.
79, page 4686 (1957)).
Among the amino acid derivatives with the activated carboxyl
groups as the starting material, the mixed acid anhydride can be
synthesized by reacting the amino acid derivative represented by
Formula [IX] with pivaloyl chloride in the presence of an organic base.
p-Nitrophenyl ester can be prepared by reacting the amino acid
derivative represented by Formula [1X] with p-nitrophenol in the
presence of a condensing agent (see Methoden der Organischen Chemie,
Vol. 15, No. 2, page 2 seq.; Georg Tliier~Te Verlng Stuttgart: 1974;
Chen tische Bc~richte ,vol. 38, page 605 (1905); Journal of the Americ~rrz
Cltentical Society, Vol. 74, page 676 (1952); and Journal of the
Arrtericart Clrontical Society, Vol. 86, page 1839 (1964)).
In addition, the compounds represented by Formula [X] can be
synthesized by means of reacting chlorobenzonitrile with 2-amino-2-
methyl-I-propanol in the presence of sodium hydride (see Japanese
Patent Application First Publication No. Sho 63-146876, Japanese Patent
Application First Publication No. Hei 5-271206, Tetrahedron Letters,
page 21, 1973).
'g 2180000
Preparation Process B
Z~ H O R3 R5 R'
R1- Z'- C - Y + NH2C- CNHC- (C)m - Z3 - (C)n- Q
R2 R4 R6 Ra
[XI]
[XII]
Z2 H O R3 RS R'
R' - Z~CNHC- CNHC- (C)m - Z3 - (C)n- Q
~4 ~ 6
R R R R
[l]
wherein Rl, R2, R3, R4, R5, R6, R~, Rg, Zl, Z2, Z3, Q, m, and
n have the same meanings as defined above, and Y represents a halogen
atom, a 4,6-dimethylpyrimidinylthio group, an R10C(O)O- group, or a
Ph
C= NO -
NC/ group (in which Ph represents a phenyl group).
Compounds of the present invention represented by Formula [1]
can be manufactured by means of reacting the compound represented by
Formula [XI] with an amine represented by Formula [XII] or the salt of
the amine derivative with an inorganic acid such as hydrochloride and
the like, or a salt of the amine derivative with an organic acid such as
tosylate and the like, in the presence of a base when required.
The present reaction can be performed in a conventional solvent.
This solvent can be any solvent that does not hinder the reaction; for
example, hydrocarbons such as pentane, hexane, heptane, cyclohexane,
petroleum ether, ligroin, benzene, toluene, xylene and the like;
hnl~~~~,nroc~ t,ydr~Fnrh~na ~cE~eh c~~ Eliehlorc~m~thnn~, diFhlarpethnn~,
79 ~ 18000
011101-OIOrIlI, carbon tetrachloride, chlorobenzene, dichlorobenzene and
the like; ethers such as diethyl ether, diisopropyl ether, ethylene glycol
dimethyl ether, tetrahydrofuran, dioxane and the like; ketones such as
acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl
ketone and the like; esters such as methyl acetate, ethyl acetate and the
like, nitriles such as acetonitrile, propionitrile, benzonitrile and the like;
aprotic polar solvents such as dimethylsulfoxide, dimethylformamide,
sulfolane and the like; water; and mixtures of solvents combining
solvents selected from the aforementioned.
The base can be any type of base generally used in this type of
reaction. For example, there can be mentioned hydroxides of alkaline
metals such as sodium hydroxide, potassium hydroxide and the like;
hydroxides of alkaline earth metals such as calcium hydroxide and the
like; carbonates of alkaline metals such as sodium carbonate, potassium
carbonate and the like; bicarbonates of alkaline metals such as sodium
bicarbonate, potassium bicarbonate and the like; organic bases such as
triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine,
pyridine, N-methylpiperidine, 1,5-diazabicyclo [4.3.0] non-5-ene
(DBN), I ,b-diazabicyclo [5.4.0] undec-7-ene (DBU), and the like, and
preferably tertiary amines such as triethylamine, pyridine, N-
methylpiperidine and the like.
The present reaction is carried out at a temperature of -20°C to
100°C, and preferably 0°C to 40°C. The reaction time is
usually 30
minutes to 20 hours.
Compounds represented by Formula [XII] as the starting material
are novel compounds, and can be manufactured, for example, by means
of treating carbamates of Formula [I] synthesized by the procedure of
preparation process A using a conventional process for removing the
amino protecting group of the amino acid, such as catalytic reduction,
or by treating with acids such as liquid hydrofluoric acid, sulfonic acids,
hydrochloric acid, hydrobromic acid, formic acid and the like.
In the following, synthesis examples of the intermediates of the
compounds according to the present invention, represented by Formula
[X], are provided as reference examples.
Reference Example 1
g° 2180000
Synthesis of 2-(4-cyanophenoxy)-1-methylethylamine (part 1)
293 g of ammonium acetate and 16.7 g of sodium
cyanoborohydride were added to a solution containing 66.5 g of 4-
cyanophenoxyacetone dissolved in 1500 ml of methanol, and the
resultant mixture was stirred for 30 hours at room temperature. The
reaction mixture was then concentrated under reduced pressure, and
acidified with concentrated hydrochloric acid. 500 ml of diethyl ether
and 300 ml of water were then added thereto. Subsequently, the
resultant water layer was made basic with a 5% aqueous solution of
sodium hydroxide, the solution was extracted with 1000 ml of diethyl
ether, and then washed with water. The organic layer was then dried
over anhydrous sodium sulfate, and the diethyl ether was removed
under reduced pressure. The obtained residue was distilled under
reduced pressure to yield 13.0 g of the desired product (19%).
Boiling point: 132°C / 0.26 mmHg.
Reference Example 2
Synthesis of 2-(4-cyanophenoxy)-1-methylethylamine (part 2)
50.0 g of 2-amino-1-propanol was added drop by drop to a
mixture containing 29.3 g of 60% sodium hydride and 300 ml of N,N-
dimethylformamide, in an ice bath, and the resultant mixture was
stirred for 30 minutes in an ice bath. A solution containing 121.2 g of
4-bromobenzonitrile dissolved in N,N-dimethylformamide was added
slowly to the reaction mixture while being stirred in an ice bath,
followed by stirnng the reaction mixture for 20 hours at room
temperature. After the completion of the reaction, the resultant mixture
was poured into water and extracted with ethyl acetate. The organic
layer was washed with water and then dried over anhydrous magnesium
sulfate, and the ethyl acetate was removed under reduced pressure. The
obtained residue was distilled under reduced pressure to yield 48.0 g of
the desired product (41 %).
Boiling point: 132°C / 0.26 mmHg.
Reference Example 3
Synthesis of 2-(4-chloro-2-methylphenoxy)-1-methylethylamine
R' 2180000
120 g of ammonium acetate and 9.8 g of sodium
cyanoborohydride were added to a solution containing 31 g of (4-
chloro-2-methylphenoxy)acetone dissolved in 700 ml of methanol, and
the resultant mixture was stirred for 20 hours at room temperature.
After the reaction mixture was concentrated under reduced pressure,
180 ml of concentrated hydrochloric acid and 100 ml of water were
added to the residue. The whole mixture was stirred for 1 hour, and
then 300 ml of diethyl ether was added thereto. The aqueous layer was
alkalified using a 5% aqueous solution of sodium hydroxide, and then
extracted with 500 ml of ethyl acetate. The organic layer was washed
with water, dried over anhydrous magnesium sulfate, and then
concentrated under reduced pressure. A fraction possessing a low
boiling point was removed from the obtained oily products to afford 25
g (yield 81 %) of the desired product.
Refractive index (n20): 1.5360.
Reference Example 4
Synthesis of 2-(4-chlorophenoxy)-1-methylpropylamine
82 g of ammonium acetate and 6.7 g of sodium cyanoborohydride
were added to a solution containing 21 g of 3-(4-chlorophenoxy)-2-
butanone dissolved in 500 ml of methanol, and the reaction mixture was
stirred for 20 hours at room temperature. After the reaction mixture
was concentrated under reduced pressure, 180 ml of concentrated
hydrochloric acid, 100 ml of water, and 300 ml of diethyl ether were
added to the residue. The obtained water layer was alkalified using a
5% aqueous solution of sodium hydroxide, and then the organic
substances were extracted with 500 ml of ethyl acetate. The organic
layer was washed with water, dried over anhydrous magnesium sulfate,
and then concentrated under reduced pressure. A fraction possessing a
low boiling point was removed from the obtained oily products to
afford 18 g (yield 86%) of the desired product.
Refractive index (n20): 1.5360.
Reference Example 5
Synthesis of 1-methyl-2-(2-methylphenoxy)ethylamine
2~aoooo
A solution containing 36 g of 2-(2-methylphenoxy)acetone oxime
O-methyl ether dissolved in I50 ml of dimethoxyethane was added
dropwise to a suspension containing 13 g of sodium borohydride in 500
ml of dimethoxyethane at room temperature. After the mixture was
stirred for 15 minutes at room temperature, a solution containing 66 g
of boron tril7uoride diethyl ether complex dissolved in 100 ml of
dimethoxyethane was added dropwise to the mixture at room
temperature. The reaction mixture was stirred for 30 minutes at room
temperature and then refluxed for 3 hours. The resultant mixture was
allowed to sit and cool naturally to room temperature and then acidified
using a 10% hydrochloric acid. The dimethoxyethane layer was
concentrated and combined with the water layer. The mixture was
alkalified using sodium carbonate, and then extracted with
dichloromethane, followed by washing with water. The organic layer
was dried over anhydrous magnesium sulfate, and then the
dichloromethane was removed under reduced pressure. The residue
was distilled under reduced pressure to obtain 6.4 g (yield 21 %) of the
desired product .
Boiling point: 65°C / 0.08 mmHg.
Reference Example 6
Synthesis of (-)-2-(4-cyanophenoxy)-1-methylethylamine
25.0 g of R-(-)-2-amino-1-propanol was added dropwise to a
stirred mixture of 14.0 g of 60% sodium hydride and 200 ml of N,N-
dimethylformamide, at 5°C ~ 10°C while being stirred. After the
reaction mixture was stirred for 30 minutes at the same temperature, a
solution containing 45.0 g of 4-chlorobenzonitrile dissolved in N,N-
dimethylformamide was added dropwise to the reaction mixture. The
resultant mixture was stirred for 20 hours at room temperature. After
the completion of the reaction, the resultant mixture was poured into
water and extracted with ethyl acetate. The organic layer was washed
with water and then dried over anhydrous magnesium sulfate. The
ethyl acetate was removed under reduced pressure. The residue was
distilled under reduced pressure to obtain 33.0 g of the desired product
(yield 56%).
Boiling point: 60°C ~ 66°C / 0.08 mmHg.
2180000
~a~D20: _ 15,7° (C: 1.0, CH30H).
Reference Example 7
Synthesis of 1-methyl-2-(2-pyrimidyloxy)ethylamine
2.0 g of 2-amino-1-propanol was added dropwise to a stirred
mixture of 1.3 g of 60% sodium hydride and 30 ml of N,N-
dimethylformamide at room temperature. After the reaction mixture
was stirred for 30 minutes, a solution containing 3.7 g of 2-
chloropyrimidine dissolved in N,N-dimethylformamide was added
dropwise to the reaction mixture. The mixture was stirred for 2 hours
at 100°C. After completion of the reaction, the reaction mixture was
cooled. The solids in the reaction mixture were filtered off. The
solvent in the filtrate was removed under reduced pressure. The
residue was purified by column chromatography on silica gel to obtain
2.1 g of the desired product (yield: 50%).
Refractive index (n20): 1.5481.
Reference Example 8
Synthesis of 1-methyl-2-(4-pyridyloxy)ethylamine
6.2 g of 2-amino-1-propanol was added dropwise to a stirred
mixture of 4.0 g of 60% sodium hydride and 50 ml of N,N-
dimethylformamide at 5°C ~ 10°C. After the reaction mixture was
stirred for 30 minutes, 12.5 g of 4-chloropyridine hydrochloride in
limited amounts was added to the reaction mixture. The mixture was
stirred for 20 hours at room temperature. After completion of the
reaction, the solids in the reaction mixture were filtered off. The
solvent in the filtrate was removed under reduced pressure. The
residue was purified by column chromatography on silica gel to obtain
3.8 g of the desired product (yield: 30%).
Refractive index (n20): 1.5469.
Reference Example 9
Synthesis of 2-(4-cyanophenoxy)-1,1-dimethylethylamine
4.0 g of 60% sodium hydride was added to a solution containing
8.9 g of 2-amino-2-methyl-1-propanol dissolved in 100 ml of N,N-
dimethylformamide in an ice bath. After the reaction mixture was
g4 2180000
stirred for 30 minutes at room temperature, 13.7 g of 4-
chlorobenzonitrile was added to the reaction mixture and the reaction
mixture was stirred for 15 hours at room temperature. The reaction
mixture was poured into water. The organic layer of the reaction
mixture was extracted with ethyl acetate, washed with water, and then
dried over anhydrous magnesium sulfate. After the solvent was
removed under reduced pressure. The fraction possessing a low boiling
point was removed from the residue, thus obtaining 15 g of the desired
product (yield: 79%).
According to the procedures similar to those in the Reference
Examples described above, the following intermediates were obtained:
(RS) 2-(2-methoxyphenoxy)-1-methylethylamine
Boiling point: 96.5°C / 0.15 mmHg.
(RS) 2-(3-methoxyphenoxy)-1-methylethylamine
Refractive Index (n20): 1.5158.
(RS) 2-(4-methoxyphenoxy)-1-methylethylamine
Boiling point: 95°C / 0.10 mmHg.
(RS) 2-(2-cyanophenoxy)-1-methylethylamine
Refractive Index (n20): 1.5566.
(RS) 2-(3-cyanophenoxy)-1-methylethylamine
Refractive Index (n20): 1.5409.
(RS) 2-(2-fluorophenoxy)-1-methylethylamine
Boiling point: 70°C / 0.22 mmHg.
(RS) 2-(3-fluorophenoxy)-1-methylethylamine
Boiling point: 74°C / 0.15 mmHg.
(RS) 2-(2-nitrophenoxy)-1-methylethylamine
Refractive Index (n20): 1.5582.
(RS) 2-(2,4-dichlorophenoxy)-1-methylethylamine
Refractive Index (n20): 1.5475.
(RS) 2-(3,4-dichlorophenoxy)-1-methylethylamine
Boiling point: 104°C / 0.16 mmHg.
(RS) 2-(3,5-dichlorophenoxy)-1-methylethylamine
Boiling point: 100°C / 0.12 mmHg.
(RS) 2-(3,4-dimethoxyphenoxy)-1-methylethylamine
Refractive Index (n20): 1.5361.
gs 2180000
(RS) 2-(3,5-dimethoxyphenoxy)-1-methylethylamine
Boiling point: 125 °C / 0.10 mmHg.
(1RS)(2R,S) 2-(4-cyanophenoxy)-I-methylethylamine
. Refractive Index (n20): 1.5480.
( 1 RS)(2R,S) 1,2-dimethyl-2-(4-nitrophenoxy)-ethylamine
Refractive Index (n20): 1.6263.
Next, the synthesis examples of the intermediates of the
compounds according to the present invention, represented by Formula
[XII] are described in the following Reference Examples.
Reference Example 10
Synthesis of NI-[2-(4-cyanophenoxy)-I-methylethyl]-L-
valinamide hydrochloride
Hydrogen chloride gas was introduced into a solution containing
3.7 g of N2-tert-butoxycarbonyl-N 1-[2-(4-cyanophenoxy)-1-
methylethyl]-L-valinamide dissolved in 100 ml of methylene chloride
for 1 hour at room temperature. After the completion of the reaction,
the methylene chloride was removed under reduced pressure, thus
yielding a crude crystal. The crude crystal was washed with acetone to
afford 3.1 g of the desired product (yield: 100%).
Melting point: 59 ~ 63°C.
Reference Example 11
Synthesis of N1-[2-(4-cyanophenoxy)-1-methyIethyl]-L-
isoleucinamide
Hydrogen chloride gas was introduced into a solution containing
15.0 g of N2-tert-butoxycarbonyl-N 1-[2-(4-cyanophenoxy)-1-
methylethyl]-L-isoleucinamide dissolved in 300 ml. of methylene
chloride for 1 hour at room temperature. After the completion of the
reaction, the methylene chloride was removed under reduced pressure,
thus yielding a crude crystal. 200 ml of a saturated aqueous solution of
sodium bicarbonate and 200 ml of methylene chloride were added to the
crude crystal, and subsequently the mixture was stirred for 30 minutes.
The organic substances were extracted with methylene chloride. The
organic layer was washed with water, and dried over anhydrous sodium
g6 2180000
sulfate. The methylene chloride was removed under reduced pressure.
The obtained crude crystal was washed with acetone to afford 10.0 g of
the desired product (yield: 90%).
Melting point: 64 ~ 67°C.
Reference Example 12
Synthesis of N1-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-L-
valinamide
Hydrogen chloride gas was introduced into a solution containing
3.7 g of N2-tort-butoxycarbonyl-N1-[2-(4-cyanophenoxy)-1,1-
dimethylethyl]-L-valinamide dissolved in 50 ml of methylene chloride
for 3 hours at room temperature. After the completion of the reaction,
the methylene chloride was removed under reduced pressure. A
saturated aqueous solution of sodium bicarbonate was added to the
residue. The organic layer in the residue was extracted with methylene
chloride, washed with water, and then dried over anhydrous magnesium
sulfate. The solvent in the organic layer was removed under reduced
pressure, thus yielding 2.4 g of the desired product (yield: 87%).
According to the procedures similar to those in the Reference
Examples described above, the following intermediates were obtained:
(RS) N1-2-(5-trifluoropyridin-2-yl)oxy-1-methylethyl]-L-valinamide
Melting point: 73°C ~ 75°C.
(RS) N-[2-(4-chlorophenoxy)-1-methylethyl]-L-2-aminobutyramide
Melting point: 43°C ~ 44°C.
(RS) N-[2-(4-cyanophenoxy)-1-methylethyl]-L-2-aminobutyramide
Refractive Index (n20): 1.5391.
(RS) N-[2-(4-cyanophenoxy)-1-methylethyl]-L-2-aminovaleramide
Refractive Index (n20): 1.5299.
(RS) N-[2-(4-cyanophenoxy)-1-methylethyl]-L-2-amino-3,3-
dimethylbutyramide
Refractive Index (n20): 1.5251.
(RS) N1-[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide
Refractive Index (n20): 1.5250.
2180000
Best Mode for Carrying Out the Invention
The IllethOds for producing the compounds according to the
present invention will be described in detail in the following Synthesis
Examples.
Synthesis Example 1
Synthesis of N2-tent-butoxycarbonyl-N I -[ 1-methyl-2-(4-
nitrophenoxy)ethyl]-L-valinamide (Compound No. 16)
0.5 g of N-methylpiperidine was added to a solution containing
I.1 g of N-teat-butoxycarbonyl-L-valine dissolved in 40 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.7 g of isobutyl chloroformate was
added to the mixture at -40°C, and subsequently the whole mixture was
stirred for I hour at -20°C. 1 g of 1-methyl-2-(4-
nitrophenoxy)ethylamine was added to this mixture at -60°C, and then
the reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 15
hours at room temperature. Water was subsequently added to the
reaction mixture. After the dichloromethane layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
residue, which was a crude crystal, was purified by column
chromatography on silica gel, thus yielding 0.7 g of the desired product
in the form of a yellow powder (yield: 55%).
Synthesis Example 2
Synthesis of Nl-[2-(4-cyanophenoxy)-1-methylethyl]-N2-
isopropenyloxycarbonyl-L-valinamide (Compound No. 77)
0.6 g of N-methylmorpholine, and subsequently 0.4 g of
isopropyl chloroformate were added to a solution containing 0.9 g of
N1-[2-(4-cyanophenoxy)-1-methylethyl)-L-valinamide hydrochloride
dissolved in 50 ml of methylene chloride at -I S°C. The mixture was
allowed to sit and warm naturally to room temperature and stirred for
15 hours at room temperature. Water was subsequently added to the
reaction mixture. After the dichloromethane layer was washed with
gg 2180000
water, the organic layer was dried over anhydrous magnesium sulfate
and then the methylene chloride was removed under reduced pressure.
The residue was purified by column chromatography on silica gel, thus
yielding 0.23 g of the desired product in the form of colorless grains
(yield: 13%).
Synthesis Example 3
Synthesis of NI-[2-(4-cyanophenoxy)-1-methylethyl]-N2-
phenoxycarbonyl-L-valinamide (Compound No. 107)
I .3 g of N-methylpiperidine was added to a solution containing 3
g of N-phenoxycarbonyl-L-valine dissolved in 50 ml of methylene
chloride, at -20°C. After the mixture was stirred for 10 minutes at the
same temperature, 1.7 g of isobutyl chloroformate was added to the
mixture at -40°C, and subsequently the whole mixture was stirred for 1
hour at -20°C. 2.2 g of 2-(4-cyanophenoxy)-1-methylethylamine was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The residue, which was
a crude crystal, was purified by column chromatography on silica gel,
thus yielding 1.1 g of the desired product in the form of a white powder
(yield: 22%).
Synthesis Example 4
Synthesis of N2-tert-butoxycarbonyl-N1-[2-(4-cyanophenoxy)-1-
methylethyl]-L-isoleucinamide (Compound No. 228)
1.3 g of N-methylpiperidine was added to a solution containing 3
g of N-tent-butoxycarbonyl-L-isoleucine dissolved in 60 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 1.8 g of isobutyl chloroformate was
added to the mixture at -40°C, and subsequently the whole mixture was
stirred for 1 hour at -20°C. 2.3 g of 2-(4-cyanophenoxy)-1-
g9 2180000
methylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
yielding 0.6 g of the desired product in the form of a white powder
(yield: 12%).
Synthesis Example 5
Synthesis of N2-tert-butoxycarbonyl-N1-(2-phenylthioethyl)-L-
valinamide (Compound No. 551 )
1 g of N-methylpiperidine was added to a solution containing 2.1
g of N-tent-butoxycarbonyl-L-valine dissolved in 40 ml of methylene
chloride, at -20°C. After the mixture was stirred for 10 minutes at the
same temperature, 1.3 g of isobutyl chloroformate was added to the
mixture, and subsequently the whole mixture was stirred for 1 hour at
-20°C. 1.5 g of 2-phenylthioethylamine was added to this mixture at
-60°C, and then the reaction mixture was allowed to sit and warm
naturally to room temperature while being stirred. The whole mixture
was stirred for 20 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed successively with a 5% aqueous solution of sodium bicarbonate
and water, the organic layer was dried over anhydrous magnesium
sulfate and the methylene chloride was removed under reduced
pressure. The residue was purified by column chromatography on
silica gel, thus yielding 0.4 g of the desired product in the form of
cream yellow grains (yield: 12%).
Synthesis Example 6
Synthesis of N2-test-butoxycarbonyl-N 1-[ 1-methyl-2-(4-
nitrophenoxy)propylJ-L-valinamide (Compound No. 606)
90 2180000
0.5 g oi' N-methylpiperidine was added to a solution containing 1
g of N-tort-butoxycarbonyl-L-valine dissolved in 40 ml of methylene
chloride, at -20°C. After the mixture was stirred for 15 minutes at the
same temperature, 0.7 g of isobutyl chloroformate was added to the
mixture, and stirred for I hour at -20°C. 1 g of I-methyl-2-(4-
nitrophenoxy)propylamine was added to this mixture at -60°C, and then
the reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
residue, which was an oily substance, was purified by column
chromatography on silica gel, thus yielding 1.1 g of the desired product
in the form of yellow viscous liquid (yield: 56%).
Synthesis Example 7
Synthesis of N2-tert-butoxycarbonyl-N1-[2-(3,5-
dimethoxyphenoxy)-1-methylethylJ-L-valinamide (Compound No. 22)
0.5 g of N-methylpiperidine was added to a solution containing
1.0 g of N-tort-butoxycarbonyl-L-valine dissolved in 100 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.7 g of isobutyl chloroformate was
added to the mixture at -40°C, and then the whole mixture was stirred
for l hour at -20°C. 1 g of 2-(3,5-dimethoxyphenoxy)-1-methylamine
was added to this mixture at -60°C, and subsequently the reaction
mixture was allowed to sit and warm naturally to room temperature
while being stirred. The whole mixture was stirred for 15 hours at
room temperature. Water was subsequently added to the reaction
mixture. After the methylene chloride layer was washed successively
with a 5% aqueous solution of sodium bicarbonate and water, the
organic layer was dried over anhydrous magnesium sulfate and the
methylene chloride was removed under reduced pressure. The residue,
which was a crude crystal, was purified by column chromatography on
218fl000
silica gel, thus yielding 1.3 g of the desired product in the form of white
powder (yield: 64%).
Synthesis Example 8
Synthesis of N2-tert-butoxycarbonyl-Nl-[1-methyl-2-(2,4,6-
trichlorophenoxy)ethyl]-L-valinamide (Compound No. 25)
1.7 g of N-methylpiperidine was added to a solution containing
3.8 g of N-tort-butoxycarbonyl-L-valise dissolved in 80 ml of
methylene chloride, at -20°C. After the mixture was stirred for 15
minutes at the same temperature, 2.4 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 4.5 g of 1-methyl-2-(2,4,6-
trichlorophenoxy)ethylamine was added to this mixture at -60°C, and
then the reaction mixture was allowed to sit and warm naturally to
room temperature while being stirred. The whole mixture was stirred
for 20 hours at room temperature. Water was subsequently added to
the reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
yielding 4.6 g of the desired product in the form of a colorless needle
crystal (yield: 58%).
Synthesis Example 9
Synthesis of N2-isopropoxycarbonyl-N1-[1-methyl-2-(4-
nitrophenoxy)ethyl]-L-valinamide (Compound No. 45)
1.2 g of N-methylpiperidine was added to a solution containing
2.5 g of N-isopropoxycarbonyl-L-valise dissolved in 100 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 1.7 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 2.2 g of 2-(4-nitrophenoxy)-1-methylethylamine
was added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
92 2 ~ ~0~~0
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The residue was
purified by column chromatography on silica gel, thus yielding 0.3 g of
the desired product in the form of a yellow vitrified substance (yield:
6%).
I H-NMR: (CDC13, 8)
1.16 ~ 1.33 (6H, m)
1.43 ~ 1.36 (9H, m)
2.56 (1H, m)
4.01 (2H, m)
4.00 ~ 5.33 (3H, m)
6.17 (1H, d)
6.87 (2H, d)
8.06 (2H, d)
Synthesis Example 10
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-
cyclohexyloxycarbonyl-L-valinamide (Compound No. 97)
0.8 g of N-methylpiperidine was added to a solution containing
2.0 g of N-cyclohexyloxycarbonyl-L-valine dissolved in 150 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 1.1 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 1.5 g of 2-(4-cyanophenoxy)-1-methylethylamine
was added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The residue was
2180000
purified by column chromatography on silica gel, thus yielding 0.5 g of
the desired product in the form of light brown powder (yield: 16%).
Synthesis Example 11
Synthesis of N1-[1-methyl-2-(4-trifluoromethylphenoxy)ethyl]-
N2-phenoxycarbonyl-L-valinamide (Compound No. 114)
1.6 g of N-methylpiperidine was added to a solution containing
4.0 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene
chloride, at -20°C. After the mixture was stirred for 15 minutes at the
same temperature, 2.2 g of isobutyl chloroformate was added to the
mixture, and subsequently the whole mixture was stirred for 1 hour at
-20°C. 3.5 g of 1-methyl-2-(4-trifluoromethylphenoxy)ethylamine was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The residue was
purified by column chromatography on silica gel, thus yielding 2.8 g of
the desired product in the form of a white crystal (yield: 40%).
Synthesis Example 12
Synthesis of N1-[1-methyl-2-(4-trifluoromethoxyphenoxy)ethyl]-
N2-phenoxycarbonyl-L-valinamide (Compound No. 115)
1.7 g of N-methylpiperidine was added to a solution containing
4.0 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene
chloride, at -20°C. After the mixture was stirred for 15 minutes at the
same temperature, 2.3 g of isobutyl chloroformate was added to the
mixture, and subsequently the whole mixture was stirred for 1 hour at
-20°C.
4.0 g of 1-methyl-2-(4-trifluoromethoxyphenoxy)ethylamine was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
94 2 ~ 8000
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The residue was
purified by column chromatography on silica gel, thus yielding 3.4 g of
the desired product in the form of a white crystal (yield: 45%).
Synthesis Example 13
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-
phenoxycarbonyl-L-valinamide (Compound Nos. I 16 and 117)
1.8 g of N-methylpiperidine was added to a solution containing
4.2 g of N-phenoxycarbonyl-L-valine dissolved in 100 ml of methylene
chloride, at -20°C. After the mixture was stirred for 10 minutes at the
same temperature, 2.4 g of isobutyl chloroformate was added to the
mixture, and subsequently the whole mixture was stirred for 1 hour at
-20°C. 3.1 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to
this mixture at -60°C, and then the reaction mixture was allowed to sit
and warm naturally to room temperature while being stirred. The
whole mixture was stirred for 20 hours at room temperature. Water
was subsequently added to the reaction mixture. After the methylene
chloride layer was washed successively with a 5% aqueous solution of
sodium bicarbonate and water, the organic layer was dried over
anhydrous magnesium sulfate and the methylene chloride was removed
under reduced pressure. The residue was purified by column
chromatography on silica gel, thus obtaining 1.0 g of a white powder.
0.6 g of the obtained white powder was purified using high pressure
liquid chromatography (hereinafter, referred to as "HPLC") (YMC-
063-15, hexane / ethyl acetate = 55 / 45) to separate two fractions. The
ingredient of the first fraction having a short retention time was 0.3 g
of a white powder (yield: 7%) having a melting point of 145 to 147°C
and the ingredient of the second fraction having a long retention time
was 0.3 g of a white powder (yield: 7%) having a melting point of 166
to 170°C.
Synthesis Example 14
95 2180000
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-(3-
methoxyphenoxycarbonyl)-L-valinamide (Compound No. 166)
1.0 g of N-methylmorpholine was added to a solution containing
1.5 g of N 1-[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide
hydrochloride dissolved in 100 ml of methylene chloride, at -20°C.
After 0.9 g of 3-methoxyphenyl chloroformate was added to the
mixture at -20°C, the reaction mixture was allowed to sit and warm
naturally to room temperature while being stirred. The whole mixture
was stirred for 2 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 0.25 g of the desired product in the form of a
white plated crystal (yield: 12%).
Synthesis Example 15
Synthesis of N2-(2-chloroethoxycarbonyl)-N1-[2-(4-
cyanophenoxy)-1-methylethyl]-L-valinamide (Compound No. 184)
0.5 g of N-methylpiperidine was added to a solution containing
1.1 g of N-(2-chloroethoxycarbonyl)-L-valine dissolved in 40 ml of
methylene chloride, at -20°C. After the mixture was stirred for 15
minutes at the same temperature, 0.7 g of isobutyl chloroformate was
added to the mixture at -40°C, and subsequently the whole mixture was
stirred for 1 hour at -20°C. 0.9 g of 2-(4-cyanophenoxy)-1-
methylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
residue, which was an oily substance, was purified by column
chromatography on silica gel, thus yielding 1.0 g of the desired product
in the form of colorless gains (yield: 52%).
96 2 ~ 8~~00
Synthesis Example 16
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-(4-
methylbenzyloxycarbonyl)-L-valinamide (Compound No. 195)
0.6 g of N-methylpiperidine was added to a solution containing
1.5 g of N-(4-methylbenzyloxycarbonyl)-L-valine dissolved in 100 ml
of methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.8 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 1.0 g of 2-(4-cyanophenoxy)-1-methylethylamine
was added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The residue, which was
a crude crystal, was purified by column chromatography on silica gel,
thus yielding 0.6 g of the desired product in the form of light white
powder (yield: 28%).
Synthesis Example 17
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-
phenoxythiocarbonyl-L-valinamide (Compound No. 208)
0.4 g of N-methylmorpholine was added to a suspension
containing 1.1 g of N1-[2-(4-cyanophenoxy)-1-methylethyl]-L-
valinamide suspended in 40 ml of methylene chloride, at -15°C. After
0.7 g of phenyl chlorothionoformate was added to the mixture at -15°C,
the reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred, and then the whole mixture was stirred
for 15 hours at room temperature. Water was subsequently added to
the reaction mixture. After the methylene chloride layer was washed
with water, the organic layer was dried over anhydrous magnesium
sulfate and the methylene chloride was removed under reduced
pressure. The residue was purified by column chromatography on
9l
silica gel, thus yielding 1.2 g of the desired product in the form of a
yellow glutinous substance (yield: 75%).
1 H-NMR: (CDC13, 8)
1.05 (6H, m)
1.35 (3H, m)
2.30 ( 1 H,
m)
4.00 (2H, m)
4.44 (1H, m)
4.54 (1 H,
m)
6.16, 6.25 ( 1 H,
d)
7.26 (9H, m)
7.51 ( 1 H,
br)
Synthesis Example 18
Synthesis of N 1-[2-(4-cyanophenoxy)-1-methylethylJ-N2-
(phenylthio)thiocarbonyl-L-valinamide (Compound No. 211)
0.5 g of N-methylmorpholine was added to a suspension
containing 1.4 g of N1-[2-(4-cyanophenoxy)-1-methylethyl]-L-
valinamide suspended in 40 ml of methylene chloride, at -15°C. After
0.9 g of phenyl chlorodithioformate was added to the mixture at -15°C,
the reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred, and subsequently the whole mixture
was stirred for 15 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 1.4 g of the desired product in the form of a
yellow glutinous substance (yield: 66%).
1H-NMR: (CDC13, 8)
0.83 (6H, m)
1.30, 1.32 (3H, d)
2.13 (1H, m)
3.96 (2H, m)
9g 2180000
4.35 (1 H, m)
4.78 (1H, dd)
6.04, 6.13 ( 1 H,
d)
6.93, 6.98 (2H, d)
7.15, 7.22 ( 1 H,
d)
7.57 (7H, m)
Synthesis Example 19
Synthesis of N1-(1-methyl-2-phenylthioethyl)-N2-
phenoxycarbonyl-L-valinamide (Compound No. 212)
1.3 g of N-methylmorpholine was added to a suspension
containing 3.0 g of N1-(1-methyl-2-phenylthioethyl)-L-valinamide
hydrochloride suspended in 80 ml of methylene chloride, at -15°C.
After 1.9 g of phenyl chloroformate was added to the mixture at -
15°C,
the reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred, and subsequently the whole mixture
was stirred for 15 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 2.3 g of the desired product in the form of a
white crystal (yield: 54%).
Synthesis Example 20
Synthesis of N1-[2-(4-chloroanilino)-1-methylethyl]-N2-
isopropoxycarbonyl-L-valinamide (Compound No. 221)
1.9 g of N-methylpiperidine was added to a solution containing
3.8 g of N-isopropoxycarbonyl-L-valine dissolved in 80 ml of
methylene chloride, at -20°C. After the mixture was stirred for 15
minutes at the same temperature, 2.6 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 3.5 g of 2-(4-chloroanilino)-1-methylethylamine
was added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
99 2
temperature. Water was subsequently added to the reaction mixture.
After the metl~ylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The residue was
purified by column chromatography on silica gel, thus yielding 3.3 g of
the desired product in the form of a white crystal (yield: 47%).
Synthesis Example 21
Synthesis of 2-tert-butoxycarbonylamino-N-[2-(4-
chlorophenoxy)-1-methylethyl]-(2S)-butyramide (Compound No. 233)
2.0 g of N-methylpiperidine was added to a solution containing
4.1 g of (2S)-2-tert-butoxycarbonylaminobutyric acid dissolved in 60
ml of methylene chloride, at -20°C. After the mixture was stirred for
minutes at the same temperature, 2.7 g of isobutyl chloroformate
was added to the mixture at -40°C, and subsequently the whole mixture
was stirred for 1 hour at -20°C. After 3.7 g of 2-(4-chlorophenoxy)-1-
methylethylamine was added to this mixture at -60°C, the reaction
mixture was allowed to sit and warm naturally to room temperature
while being stirred, and subsequently stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The obtained crude
crystal was purified by column chromatography on silica gel, thus
yielding5.6 g of the desired product in the form of a colorless glutinous
substance (yield: 76%).
Synthesis Example 22
Synthesis of 2-tert-butoxycarbonylamino-N-[2-(4-cyanophenoxy)-
1-methylethyl]-(2S)-butyramide (Compound No. 235)
0.5 g of N-methylpiperidine was added to a solution containing
1.0 g of (2S)-2-tert-butoxycarbonylaminobutyric acid dissolved in 40
ml of methylene chloride, at -20°C. After the mixture was stirred for
10 minutes at the same temperature, 0.7 g of isobutyl chloroformate
2180000
was added to the mixture at -20°C, and subsequently the whole mixture
was stirred for 1 hour at -20°C. 0.9 g of 2-(4-cyanophenoxy)-1-
methylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
yielding 1.0 g of the desired product in the form of a glutinous
substance (yield: 54%).
1 H-NMR: (CDC13, ~)
0.94 (3H, t)
1.20 ~ 1.50 (12H, m)
1.69 (2H, m)
3.83 ~ 4.56 (4H, m)
5.30 ( 1 H,
d)
6.60 ( 1 H,
m)
6.90 (2H, d)
7.50 (2H, d)
Synthesis Example 23
Synthesis of N1-[2-(4-chlorobenzyloxy)-1-methylethyl]-N2-
isopropoxycarbonyl-L-valinamide (Compound No. 246)
0.5 g of N-methylpiperidine was added to a solution containing 1
g of N-isopropoxycarbonyl-L-valine dissolved in 40 ml of methylene
chloride, at -20°C. After the mixture was stirred for 15 minutes at the
same temperature, 0.7 g of isobutyl chloroformate was added to the
mixture at -40°C, and~~subsequently the whole mixture was stirred for 1
hour at -20°C. 1 g of 2-(4-chlorobenzyloxy)-1-methylethylamine was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
,o, 2180000
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The obtained oily
residue was purified by column chromatography on silica gel, thus
yielding 0.9 g of the desired product in the form of a colorless plated
crystal (yield: 48%).
Synthesis Example 24
Synthesis of N2-tent-butoxycarbonyl-N1-[1-methyl-2-(4-
methylthiophenoxy)ethyl]-L-valinamide (Compound No. 327)
3.4 g of N-methylpiperidine was added to a solution containing
7.5 g of N-tert-butoxycarbonyl-L-valine dissolved in 100 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 4.7 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 6.8 g of 1-methyl-2-(4-
methylthiophenoxy)ethylamine was added to this mixture at -60°C, and
then the reaction mixture was allowed to sit and warm naturally to
room temperature while being stirred. The whole mixture was stirred
for 20 hours at room temperature. Water was subsequently added to
the reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous sodium sulfate and
the methylene chloride was removed under reduced pressure. The
obtained oily residue was purified by column chromatography on silica
gel, thus yielding 6.2 g of the desired product in the form of a colorless
prism-shaped crystal (yield: 46%).
Synthesis Example 25
Synthesis of N2-tert-butoxycarbonyl-N1-[1-methyl-2-(4-
methylsulfinylphenoxy)ethyl]-L-valinamide (Compound No. 328)
1.5 g of m-chloroperbenzoic acid was added to a solution
containing 3.0 g of N2-tert-butoxycarbonyl-N 1-[ 1-methyl-2-(4-
methylthiophenoxy)ethyl]-L-valinamide dissolved in 60 ml of methylene
,o~ 2180000
chloride, at 0°C. After the mixture was stirred for 5 hours at room
temperature, the reaction mixture was filtered. The filtrate was washed
successively with a saturated aqueous solution of potassium carbonate
and water, the organic layer was dried over anhydrous sodium sulfate
and the methylene chloride was removed under reduced pressure. The
obtained oily residue was purified by column chromatography on silica
gel, thus yielding 1.7 g of the desired product in the form of a colorless
crystal (yield: 56%).
Synthesis Example 26
Synthesis of N2-tert-butoxycarbonyl-N 1-[ 1-methyl-2-(4-
methylsulfonylphenoxy)ethyl]-L-valinamide (Compound No. 329)
2.1 g of m-chloroperbenzoic acid was added to a solution
containing 2.0 g of N2-tert-butoxycarbonyl-N1-[1-methyl-2-(4-
methylthiophenoxy)ethyl]-L-valinamide dissolved in 50 ml of methylene
chloride, at 0°C. After the mixture was stirred for 8 hours at a reflux
temperature, the reaction mixture was allowed to sit and cool naturally
to room temperature and filtered. The filtrate was washed successively
with a saturated aqueous solution of potassium carbonate and water, the
organic layer was dried over anhydrous sodium sulfate and the
methylene chloride was removed under reduced pressure. The obtained
residue was purified by column chromatography on silica gel, thus
yielding 1.3 g of the desired product in the form of a colorless prism-
shaped crystal (yield: 60%).
Synthesis Example 27
Synthesis of N1-[2-(4-fluorophenylsulfinyl)-1-methylethyl]-N2-
isopropoxycarbonyl-L-valinamide (Compound No. 354)
1.3 g of m-chloroperbenzoic acid was added to a solution
containing 2.5 g of Nl-[2-(4-fluorophenylthio)-1-methylethyl]-N2-
isopropoxycarbonyl-L-valinamide dissolved in 50 ml of methylene
chloride, at 0°C. After the mixture was stirred for 5 hours at room
temperature, the reaction mixture was filtered. The filtrate was washed
successively with a saturated aqueous solution of potassium carbonate
and water, the organic layer was dried over anhydrous sodium sulfate
and the methylene chloride was removed under reduced pressure. The
,~~ 2180000
obtained residue was purified by column chromatography on silica gel,
thus yielding 1.8 g of the desired product in the form of a colorless
prism-shaped crystal (yield: 69%).
Synthesis Example 28
Synthesis of Nl-[2-(4-fluorophenylsulfonyl)-1-methylethyl]-N2-
isopropoxycarbonyl-L-valinamide (Compound No. 355)
3.4 g of m-chloroperbenzoic acid was added to a solution
containing 2.2 g of Nl-[2-(4-fluorophenylthio)-1-methylethyl]-N2-
isopropoxycarbonyl-L-valinamide dissolved in 50 ml of methylene
chloride, at 0°C. After the mixture was stirred for 8 hours at a reflux
temperature, the reaction mixture was allowed to sit and cool to room
temperature, and then filtered. The filtrate was washed successively
with a saturated aqueous solution of potassium carbonate and water, the
organic layer was dried over anhydrous sodium sulfate and the
methylene chloride was removed under reduced pressure. The obtained
residue was purified by column chromatography on silica gel, thus
yielding 2.0 g of the desired product in the form of a white crystal
(yield: 83%).
Synthesis Example 29
Synthesis of N2-isopropoxycarbonyl-Nl-[1-methyl-2-(2-
methylphenylthio)ethyl]-L-valinamide (Compound No. 367)
1.9 g of N-methylpiperidine was added to a solution containing
3.9 g of N-isopropoxycarbonyl-L-valine dissolved in 80 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 2.6 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 3.5 g of l -methyl-2-(2-
methylphenylthio)ethylamine was added to this mixture at -60°C, and
then the reaction mixture was allowed to sit and warm naturally to
room temperature while being stirred. The whole mixture was stirred
for 20 hours at room temperature. Water was subsequently added to
the reaction mixture. ~ After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous sodium sulfate and
2180000
the methylene chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
yielding 3.6 g of the desired product in the form of a white crystal
(yield: 5 I %).
Synthesis Example 30
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl)-N2-(3
tetrahydrofuranyl)oxycarbonyl-L-valinamide (Compound No. 376)
1.0 g of N-methylmorpholine, and subsequently 0.7 g of 3
tetrahydrofuranyl chloroformate were added to a suspension containing
1.5 g of N I -[2-(4-cyanophenoxy)-1-methylethyl)-L-valinamide
hydrochloride suspended in 100 ml of methylene chloride at -20°C.
The mixture was allowed to sit and warm naturally to room
temperature and then stirred for 2 hours at room temperature. Water
was subsequently added to the reaction mixture. After the
dichloromethane layer was washed with water, the organic layer was
dried over anhydrous magnesium sulfate and then the methylene
chloride was removed under reduced pressure. The residue was
purified by column chromatography on silica gel, thus yielding 1.1 g of
the desired product in the form of white powder (yield: 61 %).
Synthesis Example 31
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-(3
methylcyclohexyloxycarbonyl)-L-valinamide (Compound No. 379)
0.4 g of N-methylmorpholine, and subsequently 0.8 g of 3
methylcyclohexyl chloroformate were added to a suspension containing
1.0 g of N1-[2-(4-cyanophenoxy)-1-methylethyl)-L-valinamide
suspended in 50 ml of methylene chloride at -15°C. The mixture was
allowed to sit and warm naturally to room temperature and then stirred
for 15 hours at room temperature. Water was subsequently added to
the reaction mixture. After the methylene chloride layer was washed
with water, the organic layer was dried over anhydrous magnesium
sulfate and then the methylene chloride was removed under reduced
pressure. The residue was purified by column chromatography on
silica gel, thus yielding 1.2 g of the desired product in the form of a
white crystal (yield: 80%).
2180000
Synthesis Example 32
Synthesis of NI-[2-(4-cyanophenoxy)-1-methylethyl]-N2-
propargyloxycarbonyl-L-valinamide (Compound No. 381)
0.2 g of N-methylmorpholine, and subsequently 0.2 g of
propargyl chloroformate were added to a suspension containing 0.5 g of
NI-(2-(4-cyanophenoxy)-I-methylethyl]-L-valinamide suspended in 30
ml of methylene chloride at -15°C. The mixture was allowed to sit and
warm naturally to room temperature and then stirred for 15 hours at
room temperature. Water was subsequently added to the reaction
mixture. After the methylene chloride layer was washed with water,
the organic layer was dried over anhydrous magnesium sulfate and then
the methylene chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
yielding 0.5 g of the desired product in the form of white powder
(yield: 78%).
Synthesis Example 33
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-(2-
methoxy-1-methylethyl)oxycarbonyl-L-valinamide (Compound No.
383)
L .0 g of N-methylmorpholine, and subsequently 0.7 g of 2-
methoxy-1-methylethyl chloroformate were added to a suspension
containing 1.5 g of N1-[2-(4-cyanophenoxy)-1-methylethyl]-L-
valinamide suspended in 150 ml of methylene chloride at -20°C. The
mixture was allowed to sit and warm naturally to room temperature and
then stirred for 2 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and then the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 0.37 g of the desired product in the form of a
white plated crystal (yield: 20%).
Synthesis Example 34
,o~ 2180000
Synthesis of NI-[2-(4-fluoro-N-methylanilino)-1-methylethyl]-
N2-phenoxycarbonyl-L-valinamide (Compound No. 391 )
1.6 g of N-methylpiperidine was added to a solution containing
3.9 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene
chloride, at -20°C. After the mixture was stirred for 10 minutes at the
same temperature, 2.2 g of isobutyl chloroformate was added to the
mixture, and subsequently the whole mixture was stirred for 1 hour at
-20°C. 3.0 g of 2-(4-fluoro-N-methylanilino)-1-methylethylamine was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous sodium sulfate and the methylene chloride
was removed under reduced pressure. The residue was purified by
column chromatography on silica gel, thus yielding 1.2 g of the desired
product in the form of a white crystal (yield: 19%).
Synthesis Example 35
Synthesis of N2-(4-chlorophenoxycarbonyl)-N1-[2-(4-
cyanophenoxy-1-methylethyl]-L-valinamide (Compound Nos. 395 and
396)
1.7 g of N-methylpiperidine was added to a solution containing
4.7 g of N-(4-chlorophenoxycarbonyl)-L-valine dissolved in 250 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 2.3 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 3.0 g of 2-(4-cyanophenoxy)-1-methylethylamine
was added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 15 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
2180000
~ 07
chloride was removed under reduced pressure. The obtained crude
crystal was purified by column chromatography on silica gel, thus
yielding 0.4 g of the desired product in the form of white powder. In
addition, the powder was purified by HPLC (YMC-063-15, hexane /
ethyl acetate = 55 / 45) to separate two fractions. One fraction having a
short retention time was 0.17 g of white powder having a melting point
of 137 ~ 140°C (yield: 2 %), and another fraction having a long
retention time was 0.17 g of white powder having a melting point of
174 ~ 179°C (yield: 2 %).
Synthesis Example 36
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-(2-
nitrophenoxycarbonyl-L-valinamide (Compound No. 400)
1.3 g of N-methylmorpholine, and subsequently 2.5 g of 2-
nitrophenyl chloroformate were added to a suspension containing 3.4 g
of N1-[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in
100 ml of methylene chloride at -20°C. The mixture was allowed to sit
and warm naturally to room temperature and then stirred for 2 hours at
room temperature. Water was subsequently added to the reaction
mixture. After the methylene chloride layer was washed with water,
the organic layer was dried over anhydrous magnesium sulfate and then
the methylene chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
obtaining 1.0 g of the desired product in the form of a yellow plated
crystal (yield: 18 %).
Synthesis Example 37
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-(4-
fluorophenoxycarbonyl)-L-valinamide (Compound No. 401)
1.2 g of N-methylpiperidine was added to a solution containing
3.0 g of N-(4-fluorophenoxycarbonyl)-L-valine dissolved in 80 ml of
methylene chloride, at -20°C. After the mixture was stirred for 15
minutes at the same temperature, 1.6 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 2.3 g of (-)-2-(4-cyanophenoxy)-1-
methylethylamine was added to this mixture at -60°C, and then the
2180000
ios
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and subsequently the methylene chloride was removed under reduced
pressure. The obtained crude crystal was purified by column
chromatography on silica gel, thus yielding 1.1 g of the desired product
in the form of a white crystal (yield: 23 %).
Synthesis Example 38
Synthesis of N1-[2-(4-cyanophenoxy)-1-methylethyl]-N2-(3,4-
dimethylphenoxycarbonyl)-L-valinamide (Compound No. 403)
0.6 g of N-methylmorpholine, and subsequently 1.2 g of 3,4-
dimethylphenyl chloroformate were added to a suspension containing
1.5 g of N1-[2-(4-cyanophenoxy)-I-methylethyl]-L-valinamide
suspended in 50 ml of methylene chloride at -15°C. The mixture was
allowed to sit and warm naturally to room temperature and then stirred
for L 5 hours at room temperature. Water was subsequently added to
the reaction mixture. After the methylene chloride layer was washed
with water, the organic layer was dried over anhydrous magnesium
sulfate and then the methylene chloride was removed under reduced
pressure. The residue was purified by column chromatography on
silica gel, thus yielding 1.7 g of the desired product in the form of a
white crystal (yield: 74 %).
Synthesis Example 39
Synthesis of N2-tent-butoxycarbonyl-N1-[2-(2-pyridyloxy)-1-
methylethyl]-L-valinamide (Compound No. 409)
2.0 g of N-methylpiperidine was added to a solution containing
4.3 g of N-tert-butoxycarbonyl-L-valine dissolved in 80 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 2.7 g of isobutyl chloroformate was
added to the mixture at -40°C, and subsequently the whole mixture was
stirred for 1 hour at -20°C. 3.3 g of 2-(2-pyridyloxy)-1-
2180000
109
methylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous sodium sulfate and
the methylene chloride was removed under reduced pressure. The
obtained crude crystal was purified by column chromatography on silica
gel, thus yielding 2.0 g of the desired product in the form of colorless
grains (yield: 28 %).
Synthesis Example 40
Synthesis of N1-[2-(5-chloro-2-pyridyloxy)-1-methylethyl]-N2-
isopropyloxycarbonyl-L-valinamide (Compound No. 412)
0.8 g of N-methylmorpholine, and subsequently 0.5 g of
isopropyl chloroformate were added to a suspension containing 1.4 g of
N 1-[2-(5-chloro-2-pyridyloxy)-1-methylethyl]-L-valinamide
hydrochloride suspended in 50 ml of methylene chloride at -15°C. The
mixture was allowed to sit and warm naturally to room temperature and
then stirred for 15 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and then the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 0.6 g of the desired product in the form of
colorless grains (yield: 38 %).
Synthesis example 41 ~..:,; . .
Synthesis of N1-[2-(5-chloro-2-pyridyloxy)-1-methylethyl)-N2-
phenoxycarbonyl-L-valinamide (Compound No. 413)
0.8 g of N-methylmorpholine, and subsequently 0.7 g of phenyl
chloroformate were added to a suspension containing 1.4 g of N1-[2-(5-
chloro-2-pyridyloxy)-1-methylethyl]-L-valinamide hydrochloride
suspended in 50 ml of methylene chloride at -15°C. The mixture was
allowed to sit and warm naturally to room temperature and then stirred
m 2180000
for 15 hours at room temperature. Water was subsequently added to
the reaction mixture. After the methylene chloride layer was washed
with water, the organic layer was dried over anhydrous magnesium
sulfate and then the methylene chloride was removed under reduced
pressure. The residue was purified by column chromatography on
silica gel, thus yielding 0.6 g of the desired product in the form of
colorless grains (yield: 34 %).
Synthesis Example 42
Synthesis of N1-[2-(4-fluoro-N-methylanilino)-1-methylethyl]-
N2-phenoxycarbonyl-L-isoleucinamide (Compound No. 422)
1.9 g of N-methylpiperidine was added to a solution containing
4.8 g of N-phenoxycarbonyl-L-isoleucine dissolved in 80 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 2.6 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 3.5 g of 2-(4-fluoro-N-methylanilino)-1-
methylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous sodium sulfate and
subsequently the methylene chloride was removed under reduced
pressure. The obtained crude crystal was purified by column
chromatography on silica gel, thus yielding 1.1 g of the desired product
in the form of a white crystal (yield: 13 %).
Synthesis Example 43
Synthesis of N2-(ethylthio)carbonyl-N 1-[ 1-methyl-2-(4-
nitrophenoxy)ethyl]-L-valinamide (Compound No. 432)
0.3 g of N-methylmorpholine, and subsequently 0.4 g of ethyl
chlorothioformate were added to a suspension containing 0.9 g of N1-
[1-methyl-2-(4-nitrophenoxy)ethyl]-L-valinamide suspended in 50 ml of
methylene chloride at -15°C. The mixture was allowed to sit and warm
2180000
naturally to room temperature and then stirred for 15 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed with water, the organic
Layer was dried over anhydrous magnesium sulfate, and then the
methylene chloride was removed under reduced pressure. The residue
was purified by column chromatography on silica gel, thus yielding 1.0
g of the desired product in the form of yellow grains (yield: 79 %).
Synthesis Example 44
Synthesis of N2-tent-butoxycarbonyl-N1-[2-(4-cyanophenoxy)-1-
methylethyl]-L-leucinamide (Compound No. 455)
1.5 g of N-methylpiperidine was added to a solution containing
3.4 g of N-tent-butoxycarbonyl-L-leucine dissolved in 60 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 2.0 g of isobutyl chloroformate was
added to the mixture at -40°C, and subsequently the whole mixture was
stirred for 1 hour at -20°C. 2.6 g of 2-(4-cyanophenoxy)-1-
methylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 15
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
obtained crude crystal was purified by column chromatography on silica
gel, thus yielding 5.1 g of the desired product in the form of a colorless
glutinous substance (yield: 86 %).
1 H-NMR: (CpCl3, 8)
0.92 (6H, m)
1.28, 1.32 (3H, d)
1.39, 1.43 (9H, s)
1.46, I .65 (2H, m)
1.65 ( 1 H, m)
3.98 (2H, m)
112 2 ~ $U000
4.06 ( 1 H, m)
4.35 (1H, m)
4.91 ( 1 H, br)
6.46 ( 1 H, br)
6.97 (2H, d)
7.57 (2H, dd)
Synthesis Example 45
Synthesis of N2-tert-butoxycarbonyl-N1-[2-(4-cyanophenoxy)-1-
methylethyl]-L-tert-leucinamide (Compound No. 457)
1.7 g of N-methylpiperidine was added to a solution containing 4
g of N-tent-butoxycarbonyl-L-tert-leucine dissolved in 50 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 2.4 g of isobutyl chloroformate was
added to the mixture at -40°C, and subsequently the whole mixture was
stirred for 1 hour at -20°C. 3.1 g of 2-(4-cyanophenoxy)-1-
methylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 15
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
obtained crude crystal was purified by column chromatography on silica
gel, thus yielding 3.9 g of the desired product in the form of a colorless
amorphous substance (yield: 58 %).
Synthesis Example 46
Synthesis of 2-tert-butoxycarbonylamino-3-methyl-N-[2-(4-
cyanophenoxy)-1-methylethyl]-3-butenic acid amide (Compound No.
460)
0.5 g of N-methylpiperidine was added to a solution containing
1.1 g of 2-tert-butoxycarbonylamino-3-methyl-3-butenic acid dissolved
in 40 ml of methylene chloride, at -20°C. After the mixture was stirred
for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate
"~ 2180000
was added to the mixture at -40°C, and subsequently the whole mixture
was stirred for 1 hour at -20°C. 1.9 g of 2-(4-cyanophenoxy)-1-
methylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at I'OOlll temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous magnesium sulfate
and the methylene chloride was removed under reduced pressure. The
obtained crude crystal was purified by column chromatography on silica
gel, thus yielding 0.3 g of the desired product in the form of a colorless
glutinous substance (yield: 32 %).
Synthesis Example 47
Synthesis of N-[2-(4-cyanophenoxy)-1-methylethyl]-2-
isopropoxycarbonylaminocyclopentylacetic acid amide (Compound No.
462)
0.4 g of N-methylmorpholine, and subsequently 0.5 g of
isopropyl chloroformate were added to a suspension containing 1.2 g of
2-amino-N-[2-(4-cyanophenoxy)-I-methylethyl]cyclopentylacetic acid
amide suspended in 40 ml of methylene chloride at -I S°C. The mixture
was allowed to sit and warm naturally to room temperature and then
stirred for 15 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and then the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 1.4 g of the desired product in the form of a
colorless plated crystal (yield: 90 %).
Synthesis Example 48
Synthesis of NI-[2-(4-cyanophenoxy)-1-methylethyl]-N2-
phenoxycarbonyl-L-norvalinamide (Compound No. 465)
0.5 g of N-methylmorpholine, and subsequently 0.8 g of phenyl
chlc~roformate were added to a suspension containing 1.4 g of N1-[2-(4-
2180000
cyanophenoxy)-I-methylethyl]-L-norvalinamide suspended in 40 ml of
methylene chloride at -15°C. The mixture was allowed to sit and warm
naturally to room temperature and then stirred for 15 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed with water, the organic
layer was dried over anhydrous magnesium sulfate and then the
methylene chloride was removed under reduced pressure. The residue
was purified by column chromatography on silica gel, thus yielding I .I
g of the desired product in the form of a colorless plated crystal (yield:
57 %).
Synthesis Example 49
Synthesis of NI-[2-(4-cyanophenoxy)-1-methylethyl]-N2-
phenoxycarbonyl-L-leucinamide (Compound No. 466)
0.5 g of N-methylmorpholine, and subsequently 0.8 g of phenyl
chloroformate were added to a suspension containing 1.5 g of N1-[2-(4-
cyanophenoxy)-L-methylethyl]-L-leucinamide suspended in 40 ml of
methylene chloride at -15°C. The mixture was allowed to sit and warm
naturally to room temperature and then stirred for 15 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed with water, the organic
layer was dried over anhydrous magnesium sulfate and then the
methylene chloride was removed under reduced pressure. The residue
was purified by column chromatography on silica gel, thus yielding 1.5
g of the desired product in the form of colorless powder (yield: 73 %).
Synthesis Example 50
Synthesis of 2-(4-chlorophenoxycarbonylamino)-N-[2-(4-
cyanophenoxy)-1-methylethyl]cyclopentylacetic acid amide (Compound
No. 471 )
0.4 g of N-methylmorpholine, and subsequently 0.8 g of 4-
chlorophenyl chloroformate were added to a suspension containing 1.2
g of 2-amino-N-[2-(4-cyanophenoxy)-I-methylethyl]cyclopentylacetic
acid amide suspended in 40 ml of methylene chloride at -15°C. The
mixture was allowed to sit and warm naturally to room temperature and
then stirred for I S hours at room temperature. Water was subsequently
»
2180000
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and then the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 0.6 g of the desired product in the form of
colorless grains (yield: 30 %a).
Synthesis Example 51
Synthesis of N2-benzyloxycarbonyl-N1-[2-(4-cyanophenoxy)-1-
methylethyl]-(4-chlorophenyl)glycinamide (Compound No. 475)
0.4 g of N-methylmorpholine, and subsequently 0.6 g of benzyl
chloroformate were added to a suspension containing 1.3 g of N1-[2-(4-
cyanopllenoxy)-1-methylethyl]-(4-chlorophenyl)glycinamide suspended
in 40 ml of methylene chloride at -15°C. The mixture was allowed to
sit and warm naturally to room temperature and then stirred for 15
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed with
water, the organic layer was dried over anhydrous magnesium sulfate
and then the methylene chloride was removed under reduced pressure.
The residue was purified by column chromatography on silica gel, thus
yielding 1.2 g of the desired product in the form of colorless grains
(yield: 70 % j.
Synthesis Example 52
Synthesis of N2-(1-cyano-I-methylethoxycarbonyl)-N1-[2-(4-
cyanophenoxy)-I-methylethyl]-L-valinamide (Compound No. 476)
0.5 g of N-methylmorpholine, and subsequently 0.4 g of 1-cyano-
1-methylethyl chloroformate were added to a suspension containing 0.7
g of N I -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide
hydrochloride suspended in 50 ml of methylene chloride at -20°C. The
mixture was allowed to sit and warm naturally to room temperature and
then stirred for 3 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and then the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
tt6 2180000
on silica gel, thus yielding 0.6 g of the desired product in the form of
colorless grains (yield: 71 %).
Synthesis Example 53
Synthesis of N2-(2-chlorocyclohexyloxycarbonyl)-N1-[2-(4
cyanophenoxy)-1-methylethyl]-L-valinamide (Compound No. 477)
0.4 g of N-methylmorpholine, and subsequently 0.9 g of 2
chlorocyclohexyl chloroformate were added to a suspension containing
1.0 g of N 1-[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide
hydrochloride suspended in 50 ml of methylene chloride at -15°C. The
mixture was allowed to sit and warm naturally to room temperature and
then stirred for 15 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and then the methylene chloride was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 1.1 g of the desired product in the form of a
white crystal (yield: 71 %).
Synthesis Example 54
Synthesis of N2-tert-butoxycarbonyl-N1-[2-(3-chloro-5-
trit7uoromethyl-2-pyridyloxy)-1-methylethyl]-L-valinamide (Compound
No. 479)
2.0 g of N-methylpiperidine was added to a solution containing
5.6 g of N-ter-t-butoxycarbonyl-L-valine dissolved in 100 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 2.7 g of isobutyl chloroformate was
added to the mixture at -40°C, and subsequently the whole mixture was
stirred for 1 hour at -20°C. 1.5 g of 2-(3-chloro-5-trifluoromethyl-2-
pyridyloxy)-1-methylethylamine was added to this mixture at -60°C,
and then the reaction mixture was allowed to sit and warm naturally to
r00111 temperature while being stirred. The whole mixture was stirred
for 20 hours at room temperature. Water was subsequently added to
the reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous sodium sulfate and
m 2180000
the methylene chloride was removed under reduced pressure. The
obtained crude crystal was purified by column chromatography on silica
gel, thus yielding 7.0 g of the desired product in the form of colorless
grains (yield: 77 %).
Synthesis Example 55
Synthesis of N 1-[ 1-(5-chloro-6-ethyl-4-pyrimidinyloxy)-2-
propyl]-N2-isopropoxycarbonyl-L-valinamide (Compound No. 481)
0.34 g of N-methylpiperidine was added to a solution containing
0.7 g of N-isopropoxycarbonyl-L-valine dissolved in 50 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.47 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 0.74 g of 1-(5-chloro-6-ethyl-4-pyrimidinyloxy)-
2-propylamine was added to this mixture at -60°C, and then the reaction
mixture was allowed to sit and warm naturally to room temperature
while being stirred. The whole mixture was stirred for 20 hours at
room temperature. Water was subsequently added to the reaction
mixture. After the methylene chloride layer was washed successively
with a 5% aqueous solution of sodium bicarbonate and water, the
organic layer was dried over anhydrous magnesium sulfate and the
methylene chloride was removed under reduced pressure. The obtained
crude crystal was purified by column chromatography on silica gel, thus
yielding 0.6 g of the desired product in the form of a white prism-
shaped crystal (yield: 43 %).
Synthesis Example 56
Synthesis of N-tent-butoxycarbonyl-L-valyl-N-(4-chlorophenyl)-
N-methyl-DL-alaninamide (Compound No. 490)
0.9 g of N-methylpiperidine was added to a solution containing
2.0 g of N-tent-butoxycarbonyl-L-valine dissolved in 40 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 1.3 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 2.0 g of N 1-(4-chlorophenyl)-N 1-methyl-DL-
alaninamide was added to this mixture at -60°C, and then the reaction
as 2180000
mixture was allowed to sit and warm naturally to room temperature
while being stirred. The whole mixture was stirred for 20 hours at
room temperature. Water was subsequently added to the reaction
mixture. After the methylene chloride layer was washed successively
with a 5% aqueous solution of sodium bicarbonate and water, the
organic layer was dried over anhydrous magnesium sulfate and the
methylene chloride was removed under reduced pressure. The obtained
crude crystal was purified by column chromatography on 'silica gel, thus
yielding 3.4 g of the desired product in the form of a colorless needle
crystal (yield: 87 %).
Synthesis Example 57
Synthesis of N-isopropoxycarbonyl-L-isoleucyl-N-(4-
cyanophenyl)-D-alaninamide (Compound No. 506)
0.26 g of N-methylpiperidine was added to a solution containing
0.57 b of N-isopropoxycarbonyl-L-isoleucine dissolved in 60 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.36 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 0.5 g of N ~ -(4-cyanophenyl)-D-alaninamide was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous sodium sulfate and the methylene chloride
was removed under reduced pressure. The residue was purified by
column chromatography on silica gel, thus yielding 0.5 g of the desired
product in the form of white powder (yield: 49 %).
Synthesis Example 58
Synthesis of N-cyclohexyloxycarbonyl-L-valyl-N-(4-
cyanophenyl)-D-alaninamide (Compound No. 509)
0.6 g of N-methylmorpholine, and subsequently 0.6 g of
cyclopentyl chloroformate were added to a suspension containing 1.0 g
»
9 2180000
of L-valyl-N-(4-cyanophenyl)alaninamide, hydrochloride suspended in
50 ml of methylene chloride at -20°C. The mixture was allowed to sit
and warm naturally to room temperature and then stirred for 15 hours
at room temperature. Water was subsequently added to the reaction
mixture. After the methylene chloride layer was washed with water,
the organic layer was dried over anhydrous magnesium sulfate and then
the methylene chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
yielding 0.6 g of the desired product in the form of a white crystal
(yield: 49 °~o).
Synthesis Example 59
Synthesis of N-phenoxycarbonyl-L-valyl-N-(4-chlorobenzyl)-DL-
alaninamide (Compound No. 516)
0.55 g of N-methylmorpholine, and subsequently 0.43 g of phenyl
chloroformate were added to a suspension containing 0.95 g of L-valyl-
N-(4-chlorobenzyl)-DL-alaninamide hydrochloride suspended in 50 ml
of methylene chloride at -15°C. The mixture was allowed to sit and
warm naturally to room temperature and then stirred for 15 hours at
room temperature. Water was subsequently added to the reaction
mixture. After the methylene chloride layer was washed with water,
the organic layer was dried over anhydrous magnesium sulfate and then
the methylenc chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
yielding 0.9 g of the desired product in the form of white powder
(yield: 75 %).
Synthesis Example 60
Synthesis of N-phenoxycarbonyl-L-valyl-DL-alanine phenyl ester
(Compound No. 522)
0.24 g of N-methylpiperidine was added to a solution containing
0.57 g of N-phenoxycarbonyl-L-valine dissolved in 40 ml of methylene
chloride, at -20°C. After the mixture was stirred for 10 minutes at the
same temperature, 0.33 g of isobutyl chloroformate was added to the
mixture, and subsequently the whole mixture was stirred for 1 hour at
-20°C. 0.5 g of DL-alanine phenyl ester was added to this mixture at
120 2 ~ 800
-60°C, and then the reaction mixture was allowed to sit and warm
naturally to room temperature while being stirred. The whole mixture
was stirred for 20 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed successively with a 5% aqueous solution of sodium bicarbonate
and water, the organic layer was dried over anhydrous magnesium
sulfate and the methylene chloride was removed under reduced
pressure. The residue was purified by column chromatography on
silica gel, thus yielding 0.2 g of the desired product in the form of white
powder (yield: 20 %).
Synthesis Example 61
Synthesis of NI-(4-cyanophenyl)-N2-(2-phenoxycarbonylamino)-
(2Sj-butyryl-D-alaninamide (Compound No. 524)
0.45 g of N-methylpiperidine was added to a solution containing
I .0 g of (2S)-2-phenoxycarbonylaminobutyric acid dissolved in 50 ml
of methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.61 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 0.85 g of N I -(4-cyanophenyl)-D-alaninamide was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The obtained crude
crystal was purified by column chromatography on silica gel, thus
yielding 0.8 g of the desired product in the form of white powder
(yield: 45 %).
Synthesis Example 62
Synthesis of N-isopropoxycarbonyl-L-valyl-N-(4-
cyanophenyljglycinamide (Compound No. 526)
121
0.3 g of N-methylpiperidine was added to a solution containing
0.6 g of N-isopropoxycarbonyl-L-valine dissolved in 40 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.4 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 0.5 g of N 1-(4-cyanophenyl)glycinamide was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The residue was
purified by column chromatography on silica gel, thus yielding 0.5 g of
the desired product in the form of colorless powder (yield: 49 %).
Synthesis Example 63
Synthesis of N2-tert-butoxycarbonyl-Nl-(1,2-dimethyl-2-
phenoxyethylj-L-valinamide (Compound No. 602)
0.6 g of N-methylpiperidine was added to a solution containing
1.3 g of N-terc-butoxycarbonyl-L-valine dissolved in 40 ml of
methylene chloride, at -20°C. After the mixture was stirred for 15
minutes at the same temperature, 0.8 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 1 g of 1,2-dimethyl-2-phenoxyethylamine was
added to this mixture at -60°C, and then the reaction mixture was
allowed to sit and warm naturally to room temperature while being
stirred. The whole mixture was stirred for 20 hours at room
temperature. Water was subsequently added to the reaction mixture.
After the methylene chloride layer was washed successively with a 5%
aqueous solution of sodium bicarbonate and water, the organic layer
was dried over anhydrous magnesium sulfate and the methylene
chloride was removed under reduced pressure. The obtained oily
substance was purified by column chromatography on silica gel, thus
122 2 ~ 8000
yielding 1.3 g of the desired product in the form of a white glutinous
substance (yield: 57 %).
1 H-NMR: (CDC13, b)
0.8 ~ 1.02 (6H, m)
1.18 ~ 1.45 (15H, m)
2.10 ( 1 H,
m)
3.65 ~ 4.45 (3H, m)
5.18 (1H, m)
6.38 (1 H, m)
6.72 ~ 7.35 (5H, m)
Synthesis Example 64
Synthesis of N2-tert-butoxycarbonyl-N 1-[2-(4-cyanophenoxy)-
1,2-dimethylethyl)-L-valinamide (Compound No. 607)
0.5 g of N-methylpiperidine was added to a solution containing
1.1 g of N-tent-butoxycarbonyl-L-valine dissolved in 60 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.7 g of isobutyl chloroformate was
added to the mixture, and subsequently the whole mixture was stirred
for 1 hour at -20°C. 1.0 g of 2-(4-cyanophenoxy)-1,2-
dimethylethylamine was added to this mixture at -60°C, and then the
reaction mixture was allowed to sit and warm naturally to room
temperature while being stirred. The whole mixture was stirred for 20
hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed
successively with a 5% aqueous solution of sodium bicarbonate and
water, the organic layer was dried over anhydrous sodium sulfate and
the methylene chloride was removed under reduced pressure. The
residue was purified by column chromatography on silica gel, thus
yielding 1.2 g of the desired product in the form of a colorless glassy
substance (yield: 61 %).
1 H-NMR: (CDC13, 8)
0.79 ~ 1.03 (6H, m)
1.15 -- 1.46 (15H, m)
,~~ 2180000
2.03 (1 H,
m)
3.63 ~ 4.72 (3H, m)
5.06 ( 1 H,
m)
6.30 (1H, m)
6.83 ~ 7.60 (4H, m)
Synthesis Example 65
Synthesis of N 1-[2-(4-cyanophenoxy)propyl]-N2-
phenoxycarbonyl-L-valinamide (Compound No. 750)
0.16 g of N-methylpiperidine was added to a suspension
containing 0.25 g of NI-[2-(4-cyanophenoxy)propyl]-L-valinamide
hydrochloride suspended in 20 ml of methylene chloride, at -20°C.
After the mixture was stirred for 10 minutes at the same temperature,
0.13 g of phenyl chloroformate was added drop by drop to the mixture,
and then the reaction mixture was allowed to sit and warm naturally to
room temperature while being stirred. The whole mixture was stirred
for 3 hours at room temperature. After the methylene chloride was
removed under reduced pressure, the residue was purified by column
chromatography on silica gel, thus yielding 0.2 g of the desired product
in the form of a white glutinous substance (yield: 63 %).
1 H-NMR: (CDC13, 8)
1.00 (6H, m)
1.23 (3H, d)
2.13 ( 1 H,
m)
3.31 ( 1 H,
m)
4.00 (2H, m)
4.49 ( 1 H,
m)
5.93 ( 1 H,
d)
6.52 ( 1 H,
m)
6.80 ~ 7.56 (9H, m)
Synthesis Example 66
Synthesis of N 1-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-N2-(2-
fluorophenoxycarbonyl)-L-valinamide (Compound No. 777)
124 2
0.21 g of N-methylmorpholine, and subsequently 0.36 g of 2-
l7uorophenyl chloroformate, were added to a solution containing 0.6 g
of N I -[2-(4-cyanophenoxy)-1,1-dimethylethyl]-L-valinamide dissolved
in 40 ml'of methylene chloride at -15°C. The mixture was stirred for
15 hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed with
water, the organic layer was dried over anhydrous magnesium sulfate
and then the methylene chloride was removed under reduced pressure.
The residue was purified by column chromatography on silica gel, thus
yielding 0.52 g of the desired product in the form of a colorless grain
crystal (yield: 58 %).
Synthesis Example 67
Synthesis of N 1-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-N2-(3-
fluorophenoxycarbonyl)-L-valinamide (Compound No. 779)
0.24 g of N-methylmorpholine, and subsequently 0.42 g of 3-
i7uorophenyl chloroformate were added to a solution containing 0.7 g
of N1-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-L-valinamide dissolved
in 40 ml of methylene chloride at -15°C. The mixture was stirred for
15 hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed with
water, the organic layer was dried over anhydrous magnesium sulfate
and then the methylene chloride was removed under reduced pressure.
The residue was purified by column chromatography on silica gel, thus
yielding 0.53 g of the desired product in the form of a colorless grain
crystal (yield: 51 %).
Synthesis Example 68
Synthesis of N1-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-N2-(4-
lluorophenoxycarbonyl)-L-valinamide (Compound No. 781 )
0.45 g of N-methylmorpholine, and subsequently 0.78 g of 4-
fluorophenyl chloroformate were added to a solution containing 1.3 g
of N 1-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-L-valinamide dissolved
in 50 ml of methylene chloride at -15°C. The mixture was stirred for
15 hours at room temperature. Water was subsequently added to the
reaction mixture. After the methylene chloride layer was washed with
2180000
water, the organic layer was dried over anhydrous magnesium sulfate
and then the methylene chloride was removed under reduced pressure.
The residue was purified by column chromatography on silica gel, thus
yielding 1.45 g of the desired product in the form of a colorless grain
crystal (yield: 76 %).
Synthesis Example 69
Synthesis of N1-[2-(4-cyanophenoxy)-1,1-dirnethylethyl]-N2-(4-
fluorophenoxycarbonyl)-DL-valinamide (Compound No. 782)
0.58 g of N-methylpiperidine was added to a solution containing
1.5 g of N-(4-fluorophenoxycarbonyl)-DL-valine dissolved in 50 ml of
methylene chloride, at -20°C. After the mixture was stirred for 10
minutes at the same temperature, 0.8 g of isobutyl chloroformate was
added to the mixture at -20°C, and then the reaction mixture was
stirred
for 30 minutes at the same temperature. 1.12 g of 2-(4-cyanophenoxy)-
1,1-dimethylamine was added to the reaction mixture at -60°C, and
subsequently the whole mixture was stirred for 15 hours at room
temperature. Water was added to the reaction mixture. After the
methylene chloride layer was washed with water, the organic layer was
dried over anhydrous magnesium sulfate and then the methylene
chloride was removed under reduced pressure. The residue was
purified by column chromatography on silica gel, thus yielding 1.4 g of
the desired product in the form of a colorless grain crystal (yield: 56
% ).
Synthesis Example 70
Synthesis of N1-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-N2-(2,4-
difluorophenoxycarbonyl)-L-valinamide (Compound No. 785)
0.24 g of N-methylmorpholine, and subsequently 0.45 g of 2,4-
difluorophenyl chloroformate were added to a solution containing 0.68
g of N1-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-L-valinamide
dissolved in 40 ml of methylene chloride at -15°C. The mixture was
stirred for 15 hours at room temperature. Water was subsequently
added to the reaction mixture. After the methylene chloride layer was
washed with water, the organic layer was dried over anhydrous
magnesium s~~lfate and then the methylene chloride was removed under
126
reduced pressure. The residue was purified by column chromatography
on silica gel, thus yielding 0.3 g of the desired product in the form of a
colorless grain crystal (yield: 29 %).
The agricultural or horticultural fungicide according to the
present invention includes an amino-acid amide derivative represented
by Formula [1] as an active ingredient. In the case where the
compounds according to the present invention are employed as an
agricultural or horticultural fungicide, the compounds acting as the
active ingredient can be formulated appropriately, depending on the
purpose. The active ingredient is usually diluted in an inert liquid or a
solid carrier, and a surfactant or the like is added thereto, if necessary.
The mixture is then formulated in a known manner into, for example, a
fine powder, a wettable powder, an emulsifiable concentrate, granules,
or the like.
The proportion of the active ingredient is selected as needed.
When formulated into a fine powder or granules, 0.1 % by weight to
20% by weight of the active ingredient is preferred. For an
emulsifiable concentrate or wettable powder, 5% by weight to 80% by
weight of the active ingredient is preferred.
As the suitable carriers employed in the formulation, there can be
mentioned solid carriers such as talc, bentonite, clay, kaolin,
diatomaceous earth, white carbon, vermiculite, slaked lime, siliceous
sand, ammonium sulfate, urea, or the like; and liquid carriers such as
isopropyl alcohol, xylene, cyclohexanone, methylnaphthalene, and the
like.
As the surfactants and dispersants, there can be mentioned
dinaphthylmethane disulfonate, alcohol sulfates, alkyl aryl sulfonates,
ligninesulfonates, polyoxyethylene glycol ethers, polyoxyethylene alkyl
aryl ethers, polyoxyethylene sorbitan monoalkylates, and the like. As
the auxiliary agents, there can be mentioned carboxymethylcellulose,
and the like.
The formulated agricultural or horticultural fungicide according
to the present invention can be spread in an appropriate diluted
concentration or can be applied directly.
127
The rate of application of the agricultural or horticultural
fungicide according to the present invention may vary depending on the
type of active compound employed, the kind of the pest or disease to be
controlled, the nature of occurrence of the pest or disease, the degree of
damage, environmental conditions, the form of preparation to be used,
and the like. When the agricultural or horticultural fungicide of the
present invention is applied directly in the form of fine powder or
granules, it is recommended that the rate of application of the active
ingredient be suitably chosen within the range of 0.1 g to 5 kg per 10
aces, and preferably, in the range of 1 g to 1 kg per 10 aces. In
addition, when the fungicide of the present invention is in the form of a
liquid such as an emulsifiable concentrate or a wettable powder, it is
recommended that the ratio for application of the active ingredient be
suitably chosen within the range of 0.1 ppm to 10,000 ppm, and
preferably within the range of 10 ppm to 3,000 ppm.
The agricultural or horticultural fungicide according to the
present invention can be employed for a number of purposes: for
example, treating seeds, spraying of stem and leaf portions, applying to
the soil, and injection into irrigation water. The agricultural or
horticultural fungicide of the present invention can control plant
diseases caused by fungi in the Oornycetes, Ascomycetes,
Deccteroin,ycetes, and Basidiomycetes or other pathogenic fungi.
The fungi include, but are not limited to, Pseudoperonospora
such as cucumber downy mildew (Pseudoperonospora cubensis);
Playtophthora such as tomato late blight (PlZytoplZthora infestans); and
Plasm.ohara such as grape downy mildew (Plasmopara viticola). The
compounds according to the present invention may be employed alone
or in combination with other fungicides, insecticides, herbicides, plant
growth modifiers, fertilizers or the like.
Next, the representative formulations are illustrated with
reference to the following Formulation Examples, wherein all "%"
represent "percent byveight".
Formulation Example 1: Fine powder
2% of Compound No. 15, 5% of diatomaceous earth, and 93% of
clay were uniformly mixed and ground into a fine powder.
2180000
Formulation Example 2: Wettable powder
50% of Compound No. 16, 45% of diatomaceous earth, 2% of
sodium dinaphthylmethanedisulfonate, and 3% of sodium ligninsulfonate
were uniformly mixed and ground into a wettable powder.
Formulation Example 3: Emulsifiable concentrate
30% of Compound No. 19, 20% of cyclohexanone, 11 % of
polyoxyethylene alkyl aryl ether, 4% of calcium alkylbenzenesulfonate,
and 35% of methyl naphthalene were uniformly dissolved, thus obtaining
an emulsifiable concentrate.
Formulation Example 4: Granules
5% of Compound No. 101, 2% of sodium lauryl alcohol sulfate,
5% of sodium ligninsulfonate, 2% of carboxymethylcellulose, and 86%
of clay were mixed and ground. 20% of water was added to the ground
mixture. The resulting mixture was kneaded and formed into granules
of 14 IIIeSh to 32 mesh by means of an extrusion granulator, and then
dried into the desired granules.
Effects of the Invention
The agricultural or horticultural fungicides according to the
present invention exhibit high ability to prevent fungal infection by
cucumber downy mildew (Pseeedo~eronosnora cubensis), tomato late
blight (PhytoylZthora infestans), and grape downy mildew (Plasmopara
viticola ). In addition, the agricultural or horticultural fungicides
according to the present invention not only exhibit the ability to prevent
fungal infection, but also exhibit the ability to eliminate pathogenic
fungi after it has invaded a host plant.
Furthermore, the agricultural or horticultural fungicides of the
present invention are also characterized in that they are not harmful
chemicals and exhibit excellent characteristics such as systemic action,
residual activity, and persistence after rain-fall.
129
The effects of the compounds according to the present invention
are now illustrated with reference to the following Test Examples. In
the Test Examples, the compounds mentioned below are employed as
Comparative Compounds.
Comparative Compound X:
N2-tert-butoxycarbonyl-N ~ -(2-phenoxyethyl)-D-alaninamide
(described in Japanese Patent Application First Publication No. 62-
89696)
Comparative Compound Y:
N2-tert-butoxycarbonyl-N 1-(2-phenylthioethyl)-D-alaninamide
(described in Japanese Patent Application First Publication No. 62-
89696)
Test Example 1:
Test on the Effect of Preventing Infection by Cucumber Downy
Mildew (Pseudoperonospora cube~2sis)
Cucumber seeds (variety: "Sagami hanjiro") were sown at a rate
of 10 seeds each in a square PVC (polyvinyl chloride) pot, wherein each
side is 9 cm wide. The seeds were allowed to grow in a greenhouse, for
7 days, to the cotyledonous stage. A wettable powder prepared as in
Formulation Example 2 was diluted with water to a concentration of
500 ppm of the active ingredient, and the aqueous preparation obtained
was then applied at a rate of 10 ml per pot to the cucumber seedlings at
their cotyledonous stage. After drying in the air, the plant was
inoculated with a conidiospore suspension of cucumber downy mildew
(Pseudoperon.ospora cuhensis) fungi using a spray and then placed in a
moist chamber at 22°C for 24 hours, and then placed in a greenhouse.
On the seventh day after the inoculation, the affected area was rated.
The results of the test in accordance with the standards of evaluation as
shown in Table 14 are given in Table 15.
2180000
Table 14
Standard of evaluation: Affected area
Class A: No lesions were observed
Class B: Affected area is less than 25%
Class C: Affected area is 25% or more and
less than 50%
Class D: Affected area is 50% or more
131
Table I S
Compound Evaluation Compound No. Evaluation Compound Evaluation
No. No.
1 B 1 2 4 B 2 4 6 B
2 A 1 2 9 A 3 2 3 A
4 A 1 3 4 A 3 2 6 A
6 A 1 3 5 A 3 2 ? A
7 A 1 5 4 A 3 2 8 A
8 B 1 5 7 A 3 2 9 B
1 0 A 1 6 0 A 3 3 1 B
1 3 A 1 6 3 A 3 3 3 B
1 4 B 1 6 6 A 3 3 5 A
1 6 A 1 6 9 A 3 3 6 A
1 ? A 1 8 4 A 3 3 8 A
1 8 B 1 9 3 A 3 3 9 A
19 A 195 B 340 A
23 A 204 B 341 A
2 4 B 2 0 5 A 3 4 2 A
26 B 208 A 343 A
2 ? A 2 1 1 A 3 4 4 B
2 9 A 2 1 2 A 3 4 5 A
33 A 213 A 34? A
4 2 A 2 1 4 A 3 4 8 B
4 5 A 2 1 5 A 3 4 9 A
4 B 2 1 6 A 3 5 0 B
63 A 21? A 351 A
? ? A 2 1 9 A 3 5 2 A
8 8 A 2 2 0 A 3 5 3 A
9 8 A 2 2 1 A 3 5 4 A
1 0 1 A 2 2 ? A 3 5 5 A
1 04 A 2 2 8 A 3 5 6 A
1 0 ? A 2 3 0 A 3 5 ? B
1 0 8 A 2 3 1 A 3 5 8 A
1 1 2 A 2 3 2 A 3 5 9 A
1 1 4 A 2 3 5 A 3 6 0 A
1 1 5 A 2 3 6 A 3 6 1 B
1 1 6 A 2 3 8 A 3 6 2 B
132 2180000
Table 15 (continued)
Compound Evaluation Compound Evaluation Compound Evaluation
No. No. No.
3 6 3 A 4 0 1 A 4 6 5 A
3 6 4 B 4 0 2 A 4 6 6 A
3 6 5 A 4 0 3 A 4 6 7 A
3 6 6 A 4 0 5 A 4 6 8 A
3 6 7 A 4 0 8 A 4 7 1 B
3 6 8 A 4 1 0 A 4 7 7 A
3~6 9 A 4 1 1 B 4 8 2 A
3 7 0 A 4 1 2 A 4 8 6 A
3 7 1 A 4 1 3 A 4 9 2 A
3 7 2 A 4 1 4 A 4 9 3 A
3 7 3 A 4 1 6 A 4 9 5 A
3 7 4 A 4 1 7 A 4 9 6 B
3 7 6 A 4 1 8 A 4 9 9 B
3 7 7 A 4 1 9 A 5 0 2 A
3 7 8 A 4 2 1 A 5 0 6 A
3 7 9 A 4 2 2 A 5 0 8 A
3 8 0 A 4 2 3 A 5 0 9 A
3 8 1 A 4 2 4 A 5 1 0 A
3 8 2 A 4 2 5 A 5 1 1 A
3 8 3 A 4 2 6 A 5 1 2 A
3 8 5 A 4 2 7 A 5 1 3 A
3 8 6 A 4 2 9 A 5 1 7 A
3 8 7 B 4 3 0 A 5 1 9 A
3 8 8 A 4 3 1 A 5 2 3 A
3 8 9 A 4 3 2 A 5 2 5 A
3 9 0 A 4 3 9 A 6 0 5 A
3 9 1 A 4 4 0 A 6 0 6 A
3 9 2 A 4 5 1 A 6 0 7 A
3 9 3 A 4 5 2 A 7 0 8 A
3 9 4 A 4 5 3 A 7 6 8 A
3 9 5 A 4 5 5 A 7 7 0 A
3 9 7 A 4 5 6 A Comparative D
Example
X
3 9 9 A 4 6 2 A co~"~ara~e D
Example
r
'~~ 2180000
Test Example 2:
Test on the Effect of Treating Infection by Cucumber Downy
Mildew (Pseudoperonospora cccbensis)
Cucumber seeds (variety: "Sagami hanjiro") were sown at a rate
of 10 seeds each in a square PVC (polyvinyl chloride) pot, wherein each
side is 9 cm wide. The seeds were allowed to grow in a greenhouse, for
7 days, to the cotyledonous stage. The seedlings were inoculated with a
spore suspension of cucumber downy mildew (Pseudoperonospora
cccbercsis) fungi and then placed in a moist chamber at 22°C for 24
hours. After drying in the air, a wettable powder prepared as in
Formulation Example 2 was diluted with water to a concentration of
500 ppm of the active ingredient, and the aqueous preparation obtained
was then applied at a rate of 10 ml per pot to the cucumber seedlings.
The seedlings were then placed in a green house. On the seventh day
after the inoculation, the extent or lesions was rated. The results of the
lest in accordance with the standards of evaluation shown in Table 14
are given in Table 16.
134
Table 16
Compound Evaluation Compound Evaluation Compound Evaluation
No. No. No.
4 B 1 04 A 1 6 3 A
1 0 A 1 0 ? A 1 8 4 B
1 3 A 1 0 8 B 2 1 2 A
1 6 A 1 1 4 B 2 1 3 A
1 9 B 1 1 5 A 2 1 5 A
2 9 A 1 1 6 A 2 1 6 B
3 3 A 1 2 4 A 2 1 9 A
4 2 A 1 2 9 B 2 2 0 B
4 5 A 1 3 4 A 2 2 1 A
4 B 1 3 5 A 2 2 8 B
6 3 A 1 5 4 A 2 3 0 B
7 ? B 1 5 ? A 2 3 1 A
8 8 B 1 6 0 A 2 3 2 A
135 2 ~ 80000
Table 16 (continued)
Compound Evaluation Compound Evaluation Compound Evaluation
No. No. No.
2 3 8 A 3 8 2 A 4 5 6 A
3 3 3 A 3 8 3 A 4 6 2 A
3 3 5 A 3 8 5 A 4 6 5 A
336 A 386 A 466 A
3 4 0 B 3 8 8 A 4 6 7 B
3 4 1 B 3 9 4 A 4 6 8 A
3 4 2 A 3 9 5 A 4 7 7 B
3 4 5 A 3 9 7 A 4 8 6 B
3 4 8 B 3 9 9 A 4 9 2 A
3 4 9 A 4 0 1 A 4 9 5 A
3 5 1 A 4 0 2 A 4 9 9 B
3 5 2 A 4 0 5 A 5 0 2 A
3 5 3 A 4 1 4 A 5 0 6 A
3 5 4 A 4 1 6 A 5 0 8 A
3 5 5 A 4 1 7 A 5 0 9 A
3 5 6 A 4 1 8 A 5 1 3 A
3 5 8 A 4 1 9 A 5 1 'l A
3 6 0 B 4 2 3 A 5 1 9 B
3 6 5 A 4 2 4 A 5 2 3 A
3 6 7 B 4 2 5 A 6 0 6 A
3 6 8 A 4 2 7 A 6 0 7 B
3 6 9 A 4 2 9 A 7 0 8 A
3 7 1 A 4 3 9 A 'l 6 8 B
3 7 4 A 4 5 1 A '7 7 0 B
3 7 6 A 4 5 2 A ComparativeD
Example
X
3 7 8 A 4 5 3 A ComparativeD
Example
Y
3 8 1 B 4 5 5 A
n~ 2180000
Test Example 3:
Test on the Effect of Preventing Infection by Tomato Late Blight
(Ph_ytophthora infestnns)
One tomato seedling (variety: "Ponterosa") was transplanted into
each ceramic pot (diameter: 12 cm) and grown in a greenhouse. A
wettable powder prepared as in Formulation Example 2 was diluted
with water to a concentration of 500 ppm of the active ingredient, and
the aqueous preparation obtained was then applied at a rate of 20 ml per
pot to the tomato seedlings at their 6- or 7-leaf stage. After drying in
tile air, the plant was inoculated with a zoosporangium suspension of
tomato late blight (PlZytophtlZOrn irrfestans) fungi and then placed in a
moist chamber at 22°C. On the fourth day after the inoculation, the
affected area was rated. The index of incidence was determined based
on the size of the affected area as shown in Table 17. The degree of
damage was calculated according to the following first equation and the
index of incidence and the ability to prevent the disease (controlling
activity) was calculated according to the second equation. The results
are shown in Table 18.
Table 17
Incidence Index Affected Area
0 No lesions
Less than 5%
2 5% or more and less than 33.3%
3 33.3% or more and less than 66.6%
4 66.6% or more
2180000
Equation ( 1 )
Degree of E (Incidence Index X Number of Proper Leaves)
Damage (%) -
4 X Number of Leaves Examined
EqIIWIOIl (2)
Controlling Degree of Damage
Activity (%) - ( 1 - ) X 100
Degree of Damage in Untreated Plot
2180000
Table 18
Compound At;vlolGng Compound A~.~ Compound
Controlling
No. (%) No. oiling No. %~
~ (%) vity
~
2 1 00 1 6 0 1 0 0. 3 7 8 1 0 0
4 1 00 1 6 3 1 0 0 3 7 9 1 0 0
6 1 00 1 6 6 1 0 0 3 8 0 1 0 0
7 1 00 1 6 9 1 0 0 3 8 1 1 0 0
1 1 00 1 8 4 1 0 0 3 8 2 1 0 0
0
1 1 00 1 9 3 1 0 0 3 8 6 1 0 0
3
1 1 00 2 1 3 1 0 0 3 8 8 1 0 0
6
1 1 00 2 1 5 1 0 0 3 9 0 1 0 0
7
1 1 00 2 1 7 1 0 0 3 9 1 1 0 0
9
2 1 00 2 2 0 1 0 0 3 9 3 1 0 0
3 ~
2 1 00 2 2 1 1 0 0 3 9 4 1 0 0
7
2 1 00 2 2 8 1 0 0 3 9 5 1 0 0
9
3 1 00 2 3 1 1 0 0 3 9 7 1 0 0
3
4 1 00 2 3 2 1 0 0 3 9 9 1 0 0
2
4 1 00 2 3 5 1 0 0 4 0 1 1 0 0
5
6 1 00 2 3 8 1 0 0 4 0 2 1 0 0
3
7 1 00 3 2 3 1 0 0 4 0 3 1 0 0
7
8 1 00 3 2 6 1 0 0 4 0 4 1 0 0
8
9 1 00 3 3 6 1 0 0 4 0 5 1 0 0
8
1 0 1 00 3 4 5 1 0 0 4 0 8 1 0 0
1
1 0 1 00 3 5 2 1 0 0 4 1 4 1 0 0
4
1 0 1 00 3 5 6 1 0 0 4 1 7 1 0 0
7
1 0 1 00 3 5 9 1 0 0 4 1 8 1 0 0
8
1 1 1 00 3 6 0 1 0 0 4 2 3 1 0 0
2
1 1 1 00 3 6 4 1 0 0 4 2 4 1 0 0
5
1 1 1 00 3 6 5 1 0 0 4 2 7 1 0 0
6
1 2 1 00 3 6 9 I 0 0 4 3 0 I 0 0
9
1 3 1 00 3 7 I I 0 0 ~ 4 3 9 1 0 0
4
1 3 1 00 3 7 2 I 0 0 4 4 0 1 0 0
5
1 5 1 00 3 7 3 1 0 0 4 5 1 1 0 0
4
1 5 1 00 3 7 4 I 0 0 4 6 2 I 0 0
7
139 2 ~ 80000
Table 18 (continued)
Controlling Controlling Controllin
Compound Compound Compound .
Activity Activity
No. (%) No. (%a) No. Activity
(%)
4 65 1 0 0 5 0 2 1 0 0 6 0 6 1 0 0
4 66 1 0 0 5 0 8 1 0 0 6 0 7 1 0 0
4 67 1 0 0 5 0 9 1 0 0 7 0 8 1 0 0
4 77 1 0 0 5 1 3 1 0 0 7 6 8 1 0 0
4 82 1 0 0 5 1 9 1 0 0 '7 7 0 1 0 0
4 92 1 0 0 5 2 3 1 0 0 Comparative
0
Example
X
4 95 1 0 0 6 0 5 1 0 0 pletYe 0
Exam
140 ~~ 0000
Test Example 4:
Test on the Effect of Preventing Infection by Grape Downy
Mildew (Plccs~rz.opnra viticola)
Rooted grape cuttings (variety: "Kyoho") were each grown from
a cutting, pruned, grown in a ceramic pot (diameter: 12 cm), and
maintained in a greenhouse. A wettable powder prepared as in
rormulation Example 2 was diluted with water to a concentration of
500 ppm of the active ingredient, and the aqueous preparation obtained
was then appl ied at a rate of 20 ml per pot to the grape seedlings at their
4- or 5-leas' stage. After drying in the air, the plant was inoculated with
a zoosporangi um suspension of grape downy mildew (Plasmopara
v~iticol~c) fungi and then placed in a moist chamber at 22°C for 24
hours. On the seventh day in the greenhouse after the inoculation, the
plant was again placed in a moist chamber at 22°C for 24 hours to
cultivate conidiospores. The incidence area where conidiospores grew
on each leaf was examined.
The incidence index was determined according to the standards
S110W17 111 Table 17. The degree of damage was calculated according to
Equation (1 j and the incidence index and the ability to prevent the
disease (controlling activity) was calculated according to Equation (2).
The results of the test are shown in Table 19.
2180000
Table 19
Controlling Controlling Controllin
Compound Activity Compound Activity Compound pctivi
No. (%) No. No. g
(%a)
(%)
tY
2 1 00 1 63 1 00 3 8 0 1 00
4 1 00 1 66 1 00 3 8 1 1 00
6 1 00 1 69 1 00 3 8 2 1 00
7 1 00 1 84 1 00 3 8 6 1 00
1 0 1 00 1 93 1 00 3 8 8 1 00
1 3 1 00 2 13 1 00 3 9 0 1 00
1 6 1 00 2 15 1 00 3 9 1 1 00
1 7 1 00 2 17 1 00 3 9 3 1 00
1 9 1 00 2 20 1 00 3 9 4 1 00
2 3 1 00 2 21 1 00 3 9 5 1 00
2 7 1 00 2 28 1 00 3 9 7 1 00
2 9 1 00 2 31 1 00 3 9 9 1 00
3 3 1 00 2 32 1 00 4 0 1 l 00
4 2 1 00 2 35 1 00 4 0 2 1 00
4 5 1 00 2 38 1 00 4 0 3 1 00
6 3 1 00 3 23 1 00 4 0 4 1 00
.
7 7 1 00 3 26 1 00 4 0 5 1 00
8 8 1 00 3 36 1 00 4 0 8 1 00
9 8 1 00 3 45 1 00 4 1 4 1 00
1 0 1 1 00 3 52 1 00 4 1 7 1 00
1 0 4 1 00 3 56 1 00 4 1 8 1 00
1 0 7 1 00 3 59 1 00 4 2 3 1 00
1 0 8 1 00 3 60 1 00 4 2 4 1 00
1 1 2 1 00 3 64 1 00 4 2 7 1 00
1 1 5 1 00 3 65 1 00 4 3 0 1 00
1 1 6 1 00 3 69 1 00 4 3 9 1 00
1 2 9 1 00 3 71 1 00 4 4 0 1 00
1 3 4 1 00 3 72 1 0C 4 5 1 1 00
1 3 5 1 00 3 73 1 00 4 6 2 1 00
1 5 4 1 00 3 74 1 00 4 6 5 1 00
1 5 7 1 00 3 78 1 00 4 6 6 1 00
1 6 0 1 00 3 79 1 00 4 6 7 1 00
142 2 ~ $0000
Table 19 (continued)
Controlling Controlling Controllin
Compound Compound Com ound g
No. '~~w~~ Np. Activity p Activity
(%) (%a) N0. (%)
4 7 7 1 0 0 5 0 9 1 0 0 6 0 7 1 0 0
4 8 2 1 0 0 5 1 3 1 0 0 7 0 8 1 0 0
4 9 2 1 0 0 5 1 9 1 0 0 7 6 8 1 0 0
4 9 5 1 0 0 5 2 3 1 0 0 7 7 0 1 0 0
0 2 1 0 0 6 0 5 1 0 0 Comparative
Example
X
5 0 8 1 0 0 6 0 6 1 0 0 tYe
Eo
I
amp
e
143 2 ~ 8000
Test Example 5:
Test on the Effect of Preventing Infection by Cucumber Downy
Mildew (Pseudoperonosporn cubensis)
Cucumber seeds (variety: "Sagami hanjiro") were sown at a rate
of 10 seeds each in a square PVC (polyvinyl chloride) pot, wherein each
side is 9 cm wide. The seeds were allowed to grow in a greenhouse, for
7 days, to the cotyledonous stage. A wettable powder prepared as in
Formulation Example 2 was diluted with water to a concentration of
100 ppm of the active ingredient, and the aqueous preparation obtained
was then applied at a rate of 10 ml per pot to the cucumber seedlings at
their cotyledonous stage. After drying in the air, the plant was
inoculated with a conidiospore suspension of cucumber downy mildew
(Pseudoperonosporn cubensis) fungi using a spray and then placed in a
moist chamber at 22°C for 24 hours, and then placed in a greenhouse.
On the seventh day after the inoculation, the affected area was rated.
The results of the test in accordance with the standards of evaluation as
S110W11 111 Table 14 are given in Table 20.
Table 20
Compound No. Evaluation
777 A
779 A
781 A
785 A
144 2 ~ 80000
Test Example 6:
Test on the Effect of Treating Infection by Cucumber Downy
Mildew (Pseudoperon.ospora ccrber~si.s)
Cucumber seeds (variety: "Sagami hanjiro") were sown at a rate
of 10 seeds each in a square PVC (polyvinyl chloride) pot, wherein each
side is 9 cm wide. The seeds were allowed to grow in a greenhouse, for
7 days, to the cotyledonous stage. The seedlings were inoculated with a
spore suspension of cucumber downy mildew (Pseudoperonospora
cccbecz.sisj fungi and then placed in a moist chamber at 22°C for 24
hours. After drying in the air, a wettable powder prepared as in
Formulation Example 2 was diluted with water to a concentration of
500 ppm of the active ingredient, and the aqueous preparation obtained
was then applied at a rate of 10 ml per pot to the cucumber seedlings.
The seedlings were then placed in a green house. On the seventh day
after the inoculation, the extent of lesions was rated.
The results of the test in accordance with the standards of
evaluation shown in Table 14 are given in Table 21.
Table 21
Compound No. Evaluation
777 A
779 A
781 A
785 A
145. 2 ~ 8U000
Test Example 7:
Test on the Effect of Preventing Infection by Tomato Late Blight
(PhytohlZthoro infestnns)
One tomato seedling (variety: "Ponterosa") was transplanted into
each ceramic pot (diameter: 12 cm) and grown in a greenhouse. A
wettable powder prepared as in Formulation Example 2 was diluted
with water to a concentration of 500 ppm of the active ingredient, and
the aqueous preparation obtained was then applied at a rate of 20 ml per
pot to the tomato seedlings at their 6- or 7-leaf stage. After drying in
the air, the plant was inoculated with a zoosporangium suspension of
tomato late blight (Phytophtlzorn infestnns) fungi and then placed in a
moist chamber at 22°C. On the fourth day after the inoculation, the
affected area on each leaf was rated.
The index of incidence was determined based on the size of the
affected area as shown in Table 17. The degree of damage was
calculated according to the following first equation and the index of
incidence and the ability to prevent the disease (controlling activity) was
calculated according to the second equation. The results are shown in
Table 22.
Table 22
Compound No. Controlling Activity (%)
777 100
779 100
781 100
785 100
t46 2180000
Test Example 8:
Test on the Effect of Preventing Infection by Grape Downy
Mildew (Plasr~zoparn viticoln)
Rooted grape cuttings (variety: "Kyoho") were each grown from
a cutting, pruned, grown in a porcelain pot (diameter: 12 cm), and
maintained in a greenhouse. A wettable powder prepared as in
rormulation Example 2 was diluted with water to a concentration of
500 ppm of the active ingredient, and the aqueous preparation obtained
was then applied at a rate of 20 ml per pot to the grape seedlings at their
4- or 5-leaf stage. After drying in the air, the plant was inoculated with
a zoosporangium suspension of grape downy mildew (Plasmopara
viticola) fungi and then placed in a moist chamber at 22°C for 24
hours. On the seventh day in the greenhouse after the inoculation, the
plant was again placed in a moist chamber at 22°C for 24 hours to
cultivate conidiospores. The incidence area where conidiospores grew
on each leaf was examined.
The incidence index was determined according to the standards
shown in Table 17. The degree of damage was calculated according to
Equation (I) and the incidence index and the ability to prevent the
disease (controlling activity) was calculated according to Equation (2).
The results of the test are shown in Table 23.
Table 23
Compound No. Controlling Activity (%)
777 100
779 100
781 100
785 100
