Halogen substituted 5-thiazole methane amine compounds

51 Pages·2013·4.94 MB·English

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US005214152A
United States Patent [19] 5,214,152
[11] Patent Number:
Minamida'et al. [45] Date of Patent: May 25, 1993
[54] HALOGEN SUBSTITUTED S-THIAZOLE
OTHER PUBLICATIONS
METI-IANE AMINE COMPOUNDS
Chemical Abstracts, vol. 55, No. 23, Abstract 247l9h,
[75] Inventors: Isao Minamida, Hyogo; Koichi
Berlin et a1. (Nov. 13, 1961).
Iwanaga; Tetsuo Okauchi, both of
Chemical Abstracts, vol. 70, No. 19, Abstract 87,643d,
Osaka, Japan
May 12, 1969.
Chemical Abstracts, vol. 87, No. 5, Abstract 39465b,
[73] Assignee: Takeda Chemical Industries, Ltd.,
Osaka, Japan Aug. 1, 1977, p. 520. '
Gagiu et al., “Syntheses von neuen potentiell cysto
[21] App]. No.: 655,072 statischen Thiazolverbindungen,” Journal fur praktische
Chemie, Band 311, 1969, pp. 168-170.
[22] Filed: Feb. 14, 1991
Primary Examiner-C. Warren Ivy
Assistant Examiner—-Zinna Northington Davis
Related US. Application Data Attorney, Agent, or Firm-Wegner, Cantor, Mueller &
Player
[62] Division of Ser. No. 406,515, Sep. 13, 1989, Pat. No.
5,175,301, which is a division of Ser. No. 225,367, Jul. [57] ABSTR ACI
28, 1988.
a-Unsaturated amines of the formula:
[30] Foreign Application Priority Data
Aug. 1,1987 [JP] Japan .............................. .. 62-192793
Oct. 13, 1987 [JP] Japan .................. .. 62-258856
Jan. 26, 1988 [JP] Japan ............. .. 6346259
Mar. 17, 1938 [JP] Japan ................................ .. 63-64885
[51] Int. Cl.5 .......................................... .. C07D 417/06 wherein X1 and X2 are such that one is an electron
[52] US. Cl. ............................ .. 548/181; 548/202 attracting group with the other being a hydrogen atom
[58] Field of Search ........... .. 548/181, 186, 202, 205
or an electron-attracting group; R1 is a group attached
[56] References Cited through a nitrogen atom; R2 is a hydrogen atom or a
group attached through a carbon, nitrogen or oxygen
U.S. PATENT DOCUMENTS atom; 11 is an integer equal to 0, l or 2; A is a heterocy
clic group or a cyclic hydrocarbon group, and salts
4,108,994 8/1978 Poittevin et a1. ................. .. 424/250
thereof and their agrochemical use as insecticidal and
FOREIGN PATENT DOCUMENTS /or miticidal agents are described.
0375907 7/1970 European Pat. Off. .
2641129 3/1977 Fed. Rep. of Germany .... .. 548/182 6 Claims, No Drawings
5,214,152
1 2
clic group, with the proviso that when R2 is a hydrogen
HALOGEN SUBSTITUTED S-THIAZOLE atom, R1 is a group of the formula:
METHANE AMINE COMPOUNDS
This application is a divisional application of US. 5 / R30
Ser. No. 07/406,515 ?led Sep. 13, 1989, US. Pat. No.
—N
5,175,30l; which is a divisional application of US. Ser.
R40
No. 07/225,367 ?led Jul. 28, 1988, pending.
This invention relates to agrochemically useful a
wherein R3" is a hydrogen atom, C14 alkyl, C7-9 aralkyl
unsaturated amines having insecticidal/miticidal activ
ity, their production and use. or C14 acyl and R‘‘0 is a_hydrogen atom, C14 alkyl, C14
alkoxy-CM alkyl, (di-C1.4 alkylamino)-C1.4 alkyl, tri-C1.
Among a-unsaturated amines, such compounds as (i)
cimetidine (described for example iri Journal of Medici 4 alkylsilyl-CH alkyl, C24 alkenyl, or pyridyl- or thiazo
nal Chemistry 24, 913, 1981), (ii) ranitidine (described lyl-C1.2alkyl wherein the pyridyl or thiazolyl moiety
for example in Agents Actions 11, 160, l98l) and (iii) may optionally be substituted with a halogen atom, or
15
famotidine (described for example in Journal of Medici R3" and R“ taken together with the adjacent nitrogen
nal Chemistry 27, 849, 1984) are known as histamine H2 atom constitute pyrrolidino and A‘ is pyridyl, pyrazinyl
receptor antagonists. or thiazolyl which may optionally be substituted with a
halogen C1.4a1kyl, C1_4alkylthio or C14 alkoxy, or a salt
H (i) 20 thereof, and
on; N (2) insecticidal/pesticidal compositions containing an
rlmcm I > a-unsaturated amine of the formula:
NC-N=C—NHCHZCHZSCHZ N
Xl R1 R2 [I]
25
(ii)
NHCH3 CH3
O2N—CH=C—NHCH2CH2SCH2 O CH1N<
CH3 wherein X1 and X2 are such that one is an electron
30 attracting group with the other being a hydrogen atom
..)
or an electron-attracting group; R1 is a group attached
through a nitrogen atom; R2 is a hydrogen atom or a
group attached through a carbon, nitrogen or oxygen
atom; n is an integer equal to 0, l or 2; A is a heterocy
35
clic group or a cyclic hydrocarbon group, with the
As agricultural insecticide/miticides, organophos
proviso that when R1 is B-N-pyrrolidinoethylamino and
phorus or carbamate pesticides which are highly toxic
R2 is a hydrogen atom, A is a group of the formula:
to warm-blooded animals have heretofore been em
ployed. However, there has been an emergence of nox
ious insects, particularly of the order “Hemiptera”,
/
which are resistant to these pesticides, and there has
been a long-standing need for the development of a
pesticide effective against these resistant pests.
— N Hal
Getting impetus from the aforementioned histamine
H2 receptor antagonists, the present inventors synthe 45 wherein Hal is a halogen atom (e.g. Cl, Br, F, etc.), or
sized various a-unsaturated amines and investigated a salt thereof, and their production.
their activities. As a result, we discovered surprisingly Referring to the above formulas [I’] and [I], one of
that compounds of the invention which have no alkyl
X1 and X2 is an electron-attracting group with the other
ene group or only a short alkylene group in the side
being a hydrogen atom or an electron-attracting group.
chain have agriculturally useful insecticidal/miticidal 50
The electron-attracting group represented by X1 and
activity.
X2 includes, among others, cyano, nitro, C1.4alkoxy
Based on the above ?nding, the present inventors carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.),
conducted further research and have come up with the hydroxycarbonyl, C6.10aryloxy-carbonyl (e.g. phenox
present invention.
ycarbonyl etc.), heterocycleoxycarbonyl wherein the
The invention is, thus, concerned with: 55
heterocycle moiety is as mentioned below (e.g. pyridy
(1) novel zit-unsaturated amines of the formula:
loxycarbonyl, thienyloxycarbonyl, etc.), C14alkylsulfo
nyl which may be substituted with halogen (e. g. methyl
xl sulfonyl, tri?uoromethylsulfonyl, ethylsulfonyl, etc.),
aminosulfonyl, di-C14alkoxyphosphoryl (e.g. diethoxy
phosphoryl, etc.), CHacyl which may be substituted
with halogen (e.g. a Cgalkylcarbonyl such as acetyl,
trichloroacetyl, tri?uoroacetyl, etc.), claalkylsulfonyl
wherein X1 and X2 are such that one is an electron
thiocarbamoyl (e.g. methylsulfonylthiocarbamoyl,
attracting group with the other being a hydrogen atom
or an electron-attracting group; R1 is a group attached 65 etc.), carbamoyl and so on. One of X1 and X2 may be a
through a nitrogen atom; R2 is a hydrogen atom or a halogen atom such as ?uorine, chlorine, bromine or
group attached through a carbon, nitrogen or oxygen iodine, and X1 and X2 may join together with the adja
atom; n is an integer equal to 0, 1 or 2; A’ is a heterocy cent carbon atom to form a ring such as, for example,
5,214,152
3, 4
optionally be substituted by l to 3 substituents (e.g.
hydroxyl, C1.4alkoxy such as methoxy, halogen such as
/co — 0 CH3 ?uorine, di-C1_4 alkylamino such as dimethylamino,
C X . C14 alkylthio such as i-propylthio and n-propylthio,
\ C1.3 acylamino such as acetylamino, C14 alkylsul
co - 0 CH3
fonylamino such as methylsulfonylamino, tri-C1_4 alkyl
silyl such as trimethylsilyl, pyridyl or thiazolyl which
Preferred examples of the group
may optionally be.substituted with a halogen atom,
etc.). Furthermore, R3 and R4 may, taken together with
10 the adjacent nitrogen atom, constitute a 5- or 6-mem
bered cyclic amino group such as
c= are O;NCH=.
Referring to the above formulas [1°] and [I], R1 may
N
be a group attached through a carbon, oxygen or sulfur
atom, but a group attached through a nitrogen atom is
preferred. Thus, for example, a group of the formula
and so on.
The group attached through a nitrogen atom, repre
sented by R1, includes an amino group which may op
tionally be substituted (for example by any of the alkyl,
aryl, aralkyl, heterocyclic, acyl, alkoxycarbonyl, ary
loxycarbonyl, heterocycleoxycarbonyl, arylsulfonyl,
alkylsulfonyl, dialkoxyphosphoryl, cycloalkyl, alkenyl,
can be used. In the above formula, R3 is for example a 25
cycloalkenyl and alkynyl groups mentioned in the
hydrogen atom, an alkyl group (for example, a C1.6
alkyl groups such as methyl, ethyl, n-propyl, i-propyl, above de?nition of R3 and R4) such as di-substituted
n-butyl, i-butyl, n-hexyl, etc.), an C640aryl group (for amino groups, e.g. di-C1.6 alkylamino, N-CH', alkyl-N
example, phenyl, etc.), an C7.9 aralkyl group (for exam: formylamino, etc., mono-substituted amino groups, e. g.
ple a phenylalkyl such as benzyl, etc.), a heterocyclic mono-Cm alkylamino etc., and unsubstituted amino, a
group as mentioned below (for example, pyridyl, etc.), hydrazino group which may optionally be substituted
a C1.4acyl group (for example, formyl, acetyl, propio (for example by any of the alkyl; acyl, alkoxycarbonyl,
nyl, etc.), a C640 arylcarbonyltfor example, benzoyl, alkylsulfonyl, dialkoxyphosphoryl and other groups
etc.), an alkoxycarbonyl group (for example, C14 alk mentioned in the above de?nition of R3) or a hydroxy
oxycarbonyl groups such as methoxycarbonyl, ethox 35 amino group which may optionally be substituted (for
ycarbonyl, etc.), a C640 aryloxy-carbonyl group (for example by any of the alkyl, aralkyl and other groups
example, phenoxycarbonyl, etc.), a heterocycleoxycar mentioned in the above description of R3).
bonyl group wherein the heterocycle moiety is as men R2 is a hydrogen atom or a group attached through a
tioned below (for example, furyloxycarbonyl, etc.), a carbon, nitrogen or oxygen atom. The group attached
C640 arylsulfonyl group (for example, phenylsulfonyl, through a carbon atom, R2, includes, among others,
etc.), an alkylsulfonyl group (for example,~ C1.4a.lkylsul C14 acyl (for example, formyl, acetyl, propionyl, etc.),
fonyl groups such as methylsulfonyl, etc.), a dialkoxy alkyl (for example, C14 alkyl groups such as methyl,
phosphoryl group (for example, di-C14alkoxyphospho ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,
ryl groups such as diethoxyphosphoryl, etc.), an alkoxy etc.), alkenyl (for example, C24 alkenyl groups such as
group (for example, C14 alkoxy groups such as me 45 vinyl, allyl, etc.), cycloalkyl (for example, C34 cycloal
thoxy, ethoxy, etc.), a hydroxy group, an amino group, kyl groups such as cyclopentyl, cyclohexyl, etc.), C640
a dialkylamino group (for example, di-C1.4 alkylamino aryl (for example, phenyl, naphthyl, etc.), C7-9 aralkyl
group such as dimethylamino, diethylamino, etc.), an (for example phenylalkyl such as benzyl, etc.) and het
acylamino group (for example, C14 acylamino groups erocyclic as mentioned below which has a free bond on
such as formylamino, acetylamino, propionylamino, 50 a carbon atom thereof (for example, 3- or 4-pyridyl,
etc.), an alkoxycarbonylamino groups (for example, etc.). These groups may each be substituted by l to 3
C14 alkoxy-carbonylamino groups such as methoxycar substituents (for example, C14 alkylthio groups such as
bonylamino, etc.), an alkylsulfonylamino group (for methylthio, ethylthio, etc., C14 alkoxy groups such as
example, C14 alkylsulfonylamino groups such as me methoxy, ethoxy, etc., mono- or di-C1.4 alkylamino
thylsulfonylamino, etc.), a di-alkoxyphosphorylamino 55 groups such as methylamino, dimethylamino, etc., C14
group (for example, di-C1.4 alkoxyphosphorylamino alkoxy-carbonyl groups such as methoxycarbony,
groups such as diethoxyphosphorylamino, etc.), an C7.9 ethoxycarbonyl, etc., C14 alkylsulfonyl groups such as
aralkyloxy group (for example, benzyloxy, etc.), an methylsulfonyl, ethylsulfonyl, etc., halogen atoms such
alkoxycarbonylalkyl group (for example, C14 alkoxy as fluorine, chlorine, bromine, iodine, etc., C14 acyl
carbonyl-Cia alkyl groups such as methoxycarbonyl groups including alkanoyls such as acetyl, etc., benzoyl,
methyl, etc.) or the like. R4 is for example a hydrogen pheuylsulfonyl, pyridyl and so on). The group attached
atom, or an alkyl (for example, C1.4alkyl groups such as through a nitrogen atom, R2, includes, among others,
methyl, ethyl, etc.), cycloalkyl (for example, C34 cyclo the groups mentioned in the definition of R1. The group
alkyl groups such as cyclohexyl, etc.), alkenyl (for ex attached through an oxygen atom, R2, includes, among
ample, C2.4 alkenyl groups such as vinyl, allyl, etc.), 65 others, alkoxy (for example, C14 alkoxy groups such as
cycloalkenyl (e.g. C3-6 cycloalkenyl groups such as methoxy, ethoxy, etc.), cycloalkoxy (for example, C34,
cyclohexenyl, etc.) or alkynyl (for example, C24 alky cycloalkoxy groups such as cyclohexyloxy etc.), al
nyl groups such as ethynyl, etc.) group which may kenyloxy (for example, C24 alkenyloxy groups such as
5,214,152
5 6
vinyloxy, allyloxy, etc.), cycloalkenyloxy (for example, dimethylallyl, Z-butenyl, 3-butenyl, Z-pentenyl, 4-pente
C3.6 cycloalkenyloxy groups such as cyclohexenyloxy nyl, S-hexenyl and so on.
etc.), alkynyloxy (for example, ethynyloxy etc), C640
The cycloalkenyl group is preferably a group of 3 to
aryloxy (for example, phenoxy, etc.), heterocycleoxy
6 carbon atoms, such as l-cyclopropenyl, 2-cycloprope
wherein the heterocycle moiety is as mentioned below nyl, l-cyclobutenyl, 2—cyclobutenyl, l-cyclopentenyl,
(for example, thienyloxy etc.) and hydroxyl. These Z-cyclopentenyl, 3-cyclopentenyl, l-cyclohexenyl, 2
groups may each have 1 to 3 substituents (for example, cyclohexenyl, 3-cyclohexenyl, l,3—cyclohexadien-l-yl,
halogen such as ?uorine, chlorine, bromine, phenyl and 1,4-cyclohexadien-1-yl, 1,3-cyclopentadien-l-yl, 2,4
so on). R2 is preferably a group attached through a
cyclopentadien-l-yl and so on.
carbon, nitrogen or oxygen group, such as formyl, an l0 The alkynyl group is preferably a group of 2 to 6
alkyl group (particularly C14 alkyl groups such as
carbon atoms, such as ethynyl, propargyl, Z-butyn-l-yl,
methyl, ethyl, etc.) which may optionally be substituted
3-butyn-l-yl, 3-butyn-2-yl, l-pentyn-3-yl, 3-pentyn-l~yl,
(for example by the C14 alkylthio, C14 alkoxy, mono- or
4-pentyn-2-yl, 3-hexyn-l-yl and so on.
di-C1.4 alkylamino, C14 alkoxycarbonyl, C14 alkylsulfo
The aryl group may for example be phenyl or naph
nyl, acetyl, benzoyl, phenylsulfonyl, pyridyl, etc.), an
15 thyl.
amino group which may optionally be substituted (for
The aralkyl group may for example be benzyl, phen
example, those mentioned in the de?nition of R1) and a
hydroxyl group which may optionally be substituted, ethyl, naphthylmethyl or the like.
for example by the above-mentioned C14 alkyl, C34; The heterocyclic group includes, among others, S-to
cycloalkyl, C24 alkenyl, C34 cycloalkenyl, C24 alkynyl, S-membered rings each containing 1 to 5 hetero atoms
20
C640 aryl and heterocyclic groups (particularly C14 such as oxygen, sulfur and nitrogen or fused rings de
alkoxy groups such as methoxy and so on). The symbol rived therefrom, such as 2- or 3-thienyl, 2- or 3-furyl, 2
11 means 0, l or 2. Therefore, —C,,H1,,—— in the formulas or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5»oxazolyl, 2-,
[1°] and [I] represents a single bond, —-CH2—, —CH2C 4- or S-thiazolyl, 3-, 4- or 5-pyrazoly1, 2-, 4- or 5
H2--—, 01' 25 imidazolyl, 3-, 4- or S-isoxazolyl, 3-, 4-or 5-isothiazolyl,
3-' or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5
(l,'2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5-(l,2,3
thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4
triazolyl, lH- or 2H tetrazolyl, N-oxido- 2-, 3- or 4-pyri
although the single bond or —CH;— is preferred. The 30 dyl, 2-, 4- or S-pyrimidinyl, N-oxido-2-, 4- or 5
pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3
symbols A° and A mean a heterocyclic group as men
or 4-pyridazinyl, benzofuryl, benzothiazolyl, benzoxaz
tioned below (such as 3-pyridyl, 6-chloro-3-pyridyl,
olyl, triazinyl, oxotriazinyl, tetrazolo[l,5-b]pyridazinyl,
6-methoxy-3-pyridyl, 6-methyl-3-pyridyl, 3-quinolyl,
triazolo[4,5-b]pyridazinyl, oxoimidazinyl, dioxotriazi
etc.), preferably one which may optionally be substi
tuted with one to three of the choices (i), (iv), (Viii), 35 nyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl,
1,4-oxazinyl, morpholinyl, l,4~thiazinyl, 1,3-thiazinyl,
(XVii), (XLVi), (XLViii) and so on as mentioned be
piperazinyl, benzimidazolyl, quinolyl, isoquinolyl, cin
low, or a cyclic hydrocarbon group as mentioned below
(such as cyclopropyl, cyclohexyl, phenyl, p-chlorophe nolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, in
nyl and so on), preferably one which may optionally be dolizinyl, quinolizinyl, 1,8-naphthyridinyl, purinyl,
pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phe
substituted with one or two of the choice (XVii) as
mentioned below. The heterocyclic group of A° or A is nanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl
more preferably a pyridyl or thiazolyl group which may and so on.
optionally be substituted, such as 3-pyridyl, 6-chloro-3 The cyclic hydrocarbon group includes, among oth
pyridyl, 6-bromo-3-pyridyl, 2-chloro-5-thiazolyl and so ers, C34 cycloalkyl groups such as cyclopropyl, cyclo
on. The cyclic hydrocarbon group A is more preferably butyl, cyclopentyl, cyclohexyl, etc., C355 cycloalkenyl
a halophenyl group such as p-chlorophenyl and so on. groups such as l-cyclopropenyl, 2-cyclobutenyl, l
As the alkyl, cycloalkyl, alkenyl, cycloalkenyl, alky cyclohexenyl, 2-cyclohexenyl, 1,3-cyclohexadien-l-yl,
nyl, aryl, aralkyl, heterocyclic and cyclic hydrocarbon
etc., andCMo aryl groups such as phenyl, naphthyl and
groups in the de?nitions of X1, X2, R1, R2, R3, R4, A°
so on.
and A, the following groups, among others, may be (i) C14 Alkyl groups such as methyl, ethyl, propyl,
employed and each of these groups may have 1 to 5 isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
substituents such as (i) through (Lii) which appear here
are used.
inafter.
(ii) C3.6 Cycloalkyl groups such as cyclopropyl, cyclo
The alkyl group preferably contains 1 to 20 carbon
butyl, cyclopentyl, cyclohexyl, etc. are used.
atoms and is more preferably a group of l to 8 carbon 55
(iii) C610 Aryl groups such as phenyl, naphthyl, etc. are
atoms. This alkyl group may be straight-chain or
branched. Speci?c examples of the alkyl group include used.
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec (iv) C14 Alkoxy groups such as methoxy, ethoxy,
butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, propoxy, isopropoxy, butoxy, tert-butoxy, etc. are
2-ethylhexyl, deeyl, undecyl, dodecyl, tridecyl, tetra used.
decyl, pentadecyl, hexadecyl, octadecyl, nonadecyl, (v) C34 Cycloalkyloxy groups such as cyclopropyloxy,
cyclopentyloxy, cyclohexyloxy, etc. are used.
eicosyl and so on. _
The cycloalkyl group is preferably a group of 3 to 6 (vi) C640 Aryloxy groups such as phenoxy, naph
carbon atoms, such as cyclopropyl, cyclobutyl, cyclo thyloxy, etc. are used.
pentyl, cyclohexyl and so on. 65 (vii) C742 Aralkyloxy groups such as benzyloxy, 2
The alkenyl group is preferably a group of 2 to 6 phenethyloxy, l-phenethyloxy, etc. are used.
carbon atoms. Speci?c examples of such alkenyl group (viii) C14 Alkylthio groups such as methylthio, eth
include vinyl, allyl, isopropenyl, methallyl, 1,1 ylthio, propylthio, butylthio, etc. are used.
5,214,152
7 8
(ix) C3_6 Cycloalkylthio groups such as cyclopro (xxx) Substituted sulfonylamino groups such as me
pylthio, cyclopentylthio, cyclohexylthio, etc. are thanesulfonylamino, ethanesulfonylamino, butanesul
used. fonylamino, benzensulfonylamino, toluenesul
(x) C640 Arylthio groups such as phenylthio, napht fonylamino, naphthalenesulfonylamino, tri?uorome
hylthio, etc. are used. thanesulfonylamino, 2-chloroethanesulfonylamino,
(xi) C742 Aralkylthio groups such as benzylthio, 2 2,2,Z-tri?uoromethanesulfonylamino, etc. are used.
phenethylthio, I-phenethylthio, etc. are used. (xxxi) Heterocyclic groups nuclearly containing 1 to 5
(xii) Mono-C14 alkylamino groups such as me hetero atoms of N, O and/or S, such as pyrrolidinyl,
thylamino, ethylamino, propylamino, iso pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazo
propylamino, butylamino, isobutylamino, tert lyl, isoxazolyl, isothiazolyl, thiazolyl, piperidinyl,
butylamino, etc. are used. pyridyl, piperazinyl, pyrimidinyl, pyranyl, tetrahy
(xiii) Di-C1.4 alkylamino groups such as dimethylamino, dropyranyl, tetrahydrofuryl, indolyl, quinolyl, 1,3,4
diethylamino, dipropylamino, dibutylamino, N-rneth oxadiazolyl, thieno[2,3-d]pyridyl, 1,2,3-thiadiazolyl,
yl-N-ethylamino, N-methyl-N-propylamino, N~meth 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
yl-N-butylamino, etc. are used. 15 1,3,4-triazolyl, tetrazolyl, 4,5-dihydro-1,3-dioxazolyl,
(xiv) C3.6 Cycloalkylamino groups such as cyclo tetrazolo[l,5-b]pyridazinyl, benzothiazolyl, benzox
propylamino, cyclopentylamino, cyclohexylamino, azolyl, benzimidazolyl, benzothienyl, etc. are used.
etc. are used. (xxxii)Heterocyclethio, heterocycleoxy, heterocy
(xv) C510 Arylamino groups such as anilino etc. are cleamino, and heterocyclecarbonylamino groups and
used. 20 groups derived therefrom by attachment of any of
(xvi) C742 Aralkylamino groups such as benzylamino, heterocyclic groups
Z-phenethylamino, l-phenethylamino, etc. are used. (xxxi) to the S, O, N atom or the carbonylamino group
(xvii) Halogen atoms such as ?uorine, chlorine, bromine
are used. ‘
and iodine are used. (xxxiii)Di-.C1_4 alkylphosphinothioylamino groups such
(xviii) C14 Alkoxycarbonyl groups such as methoxycar 25 _ as-dimethylphosphinothioylamino, diethylphosphino
bonyl, ethoxycarbonyl, propoxycarbonyl, isopropox thioylamino, etc. are used.
ycarboyl, butoxycarbonyl, tert-butoxycarbonyl, (xxxiv)Alkoxyimino groups such as methoxyimino,
isobutoxycarbonyl, etc. are used. ethoxyimino, 2-?uoroethoxyimino, carboxymethox
(xix) C540 Aryloxycarbonyl groups such as phenox yimino, l-carboxy-l-methylethoxyimino, 2,2,2-tri
ycarbonyl etc. are used. ' 30 chloroethoxycarbonylmethoxyimino, l-(2,2,2-tri
(xx) C34; Cycloalkyloxycarbonyl groups such as cyclo ch1oroethoxycarbonyl)-l-methylethoxyimino, (2
propyloxycarbonyl, cyclopentyloxycarbonyl, cy arninothiazol-4-y1)methoxyimino, (lH-imidazol-4
clohexyloxycarbonyl, etc. are used. y1)methoxyimino, etc. are used.
(xxi) C742 Aralkyloxycarbonyl groups such as ben (xxxv)C1.4 Alkylsulfonyloxy groups such as me
zyloxycarbonyl, l-phenethyloxycarbonyl, 2-phene 35 thanesulfonyloxy, ethanesulfonyloxy, butanesul
thyloxycarbonyl, etc. are used. fonyloxy, etc. are used.
(xxii)C1.5 Alkanoyl groups such as formyl, acetyl, pro (xxxvi)C@10 Arylsulfonyloxy groups such as ben
pionyl, butyryl, pivaloyl, etc. are used. zenesulfonyloxy, toluenesulfonyloxy, etc. are used.
(xxiii)C1.15 Alkanoyloxy groups such as formyloxy, (xxxvii) Di-CMO arylphosphinothioylamino groups
acetoxy, butyryloxy, pivaloyloxy, pentanoyloxy, hex 40 such as diphenylphosphinothioylamino, etc. are used.
anoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, (xxxviii)Thiocarbamoylthio groups which may option
decanoyloxy, undecanoyloxy, dodecanoyloxy, ally be substituted, such as thiocarbamoylthio, N
tridecanoyloxy, tetradecanoyloxy, pen methylthiocarbamoylthio, N,N-dimethylthiocarbam
tadecanoyloxy, etc. are used. oylthio, N-ethylthiocarbamoylthio, N-benzylthiocar
(xxiv) Carbamoyl groups which may optionally be sub 45 bamoylthio, N,N-dibenzylthiocarbamoylthio, N
stituted, such as carbamoyl, N-methylcarbamoyl, phenylthiocarbamoylthio, etc. are used.
N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N,N (xxxix)Silyloxy groups such as trimethylsilyloxy, t
diethylcarbamoyl, N-phenylcarbamoyl, pyr butyldimethylsilyloxy, t-butyldiphenylsilyloxy, dime
rolidinocarbamoyl, piperidinocarbamoyl, piperazino
thylphenylsilyloxy, etc. are used.
carbamoyl, morpholinocarbamoyl, N-benzylcarbam~ 50 (xL) Silyl groups such as trimethylsilyl, t-butyldime
oyl, etc. are used. thylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl,
(xxv) Substituted carbamoyloxy groups such as N etc. are used.
rnethylcarbamoyloxy, N,N-dimethylcarbamoyloxy, (xLi) C14 Alkylsul?nyl groups such as methylsul?nyl,
N-ethylcarbamoyloxy, N-benzylcarbamoyloxy, N,N ethylsul?nyl, propylsul?nyl, butylsul?nyl, etc. are
dibenzylcarbamoyloxy, N-phenylcarbamoyloxy, etc. 55 used.
are used. (xLii)C€t10 Arylsuli'myl groups such as phenylsult'myl,
(xxvi)C1_4 Alkanoylamino groups such as formylamino, naphthylsul?nyl, etc. are used.
acetamido, propionamide, butyramido, etc. are used. (xLiii)Cl.4 Alkylsulfonyl groups such as methanesulfo
(xxvii)C6.10 Arylcarbonylamino groups such as ben nyl, ethanesulfonyl, butanesulfonyl, etc. are used.
zamido etc. are used. (XLiV)C6.1Q Arylsulfonyl groups such as benzenesulfo
(xxviii)C1_4 Alkoxycarbonylamino groups such as me nyl, toluenesulfonyl, etc. are used.
thoxycarbonylarnino, ethoxycarbonylamino, butox (xLv) C14 Alkoxycarbonyloxy groups such as methox
ycarbonylamino, tert-butoxycarbonylamino, etc. are ycarbonyloxy, ethoxycarbonyloxy, tert-butoxycar
used. bonyloxy, etc. are used.
(xxix)C7.12 Aralkyloxycarbonylamino groups such as 65 (xLvi)Halo-C1.4 alkyl groups such as tri?uoromethyl,
benzyloxycarbonylamino, 4-methoxybenzyloxycar 1,1,2,2-tetra?uoroethyl, di?uoromethyl, mono
bonylamino, 4-nitrobenzyloxycarbonylamino, 4 fluoromethyl, trichloromethyl, dichloromethyl,
chlorobenzyloxycarbonylamino, etc. are used. monochloromethyl, etc. are used.
5,214,152
10
(xLvii)Hal0-C1-4 alkoxy, halo-C14 alkylthio, halo-C14 butyl-N-forrnylamino, N-n-hexyl-N-formylamino, etc.
alkylsulfinyl and halo-C14 alkylsulfonyl groups as
and preferably N-C1_4 alkyl-N-formylamino groups
well as groups derived therefrom by attachement of
such as N-methyl-N-formylamino, N-ethyl-N-for
any of halo-C14 alkyl groups (xL'vi) to the O, S, sul?
nyl and sulfonyl moieties thereof are used. mylamino and so on. The di-C1-6_alkylamino group
(xLviii)Cyano, nitro, hydroxy, carboxyl, sulfo and represented by Rlciincludes, among others, dimethyl
phosphono groups are used. ' amino, N-ethyl-N-methylamino, diethylamino, di-n
(xLix)C1.4 Alkyloxysulfonyl groups such as methox propylamino, di-i-propylamino, di-n-butylamino, di-i
ysulfonyl, ethoxysulfonyl, butoxysulfonyl, etc. are butylamino, di-n-pentylamino, di-i-pentylamino, di-n
used.
hexylamino, etc. and preferably di-C14 alkylamino
(L) C5.10Aryloxysulfonyl groups such as phenoxysulfo
groups such as dimethylamino, N-ethyl-N-methylamino
nyl, tolyloxysulfonyl, etc. are used.
(Li) C742 Aralkyloxysulfonyl groups such as benzylox and diethylamino. The C14 alkyl group represented by
ysulfonyl, Z-phenethyloxysulfonyl, l-phenethylox- ' R2“ or Rzc includes, among others, the alkyl groups
ysulfonyl, etc. are used. 15 mentioned in the de?nition of R2 above and preferably
(Lii) Di-C1_4-alkyloxyphosphoryl groups such as dime
methyl, ethyl and so on. The CM alkoxy group repre
thoxyphosphoryl, diethoxyphosphoryl, dibutoxy
sented by R2a includes, among others, the alkoxy groups
phosphoryl, etc. are used.
mentioned in the de?nition of R2 above and preferably
Preferred examples of the unsaturated amines of for
mulas [I°] and [I] or salts thereof include: methoxy, ethoxy and so on. The chloropyridyl group
20
The a-unsaturated amines of the formula: represented by A‘2 or Al’ includes, among others, 2
chloro-3-pyridyl, 4-chloro-3-pyridyl, 5-chloro-3-pyri
Rla R20 dyl, 6-chloro-3-pyridyl, 3-chloro-4-pyridyl, etc. and
preferably 6-chloro-3-pyridyl and so on. The pyridyl
group represented by Ab includes 3-pyridyl, 4-pyridyl,
etc. and preferably B-pyridyl.
wherein R1‘: is a mono-CM alkylamino group, an N-C]
6 alkyl-N-formylamino group or an amino group; R2“ is Typical a-unsaturated amines of formulas [1°] and [I]
an C14 alkyl group or an C14 alkoxy group; A‘1 is a or salts thereof include:
chloropyridyl group, or salts thereof; The a-unsaturated amines of the formula:
the a-unsaturated amines of the formula: 30
Rib [lb] Rla R4a [F]
35
wherein Rib is a mono-CM alkylamino group or an x20
N-C1-6 alkyl-N-forrnylamino group; A0 has the meaning
de?ned hereinbefore, or salts thereof;
wherein X2a is a hydrogen atom, C1.4alkoxycarbonyl or
the a-unsaturated amines of the formula:
C14 alkylsulfonylthiocarbamoyl; R26 is a hydrogen
atom, C1.3 acyl, C14 alkyl, mono- or di-C1.4 alkoxy-C1.4
alkyl, C7.9 aralkyl, mono- or di-C1.4 alkylamino or C14
alkoxy; Ac is 3- or 4-pyridyl, pyrazinyl or 4- or S-thiazo
lyl which may optionally be substituted with halogen,
wherein R16 is a di-C1.6 alkylamino group; R“ is a hy 45
C14 alkyl or C14 alkoxy; and R3", R"‘1 and n are as
drogen atom, a formyl group or an C1.4alkyl group; Ab
de?ned above, or salts thereof;
is a pyridyl group or a chloropyridyl group, or salts
thereof; and the a-unsaturated amines of the formula:
the a-unsaturated amines of the formula:
X241
S5
wherein X24 is a hydrogen atom, C14 alkoxycarbonyl or
wherein the symbols have the meanings de?ned herein
C14 alkylsulfonylthiocarbamoyl; R1d is amino, mono-or
before, or salts thereof.
di- C14 ‘alkylamino, N-' C14 alkyl-N~C1_3 acylamino,
Referring to the above formulas [1”], [Ib] and [1c], the
mono-C14 alkylamino group represented by R“ or R“’ C7.9 aralkylamino, halogenothiazolyl-C1.2 alkylamino
includes, among others, monomethylamino, monoe or CH alkoxy-Cm alkylamino; R20 is a hydrogen atom,
thylamino, mono-n-propylamino, mono-i-propylamino,
C1-3 acyl, C14 alkyl, mono- or (ii-C14 alkoxy-CH alkyl,
mono-n-butylamino, mono-i-butylamino, mono-n-hex
C7.9 aralkyl, mono- or di-C1.4 alkylamino or CH alk
ylamino, etc. and preferably mono-CM-alkyl amino
oxy; n is an integer equal to 0, 1 or 2; and Ad is 3- or
groups such as mono-methylamino, monoethylamino
4-pyridyl, pyrazinyl or S-thiazolyl which may option
and so on. The N-C1-6 alkyl-N-formylamino group rep 65
ally be substituted with halogen, C14 alkyl or C14 alk
resented by Rla or Rlbincludes, among others, N-meth
yl-N-formylamino, N-ethyl-N-formylamino, N-n-pro
oxy, or salts thereof; _
pyl-N-formylamino, N-i-propyl-N-formylamino, N-n the a-unsaturated amines of the formula:
5,214,152
11
x217
wherein X2!’ is a hydrogen atom or C1.2alkylsulfonylthi
ocarbamoyl; R18 is amino, mono- or di-C1.2alkylamino
or N-C1.2alkyl-N-formylamino; R1d is a hydrogen atom,
C1-1alkyl or C1-3acyl; and A‘’ is a group of the formula:
N wherein X1, X2, R‘, R2, 11 and A have the meanings
de?ned hereinbefore; R5 is an C14 alkyl group such as
- N s Hal methyl, ethyl, etc. or an C7.9aralkyl group such as ben
zyl etc.; Y is a hydrogen atom or an alkali metal such as
wherein Hal is a halogen atom, or salts thereof; 20 sodium, potassium, etc.
the a-unsaturated amines of the formula:
RIfRZd
25
NHR3 R2
wherein X26 is a hydrogen atom or methylsulfonylthi
ocarbamoyl; RV is amino, methylamino, dimethylamino
or N-methyl-N-formylamino; R2d is a hydrogen atom,
[VIII]
formyl or C1.2alkyl; and A8 is a group of the formula:
N 35
/ \ FL
- N 5 Hal
NHR3 R2
wherein Hal is a halogen atom, or salts thereof; and
the a-unsaturated amines of the formula:
[1-1]
R le R 22 [If]
45
N
wherein R16 is amino, rnono- or di-C1-2alkylamino or R2
N-C1-2alkyl-N-formylamino; R28 is Cmalkyl or formyl;
and Hal is a halogen atom, or salts thereof.
In the above formulas [I2] to [I'], the groups repre
sented by X14, X21’ and X26, the groups represented by
R”, Rleand RV, the groups represented by R”, R” and
R2", and the groups represented by Ac, Ad and Ae are as 55
mentioned above in the case of X2, R1, R2, A° and A.
The compound [I] or its salt can be produced by the
analogous known processes and further by the follow
ing processes, for instance.
65 RI-I-IH
5,214,152
13 14
wherein X1, X2, R1, R2, Hal, n and A have the meanings
de?ned hereinbefore.
Process 62
x3 R1 R2
| | . r
c_—c _ N _ C"H2" _ A QiiI) -DIeycdraorlbyosxtysl ation ;
R6OOC [XIX]
x3 R1 R2
‘ I l
C=C-N-C,,H2,,—A
1-! [1-4]
15
wherein R1, R2, 11, A and R5 have the meanings de?ned
"2 [1-3] hereinbefore; X3 is an electron-attracting group.
wherein X1, X2, R1, R2, R3, R4, R5, n and A have the
meanings de?ned hereinbefore.
20
Process 3 !
Ha] X2 [1-51
25
Hal
Alkylation,
acylation,
alkoxycarbonylation,
sulfonylation or
[X11] phosphorylation a [I]
30
X2 [1-6]
[X1] or [x111 [I]
wherein X1, X2, R1, R2, n and A have the meanings
wherein Hal is the meanings de?ned hereinbefore. de?ned hereinbefore; R6 is a group attached through a
35
nitrogen atom containing at least one hydrogen atom.
Process4 In the processes 1) to 7) the compounds [III], [IV]
[V], [VI], [1X], IIX'], IIX"], [X], [XIV], [XVI], [XVII],
x1 R1
[XVIII], [XIX], [1-5], [1-6] and so on may be used in a
CH_COIL._C H2 __A halo enatin a ent
II n form of a salt (e.g. one as mentioned below in a salt of
the compound [1]).
X2 [x111]
In accordance with the aforementioned Process 1), a
x1 Hal R2 compound of general formula [II] is reacted with an
amino compound of general formula [III] or a salt
c_—c ——N-—cnH2n—A —[—V]- > [11
thereof to give a compound of general formula [IV]
45
X2 WV] which is then reacted with an amino compound of gen
eral formula [V] or a salt thereof, or a compound of
01' general formula [II] is reacted with a compound of
general formula [V] ‘to give a compound of general
XI
50 formula [VI] which is then reacted with a compound of
\ ctr-00Rl —haglo— e—na—ti—n La $c—nt -9 general formula [III], to thereby give a compound [I].
2/
In practicing the Process 1), the reactions of [II]—>[IV],
X [XV] [IV]—>[I], [II]->[IV] and [VI]—>[I] and respectively be
conducted in an appropriate solvent. There is no limita
x1 R1
\ I n tion on such a solvent provided that it does not interact
C=C—Hal LL19 [1] with the reactant, reagent or_reaction product to give
byproducts but a solvent capable of dissolving both the
X2 [XVI]
reactant and reagent is preferred. As examples of such
solvent, there may be mentioned alcohols such as meth
wherein X1, X2, R1, R2, Hal, n and A have the meanings
anol, ethanol, propanol, butanol, etc., aromatic hydro
de?ned hereinbefore.
carbons such as benzene, toluene, xylene, etc., ethers
such as diethyl ether, dipropyl ether, dibutyl ether,
Process 5! tetrahydrofuran, dioxane, etc., nitriles such as acetoni
x1 R1 R1 [XVIII] trile, propionitrile, etc., acid amides such as dimethyl
I I A—C,,H2,,—Hal formamide, dimethylacetamide, etc., sulfoxides such as
C=C—NH ——————+ [1]
dimethyl fulfoxide, etc., sulfones such as sulfolane, etc.,
X2 [XVII] and phosphoramides such as hexamethylphosphora
mide etc., as well as various mixtures thereof and mix
5,214,152
15 16
tures thereof with water. While each of the above reac formula [IX], and reacting [IX] with an active methy
tions is generally conducted at atmospheric pressure, it lene compound of general formula [X], (2) reacting an
is possible to conduct the reaction under reduced pres amino compound of general formula [III] (Y=H) or an
sure as taught by Japanese Unexamined Patent applica alkali metal salt thereof with an isothiocyanic ester
tion KOKAI-62-l38478 (1987) to remove the by [VII'], then reacting the resulting thiourea [VIII'] with
product low-boiling thiol and thereby suppress the sec the compound of the formula: R51 (e.g. methyl iodide,
ondary reaction. When a low-boiling solvent is used, etc.) to give an isothiourea-[IX] and reacting [IX'] with
the reaction is preferably conducted at supratmospheric an active methylene compound [X], or (3) reacting an
pressure. For the aforesaid respective reactions, the amino compound of general formula [V] (Yzl-I) or an
reaction temperature may range from 30° to 150° C. and alkali metal salt thereof with an isothiocyanic acid ester
preferably from 50° to 150° C. The reaction time is [VII"], reacting the resulting thiourea [VIII"] with the
generally 5 minutes to 48 hours, depending on the reac compound of the formula: R51 (e.g. methyl iodide, etc.),
tion temperature, reactant, reagent and solvent. The and reacting the resulting isothiourea [IX"] with an
proportions of reagents [III] and [V] in the reactions active methylene compound, to thereby give the de
[II]->[IV]-and [II]->[VI] may each be 1 to 1.2 molar sired compound [1].
equivalents relative to [II]. The use of [III] and [V] in Referring to Process 2), the reactions [III] y=H-—>
further excess is preferably avoided to prevent by-pro [VIII], [III] Y=H—>[VIII'] and [V]Y=H—+[VIII"] and the
duction of the diamino compound. As the reaction reactions [VIII]->[IX], [VIII']—>[IX'] and [VIII']
[II]->[IV] and [II]->[VI] in a concentrated reaction ->[IX"] can each be conducted by the known proce
mixture may occasionally give the by-product, the di 20 dures described in the literature or by procedures analo
amino compound, it is desirable to avoid the reactions in gous thereto. As said literature, there may be mentioned
such condition. The proportions of reagents [V] and Chemical Society of Japan (ed.): Shin Jikken Kagaku
[III] in the reactions [IV]—>[I] and [VI]->[I] are gener Koza (New Series of Experimental Chemistry), V0. 14,
ally l to 1.5 molar equivalents and, unlike in the reac III, Maruzen (1978), Chapters 7 and 21; Organic Func
tions [II]—>[IV] and [II]—>[VI], the use of [V] or [III] in 25 tional Group Preparations, Vol. 2, Academic Press
greater excess may not occasionally induce byproduct (1971), Chapters 6 and 7, ditto The Second Edition
formation. A base may be permitted to be concomi (1986), and so on.
tantly present for the purpose of promoting the reaction Each of the reactions [III]Y=H—>[VIII], [III] y=11—>
or suppressing secondary reactions. As the base for such [VIII'], and [V] y=H—>[VIII"] can be conducted in an
purposes, there may be used organic bases such as tri appropriate solvent. There is no limitation on such a
ethylamine, N-methylmorpholine, pyridine, 1,8 solvent provided that it does not interact with the reac
diazabicyclo[5,4,0]-7-undecene, l,5-azabicyclo[4,3,0]
tant or the reagent but it is preferable to select a solvent
‘ ‘non-S-ene, etc. and inorganic bases such as potassium capable of dissolving both the reactant and reagent. As
carbonate, potassium hydrogen carbonate, sodium car examples of such solvent, there may be mentioned aro
bonate, sodium hydrogen carbonate, lithium carbonate, 35 matic hydrocarbons such as benzene, toluene, xylene,
lithium hydrogen carbonate and so on. Where an alkali etc.; aliphatic hydrocarbons such as pentane, hexane,
metal salt of reagent [III] or [V] is used, the sodium salt, heptane, petroleum ether, ligroine, petroleum benzene,
lithium salt, potassium salt, etc. can be employed. The etc.; ethers such as diethyl ether, dipropyl ether, dibutyl
compound [IV] or [VI] may be isolated and puri?ed by ether, tetrahydrofuran, dioxane, etc.; acid amides such
conventional procedures such as concentration, con 40 as dimethylformamide, dimethylacetamide, etc.; sulfox
centration under reduced pressure, pH adjustment, re ides such as dimethyl sulfoxide etc.; sulfones such as
distribution, solvent extraction, distillation, crystalliza sulfolane etc.; phosphoramides such as hexamethyl
tion, recrystallization, chromatography, etc. and sub phosphoramide etc.; and halogenated hydrocarbons
jected to the next reaction. Alternatively the reaction such as chloroform, dichloromethane, carbon tetrachlo
mixture containing [IV] or [VI] may be such be directly 45 ride, 1,2-dichloroethane, etc. as well as various mixtures
used as the starting reactant for the next reaction. thereof. The reaction temperature is about — 30‘ to 200°
The starting compound of general formula [II] for C. and preferably 0° to 150° C. The reaction time varies
Process 1) can be synthesized by the procedures de with such conditions as reaction temperature, reactant,
scribed in Chem. Ber. 100, 591 (1967), Acta. Chem. reagent, reaction system concentration and solvent, but
Scand. 22, 1107 (1968), Synthesis 1986, 967, Chem. Ber. 50 generally in the range of 1 minute to 24 hours.
95, 2861 (1962), Tetraheron 30, 2413 (1974), Synthesis The proportions of compounds [VII], [VII’] .and
1984, 797 and other literature or by procedures analo [VII"] required for the respective reactions may range
gous thereto. The compound [III] can be synthesized by from 0.5 to 2 molar equivalents, preferably 0.8 to 1.2
the procedures described in Organic Functional Group molar equivalents, relative to [III]Y=H, [III]Y=H and
Preparations, Academic Press, Vol 1, Chapter 13 (1968) 55 [V]y=11. The compounds [VIII], [VIII'] and [VIII"]
and Vol 3, Chapter 10 (1972) and other literature or by thus obtained can each be subjected to the next reaction
procedures analogous thereto, and the compound [V] either without isolation or after isolation from the reac
can be synthesized by the procedures described in Sur tion mixture by the known procedure.
vey of Organic Syntheses, Wiley-Interscience (1970), Each of the reactions [VIII]—>[IX], [VIII']->[IX’]
Chapter 8 and other literature or by procedures analo and [VIII"]->[IX"] may also be conducted in a solvent.
gous thereto. In addition to the solvents mentioned for the reactions
The aforementioned Process 2) comprises (1) react [III] Y=H—->[VIII], [HIlY=H—>[VIII'] and [V]Y=J1—+
ing an amino compound of general formula [III] (Y: H) [VIIY’], such other solvents as alcohols, e.g. methanol,
or an alkali metal salt (e.g. Na or K salt) with an isothio ethanol, propanol, butanol, etc.; ketones, e.g. acetone,
cyanic ester of general formula [VII] to give a thiourea 65 methyl ethyl ketone, etc.; and esters, e.g. methyl ace
of general formula [VIII], then reacting said thiourea tate, ethyl acetate, butyl acetate, methyl formate, ethyl
[VIII] with the compound of the formula: R51 (e.g. formate, ethyl propionate, etc. can also be employed.
methyl iodide, etc.) to give an isothiourea of general The reagent methyl iodide may be utilized as the sol
5,214,152
17 18
vent. For the purpose of promoting the reaction and general formula [III] or a salt thereof (e.g. the salt of an
minimizing the formation of byproducts, a base may be alkali metal such as Na or K) and reacting the resulting
permitted ‘to be present in the reaction system or permit product further with an amino compound of general
ted to act on the reaction system before or after the formula [V] or a salt (alkali metal salt) thereof or, alter
reaction and there are cases in which such practice natively, reacting a compound [XI] or [XII] with an
contributes to improved results, As the base that can be amino compound of general formula [V] or a salt
' used for the above purpose, there may be mentioned thereof and then reacting the resulting product with an
sodium hydride, sodium metal, alcoholates such as so amino compound of general formula [III] or a salt
dium ethoxide, sodium methoxide, potassium tertbutox thereof to give the desired compound [I].
ide, etc., organic bases such as triethylamine, diiso The reactions in Process 3) can be conducted in the
propylethylamine, pyridine, N,N-dimethylaniline, etc. same manner as those in Process 1) and the reaction
and inorganic bases such as potassium carbonate and so conditions described for Process 1) can be utilized.
on. The proportion of the base is preferably 0.8 to 1.2 However, since compounds [XI] and [XII] are gener
molar equivalents relative to [VIII], [VIII'] or [VIII"]. ally more reactive than compound [II], the reactions are
In the absence of a base in the reaction system, [IX], preferably conducted under somewhat milder condi
[IX’] or [IX”] is formed as the hydroiodide so that this tions as compared with Process 1).
hydroiodide must be neutralized to obtain [IX], [IX’] or The compounds [XI] and [XII] can be prepared by
[IX"]. The base for this purpose is preferably a water procedures described in Chemical Abstracts 44, 1011f,
soluble inorganic base such as sodium carbonate, so Journal of Organic Chemistry 25, 1312 (1960) and other
dium hydrogen carbonate, potassium hydrogen carbon 20 literature or by procedures analogous thereto.
ate, potassium carbonate, sodium hydroxide, potassium The aforementioned Process 4) comprises reacting an
hydroxide and so on. The reaction temperature is 0' to acid amide of general formula [XIII] or an acid amide of
100° C. and preferably 20° to 80° C. The reaction time general formula [XV] with a halogenating agent to give
is generally 0.l to 24 hours. The proportion of methyl a halide of general formula [XIV] or [XVI] and reacting
iodide required for the reaction is not less than 1 molar 25 the halide with an amino compound of general formula
equivalent relative to [VIII], [VIII’] or [VIII"] and may [V] or a salt thereof or an amino compound of general
be used in a larger amount as the solvent. The [IX], [IX’] formula [III] or a salt thereof to give the desired com
or [IX”] thus produced may be isolated by the conven pound [I].
tional procedure before submission to the next reaction The reaction of [XIII]—>[XIV] and that of
or the reaction product mixture may be directly used as 30 [XV]—>[XVI] are preferably conducted in a solvent. As
the starting material in the next reaction. - such solvent, there may be mentioned halogenated hy
Each of the reactions [IX]-—>[l-l], [IX’]->[I-2] and drocarbons such as dichloromethane, chloroform, car
[IX"]—->[I-3] can be conducted in accordance with the bon tetrachloride, l,2-di’chloroethane, etc., ethers such
procedures described in Tetrahedron 37, 1453 (1981) as diethyl ether, tetrahydrofuran, dioxane, etc., nitriles
Indian Journal of Chemistry 15B, 297 (1977) and other 35 such as acetonitrile, propionitn'le, etc. and so on. This
literature. The reaction may be conducted using the reaction is preferably carried out under anhydrous con
active methylene compound [X] in excess as a solvent ditions. The halogenating agent may for example be
or may be carried out in a different solvent. As the phosphorus pentachloride, hosphorus oxychloride,
solvent just mentioned above, there may be used aro phosphorus trichloride, thionyl chloride, oxalyl chlo
matic hydrocarbons such as benzene, toluene, xylene, 40 ride or the like. The proportion of the halogenating
etc., aprotic polar solvents such as dimethylformamide, agent is l to 10 molar equivalents, preferably 1 to 5
dimethylacetamide, dimethyl sulfoxide, sulfolane, hex molar equivalents, relative to [XIII] or [XV]. Preferably
amethylphosphoramide, etc., and ethers such as tetra a base is permitted to be present in the reaction system
hydrofuran, dioxane and so on. Particularly where an in order to trap the byproduct hydrogen chloride, and
aprotic polar solvent is used and the reaction is con 45 as such base, there may be used various organic bases
ducted under reduced pressure with the byproduct such as pyridine, triethylamine, diisopropylethylamine,
methylrnercaptan being dispelled out of the reaction N-methylmorpholine, N,N-dimethylaniline, N,N-die
system, the formation of byproducts can be suppressed thylamine and so on. The reaction temperature is —80°
and the reaction yield improved. The reaction may also to 100° C. and preferably —50° to 50° C. The reaction
be conducted in the presence of a catalyst. As such time is generally 0.1 to 24 hours, depending on the
catalyst, there may be employed zinc chloride, zinc reactant, base, solvent, reaction concentration and reac
bromide, zinc iodide, cupric chloride and so on. The tion temperature. The products [XIV] and [XVI] can be
reaction temperature is 30° to 200° C., preferably isolated and purified by the aforementioned known
50°-150° C. The reaction time is generally 0.1 to 48 procedures before submission to the next reaction or the
hours. The proportion of active methylene compound 55 reaction product mixture may be directly used in the
[X] necessary for the reaction is l to 5 molar equivalents next reaction.
relative to [IX], [IX’] or [IX"]. Where [X] is a low-boil The reaction of [XIV]->[I] and that of [XVI]—>[I] can
ing compound, it can be used in a solvent amount. each be conducted in a solvent similar to those men
The starting compounds [VII], [VII'] and [VII"] can tioned for the reactions of [XIII]—>[XIV] and
be synthesized by the procedures described in Organic 60 [XV]—>[XVI], preferably under anhydrous conditions.
Functional Group Preparations, Vol. 1, Academic The proportion of [V] or a salt thereof and that of [III]
Press (1968), Chapter 12 and other literature or by pro or a salt thereof are l to 10 molar equivalents, prefera
cedures analogous thereto, and the compound [X] can bly l to 5 molar equivalents, relative to [XIV] and
be synthesized by procedures described in Formation of [XVI], respectively. For the purpose of trapping the
C-—-C Bonds, Vol. 1, Georg Thieme Publishers, Stutt 65 byproduct hydrogen chloride, [V] or a salt thereof or
gart (1973) and other literature. [III] or a salt thereof can be used in excess but for econ
The aforementioned Process 3) comprises reacting a omy, a different base is preferably permitted to be pres
compound [XI] or [XII] with an amino compound of ent. A such base, there may be used any of the bases