U.S. patent application number 15/329104 was filed with the patent office on 2018-03-29 for process for preparing pyrazoles.
The applicant listed for this patent is BASF SE. Invention is credited to Birgit Gockel, Michael Rack, Daniel Saelinger, Sebastian Soergel.
Application Number | 20180086715 15/329104 |
Document ID | / |
Family ID | 51257363 |
Filed Date | 2018-03-29 |
United States Patent
Application |
20180086715 |
Kind Code |
A9 |
Gockel; Birgit ; et
al. |
March 29, 2018 |
PROCESS FOR PREPARING PYRAZOLES
Abstract
The present invention relates to a process for preparing a
pyrazole compound of formula V, the process including cyclizing a
hydrazone substituted .alpha.,.beta.-unsaturated carbonyl compound
of formula IV by reacting it with a suitable reagent, e.g. a
reducing agent, an organometallic reagent or a nucleophilic
reagent. The compounds of formula V are versatile reaction tools
for the preparation of pyrazole derived fine chemicals. The present
invention also relates to pyrazole compounds of formulae Va, Vb,
Vc, and VI.
Inventors: |
Gockel; Birgit;
(Ludwigshafen, DE) ; Saelinger; Daniel;
(Ludwigshafen, DE) ; Soergel; Sebastian;
(Ludwigshafen, DE) ; Rack; Michael; (Eppelheim,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BASF SE |
Ludwigshafen |
|
DE |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20170210712 A1 |
July 27, 2017 |
|
|
Family ID: |
51257363 |
Appl. No.: |
15/329104 |
Filed: |
July 30, 2015 |
PCT Filed: |
July 30, 2015 |
PCT NO: |
PCT/EP2015/067507 PCKC 00 |
371 Date: |
January 25, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/06 20130101;
C07D 403/12 20130101; C07D 401/12 20130101; C07D 231/14
20130101 |
International
Class: |
C07D 231/14 20060101
C07D231/14; C07D 405/06 20060101 C07D405/06; C07D 401/12 20060101
C07D401/12; C07D 403/12 20060101 C07D403/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 31, 2014 |
EP |
14179249.9 |
Claims
1. A process for preparing a pyrazole compound of formula V, or a
salt, stereoisomer, tautomer or N-oxide thereof ##STR00047##
comprising the step of cyclizing a hydrazone substituted
.alpha.,.beta.-unsaturated carbonyl compound of formula IV
##STR00048## by reacting it with a reagent comprising a R.sup.6
group, wherein R.sup.1 is selected from H, halogen, CN, NO.sub.2,
C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, wherein the C-atoms be unsubstituted, may
be partially or fully halogenated or may be substituted by 1, 2 or
3 identical or different substituents R.sup.x; OR.sup.a, SR.sup.a,
C(Y)OR.sup.c, S(O).sub.mR.sup.d, S(O).sub.mY.sup.1R.sup.d,
NR.sup.eR.sup.f, C(Y)NR.sup.gR.sup.h, heterocyclyl, hetaryl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkenyl and
aryl, wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 identical or different substituents
selected from the radicals R.sup.y and R.sup.x; R.sup.2 is selected
from H, C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, wherein the C-atoms may be unsubstituted,
may be partially or fully halogenated or may be substituted by 1, 2
or 3 identical or different substituents R.sup.x; C(Y)OR.sup.c,
C(Y)NR.sup.gR.sup.h, heterocyclyl, hetaryl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkenyl and
aryl, wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 identical or different substituents
selected from the radicals R.sup.y and R.sup.x; and R.sup.3 is
selected from H, halogen, CN, NO.sub.2, C.sub.1-C.sub.10-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, wherein the
C-atoms may be unsubstituted, may be partially or fully halogenated
or may be substituted by 1, 2 or 3 identical or different
substituents R.sup.x; OR.sup.a, SR.sup.a, C(Y)OR.sup.c,
S(O).sub.mR.sup.d, S(O).sub.mY.sup.1R.sup.d, NR.sup.eR.sup.f,
C(Y)NR.sup.gR.sup.h, heterocyclyl, hetaryl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkenyl, and
aryl, wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 identical or different substituents
selected from the radicals R.sup.y and R.sup.x; and wherein R.sup.4
and R.sup.5 are independently of each other selected from H,
NO.sub.2, C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, wherein the C-atoms may be unsubstituted,
may be partially or fully halogenated or may be substituted by 1, 2
or 3 identical or different substituents R.sup.x;
C.sub.1-C.sub.10-haloalkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.10-alkyl, wherein the C-atoms
may be unsubstituted, or partially or fully substituted by
identical or different substituents R.sup.y; C(Y)OR.sup.c,
C(Y)NR.sup.gR.sup.h, C(Y)NR.sup.iNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-OR.sup.a, C.sub.1-C.sub.5-alkylen-CN,
C.sub.1-C.sub.5-alkylen-C(Y)OR.sup.c,
C.sub.1-C.sub.5-alkylen-NR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-C(Y)NR.sup.gR.sup.h,
C.sub.1-C.sub.5-alkylen-S(O).sub.mR.sup.d,
C.sub.1-C.sub.5-alkylen-S(O).sub.mNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-NR.sup.iNR.sup.eR.sup.f, heterocyclyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkenyl,
hetaryl, aryl, heterocyclyl-C.sub.1-C.sub.5-alkyl,
C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.5-alkyl,
C.sub.3-C.sub.10-cycloalkenyl-C.sub.1-C.sub.5-alkyl,
hetaryl-C.sub.1-C.sub.5-alkyl, aryl-C.sub.1-C.sub.5-alkyl, wherein
the cyclic moieties may be unsubstituted or may be substituted by
1, 2, 3, 4, or 5 identical or different substituents R.sup.y;
groups -D-E, wherein D is a direct bond, C.sub.1-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene, or C.sub.2-C.sub.6-alkynylene, which
carbon chains can be partially or fully substituted by R.sup.n, and
E is a non-aromatic 3- to 12-membered carbo- or heterocycle, which
may contain 1, 2, 3, or 4 heteroatoms selected from N--R.sup.l, O,
and S, wherein S may be oxidized, which carbo- or heterocycle may
be partially or fully substituted by R.sup.n; and groups
-A-SO.sub.m-G, wherein A is C.sub.1-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene and C.sub.2-C.sub.6-alkynylene, wherein
the C-atoms may be unsubstituted, or partially or fully substituted
by R.sup.p, and G is C.sub.1-C.sub.4-haloalkyl or
C.sub.3-C.sub.6-cycloalkyl which may be halogenated; or R.sup.4 and
R.sup.5 together with the carbon atom to which they are attached
form a 3- to 12-membered non-aromatic carbo- or heterocycle, which
heterocycle may contain 1, 2, 3, 4, or 5 heteroatoms selected from
N--R.sup.l, O, and S, wherein S may be oxidized, and which carbo-
or heterocycle may be partially or fully substituted by R.sub.j;
and wherein R.sup.6 is selected from H, CN,
C.sub.1-C.sub.6-fluoroalkyl, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl,
C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cyclo-alkenyl-C.sub.1-C.sub.2-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.2-alkyl, aryl,
aryl-C.sub.1-C.sub.2-alkyl, hetaryl, hetaryl-C.sub.1-C.sub.2-alkyl,
wherein the carbon chains or cyclic moieties may be unsubstituted,
partially or fully substituted by identical or different
substituents R.sup.x; OR.sup.a, SR.sup.a, NR.sup.eR.sup.f, and
groups of general formula (i) ##STR00049## and wherein R.sup.a,
R.sup.b are independently of each other selected from H,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl and hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4 or 5 substituents which, independently of
each other, are selected from halogen, CN, C(O)NH.sub.2, NO.sub.2,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; R.sup.c is
selected from H, C.sub.1-C.sub.10-alkyl,
C.sub.1-C.sub.10-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkylmethyl, C.sub.3-C.sub.10-halocycloalkyl,
C.sub.3-C.sub.6-cycloalkenyl, C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl and hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the ring in the six last mentioned radicals may be
unsubstituted or may be substituted by 1, 2, 3, 4 or 5 substituents
which, independently of each other, are selected from halogen, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; or R.sup.c together with the C(Y)O
group forms a salt [C(Y)O].sup.-NR.sub.4.sup.+,
[C(Y)O].sup.-M.sub.a.sup.+ or [C(Y)O].sup.-1/2M.sub.ea.sup.2+,
wherein M.sub.a is an alkali metal and M.sub.ea is an alkaline
earth metal, and wherein the substituents R at the nitrogen atom
are independently of each other selected from H,
C.sub.1-C.sub.10-alkyl, phenyl and phenyl-C.sub.1-C.sub.4-alkyl;
R.sup.d is selected from C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl and hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 substituents which are
independently of each other selected from halogen, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; R.sup.e, R.sup.f are independently of
each other selected from H, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkylmethyl, C.sub.3-C.sub.6-halocycloalkyl,
C.sub.3-C.sub.6-cycloalkenyl, C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl,
C.sub.1-C.sub.4-alkylsulfonyl, C.sub.1-C.sub.4-haloalkylsulfonyl,
heterocyclyl, heterocyclyl-C.sub.1-C.sub.4-alkyl,
heterocyclylcarbonyl, heterocyclyl-C.sub.1-C.sub.4-sulfonyl, aryl,
arylcarbonyl, arylsulfonyl, hetaryl, hetarylcarbonyl,
hetarylsulfonyl, aryl-C.sub.1-C.sub.4-alkyl and
hetaryl-C.sub.1-C.sub.4-alkyl, wherein the cyclic moieties may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5
substituents which, independently of each other, are selected from
halogen, CN, C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; or R.sup.e and R.sup.f together with
the N atom to which they are bonded form a 5- or 6-membered,
saturated or unsaturated heterocycle, which may be substituted by a
further heteroatom being selected from O, S and N as a ring member
atom and wherein the heterocycle may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 substituents which are
independently of each other selected from halogen, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; R.sup.g, R.sup.h are independently of
each other selected from H, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl and hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 substituents which are
independently of each other selected from halogen, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; R.sup.i is selected from H,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, aryl, and
aryl-C.sub.1-C.sub.4-alkyl, wherein the aryl ring may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5
substituents which are independently of each other selected from
halogen, CN, C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; R.sup.j is halogen, OH, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.10-alkyl,
C.sub.1-C.sub.10-haloalkyl, C.sub.1-C.sub.10-alkoxy,
C.sub.1-C.sub.10-haloalkoxy, benzyloxy, S(O).sub.mR.sup.k,
C.sub.3-C.sub.6-cycloalkyl, or a 3- to 6-membered heterocycle,
which may contain 1 or 2 heteroatoms selected from N--R.sup.l, O,
and S, wherein S may be oxidized, which R.sup.j groups are
unsubstituted or partially or fully substituted by R.sup.m, and
wherein two groups R.sup.j connected to the same or adjacent ring
atoms may together form a 3- to 6-membered carbo- or heterocycle
which heterocycle may contain 1 or 2 heteroatoms selected from
N--R.sup.l, O, and S, wherein S may be oxidized, which cycles may
be partially or fully substituted by R.sup.m radicals; R.sup.k is
H, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, or
C.sub.3-C.sub.6-cycloalkyl, which cycle may be partially or fully
substituted by R.sup.l; R.sup.l is H, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkylcarbonyl, or C.sub.1-C.sub.4-alkoxycarbonyl;
R.sup.m is halogen, OH, CN, C(O)NH.sub.2, NO.sub.2,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, or S(O).sub.mR.sup.k; R.sup.n is
halogen, CN, C(Y)OR.sup.c, C(O)NH.sub.2, NO.sub.2,
C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkenyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyliden, or S(O).sub.mR.sup.o, two adjacent
groups R.sup.n may form together with the atoms to which they are
bonded a 3- to 8-membered carbo- or heterocycle, which may contain
1, 2, 3, or 4 heteroatoms selected from N--R.sup.l, O, and S,
wherein S may be oxidized, which cyclic R.sup.n moieties may be
substituted by halogen, R.sup.o, or R.sup.l; R.sup.o is H,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, or C.sub.1-C.sub.4-alkoxy; R.sup.p is
halogen, CN, C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.2-alkyl,
C.sub.1-C.sub.2-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.4-alkoxy, or C.sub.1-C.sub.2-haloalkoxy, or two
groups R.sup.p can together form a 3- to 6-membered carbo- or
heterocyclic ring, which heterocycle contains 1 or 2 heteroatoms
selected from N--R.sup.l, O, and S, wherein S may be oxidized,
which carbo- or heterocyclic ring is unsubstituted or partly or
fully substituted by groups R.sup.q; R.sup.q is halogen, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.4-alkoxy, or C.sub.1-C.sub.4-haloalkoxy; R.sup.r and
R.sup.s are independently of each other selected from R.sup.b,
OR.sup.c1, and NR.sup.gR.sup.h; R.sup.c1 is C.sub.1-C.sub.10-alkyl,
C.sub.1-C.sub.10-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkylmethyl, C.sub.3-C.sub.10-halocycloalkyl,
C.sub.3-C.sub.6-cycloalkenyl, C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl or hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the ring in the six last mentioned radicals may be
unsubstituted or may be substituted by 1, 2, 3, 4 or substituents
which, independently of each other, are selected from halogen, CN,
C(O)NH
.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy or C.sub.1-C.sub.4-haloalkoxy; R.sup.t is H
or R.sup.a; R.sup.x is halogen, CN, C(Y)OR.sup.c,
C(Y)NR.sup.gR.sup.h, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, S(O).sub.mR.sup.d,
S(O).sub.mNR.sup.eR.sup.f, C.sub.1-C.sub.5-alkylen-NHC(O)OR.sup.c,
C.sub.1-C.sub.10-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl,
C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.1-C.sub.4-haloalkoxycarbonyl,
C.sub.3-C.sub.6-cycloalkyl, 5- to 7-membered heterocyclyl, 5- or
6-membered hetaryl, aryl, C.sub.3-C.sub.6-cycloalkoxy, 3- to
6-membered heterocyclyloxy, or aryloxy, wherein the cyclic moieties
may be unsubstituted or may be substituted by 1, 2, 3, 4, or 5
radicals R.sup.y; and R.sup.y is selected from halogen, CN,
C(Y)OR.sup.c, C(Y)NR.sup.gR.sup.h, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, benzyloxymethyl, S(O).sub.mR.sup.d,
S(O).sub.mNR.sup.eR.sup.f, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.1-C.sub.4-haloalkylcarbonyl, C.sub.1-C.sub.4-alkoxycarbonyl,
C.sub.1-C.sub.4-haloalkoxycarbonyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl and
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl; and wherein Y is O or
S; Y.sup.1 is O, S, or N--R.sup.1a; R.sup.1a is H,
C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.12-cycloalkyl, aryl, or
hetaryl; and m is 0, 1 or 2.
2. The process according to claim 1, wherein R.sup.1 is H, halogen,
CN, NO.sub.2, C.sub.1-C.sub.10-alkyl, which may be unsubstituted,
may be partially or fully halogenated, or may be substituted by 1,
2, or 3 identical or different substituents R.sup.x, C(Y)OR.sup.c,
S(O).sub.mR.sup.d, S(O).sub.mY.sup.1R.sup.d,
C.sub.3-C.sub.12-cycloalkyl, aryl, or hetaryl, wherein the cyclic
moieties may be unsubstituted or may be substituted by 1, 2, 3, 4,
or 5 identical or different substituents selected from the radicals
R.sup.y and R.sup.x; wherein R.sup.c is H, C.sub.1-C.sub.4-alkyl or
aryl-C.sub.1-C.sub.4-alkyl, or wherein R.sup.c together with the
C(Y)O group forms a salt [C(Y)O].sup.-NH.sub.4.sup.+,
[C(Y)O].sup.-M.sub.a.sup.+ or [C(Y)O].sup.-1/2M.sub.ea.sup.2+,
wherein M.sub.a is an alkali metal and M.sub.ea is an alkaline
earth metal; wherein R.sup.d is C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl, aryl, or hetaryl; wherein Y is O; and
wherein Y.sup.1 is O or NR.sup.1a, wherein R.sup.1a is
C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, aryl, or
hetaryl; and wherein preferably R.sup.1 is CN, C(Y)OR.sup.c,
wherein Y is O, and R.sup.c is C.sub.1-C.sub.4-alkyl or benzyl.
3. The process according to claim 1, wherein R.sup.2 is
C.sub.1-C.sub.10-alkyl, which may be unsubstituted, may be
partially or fully halogenated, or may be substituted by 1, 2 or 3
identical or different substituents R.sup.x,
C.sub.3-C.sub.12-cycloalkyl, aryl, or hetaryl, wherein the cyclic
moieties may be unsubstituted or may be substituted by 1, 2, 3, 4,
or 5 identical or different substituents selected from the radicals
R.sup.y and R.sup.x.
4. The process according to claim 1, wherein R.sup.3 is H,
C.sub.1-C.sub.10-alkyl, which may be unsubstituted, may be
partially or fully halogenated, or may be substituted by 1, 2 or 3
identical or different substituents R.sup.x,
C.sub.3-C.sub.12-cycloalkyl, aryl, or hetaryl, wherein the cyclic
moieties may be unsubstituted or may be substituted by 1, 2, 3, 4,
or 5 identical or different substituents selected from the radicals
R.sup.y and R.sup.x.
5. The process according to claim 1, wherein R.sup.2 and R.sup.3
are different from each other.
6. The process according to claim 1, wherein R.sup.4 is selected
from C.sub.1-C.sub.10-alkyl, which may be unsubstituted, may be
partially or fully halogenated, or may be substituted by 1, 2 or 3
identical or different substituents R.sup.x, and
C.sub.3-C.sub.10-cycloalkyl, which may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 identical or different substituents
R.sup.y; and R.sup.5 is selected from C.sub.1-C.sub.10-alkyl, which
may be unsubstituted, may be partially or fully halogenated, or may
be substituted by 1, 2 or 3 identical or different substituents
R.sup.x, and C.sub.3-C.sub.10-cycloalkyl, which may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5 identical
or different substituents R.sup.y.
7. The process according to claim 1, wherein the reagent comprising
the R.sup.6 group is one of (i) a reducing agent, wherein R.sup.6
is H, (ii) an organometallic reagent, wherein R.sup.6 is selected
from C.sub.1-C.sub.6-fluoroalkyl, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl,
C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cycloalkenyl-C.sub.1-C.sub.2-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.2-alkyl, aryl,
aryl-C.sub.1-C.sub.2-alkyl, hetaryl, hetaryl-C.sub.1-C.sub.2-alkyl,
wherein the carbon chains or cyclic moieties may be unsubstituted,
partially or fully substituted by identical or different
substituents R.sup.x, and (iii) a nucleophilic reagent of formula
H--R.sup.6, M.sub.a.sup.+R.sup.6- or 1/2M.sub.ea.sup.2+R.sup.6-,
wherein M.sub.a is an alkaline metal and M.sub.ae is an alkaline
earth metal, and wherein R.sup.6 is selected from CN, OR.sup.a,
SR.sup.a, NR.sup.eR.sup.f, and groups of the general formula (i)
##STR00050##
8. The process according to claim 1, wherein R.sup.6 is selected
from H, CN, and C.sub.1-C.sub.2-fluoroalkyl.
9. The process according to claim 1, further comprising the step of
preparing the hydrazone substituted .alpha.,.beta.-unsaturated
carbonyl compound of formula IV ##STR00051## by reacting an
.alpha.,.beta.-unsaturated carbonyl compound of formula III
##STR00052## with a hydrazone compound of formula II ##STR00053##
wherein X is a leaving group.
10. The process according to claim 9, wherein X is halogen, OH,
C.sub.1-C.sub.10-alkoxy, C.sub.3-C.sub.10-cycloalkoxy,
C.sub.1-C.sub.10-alkyl-C(O)O--,
C.sub.1-C.sub.10-alkyl-S(O).sub.2O--,
C.sub.1-C.sub.10-haloalkyl-S(O).sub.2O--, phenyl-S(O).sub.2O--,
tolyl-S(O).sub.2O--, (C.sub.1-C.sub.10-alkyloxy).sub.2P(O)O--,
C.sub.1-C.sub.10-alkylthio, C.sub.3-C.sub.10-cycloalkylthio,
C.sub.1-C.sub.10-alkyl-C(O)S--, NH.sub.2,
C.sub.1-C.sub.10-alkylamino, C.sub.1-C.sub.10-dialkylamino,
morpholino, N-methylpiperazino or
aza-C.sub.3-C.sub.10-cycloalkyl.
11. The process according to claim 9, further comprising the step
of preparing the hydrazone compound of formula II ##STR00054## by
reacting a carbonyl compound of formula I ##STR00055## with
hydrazine or a salt thereof.
12. The process according to claim 1, wherein the compound of
formula V is a compound of formula Va or Vb ##STR00056## and
wherein the process further comprises the step of converting the
compound of formula Va or Vb into a compound of formula Vc
##STR00057## wherein R.sup.c in formula Va is C.sub.1-C.sub.4-alkyl
or aryl-C.sub.1-C.sub.4-alkyl.
13. A process according to claim 1, wherein the process further
comprises the step of converting a compound of formula Vc into a
compound of formula VI ##STR00058## wherein X.sup.1 is a leaving
group selected from halogen, N.sub.3, p-nitrophenoxy, and
pentafluorophenoxy.
14. The process according to claim 13, wherein the process further
comprises the step of converting the compound of formula VI into a
compound of formula VIII ##STR00059## by reacting the compound of
formula VI with a compound of formula VII ##STR00060## U is N or
CR.sup.U; R.sup.P1, R.sup.P2, R.sup.P3, and Ru are independently of
each other selected from H, halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.3-haloalkoxy, C.sub.1-C.sub.4-alkylthio,
C.sub.1-C.sub.3-haloalkylthio, C.sub.1-C.sub.4-alkylsulfinyl,
C.sub.1-C.sub.3-haloalkylsulfinyl, C.sub.1-C.sub.4-alkylsulfonyl,
C.sub.1-C.sub.3-haloalkylsulfonyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl and
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl; and R.sup.1N is H,
CN, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-haloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-halocycloalkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-haloalkenyl,
C.sub.2-C.sub.10-alkynyl, C.sub.3-C.sub.10-haloalkynyl,
C.sub.1-C.sub.5-alkylen-CN, OR.sup.a,
C.sub.1-C.sub.5-alkylen-OR.sup.a, C(Y)R.sup.b,
C.sub.1-C.sub.5-alkylen-C(Y)R.sup.b, C(Y)OR.sup.c,
C.sub.1-C.sub.5-alkylen-C(Y)OR.sup.c, S(O).sub.2R.sup.d,
NR.sup.eR.sup.f, C.sub.1-C.sub.5-alkylen-NR.sup.eR.sup.f,
C(Y)NR.sup.gR.sup.h, C.sub.1-C.sub.5-alkylen-C(Y)NR.sup.gR.sup.h,
S(O).sub.mNR.sup.eR.sup.f, C(Y)NR.sup.iNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-S(O).sub.2R.sup.d,
C.sub.1-C.sub.5-alkylen-S(O).sub.mNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-C(Y)NR.sup.iNR.sup.eR.sup.f, aryl,
heterocyclyl, hetaryl, aryl-C.sub.1-C.sub.5-alkyl,
C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.5-alkyl,
heterocyclyl-C.sub.1-C.sub.5-alkyl or
hetaryl-C.sub.1-C.sub.5-alkyl, wherein the cyclic moieties may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5 identical
or different substituents selected from the radicals R.sup.y and
R.sup.x.
15. The process according to claim 14, wherein U is N or CH;
R.sup.P1, R.sup.P2, R.sup.P3 are H; and R.sup.1N is H,
C.sub.1-C.sub.2-alkyl or
C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl.
16. A compound of formula Va or a salt, stereoisomer, tautomer or
N-oxide thereof ##STR00061## wherein R.sup.2 is CH.sub.3, R.sup.3
is H, R.sup.4 is CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and
R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H, R.sup.4 is
CHFCH.sub.3, R.sup.5 is CH.sub.3 and R.sup.6 is H; or R.sup.2 is
CH.sub.3, R.sup.3 is H, R.sup.4 is 1-CN-cC.sub.3H.sub.4, R.sup.5 is
CH.sub.3 and R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H,
R.sup.4 is 1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and
R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H, R.sup.4 and
R.sup.5 together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and
R.sup.6 is H; and wherein R.sup.c is C.sub.1-C.sub.4-alkyl or
aryl-C.sub.1-C.sub.4-alkyl, or wherein R.sup.c together with the
C(O)O group forms a salt [C(O)O].sup.-NR.sub.4.sup.+,
[C(O)O].sup.-M.sub.a.sup.+ or [C(O)O].sup.-1/2M.sub.ea.sup.2+,
wherein M.sub.a is an alkali metal and M.sub.ea is an alkaline
earth metal; and wherein the substituents R at the nitrogen atom
are independently of each other selected from H,
C.sub.1-C.sub.10-alkyl, phenyl and
phenyl-C.sub.1-C.sub.4-alkyl.
17. A compound of formula Vc or a salt, stereoisomer, tautomer or
N-oxide thereof ##STR00062## wherein R.sup.2 is CH.sub.3, R.sup.3
is H, R.sup.4 is CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and
R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H, R.sup.4 is
CHFCH.sub.3, R.sup.5 is CH.sub.3 and R.sup.6 is H; or R.sup.2 is
CH.sub.3, R.sup.3 is H, R.sup.4 is 1-CN-cC.sub.3H.sub.4, R.sup.5 is
CH.sub.3 and R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H,
R.sup.4 is 1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and
R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H, R.sup.4 and
R.sup.5 together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and
R.sup.6 is H.
18. A compound of formula IV or a salt, stereoisomer, tautomer or
N-oxide thereof ##STR00063## wherein R.sup.1 is CN, C(O)OCH.sub.3,
C(O)OCH.sub.2CH.sub.3, C(O)OC(CH.sub.3).sub.3,
C(O)OCH.sub.2C.sub.6H.sub.5, or COOH; R.sup.2 is CH.sub.3, R.sup.3
is H, and R.sup.4 is CH(CH.sub.3).sub.2, and R.sup.5 is CH.sub.3;
or R.sup.4 is CHFCH.sub.3, and R.sup.5 is CH.sub.3; or R.sup.4 is
1-CN-cC.sub.3H.sub.4, and R.sup.5 is CH.sub.3; or R.sup.4 is
1-C(O)NH.sub.2-cC.sub.3H.sub.4, and R.sup.5 is CH.sub.3; or R.sup.4
and R.sup.5 together are
CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2.
19. The process according to claim 6, wherein R.sup.4 is selected
from C.sub.1-C.sub.4-alkyl, which may be unsubstituted, may be
partially or fully halogenated, or may be substituted by 1 or 2
identical or different substituents R.sup.x, wherein R.sup.x is
selected from CN and C(O)NH.sub.2, and C.sub.3-C.sub.6-cycloalkyl,
which may be unsubstituted or may be substituted by 1, 2, or 3
identical or different substituents R.sup.y, wherein R.sup.y is
selected from halogen, CN and C(O)NH.sub.2; and R.sup.5 is selected
from C.sub.1-C.sub.4-alkyl, which may be unsubstituted, may be
partially or fully halogenated, or may be substituted by 1 or 2
identical or different substituents R.sup.x, wherein R.sup.x is
selected from CN and C(O)NH.sub.2, and C.sub.3-C.sub.6-cycloalkyl,
which may be unsubstituted or may be substituted by 1, 2 or 3
identical or different substituents R.sup.y, wherein R.sup.y is
selected from halogen, CN and C(O)NH.sub.2.
20. A compound of formula Vb or a salt, stereoisomer, tautomer or
N-oxide thereof ##STR00064## wherein R.sup.2 is CH.sub.3, R.sup.3
is H, R.sup.4 is CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and
R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H, R.sup.4 is
CHFCH.sub.3, R.sup.5 is CH.sub.3 and R.sup.6 is H; or R.sup.2 is
CH.sub.3, R.sup.3 is H, R.sup.4 is 1-CN-cC.sub.3H.sub.4, R.sup.5 is
CH.sub.3 and R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H,
R.sup.4 is 1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and
R.sup.6 is H; or R.sup.2 is CH.sub.3, R.sup.3 is H, R.sup.4 and
R.sup.5 together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and
R.sup.6 is H.
Description
[0001] The present invention relates to a process for preparing a
pyrazole compound according to the following reaction sequence:
##STR00001##
[0002] In particular, the present invention is directed to a
process of preparing a pyrazole compound of formula V, which
comprises cyclizing a hydrazone substituted
.alpha.,.beta.-unsaturated carbonyl compound of formula IV by
reacting it with a suitable reagent, e.g. a reducing agent, an
organometallic reagent or a nucleophilic reagent (step (c)). The
process may further comprise preparing the hydrazone substituted
.alpha.,.beta.-unsaturated carbonyl compound of formula IV by
reacting an .alpha.,.beta.-unsaturated carbonyl compound of formula
III, which contains a leaving group in the .beta.-position, with a
hydrazone compound of formula II (step (b)), and preparing said
hydrazone compound of formula II by reacting a carbonyl compound of
formula I with hydrazine (step (a)).
[0003] The process of the present invention may further comprise
steps of converting certain 4-substituted pyrazole compounds into
activated 4-pyrazole carboxylic acid derivatives according to the
following reaction sequence:
##STR00002##
[0004] In particular, the process of the invention may optionally
further comprise converting a pyrazole compound of formula Va,
which comprises an ester group in the 4-position, or a pyrazole
compound of formula Vb, which comprises a cyano group in the
4-position, into a 4-pyrazole carboxylic acid compound of formula
Vc (step (d)). Moreover, the process may further comprise
converting a 4-pyrazole carboxylic acid compound of formula Vc into
an activated 4-pyrazole carboxylic acid derivative of formula VI
(step (e)).
[0005] The process of the present invention may still further
comprise the step of converting 4-activated pyrazole carboxylic
acid derivatives into 4-pyrazole N-(het)arylamide compounds, which
are known as pesticidally active compounds, according to the
following reaction:
##STR00003##
[0006] In particular, the process may still further comprise the
step of reacting an activated 4-pyrazole carboxylic acid derivative
of formula VI with a suitable N-(het)arylamine compound of formula
VII to yield a 4-pyrazole N-(het)arylamide compound of formula VIII
(step (f)).
[0007] The present invention also relates to novel pyrazole
compounds of formulae Va, Vb, Vc and VI.
[0008] Pyrazole compounds, in particular 4-pyrazole carboxylic acid
derivatives, such as esters, nitriles, acids and activated acid
derivatives, are versatile intermediate compounds for the
preparation of pyrazole derived fine chemicals, such as compounds
in the pharmaceutical or agrochemical field. In particular the
compounds are versatile intermediate compounds for the preparation
of pyrazole derived pesticides, such as 4-pyrazole N-(het)arylamide
compounds, which are known to be particularly useful for combating
invertebrate pests (see WO 2009/027393, WO 2010/034737, WO
2010/034738, and WO 2010/112177). Of particular interest are
pyrazole compounds and 4-pyrazole carboxylic acid derivatives,
which are substituted at one nitrogen atom and optionally also
substituted in the 3- and/or 5-position because also the pyrazole
derived pesticides including the above mentioned 4-pyrazole amide
compounds often comprise pyrazole moieties, which are substituted
accordingly.
[0009] In view of the above, there is a need for a process for
preparing N-substituted pyrazole compounds and optionally further
converting them into pyrazole derived pesticides. A particular
problem accompanying the preparation of N-substituted pyrazole
compounds is the regioselectivity, if substituents are present in
the 3- and/or 5-position of the pyrazole ring, in particular, if a
substituent is present in the 3-position, but not in the
5-position, if a substituent is present in the 5-position, but not
in the 3-position, or if different substituents are present in the
3- and 5-position. Accordingly, there is a particular need for a
process for regioselectively preparing N-substituted pyrazole
compounds, which have a substituent either in the 3- or in the
5-position or different substituents in the 3- and 5-position of
the pyrazole ring. In view of the preparation of 4-pyrazole
N-(het)arylamide compounds as pesticides, such a process should
particularly be suitable for regioselectively obtaining
N-substituted 4-pyrazole carboxylic acid derivatives, which have a
substituent either in the 3- or in the 5-position or different
substituents in the 3- and 5-position of the pyrazole ring.
[0010] It is noted that the numbering of the atoms of an
N-substituted pyrazole compound is usually as follows.
##STR00004##
[0011] The positions of the substituents are indicated by the same
numbers. The substituent at the nitrogen atom is typically referred
to as the N-substituent rather than as substituent in the
1-position, although this is also suitable. The 2-position, i.e.
the second nitrogen atom of the N-substituted pyrazole compounds,
is typically unsubstituted. In contrast, the 3-, 4- and 5-positions
may each be substituted.
[0012] There are principally two processes known for the
preparation of N-substituted 4-pyrazole carboxylic acid
derivatives, which are 3- and/or 5-substituted.
[0013] Firstly, such N-substituted 4-pyrazole carboxylic acid
derivatives can be prepared by reacting an
.alpha.,.beta.-unsaturated carbonyl compound, e.g. an
.alpha.,.beta.-unsaturated ketone, which contains a leaving group
in the .beta.-position, with a hydrazine derivative, which has a
substituent at one of the two nitrogen atoms. In view of the fact
that the substituted hydrazine derivative comprises two amino
groups, which are often very similar in terms of their nucleophilic
reactivity, two regioisomers of the desired N-substituted pyrazole
compound are usually obtained because either the substituted
nitrogen atom or the unsubstituted nitrogen atom of the hydrazine
derivative may react. Reactions, wherein the substituted hydrazine
derivatives are used in the form of salts, have already been
described, e.g., in JP 2007/326784, WO 2010/142628, and WO
2012/019015, and reactions, wherein mono-protected substituted
hydrazine derivatives are used, have been described in WO
2012/019015. However, the regioselectivity problem in terms of the
3-/5-substitution pattern of the resulting N-substituted 4-pyrazole
carboxylic acid derivatives could not be solved.
[0014] Secondly, N-substituted 4-pyrazole carboxylic acid
derivatives, which are 3- and/or 5-substituted, can be prepared by
reacting an .alpha.,.beta.-unsaturated carbonyl compound, e.g. an
.alpha.,.beta.-unsaturated ketone, which contains a leaving group
in the .beta.-position, with hydrazine and then N-alkylating the
resulting pyrazole derivative. Due to the tautomerism of the
pyrazole compound, which is obtained as an intermediate, two
regioisomers of the desired N-substituted pyrazole compound are
usually obtained upon alkylation. Such reaction sequences have,
e.g., been described in Heterocycles 2000, 2775, Liebigs Analen der
Chemie 1985, 794, or Journal of Heterocyclic Chemistry 1985,
1109.
[0015] A process for regioselectively preparing N-substituted
4-pyrazole carboxylic acid derivatives, which are 3-substituted or
3- and 5-substituted with different substituents, was published by
Glorius et al. in Angew. Chem. Int. Ed. 2010, 7790, and Green Chem.
2012, 14, 2193. Said process is performed by reacting an enamine
compound with an excess of a suitable nitrile compound in the
presence of stochiometric or catalytic amounts of copper.
[0016] Although the process regioselectively provides N-substituted
4-pyrazole carboxylic acid derivatives, which are 3-substituted or
3- and 5-substituted with different substituents, the process is
disadvantageous in that copper is involved as a heavy metal, and an
excess of at least three equivalents of the nitrile compound has to
be used, so that the process is not environmentally friendly and
not economical. Furthermore, the process has not been described for
HCN as nitrile compound, most likely for the reason that HCN would
polymerize under the reaction conditions, so that a cyclization
reaction with the enamine compound according to the above reaction
scheme would not take place. As a consequence, N-substituted
4-pyrazole carboxylic acid derivatives, which are 5-substituted,
but not 3-substituted, can obviously not be obtained according to
the process described by Glorius et al.
[0017] In view of the above, it is an object of the invention to
provide a process for preparing N-substituted pyrazole compounds
and optionally further converting them into pyrazole derived
pesticides. In particular, it is an object to provide a process for
preparing N-substituted pyrazole compounds, which are substituted
e.g. in the 3- and/or 5-position and/or in the 4-position, wherein
these substituents may be identical or different, preferably
different.
[0018] It is another object of the invention to provide a process
for regioselectively preparing N-substituted pyrazole compounds,
which are 3- and/or 5-substituted. In particular, it is an object
to provide regioselective access to a variety of N-substituted
pyrazole compounds, which are 3-substituted, 5-substituted or 3-
and 5-substituted with different substituents, and preferably
5-substituted, but not 3-substituted.
[0019] It is yet another object of the invention to provide a
process for regioselectively preparing N-substituted 4-pyrazole
carboxylic acid derivatives, for example esters or nitriles, which
are 3- and/or 5-substituted. In particular, it is an object to
provide regioselective access to a variety of N-substituted
4-pyrazole carboxylic acid derivatives, which are 3-substituted,
5-substituted or 3- and 5-substituted with different substituents,
and preferably 5-substituted, but not 3-substituted.
[0020] In connection with the above objects, it is a further object
to provide a process, which can be performed from readily and
cheaply available starting materials. Furthermore, it is an object
in connection with the above objects to provide a process, which is
economical in terms of the yields and the amounts of the reactants,
which are reacted with each other. Moreover, it is an object in
connection with the above objects to provide a process, which is
suitable for a technical scale.
[0021] It is yet another object of the invention to provide a
process, which further allows for the provision of the free
N-substituted 4-pyrazole carboxylic acids and activated derivatives
thereof, wherein said compounds are preferably 3- and/or
5-substituted, e.g. 3-substituted, 5-substituted or 3- and
5-substituted with different substituents, and particularly
preferably 5-substituted, but not 3-substituted.
[0022] It is yet another object of the invention to provide a
process, which further allows for the provision of N-substituted
4-pyrazole amides, wherein the pyrazole moiety is preferably 3-
and/or 5-substituted, e.g. 3-substituted, 5-substituted or 3- and
5-substituted with different substituents, and particularly
preferably 5-substituted, but not 3-substituted.
[0023] Furthermore, it is an object of the invention to provide
N-substituted 4-pyrazole carboxylic acid derivatives, for example
esters or nitriles, N-substituted 4-pyrazole carboxylic acids and
activated derivatives thereof, which may in each case be 3- and/or
5-substituted, e.g. 3-substituted, 5-substituted or 3- and
5-substituted with different substituents, and preferably
5-substituted, but not 3-substituted. In particular, it is an
object to provide N-substituted 4-pyrazole carboxylic acid
derivatives, N-substituted 4-pyrazole carboxylic acids and
activated derivatives thereof, which have specific N-substituents
and specific substituents in the 5-position, but are unsubstituted
in the 3-position, because such pyrazole compounds are suitable for
the preparation of 4-pyrazole N-(het)arylamide compounds with an
exceptionally high pesticidally activity.
[0024] The above objects are achieved by the processes and
compounds described in detail in the claims and hereinafter.
[0025] In one aspect, the present invention relates to preparing a
pyrazole compound of formula V or a salt, stereoisomer, tautomer or
N-oxide thereof
##STR00005##
comprising the step of cyclizing a hydrazone substituted
.alpha.,.beta.-unsaturated carbonyl compound of formula IV
##STR00006##
by reacting it with a reagent comprising a R.sup.6 group, wherein
[0026] R.sup.1 is selected from H, halogen, CN, NO.sub.2,
C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, wherein the C-atoms be unsubstituted, may
be partially or fully halogenated or may be substituted by 1, 2, or
3 identical or different substituents R.sup.x; [0027] OR.sup.a,
SR.sup.a, C(Y)OR.sup.c, S(O).sub.mR.sup.d,
S(O).sub.mY.sup.1R.sup.d, NR.sup.eR.sup.f, C(Y)NR.sup.gR.sup.h,
heterocyclyl, hetaryl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkenyl and aryl, wherein the cyclic moieties
may be unsubstituted or substituted by 1, 2, 3, 4, or 5 identical
or different substituents selected from the radicals R.sup.y and
R.sup.x; [0028] R.sup.2 is selected from H, C.sub.1-C.sub.10-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, wherein the
C-atoms may be unsubstituted, may be partially or fully halogenated
or may be substituted by 1, 2, or 3 identical or different
substituents R.sup.x; [0029] C(Y)OR.sup.c, C(Y)NR.sup.gR.sup.h,
heterocyclyl, hetaryl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkenyl and aryl, wherein the cyclic moieties
may be unsubstituted or may be substituted by 1, 2, 3, 4, or 5
identical or different substituents selected from the radicals
R.sup.y and R.sup.x; and [0030] R.sup.3 is selected from H,
halogen, CN, NO.sub.2, C.sub.1-C.sub.10-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, wherein the
C-atoms may be unsubstituted, may be partially or fully halogenated
or may be substituted by 1, 2, or 3 identical or different
substituents R.sup.x; [0031] OR.sup.a, SR.sup.a, C(Y)OR.sup.c,
S(O).sub.mR.sup.d, S(O).sub.mY.sup.1R.sup.d, NR.sup.eR.sup.f,
C(Y)NR.sup.gR.sup.h, heterocyclyl, hetaryl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkenyl and
aryl, wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 identical or different substituents
selected from the radicals R.sup.y and R.sup.x; and wherein [0032]
R.sup.4 and R.sup.5 are independently of each other selected from
H, NO.sub.2, C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, wherein the C-atoms may be unsubstituted,
may be partially or fully halogenated or may be substituted by 1, 2
or 3 identical or different substituents R.sup.x; [0033]
C.sub.1-C.sub.10-haloalkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.10-alkyl, wherein the C-atoms
may be unsubstituted, or partially or fully substituted by
identical or different substituents R.sup.y; [0034] C(Y)OR.sup.c,
C(Y)NR.sup.gR.sup.h, C(Y)NR.sup.iNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-OR.sup.a, C.sub.1-C.sub.5-alkylen-CN,
C.sub.1-C.sub.5-alkylen-C(Y)OR.sup.c,
C.sub.1-C.sub.5-alkylen-NR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-C(Y)NR.sup.gR.sup.h,
C.sub.1-C.sub.5-alkylen-S(O).sub.mR.sup.d,
C.sub.1-C.sub.5-alkylen-S(O).sub.mNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-NR.sup.iNR.sup.eR.sup.f; [0035]
heterocyclyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkenyl, hetaryl, aryl,
heterocyclyl-C.sub.1-C.sub.5-alkyl,
C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.5-alkyl,
C.sub.3-C.sub.10-cycloalkenyl-C.sub.1-C.sub.5-alkyl,
hetaryl-C.sub.1-C.sub.5-alkyl, aryl-C.sub.1-C.sub.5-alkyl, wherein
the cyclic moieties may be unsubstituted or may be substituted by
1, 2, 3, 4, or 5 identical or different substituents R.sup.y;
[0036] groups -D-E, wherein [0037] D is a direct bond,
C.sub.1-C.sub.6-alkylene, C.sub.2-C.sub.6-alkenylene, or
C.sub.2-C.sub.6-alkynylene, which carbon chains can be partially or
fully substituted by R.sup.n, and [0038] E is a non-aromatic 3- to
12-membered carbo- or heterocycle, which may contain 1, 2, 3, or 4
heteroatoms selected from N--R.sup.l, O, and S, wherein S may be
oxidized, which carbo- or heterocycle may be partially or fully
substituted by R.sup.n; [0039] and [0040] groups -A-SO.sub.m-G,
wherein [0041] A is C.sub.1-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene and C.sub.2-C.sub.6-alkynylene, wherein
the C-atoms may be unsubstituted, or partially or fully substituted
by R.sup.p, and [0042] G is C.sub.1-C.sub.4-haloalkyl or
C.sub.3-C.sub.6-cycloalkyl which may be halogenated; or [0043]
R.sup.4 and R.sup.5 together with the carbon atom to which they are
attached form a 3- to 12-membered non-aromatic carbo- or
heterocycle, which heterocycle may contain 1, 2, 3, 4, or 5
heteroatoms selected from N--R.sup.l, O, and S, wherein S may be
oxidized, and which carbo- or heterocycle may be partially or fully
substituted by R.sup.j; and wherein [0044] R.sup.6 is selected from
H, CN, C.sub.1-C.sub.6-fluoroalkyl, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl,
C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cycloalkenyl-C.sub.1-C.sub.2-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.2-alkyl, aryl,
aryl-C.sub.1-C.sub.2-alkyl, hetaryl, hetaryl-C.sub.1-C.sub.2-alkyl,
wherein the carbon chains or cyclic moieties may be unsubstituted,
partially or fully substituted by identical or different
substituents R.sup.x; [0045] OR.sup.a, SR.sup.a, NR.sup.eR.sup.f,
and [0046] groups of general formula (i)
##STR00007##
[0046] and wherein [0047] R.sup.a, R.sup.b are independently of
each other selected from H, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkylmethyl, C.sub.3-C.sub.6-halocycloalkyl,
C.sub.3-C.sub.6-cycloalkenyl, C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl and hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 substituents which, independently
of each other, are selected from halogen, CN, C(O)NH.sub.2,
NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; [0048]
R.sup.c is selected from H, C.sub.1-C.sub.10-alkyl,
C.sub.1-C.sub.10-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkylmethyl, C.sub.3-C.sub.10-halocycloalkyl,
C.sub.3-C.sub.6-cycloalkenyl, C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl and hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the ring in the six last mentioned radicals may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5
substituents which, independently of each other, are selected from
halogen, CN, C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; or [0049] R.sup.c together with the
C(Y)O group forms a salt [C(Y)O].sup.-NR.sub.4.sup.+,
[C(Y)O].sup.-M.sub.a.sup.+ or [C(Y)O].sup.-1/2M.sub.ea.sup.2+,
wherein M.sub.a is an alkali metal and M.sub.ea is an alkaline
earth metal, and wherein the substituents R at the nitrogen atom
are independently of each other selected from H,
C.sub.1-C.sub.10-alkyl, phenyl and phenyl-C.sub.1-C.sub.4-alkyl;
[0050] R.sup.d is selected from C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl and hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 substituents which are
independently of each other selected from halogen, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; [0051] R.sup.e, R.sup.f are
independently of each other selected from H, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkylmethyl, C.sub.3-C.sub.6-halocycloalkyl,
C.sub.3-C.sub.6-cycloalkenyl, C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl,
C.sub.1-C.sub.4-alkylsulfonyl, C.sub.1-C.sub.4-haloalkylsulfonyl,
heterocyclyl, heterocyclyl-C.sub.1-C.sub.4-alkyl,
heterocyclylcarbonyl, heterocyclyl-C.sub.1-C.sub.4-sulfonyl, aryl,
arylcarbonyl, arylsulfonyl, hetaryl, hetarylcarbonyl,
hetarylsulfonyl, aryl-C.sub.1-C.sub.4-alkyl and
hetaryl-C.sub.1-C.sub.4-alkyl, wherein the cyclic moieties may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5
substituents which, independently of each other, are selected from
halogen, CN, C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; or [0052] R.sup.e and R.sup.f together
with the N atom to which they are bonded form a 5- or 6-membered,
saturated or unsaturated heterocycle, which may comprise a further
heteroatom being selected from O, S and N as a ring member atom and
wherein the heterocycle may be unsubstituted or may by substituted
by 1, 2, 3, 4, or 5 substituents which are independently of each
other selected from halogen, CN, C(O)NH.sub.2, NO.sub.2,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; [0053]
R.sup.g, R.sup.h are independently of each other selected from H,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl,
C.sub.3-C.sub.6-cycloalkenyl, C.sub.3-C.sub.6-halocycloalkenyl,
C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-haloalkenyl,
C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl and hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the cyclic moieties may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 substituents which are
independently of each other selected from halogen, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; [0054] R.sup.i is selected from H,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, aryl,
aryl-C.sub.1-C.sub.4-alkyl, wherein the aryl ring may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5
substituents which are independently of each other selected from
halogen, CN, C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-haloalkoxy; [0055] R.sup.j is halogen, OH, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.10-alkyl,
C.sub.1-C.sub.10-haloalkyl, C.sub.1-C.sub.10-alkoxy,
C.sub.1-C.sub.10-haloalkoxy, benzyloxy, S(O).sub.mR.sup.k,
C.sub.3-C.sub.6-cycloalkyl, or a 3- to 6-membered heterocycle,
which may contain 1 or 2 heteroatoms selected from N--R.sup.l, O,
and S, wherein S may be oxidized, which R.sup.j groups are
unsubstituted or partially or fully substituted by R.sup.m, and
wherein two groups R.sup.j connected to the same or adjacent ring
atoms may together form a 3- to 6-membered carbo- or heterocycle
which heterocycle may contain 1 or 2 heteroatoms selected from
N--R.sup.l, O, and S, wherein S may be oxidized, which cycles may
be partially or fully substituted by R.sup.m radicals; [0056]
R.sup.k is H, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, or
C.sub.3-C.sub.6-cycloalkyl, which cycle may be partially or fully
substituted by R.sup.l; [0057] R.sup.l is H, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkylcarbonyl, or C.sub.1-C.sub.4-alkoxycarbonyl;
[0058] R.sup.m is halogen, OH, CN, C(O)NH.sub.2, NO.sub.2,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, or S(O).sub.mR.sup.k; [0059] R.sup.n is
halogen, CN, C(Y)OR.sup.c, C(O)NH.sub.2, NO.sub.2,
C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkenyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyliden, or S(O).sub.mR.sup.o, two adjacent
groups R.sup.n may form together with the atoms to which they are
bonded a 3- to 8-membered carbo- or heterocycle, which may contain
1, 2, 3, or 4 heteroatoms selected from N--R.sup.l, O, and S,
wherein S may be oxidized, which cyclic R.sup.n moieties may be
substituted by halogen, R.sup.o, or R.sup.l; [0060] R.sup.o is H,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, or C.sub.1-C.sub.4-alkoxy; [0061]
R.sup.p is halogen, CN, C(O)NH.sub.2, NO.sub.2,
C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkoxy, or
C.sub.1-C.sub.2-haloalkoxy, or two groups R.sup.p can together form
a 3- to 6-membered carbo- or heterocyclic ring, which heterocycle
contains 1 or 2 heteroatoms selected from N--R.sup.l, O, and S,
wherein S may be oxidized, which carbo- or heterocyclic ring is
unsubstituted or partly or fully substituted by groups R.sup.q;
[0062] R.sup.q is halogen, CN, C(O)NH.sub.2, NO.sub.2,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkoxy, or
C.sub.1-C.sub.4-haloalkoxy; [0063] R.sup.r and R.sup.s are
independently of each other selected from R.sup.b, OR.sup.c1, and
NR.sup.gR.sup.h; [0064] R.sup.c1 is C.sub.1-C.sub.10-alkyl,
C.sub.1-C.sub.10-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkylmethyl, C.sub.3-C.sub.10-halocycloalkyl,
C.sub.3-C.sub.6-cycloalkenyl, C.sub.3-C.sub.6-cycloalkenylmethyl,
C.sub.3-C.sub.6-halocycloalkenyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-haloalkenyl, C.sub.2-C.sub.4-alkynyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.4-alkyl, aryl, hetaryl,
aryl-C.sub.1-C.sub.4-alkyl or hetaryl-C.sub.1-C.sub.4-alkyl,
wherein the ring in the six last mentioned radicals may be
unsubstituted or may be substituted with 1, 2, 3, 4 or substituents
which, independently of each other, are selected from halogen, CN,
C(O)NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy or
C.sub.1-C.sub.4-haloalkoxy; [0065] R.sup.t is H or R.sup.a; [0066]
R.sup.x is halogen, CN, C(Y)OR.sup.c, C(Y)NR.sup.gR.sup.h,
NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
S(O).sub.mR.sup.d, S(O).sub.mNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-NHC(O)OR.sup.c,
C.sub.1-C.sub.10-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl,
C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.1-C.sub.4-haloalkoxycarbonyl,
C.sub.3-C.sub.6-cycloalkyl, 5- to 7-membered heterocyclyl, 5- or
6-membered hetaryl, aryl, C.sub.3-C.sub.6-cycloalkoxy, 3- to
6-membered heterocyclyloxy, or aryloxy, wherein the cyclic moieties
may be unsubstituted or may be substituted by 1, 2, 3, 4, or 5
radicals R.sup.y; and [0067] R.sup.y is selected from halogen, CN,
C(Y)OR.sup.c, C(Y)NR.sup.gR.sup.h, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, benzyloxymethyl, S(O).sub.mR.sup.d,
S(O).sub.mNR.sup.eR.sup.f, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.1-C.sub.4-haloalkylcarbonyl, C.sub.1-C.sub.4-alkoxycarbonyl,
C.sub.1-C.sub.4-haloalkoxycarbonyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl and
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl; and wherein [0068] Y
is O or S; [0069] Y.sup.1 is O, S, or N--R.sup.1a; [0070] R.sup.1a
is H, C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.12-cycloalkyl, aryl, or
hetaryl; and [0071] m is 0, 1 or 2.
[0072] Preferably, formula IV is to be understood as not only
covering the compounds as such, but also as covering salts,
stereoisomers, tautomers or N-oxides of the compounds of formula
IV.
[0073] The process as defined above is suitable for providing a
variety of N-substituted pyrazole compounds of formula V, which may
be further converted to give pyrazole derived pesticides.
[0074] Furthermore, it has surprisingly been found that the process
is suitable for regioselectively preparing a variety of
N-substituted pyrazole compounds, which are 3- or 5-substituted or
substituted with different substituents in the 3- and 5-position.
In particular, the substitution pattern of the compounds of formula
IV predefines the substitution pattern of the resulting
N-substituted pyrazole compounds, so that the problem of
regioselectivity can completely be avoided. The compound of formula
IV can be selected as such, that a variety of substituents in the
3- and/or 5- as well as in the 4-position of the N-substituted
pyrazole compounds can be realized. In this context, it has also
been found that N-substituted 4-pyrazole carboxylic acid
derivatives, which are 3- or 5-substituted or substituted with
different substituents in the 3- and 5-position, can
regioselectively be obtained by the process according to the
present invention.
[0075] The process provides the N-substituted pyrazole compounds of
formula V in high yields based on the amounts of the compounds of
formula IV.
[0076] Furthermore, it is an advantage of the process that the
compounds of formula IV can be obtained from readily and cheaply
available starting materials. In particular, it is an advantage
that the compounds of formula IV can be obtained by reacting
.alpha.,.beta.-unsaturated carbonyl compounds of formula III, which
contain a leaving group in the .beta.-position, with hydrazone
compounds of formula II, wherein the .alpha.,.beta.-unsaturated
carbonyl compounds of formula III are readily available either
commercially or by methods known in the art, and the hydrazone
compounds of formula II can easily be obtained by reacting
commercially available carbonyl compounds of formula I with
hydrazine. This will be outlined in further detail below. By
varying the carbonyl compounds of formula I and the
.alpha.,.beta.-unsaturated carbonyl compounds of formula III, a
variety of compounds of formulae II, IV and V can thus easily be
obtained.
[0077] Furthermore, the compounds of formula V can be further
converted into pyrazole derived pesticides. For example, if the
pyrazole compound of formula V is a pyrazole compound of formula Va
or Vb with an ester or a cyano group in the 4-position, said
compound can easily be converted into the corresponding 4-pyrazole
carboxylic acid compound of formula Vc. Alternatively, such
4-pyrazole carboxylic acid compounds of formula Vc may directly be
obtained from suitable compounds of formula IV. From the 4-pyrazole
carboxylic acid compound of formula Vc, activated 4-pyrazole
carboxylic acid derivatives of formula VI can be obtained by
standard activation processes. The compounds of formula VI may then
be converted into 4-pyrazole N-(het)arylamide compounds of formula
VIII, which may represent highly active pesticides.
[0078] In view of the above, certain preferred embodiments of the
invention relate to a process, wherein the hydrazone substituted
.alpha.,.beta.-unsaturated carbonyl compound of formula IV
##STR00008##
[0079] is prepared by reacting an .alpha.,.beta.-unsaturated
carbonyl compound of formula III
##STR00009##
[0080] with a hydrazone compound of formula II
##STR00010##
[0081] wherein
[0082] X is a leaving group
[0083] and R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
defined above.
[0084] Furthermore, certain more preferred embodiments of the
invention relate to a process, wherein the above hydrazone compound
of formula II is prepared by reacting a carbonyl compound of
formula I
##STR00011##
[0085] with hydrazine or a salt thereof,
[0086] wherein R.sup.4 and R.sup.5 are as defined above.
[0087] Preferably, formulae I, II, III and IV are to be understood
as not only covering the compounds as such, but also as covering
salts, stereoisomers, tautomers or N-oxides of these compounds.
However, N-oxides are of course only possible, if a nitrogen atom
is present in the compounds.
[0088] In view of the above, certain preferred embodiments of the
invention further relate to a process, wherein the compound of
formula V is a compound of formula Va or Vb
##STR00012##
[0089] and wherein said compound of formula Va or Vb is converted
into a compound of formula Vc
##STR00013##
[0090] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
as defined above,
[0091] and wherein R.sup.c in formula Va is C.sub.1-C.sub.4-alkyl
or aryl-C.sub.1-C.sub.4-alkyl.
[0092] Preferably, formulae Va, Vb and Vc are to be understood as
not only covering the compounds as such, but also as covering
salts, stereoisomers, tautomers or N-oxides of these compounds.
[0093] Furthermore, certain preferred embodiments of the invention
relate to a process, wherein a compound of formula Vc is converted
into a compound of formula VI
##STR00014##
[0094] wherein X.sup.1 is a leaving group, and wherein R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above.
[0095] With regard to X.sup.1, it is noted that X.sup.1 may be any
leaving group, preferably a leaving group, which is suitable for
amide coupling reactions.
[0096] For example, X.sup.1 may be a leaving group, which is based
on a peptide coupling reagent. Suitable peptide coupling reagents
are described by Han et al. in Tetrahedron 60 (2004) 2447-2467. In
this regard, N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride
(BOP--Cl) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) are preferred according to the present
invention.
[0097] Furthermore, X.sup.1 may be a leaving group selected from
active esters, azide and halogens.
[0098] Preferably, X.sup.1 is selected from halogen, N.sub.3,
p-nitrophenoxy, and pentafluorophenoxy, and is particularly
preferably halogen, such as Cl.
[0099] Preferably, formula VI is again to be understood as not only
covering the compounds as such, but also as covering salts,
stereoisomers, tautomers or N-oxides of these compounds.
[0100] Moreover, certain more preferred embodiments of the
invention relate to a process, wherein the above compound of
formula VI is converted into a compound of formula VIII
##STR00015##
[0101] by reacting it with a compound of formula VII
##STR00016##
[0102] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
as defined above, and wherein U is N or CR.sup.U; [0103] R.sup.P1,
R.sup.P2, R.sup.P3, and R.sup.U are independently of each other
selected from H, halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.3-haloalkoxy, C.sub.1-C.sub.4-alkylthio,
C.sub.1-C.sub.3-haloalkylthio, C.sub.1-C.sub.4-alkylsulfinyl,
C.sub.1-C.sub.3-haloalkylsulfinyl, C.sub.1-C.sub.4-alkylsulfonyl,
C.sub.1-C.sub.3-haloalkylsulfonyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-halocycloalkyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl and
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl; and [0104] R.sup.1N
is H, CN, C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-haloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-halocycloalkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-haloalkenyl,
C.sub.2-C.sub.10-alkynyl, C.sub.3-C.sub.10-haloalkynyl,
C.sub.1-C.sub.5-alkylen-CN, OR.sup.a,
C.sub.1-C.sub.5-alkylen-OR.sup.a, C(Y)R.sup.b,
C.sub.1-C.sub.5-alkylen-C(Y)R.sup.b, C(Y)OR.sup.c,
C.sub.1-C.sub.5-alkylen-C(Y)OR.sup.c, S(O).sub.2R.sup.d,
NR.sup.eR.sup.f, C.sub.1-C.sub.5-alkylen-NR.sup.eR.sup.f,
C(Y)NR.sup.gR.sup.h, C.sub.1-C.sub.5-alkylen-C(Y)NR.sup.gR.sup.h,
S(O).sub.mNR.sup.eR.sup.f, C(Y)NR.sup.iNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-S(O).sub.2R.sup.d,
C.sub.1-C.sub.5-alkylen-S(O).sub.mNR.sup.eR.sup.f,
C.sub.1-C.sub.5-alkylen-C(Y)NR.sup.iNR.sup.eR.sup.f, aryl,
heterocyclyl, hetaryl, aryl-C.sub.1-C.sub.5-alkyl,
C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.5-alkyl,
heterocyclyl-C.sub.1-C.sub.5-alkyl or
hetaryl-C.sub.1-C.sub.5-alkyl, wherein the cyclic moieties may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5 identical
or different substituents selected from the radicals R.sup.y and
R.sup.x.
[0105] Preferably, formulae VI and VIII are again to be understood
as not only covering the compounds as such, but also as covering
salts, stereoisomers, tautomers or N-oxides of these compounds.
[0106] In another aspect, the present invention relates to a
compound of formula Va or a salt, stereoisomer, tautomer or N-oxide
thereof
##STR00017##
[0107] wherein [0108] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and R.sup.6 is H; or [0109]
R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is CHFCH.sub.3, R.sup.5
is CH.sub.3 and R.sup.6 is H; or [0110] R.sup.2 is CH.sub.3,
R.sub.3 is H, R.sup.4 is 1-CN-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3
and R.sup.6 is H; or [0111] R.sup.2 is CH.sub.3, R.sub.3 is H,
R.sup.4 is 1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and
R.sup.6 is H; or [0112] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4
and R.sup.5 together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2,
and R.sup.6 is H;
[0113] and wherein [0114] R.sup.c is C.sub.1-C.sub.4-alkyl or
aryl-C.sub.1-C.sub.4-alkyl, or wherein R.sup.c together with the
C(O)O group forms a salt [C(O)O].sup.-NR.sub.4.sup.+,
[C(O)O].sup.-M.sub.a.sup.+ or [C(O)O].sup.-1/2%2M.sub.ea.sup.2+,
wherein M.sub.a is an alkali metal and M.sub.ea is an alkaline
earth metal; and wherein the substituents R at the nitrogen atom
are independently of each other selected from H,
C.sub.1-C.sub.10-alkyl, phenyl and
phenyl-C.sub.1-C.sub.4-alkyl.
[0115] In yet another aspect, the present invention relates to a
compound of formula Vb or a salt, stereoisomer, tautomer or N-oxide
thereof
##STR00018##
[0116] wherein
[0117] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0118] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is CHFCH.sub.3,
R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0119] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-CN-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0120] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is
H; or
[0121] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 and R.sup.5
together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and R.sup.6
is H.
[0122] The compounds of formula Va and Vb represent precursors for
N-substituted 4-pyrazole carboxylic acids Vc, which itself
represent versatile reaction tools for the preparation of certain
4-pyrazole N-(het)arylamide compounds of formula VIII, which are
highly active pesticides.
[0123] Thus, in another aspect, the present invention relates to a
compound of formula Vc or a salt, stereoisomer, tautomer or N-oxide
thereof
##STR00019##
[0124] wherein
[0125] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0126] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is CHFCH.sub.3,
R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0127] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-CN-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0128] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is
H; or
[0129] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 and R.sup.5
together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and R.sup.6
is H.
[0130] The 4-pyrazole carboxylic acid compounds of formula Vc can
easily be activated for a subsequent amidation reaction to give the
4-pyrazole N-(het)arylamide compounds of formula VIII.
[0131] Thus, in yet another aspect, the present invention relates
to a compound of formula VI or a salt, stereoisomer, tautomer or
N-oxide thereof
##STR00020##
[0132] wherein [0133] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and R.sup.6 is H; or [0134]
R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is CHFCH.sub.3, R.sup.5
is CH.sub.3 and R.sup.6 is H; or [0135] R.sup.2 is CH.sub.3,
R.sub.3 is H, R.sup.4 is 1-CN-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3
and R.sup.6 is H; or [0136] R.sup.2 is CH.sub.3, R.sub.3 is H,
R.sup.4 is 1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and
R.sup.6 is H; or [0137] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4
and R.sup.5 together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2,
and R.sup.6 is H;
[0138] and wherein [0139] X.sup.1 is a leaving group, which is
preferably selected from halogen, N.sub.3, p-nitrophenoxy, and
pentafluorophenoxy, and which is particularly preferably Cl.
[0140] The compounds of formula VI represent activated species,
which can either be formed in situ or isolated after activation of
the 4-pyrazole carboxylic acid compounds of formula Vc, and which
can be easily converted into the 4-pyrazole N-(het)arylamide
compounds of formula VIII by reacting them with a suitable
N-(het)arylamine.
[0141] Further embodiments of the present invention can be found in
the claims, the description and the examples. It is to be
understood that the features mentioned above and those still to be
illustrated below of the subject matter of the invention can be
applied not only in the respective given combination but also in
other combinations without leaving the scope of the invention.
[0142] In the context of the present invention, the terms used
generically are each defined as follows:
[0143] The term "compound(s) according to the invention" in the
context of the compounds of formulae I, II, III, IV, V, Va, Vb, Vc,
VI, VII and VIII comprises the compound(s) as defined herein as
well as stereoisomers, salts, tautomers or N-oxides thereof. The
term "compound(s) of the present invention" is to be understood as
equivalent to the term "compound(s) according to the
invention".
[0144] N-oxides of the compounds of the present invention can only
be obtained, if the compounds contain a nitrogen atom, which may be
oxidized. This is principally the case for the compounds of
formulae II, IV, V, Va, Vb, Vc, VI, VII and VIII, but not
necessarily the case for compounds of formulae I and III.
Accordingly, the term "compound(s) according to the invention" will
only cover stereoisomers, salts and tautomers of the compounds of
formulae I and III, if these compounds do not contain a nitrogen
substituent, which would allow for the formation of an N-oxide.
N-oxides may principally be prepared by standard methods, e.g. by
the method described in Journal of Organometallic Chemistry 1989,
370, 17-31. However, it is preferred according to the invention
that the intermediate compounds I, II, III and IV in the
preparation of the compounds of formula V are not present in the
form of the N-oxides. Furthermore, if it is desired to convert
compounds of formula Va or Vb into compounds of formula Vc, or to
convert compounds of formula Vc into compounds of formula VI, or to
convert compounds of formula VI into compounds of formula VIII, it
is also preferred that the compounds are not present in the form of
N-oxides. On the other hand, under certain reaction conditions, it
cannot be avoided that N-oxides are formed at least
intermediary.
[0145] Stereoisomers of the compounds of formulae I, II, III, IV,
V, Va, Vb, Vc, VI, VII and VIII will be present, if the compounds
contain one or more centers of chirality in the substituents. In
this case, the compounds will be present in the form of different
enantiomers or diastereomers, if more than one center of chirality
is present. The compounds of the present invention cover every
possible stereoisomer, i.e. single enantiomers or diastereomers, as
well as mixtures thereof. With regard to the compounds of formula
V, it is noted that a center of chirality is also present in the
generic formula, if the substituents R.sup.4, R.sup.5 and R.sup.6
are different from each other. Said center of chirality is newly
formed, when the compounds of formula V are prepared from the
compounds of formula IV. In particular, the sp.sup.2-hybridized
carbon atom, to which the substituents R.sup.4 and R.sup.5 are
attached in the compounds of formula IV, may be attacked by the
reagent comprising the R.sup.6 group from two sides, so that
principally two configurations can be obtained at the resulting
sp.sup.3-hybridized carbon atom. The two possible stereoisomers of
the compounds of formula V, V:SI-A and V:SI-B, which can be
obtained according to the process according to the present
invention, are depicted below.
##STR00021##
[0146] Analogous stereoisomers are also possible for the compounds
of formula Va, Vb, Vc, VI and VIII. Thus, if the substituents
R.sup.4, R.sup.5 and R.sup.6 are different from each other, so that
a center of chirality is present, the generic formulae V, Va, Vb,
Vc, VI and VIII as used herein are in each case intended to cover
two stereoisomers analogous to the two stereoisomers as depicted
above. For reasons of clarity, it is not distinguished between the
two stereoisomers of the generic formulae V, Va, Vb, Vc, VI and
VIII throughout the specification. Instead the
--CR.sup.4R.sup.5R.sup.6 group is depicted without any indication
regarding the three dimensional structure, but it is to be
understood that the generic formulae V, Va, Vb, Vc, VI and VIII in
each case embrace both possible stereoisomers, if the
--CR.sup.4R.sup.5R.sup.6 group is chiral due to different meanings
of R.sup.4, R.sup.5 and R.sup.6.
[0147] Geometric isomers of the compounds of the present invention
are usually possible, if the compounds contain at least one
carbon-carbon or carbon-nitrogen double bond because E- and
Z-isomers of the compounds may then be present. The compounds of
the present invention cover every possible geometric isomer, i.e.
single E- or Z-isomers as well as mixtures thereof. With regard to
the compounds of formulae II, III and IV, it is noted that a
carbon-carbon double bond and/or a carbon-nitrogen double bond is
already present in the generic formula. As in each case the E- and
Z-isomers are both intended to be covered, the generic formulae are
depicted with wavy lines to the substituents, which indicates that
the two substituents at one sp.sup.2-hybridized carbon atom may be
present in each position. The possible E- and Z-isomers for the
compounds of formula II (i.e. II:GI-A.sup.1 and II:GI-B.sup.1), Ill
(i.e. III:GI-A.sup.2 and III:GI-B.sup.2) and IV (i.e.
IV:GI-A.sup.1A.sup.2, IV:GI-B.sup.1A.sup.2, IV:GI-A.sup.1B.sup.2
and IV:GI-B.sup.1B.sup.2) are depicted below.
##STR00022##
[0148] Thus, if E- and Z-isomers are possible, the generic formulae
II, III and IV as used herein are in each case intended to cover
all geometric isomers as depicted above, which is indicated by the
wavy lines to the substituents in the generic formulae.
[0149] Tautomers of the compounds of formulae I, II, III, IV, V,
Va, Vb, Vc, VI, VII and VIII include keto-enol tautomers,
imine-enamine tautomers, amide-imidic acid tautomers and the like.
Such tautomerism is possible, e.g., for the generic formulae I, II,
III, IV and VIII (if R.sup.1N is H). Depending on the substituents,
which are defined for the compounds of formulae I, II, III, IV, V,
Va, Vb, Vc, VI, VII and VIII, further tautomers may be formed. The
compounds of the present invention cover every possible
tautomer.
[0150] Depending on the acidity or basicity as well as the reaction
conditions, the compounds of formulae I, II, III, IV, V, Va, Vb,
Vc, VI, VII and VIII may be present in the form of salts. Such
salts will typically be obtained by reacting the compound with an
acid, if the compound has a basic functionality such as an amine,
or by reacting the compounds with a base, if the compound as an
acidic functionality such as a carboxylic acid group. For example,
the compounds of formula Vb include 4-pyrazole carboxylic acid
salts, wherein the cation stems from the base, with which the
4-pyrazole carboxylic acid has been reacted to give an anionic
carboxylate. If a carboxylic acid group COOH is present in the form
of a carboxylate, said anion may be referred to as [C(O)O].sup.-,
wherein the negative charge is typically delocalized over the two
oxygen atoms of the carboxylate group. On the other hand, the
cationic charge of an ammonium cation, which may be formed from an
amino group in the presence of an acid, is typically not
delocalized.
[0151] Cations, which stem from a base, with which the compounds of
the present invention are reacted, are e.g. alkali metal cations
M.sub.a.sup.+, alkaline earth metal cations M.sub.ea.sup.2+ or
ammonium cations NR.sub.4.sup.+, wherein the alkali metals are
preferably sodium, potassium or lithium and the alkaline earth
metal cations are preferably magnesium or calcium, and wherein the
substituents R of the ammonium cation NR.sub.4.sup.+ are preferably
independently selected from H, C.sub.1-C.sub.10-alkyl, phenyl and
phenyl-C.sub.1-C.sub.2-alkyl.
[0152] Anions, which stem from an acid, with which the compounds of
the present invention have been reacted, are e.g. chloride,
bromide, fluoride, hydrogensulfate, sulfate, dihydrogen-phosphate,
hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate,
hexafluorosilicate, hexafluorophosphate, benzoate, and the anions
of C.sub.1-C.sub.4-alkanoic acids, preferably formate, acetate,
propionate and butyrate.
[0153] The compounds of the invention may be in the form of solids
or liquids. If the compounds are present as solids, the compounds
may be amorphous or may exist in one or more different crystalline
forms. The compounds of the present invention cover mixtures of
different crystalline forms of the respective compounds as well as
amorphous or crystalline salts thereof.
[0154] The organic moieties mentioned in the above definitions of
the variables are--like the term halogen--collective terms for
individual listings of the individual group members. The prefix
C.sub.n-C.sub.m indicates in each case the possible number of
carbon atoms in the group.
[0155] The term "halogen" denotes in each case fluorine, bromine,
chlorine or iodine, in particular fluorine, chlorine or
bromine.
[0156] The term "alkyl" as used herein and in the alkyl moieties of
alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl
and alkoxyalkyl denotes in each case a straight-chain or branched
alkyl group having usually from 1 to 10 carbon atoms, frequently
from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more
preferably from 1 to 3 carbon atoms. Examples of an alkyl group are
methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl,
tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl,
1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl.
[0157] The term "haloalkyl" as used herein and in the haloalkyl
moieties of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio,
haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and
haloalkoxyalkyl, denotes in each case a straight-chain or branched
alkyl group having usually from 1 to 10 carbon atoms, frequently
from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms,
wherein the hydrogen atoms of this group are partially or totally
replaced with halogen atoms. Preferred haloalkyl moieties are
selected from C.sub.1-C.sub.4-haloalkyl, more preferably from
C.sub.1-C.sub.3-haloalkyl or C.sub.1-C.sub.2-haloalkyl, in
particular from C.sub.1-C.sub.2-fluoroalkyl such as fluoromethyl,
difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the
like.
[0158] The term "alkoxy" as used herein denotes in each case a
straight-chain or branched alkyl group which is bonded via an
oxygen atom and has usually from 1 to 10 carbon atoms, frequently
from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples
of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the
like.
[0159] The term "alkoxyalkyl" as used herein refers to alkyl
usually comprising 1 to 10, frequently 1 to 4, preferably 1 to 2
carbon atoms, wherein 1 carbon atom is substituted by an alkoxy
radical usually comprising 1 to 4, preferably 1 or 2 carbon atoms
as defined above. Examples are CH.sub.2OCH.sub.3,
CH.sub.2--OC.sub.2H.sub.5, 2-(methoxy)ethyl, and
2-(ethoxy)ethyl.
[0160] The term "haloalkoxy" as used herein denotes in each case a
straight-chain or branched alkoxy group having from 1 to 10 carbon
atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4
carbon atoms, wherein the hydrogen atoms of this group are
partially or totally replaced with halogen atoms, in particular
fluorine atoms. Preferred haloalkoxy moieties include
C.sub.1-C.sub.4-haloalkoxy, in particular
C.sub.1-C.sub.2-fluoroalkoxy, such as fluoromethoxy,
difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy,
2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,
2-chloro-2,2-difluoro-ethoxy, 2,2-dichloro-2-fluorethoxy,
2,2,2-trichloroethoxy, pentafluoroethoxy and the like.
[0161] The term "alkylthio "(alkylsulfanyl: alkyl-S--)" as used
herein refers to a straight-chain or branched saturated alkyl group
having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms
(=C.sub.1-C.sub.4-alkylthio), more preferably 1 to 3 carbon atoms,
which is attached via a sulfur atom.
[0162] The term "haloalkylthio" as used herein refers to an
alkylthio group as mentioned above wherein the hydrogen atoms are
partially or fully substituted by fluorine, chlorine, bromine
and/or iodine.
[0163] The term "alkylsulfinyl" (alkylsulfoxyl:
C.sub.1-C.sub.6-alkyl-S(.dbd.O)--), as used herein refers to a
straight-chain or branched saturated alkyl group (as mentioned
above) having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms
(=C.sub.1-C.sub.4-alkylsulfinyl), more preferably 1 to 3 carbon
atoms bonded through the sulfur atom of the sulfinyl group at any
position in the alkyl group.
[0164] The term "haloalkylsulfinyl" as used herein refers to an
alkylsulfinyl group as mentioned above wherein the hydrogen atoms
are partially or fully substituted by fluorine, chlorine, bromine
and/or iodine.
[0165] The term "alkylsulfonyl" (alkyl-S(.dbd.O).sub.2--) as used
herein refers to a straight-chain or branched saturated alkyl group
having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms
(=C.sub.1-C.sub.4-alkylsulfonyl), preferably 1 to 3 carbon atoms,
which is bonded via the sulfur atom of the sulfonyl group at any
position in the alkyl group.
[0166] The term "haloalkylsulfonyl" as used herein refers to an
alkylsulfonyl group as mentioned above wherein the hydrogen atoms
are partially or fully substituted by fluorine, chlorine, bromine
and/or iodine.
[0167] The term "alkylcarbonyl" refers to an alkyl group as defined
above, which is bonded via the carbon atom of a carbonyl group
(C.dbd.O) to the remainder of the molecule.
[0168] The term "haloalkylcarbonyl" refers to an alkylcarbonyl
group as mentioned above, wherein the hydrogen atoms are partially
or fully substituted by fluorine, chlorine, bromine and/or
iodine.
[0169] The term "alkoxycarbonyl" refers to an alkylcarbonyl group
as defined above, which is bonded via an oxygen atom to the
remainder of the molecule.
[0170] The term "haloalkoxycarbonyl" refers to an alkoxycarbonyl
group as mentioned above, wherein the hydrogen atoms are partially
or fully substituted by fluorine, chlorine, bromine and/or
iodine.
[0171] The term "alkenyl" as used herein denotes in each case a
singly unsaturated hydrocarbon radical having usually 2 to 10,
frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. vinyl,
allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl
(2-methylprop-2-en-1-yl), 2-buten-1-yl, 3-buten-1-yl,
2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl,
2-ethylprop-2-en-1-yl and the like.
[0172] The term "haloalkenyl" as used herein refers to an alkenyl
group as defined above, wherein the hydrogen atoms are partially or
totally replaced with halogen atoms.
[0173] The term "alkynyl" as used herein denotes in each case a
singly unsaturated hydrocarbon radical having usually 2 to 10,
frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. ethynyl,
propargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl),
2-butyn-1-yl, 3-butyn-1-yl, 1-pentyn-1-yl, 3-pentyn-1-yl,
4-pentyn-1-yl, 1-methylbut-2-yn-1-yl, 1-ethylprop-2-yn-1-yl and the
like.
[0174] The term "haloalkynyl" as used herein refers to an alkynyl
group as defined above, wherein the hydrogen atoms are partially or
totally replaced with halogen atoms.
[0175] The term "cycloalkyl" as used herein and in the cycloalkyl
moieties of cycloalkoxy and cycloalkylthio denotes in each case a
monocyclic cycloaliphatic radical having usually from 3 to or from
3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0176] The term "halocycloalkyl" as used herein and in the
halocycloalkyl moieties of halocycloalkoxy and halocycloalkylthio
denotes in each case a monocyclic cycloaliphatic radical having
usually from 3 to 10 C atoms or 3 to 6 C atoms, wherein at least
one, e.g. 1, 2, 3, 4, or 5 of the hydrogen atoms, are replaced by
halogen, in particular by fluorine or chlorine. Examples are 1- and
2-fluorocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl,
1,2,2-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclpropyl, 1- and
2-chlorocyclopropyl, 1,2-, 2,2- and 2,3-dichlorocyclopropyl,
1,2,2-trichlorocyclopropyl, 2,2,3,3-tetrachlorocyclpropyl, 1-,2-
and 3-fluorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-,
2,5-difluorocyclopentyl, 1-,2- and 3-chlorocyclopentyl, 1,2-, 2,2-,
2,3-, 3,3-, 3,4-, 2,5-dichlorocyclopentyl and the like.
[0177] The term "cycloalkoxy" refers to a cycloalkyl group as
defined above, which is bonded via an oxygen atom to the remainder
of the molecule.
[0178] The term "halocycloalkoxy" refers to a halocycloalkyl group
as defined above, which is bonded via an oxygen atom to the
remainder of the molecule.
[0179] The term "cycloalkylthio" refers to a cycloalkyl group as
defined above, which is bonded via a sulfur atom to the remainder
of the molecule.
[0180] The term "halocycloalkylthio" refers to a halocycloalkyl
group as defined above, which is bonded via a sulfur atom to the
remainder of the molecule.
[0181] The term "cycloalkylalkyl" refers to a cycloalkyl group as
defined above which is bonded via an alkyl group, such as a
C.sub.1-C.sub.5-alkyl group or a C.sub.1-C.sub.4-alkyl group, in
particular a methyl group (=cycloalkylmethyl), to the remainder of
the molecule.
[0182] The term "cycloalkenyl" as used herein and in the
cycloalkenyl moieties of cycloalkenyloxy and cycloalkenylthio
denotes in each case a monocyclic singly unsaturated non-aromatic
radical having usually from 3 to 10, e.g. 3, or 4 or from 5 to 10
carbon atoms, preferably from 3- to 8 carbon atoms. Exemplary
cycloalkenyl groups include cyclopropenyl, cycloheptenyl or
cyclooctenyl.
[0183] The term "halocycloalkenyl" as used herein and in the
halocycloalkenyl moieties of halocycloalkenyloxy and
halocycloalkenylthio denotes in each case a monocyclic singly
unsaturated non-aromatic radical having usually from 3 to 10, e.g.
3, or 4 or from 5 to 10 carbon atoms, preferably from 3- to 8
carbon atoms, wherein at least one, e.g. 1, 2, 3, 4, or 5 of the
hydrogen atoms, are replaced by halogen, in particular by fluorine
or chlorine. Examples are 3,3-difluorocyclopropen-1-yl and
3,3-dichlorocyclopropen-1-yl.
[0184] The term "cycloalkenyloxy" refers to a cycloalkenyl group as
defined above, which is bonded via an oxygen atom to the remainder
of the molecule.
[0185] The term "halocycloalkenyloxy" refers to a halocycloalkenyl
group as defined above, which is bonded via an oxygen atom to the
remainder of the molecule.
[0186] The term "cycloalkenylthio" refers to a cycloalkenyl group
as defined above, which is bonded via a sulfur atom to the
remainder of the molecule.
[0187] The term "halocycloalkenylthio" refers to a halocycloalkenyl
group as defined above, which is bonded via a sulfur atom to the
remainder of the molecule.
[0188] The term "cycloalkenylalkyl" refers to a cycloalkenyl group
as defined above which is bonded via an alkyl group, such as a
C.sub.1-C.sub.5-alkyl group or a C.sub.1-C.sub.4-alkyl group, in
particular a methyl group (=cycloalkenylmethyl), to the remainder
of the molecule.
[0189] The term "carbocycle" or "carbocyclyl" includes in general a
3- to 12-membered, preferably a 3- to 8-membered or a 5- to
8-membered, more preferably a 5- or 6-membered monocyclic,
non-aromatic ring comprising 3 to 12, preferably 3 to 8 or 5 to 8,
more preferably 5 or 6 carbon atoms. Preferably, the term
"carbocycle" covers cycloalkyl and cycloalkenyl groups as defined
above.
[0190] The term "heterocycloalkyl" includes in general 3- to
8-membered, in particular 6-membered monocyclic saturated
heterocyclic non-aromatic radicals. The heterocyclic non-aromatic
radicals usually comprise 1, 2, or 3 heteroatoms selected from N, O
and S as ring members, where S-atoms as ring members may be present
as S, SO or SO.sub.2.
[0191] The term "heterocycloalkenyl" includes in general 3- to
8-membered, in particular 6-membered monocyclic singly unsaturated
heterocyclic non-aromatic radicals. The heterocyclic non-aromatic
radicals usually comprise 1, 2, or 3 heteroatoms selected from N, O
and S as ring members, where S-atoms as ring members may be present
as S, SO or SO.sub.2.
[0192] The term "heterocycle" or "heterocyclyl" includes in general
3- to 12-membered, preferably 3- to 8-membered or 5- to 8-membered,
more preferably 5- or 6-membered, in particular 6-membered
monocyclic heterocyclic non-aromatic radicals. The heterocyclic
non-aromatic radicals usually comprise 1, 2, 3, 4, or 5, preferably
1, 2 or 3 heteroatoms selected from N, O and S as ring members,
where S-atoms as ring members may be present as S, SO or SO.sub.2.
Examples of 5- or 6-membered heterocyclic radicals comprise
saturated or unsaturated, non-aromatic heterocyclic rings, such as
oxiranyl, oxetanyl, thietanyl, thietanyl-S-oxid (S-oxothietanyl),
thietanyl-S-dioxid (S-dioxothiethanyl), pyrrolidinyl, pyrrolinyl,
pyrazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl,
thiolanyl, S-oxothiolanyl, S-dioxothiolanyl, dihydrothienyl,
S-oxodihydrothienyl, S-dioxodihydrothienyl, oxazolidinyl,
oxazolinyl, thiazolinyl, oxathiolanyl, piperidinyl, piperazinyl,
pyranyl, dihydropyranyl, tetrahydropyranyl, 1,3- and 1,4-dioxanyl,
thiopyranyl, S.oxothiopyranyl, S-dioxothiopyranyl,
dihydrothiopyranyl, S-oxodihydrothiopyranyl,
S-dioxodihydrothiopyranyl, tetrahydrothiopyranyl,
S-oxotetrahydrothiopyranyl, S-dioxotetrahydrothiopyranyl,
morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl,
S-dioxothiomorpholinyl, thiazinyl and the like. Examples for
heterocyclic ring also comprising 1 or 2 carbonyl groups as ring
members comprise pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl,
imidazolidin-2-onyl, oxazolidin-2-onyl, thiazolidin-2-onyl and the
like.
[0193] The term "aryl" includes mono-, bi- or tricyclic aromatic
radicals having usually from 6 to 14, preferably 6, 10, or 14
carbon atoms. Exemplary aryl groups include phenyl, naphthyl and
anthracenyl. Phenyl is preferred as aryl group.
[0194] The term "hetaryl" includes monocyclic 5- or 6-membered
heteroaromatic radicals comprising as ring members 1, 2, 3, or 4
heteroatoms selected from N, O and S. Examples of 5- or 6-membered
heteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl,
pyrimidinyl, i.e. 2-, 4-, or 5-pyrimidinyl, pyrazinyl, pyridazinyl,
i.e. 3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl,
i.e. 2- or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e.
2-, 3-, or 5-oxazolyl, isoxazolyl, i.e. 3-, 4-, or 5-isoxazolyl,
thiazolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4-,
or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4-, or 5-pyrazolyl, i.e.
1-, 2-, 4-, or 5-imidazolyl, oxadiazolyl, e.g. 2- or
5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxadiazol)yl, 3- or
5-(1,2,4-oxadiazol)yl, 2- or 5-(1,3,4-thiadiazol)yl, thiadiazolyl,
e.g. 2- or 5-(1,3,4-thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3-
or 5-(1,2,4-thiadiazol)yl, triazolyl, e.g. 1H-, 2H- or
3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or
4H-1,2,4-triazolyl and tetrazolyl, i.e. 1H- or 2H-tetrazolyl. The
term "hetaryl" also includes bicyclic 8 to 10-membered
heteroaromatic radicals comprising as ring members 1, 2 or 3
heteroatoms selected from N, O and S, wherein a 5- or 6-membered
heteroaromatic ring is fused to a phenyl ring or to a 5- or
6-membered heteroaromatic radical. Examples of a 5- or 6-membered
heteroaromatic ring fused to a phenyl ring or to a 5- or 6-membered
heteroaromatic radical include benzofuranyl, benzothienyl, indolyl,
indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl,
benzothiadiazolyl, benzoxazinyl, chinolinyl, isochinolinyl,
purinyl, 1,8-naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl or
pyridoimidazolyl and the like. These fused hetaryl radicals may be
bonded to the remainder of the molecule via any ring atom of 5- or
6-membered heteroaromatic ring or via a carbon atom of the fused
phenyl moiety.
[0195] The terms "heterocyclyloxy", "hetaryloxy", "aryloxy" and
"phenoxy" refer to heterocyclyl, hetaryl and aryl as defined above
and phenyl, which are bonded via an oxygen atom to the remainder of
the molecule.
[0196] The terms "heterocyclylsulfonyl", "hetarylsulfonyl",
"arylsulfonyl", and "phenylsulfonyl" refer to heterocyclyl, hetaryl
and aryl as defined above, and phenyl, respectively, which are
bonded via the sulfur atom of a sulfonyl group to the remainder of
the molecule.
[0197] The terms "heterocyclylcarbonyl", "hetarylcarbonyl",
"arylcarbonyl", and "phenylcarbonyl" refer to heterocyclyl, hetaryl
and aryl as defined above, and phenyl, respectively, which are
bonded via the carbon atom of a carbonyl group (C.dbd.O) to the
remainder of the molecule.
[0198] The terms "heterocyclylalkyl" and "hetarylalkyl" refer to
heterocyclyl or hetaryl, respectively, as defined above which are
bonded via a C.sub.1-C.sub.5-alkyl group or a C.sub.1-C.sub.4-alkyl
group, in particular a methyl group (=heterocyclylmethyl or
hetarylmethyl, respectively), to the remainder of the molecule.
[0199] The terms "arylalkyl" and "phenylalkyl" refer to aryl as
defined above and phenyl, respectively, which are bonded via
C.sub.1-C.sub.5-alkyl group or a C.sub.1-C.sub.4-alkyl group, in
particular a methyl group (=arylmethyl or phenylmethyl), to the
remainder of the molecule, examples including benzyl,
1-phenylethyl, 2-phenylethyl, etc.
[0200] The term "arylalkoxy" and "benzyloxy" refer to arylalkyl as
defined above and phenyl-Ci-alkyl, respectively, which are bonded
via an oxygen atom, to the remainder of the molecule.
[0201] The terms "alkylene", "cycloalkylene",
"heterocycloalkylene", "alkenylene", "cycloalkenylene",
"heterocycloalkenylene" and "alkynylene" refer to alkyl,
cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,
heterocycloalkenyl and alkynyl as defined above, respectively,
which are bonded to the remainder of the molecule, via two atoms,
preferably via two carbon atoms, of the respective group, so that
they represent a linker between two moieties of the molecule.
[0202] The term "cyclic moiety" can refer to any cyclic groups,
which are present in the compounds of the present invention, and
which are defined above, e.g. cycloalkyl, cycloalkenyl, carbocycle,
heterocycloalkyl, heterocycloalkenyl, heterocycle, aryl, hetaryl
and the like.
[0203] The remarks made below concerning preferred embodiments of
the variables of the compounds of formulae I, II, III, IV, V, Va,
Vb, Vc, VI, VII and VIII, and their subvariants are valid on their
own as well as preferably in combination with each other as well as
concerning the processes and the compounds according to the
invention.
[0204] As already indicated above, the present invention relates in
one embodiment to a process for preparing a pyrazole compound of
formula V comprising the step of cyclizing a hydrazone substituted
.alpha.,.beta.-unsaturated carbonyl compound of formula IV by
reacting it with a reagent comprising a R.sup.6 group. Preferred
embodiments of the invention relate to the preparation of the
compounds of formula IV and to further conversions of specific
compounds falling under the generic formula V, in particular Va,
Vb, and Vc.
[0205] In view of the fact that the compounds of formula V of the
present invention can be obtained according to the sequence
comprising the steps (a) I->II, (b) II+III->IV, and (c)
IV->V as described above and herein after, and in view of the
fact that the compounds of formula V, if provided e.g. as compounds
of formula Va and Vb, may be further converted according to the
sequence comprising the steps (d) Va or Vb->Vc, (e) Vc->VI,
and (f) VI+VII->VIII as described above and herein after, the
substituents, which are preferred for the compounds of formula V
will also be preferred for its precursors I, II, III and IV,
provided that the substituents are present, and the same
substituents will also be preferred for the compounds, which are
obtainable from the compounds of formula Va, Vb and Vc, i.e. the
compounds of formula VI and VIII, provided that the substituents
are present.
[0206] The substituent R.sup.1 is present in the 4-position of the
pyrazole ring of the compounds of formula V. The substituent
R.sup.1 is also present in the precursors III and IV of the
compounds of formula V.
[0207] In a preferred embodiment of the invention, R.sup.1 is
[0208] H, halogen, CN, NO.sub.2, C.sub.1-C.sub.10-alkyl, which may
be unsubstituted, may be partially or fully halogenated, or may be
substituted by 1, 2 or 3 identical or different substituents
R.sup.x,
[0209] C(Y)OR.sup.c, S(O).sub.mR.sup.d, S(O).sub.mY.sup.1R.sup.d,
C.sub.3-C.sub.12-cycloalkyl, aryl, or hetaryl, wherein the cyclic
moieties may be unsubstituted or may be substituted by 1, 2, 3, 4,
or 5 identical or different substituents selected from the radicals
R.sup.y and R.sup.x;
[0210] wherein R.sup.c is H, C.sub.1-C.sub.4-alkyl or
aryl-C.sub.1-C.sub.4-alkyl, or wherein R.sup.c together with the
C(Y)O group forms a salt [C(Y)O].sup.-NH.sub.4.sup.+,
[C(Y)O].sup.-M.sub.a.sup.+ or [C(Y)O].sup.-1/2M.sub.ea.sup.2+,
wherein M.sub.a is an alkali metal and M.sub.ea is an alkaline
earth metal;
[0211] wherein R.sup.d is C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl, aryl or hetaryl;
[0212] wherein Y is O; and
[0213] wherein Y.sup.1 is O or NR.sup.1a, wherein R.sup.1a is
C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, aryl or
hetaryl.
[0214] In a more preferred embodiment of the invention, R.sup.1 is
CN or C(Y)OR.sup.c, wherein Y is O and R.sup.c is
C.sub.1-C.sub.4-alkyl or benzyl, preferably ethyl or
tert-butyl.
[0215] Compounds of formula V, wherein R.sup.1 is C(Y)OR.sup.c with
Y being O and R.sup.c being C.sub.1-C.sub.4-alkyl or
aryl-C.sub.1-C.sub.4-alkyl, or wherein R.sup.c together with the
C(O)O group forms a salt [C(O)O].sup.-NR.sub.4,
[C(O)O].sup.-M.sub.a.sup.+ or [C(O)O].sup.-1/2M.sub.ea.sup.2+,
wherein M.sub.a is an alkali metal and M.sub.ea is an alkaline
earth metal; and wherein the substituents R at the nitrogen atom
are independently of each other selected from H,
C.sub.1-C.sub.10-alkyl, phenyl and phenyl-C.sub.1-C.sub.4-alkyl,
are referred to as compounds of formula Va.
##STR00023##
[0216] Compounds of formula V, which correspond to compounds of
formula Va, are preferred according to the present invention. The
compounds of formula Va may be directly obtained from the compounds
of formula IV according to the process of the invention, and they
can easily be converted into the compounds of formula Vc to prepare
compounds of formula VIII via the activated compounds of formula
VI.
[0217] In a particular preferred embodiment of the invention, the
compound of formula V is a compound of formula Va, wherein R.sup.c
is C.sub.1-C.sub.4-alkyl or aryl-C.sub.1-C.sub.4-alkyl, preferably
C.sub.1-C.sub.4-alkyl or benzyl.
[0218] Compounds of formula V, wherein R.sup.1 is CN, are referred
to as compounds of formula Vb.
##STR00024##
[0219] Compounds of formula V, which correspond to compounds of
formula Vb, are preferred according to the present invention. The
compounds of formula Vb may be directly obtained from the compounds
of formula IV according to the process of the invention, and they
can easily be converted into the compounds of formula Vc to prepare
compounds of formula VIII via the activated compounds of formula
VI.
[0220] Compounds of formula V, wherein R.sup.1 is C(Y)OR.sup.c with
Y being O and R.sup.c being H, are referred to as compounds of
formula Vc.
##STR00025##
[0221] Compounds of formula V, which correspond to compounds of
formula Vc, are preferred according to the present invention. In
certain situations, the compounds of formula Vc may be directly
obtained from the compounds of formula IV according to the process
of the invention. However, it can be preferred to perform the
cyclization of the compounds of formula IV with the carboxylic acid
group being masked as an ester or a nitrile group. Thus, the
compounds of formula Vc are may also be obtained from the compounds
of formula Va or Vb as described above. The compounds of formula Vc
then represent versatile reaction tools for the preparation of
4-pyrazole N-(het)arylamide compounds of formula VIII, as they can
easily be activated for a subsequent amidation reaction to give the
4-pyrazole N-(het)arylamide compounds of formula VIII.
[0222] The substituent R.sup.2 is present in the 5-position of the
pyrazole ring of the compounds of formulae V, Va, Vb, Vc, VI and
VIII. Furthermore, the substituent R.sup.2 is present in the
precursors III and IV of the compounds of formula V.
[0223] In a preferred embodiment of the invention R.sup.2 is
[0224] C.sub.1-C.sub.10-alkyl, which may be unsubstituted, may be
partially or fully halogenated, or may be substituted by 1, 2 or 3
identical or different substituents R.sup.x,
[0225] C.sub.3-C.sub.12-cycloalkyl, aryl, or hetaryl, wherein the
three last mentioned radicals may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 identical or different substituents
selected from the radicals R.sup.y and R.sup.x.
[0226] In a more preferred embodiment of the invention, R.sup.2 is
C.sub.1-C.sub.4-alkyl, which may be unsubstituted, or may be
partially or fully halogenated.
[0227] It is even more preferred that R.sup.2 is CH.sub.3,
CH.sub.2CH.sub.3 or fluoromethyl, and particularly preferred that
R.sup.2 is CH.sub.3, CF.sub.2H or CF.sub.3.
[0228] The substituent R.sup.3 is present in the 3-position of the
pyrazole ring of the compounds of formulae V, Va, Vb, Vc, VI and
VIII. Furthermore, the substituent R.sup.3 is present in the
precursors III and IV of the compounds of formula V.
[0229] In a preferred embodiment of the invention R.sup.2 is [0230]
H, C.sub.1-C.sub.10-alkyl, which may be unsubstituted, may be
partially or fully halogenated, or may be substituted by 1, 2 or 3
identical or different substituents R.sup.x, [0231]
C.sub.3-C.sub.12-cycloalkyl, aryl, or hetaryl, wherein the cyclic
moieties may be unsubstituted or may be substituted by 1, 2, 3, 4,
or 5 identical or different substituents selected from the radicals
R.sup.y and R.sup.x.
[0232] In a more preferred embodiment of the invention, R.sup.3 is
H.
[0233] As already indicated above, the process according to the
present invention is particularly advantageous for regioselectively
preparing N-substituted pyrazole compounds, which are 3- or
5-substituted or substituted with different substituents in the 3-
and 5-position. Thus, compounds of formula V, wherein R.sup.3 and
R.sup.2 are different from each other are particularly preferred.
It is particularly preferred that one of R.sup.3 and R.sup.2 is H
and the other one is different from H. Alternatively, it can be
preferred that R.sup.3 and R.sup.2 are both different from H, and
different from each other.
[0234] Compounds of formula V, wherein R.sup.3 is different from H
and wherein R.sup.2 is H, are to be understood as 3-substituted
N-substituted pyrazole compounds and are referred to as compounds
of formula V.3-R.sup.3.sub.subst.5-H, wherein R.sup.3.sub.subst
refers to a substituent defined for R.sup.3, which is other than
H.
[0235] Compounds of formula V, wherein R.sup.3 is H and wherein
R.sup.2 is different from H, are to be understood as 5-substituted
N-substituted pyrazole compounds and are referred to as compounds
of formula V.3-H.5-R.sup.2.sub.subst, wherein R.sup.2.sub.subst
refers to a substituent defined for R.sup.2, which is other than
H.
[0236] Compounds of formula V, wherein R.sup.3 and R.sup.2 are
different from H and different from each other, are to be
understood as 3- and 5-substituted N-substituted pyrazole
compounds, wherein the substituents in the 3- and 5-position are
different from each other. Such compounds are referred to as
compounds of formula V.3-R.sup.3.sub.subst.5-R.sup.2.sub.subst,
wherein R.sup.3.sub.subst refers to a substituent defined for
R.sup.3, which is other than H, and wherein R.sup.2.sub.subst
refers to a substituent defined for R.sup.2, which is other than H,
with the proviso that R.sup.3.sub.subst and R.sup.2.sub.subst are
different from each other. The compounds are depicted below.
##STR00026##
[0237] The meanings for R.sup.2 and R.sup.3, i.e. that one of
R.sup.3 and R.sup.2 is H and the other one is different from H, or
that R.sup.3 and R.sup.2 are both different from H, and different
from each other, are also preferred for the precursors III and IV
as well as for the compounds of formulae Va, Vb, Vc, VI and
VIII.
[0238] Compounds of formula V.3-H.5-R.sup.2.sub.subst and
analogously substituted compounds of formulae III, IV, Va, Vb, Vc,
VI and VIII are particularly preferred according to the present
invention.
[0239] The substituents R.sup.4 and R.sup.5 are present in the
compounds of formulae I, II, IV, V, Va, Vb, Vc, VI and VIII.
[0240] In one preferred embodiment of the invention, [0241] R.sup.4
is selected from C.sub.1-C.sub.10-alkyl, which may be
unsubstituted, may be partially or fully halogenated, or may be
substituted by 1, 2 or 3 identical or different substituents
R.sup.x, and C.sub.3-C.sub.10-cycloalkyl, which may be
unsubstituted or may be substituted by 1, 2, 3, 4, or 5 identical
or different substituents R.sup.y; and [0242] R.sup.5 is selected
from C.sub.1-C.sub.10-alkyl, which may be unsubstituted, may be
partially or fully halogenated, or may be substituted by 1, 2 or 3
identical or different substituents R.sup.x, and
C.sub.3-C.sub.10-cycloalkyl, which may be unsubstituted or may be
substituted by 1, 2, 3, 4, or 5 identical or different substituents
R.sup.y.
[0243] In a more preferred embodiment of this embodiment, [0244]
R.sup.4 is selected from C.sub.1-C.sub.4-alkyl, which may be
unsubstituted, may be partially or fully halogenated, or may be
substituted by 1 or 2 identical or different substituents R.sup.x,
wherein R.sup.x is selected from CN and C(O)NH.sub.2, and [0245]
C.sub.3-C.sub.6-cycloalkyl, which may be unsubstituted or may be
substituted by 1, 2 or 3 identical or different substituents
R.sup.y, wherein R.sup.y is selected from halogen, CN and
C(O)NH.sub.2; and [0246] R.sup.5 is selected from
C.sub.1-C.sub.4-alkyl, which may be unsubstituted, may be partially
or fully halogenated, or may be substituted by 1 or 2 identical or
different substituents R.sup.x, wherein R.sup.x is selected from CN
and C(O)NH.sub.2, and [0247] C.sub.3-C.sub.6-cycloalkyl, which may
be unsubstituted or may be substituted by 1, 2 or 3 identical or
different substituents R.sup.y, wherein R.sup.y is selected from
halogen, CN and C(O)NH.sub.2.
[0248] In an even more preferred embodiment of this embodiment,
[0249] R.sup.4 is selected from C.sub.1-C.sub.4-alkyl, which may be
unsubstituted, may be partially or fully halogenated, or may be
substituted by 1 or 2 identical or different substituents R.sup.x,
wherein R.sup.x is selected from CN and C(O)NH.sub.2, and [0250]
C.sub.3-C.sub.6-cycloalkyl, which may be unsubstituted or may be
substituted by 1, 2 or 3 identical or different substituents
R.sup.y, wherein R.sup.y is selected from halogen, CN and
C(O)NH.sub.2; and [0251] R.sup.5 is selected from
C.sub.1-C.sub.2-alkyl, which may be unsubstituted, may be partially
or fully halogenated, or may be substituted by 1 or 2 identical or
different substituents R.sup.x, wherein R.sup.x is selected from CN
and C(O)NH.sub.2, and [0252] C.sub.3-C.sub.4-cycloalkyl, which may
be unsubstituted or may be substituted by 1, 2 or 3 identical or
different substituents R.sup.y, wherein R.sup.y is selected from
halogen, CN and C(O)NH.sub.2.
[0253] It is particularly preferred according to this embodiment of
the present invention that R.sup.4 and R.sup.5 are different from
each other. For example, R.sup.5 may be C.sub.1-C.sub.2-alkyl,
which is unsubstituted, or C.sub.3-C.sub.4-cycloalkyl, which is
unsubstituted, while R.sup.4 may be C.sub.1-C.sub.4-alkyl, which
may be unsubstituted, or partially or fully halogenated, or
substituted with 1 or 2 identical or different substituents R.sup.x
selected from CN and C(O)NH.sub.2, or may be
C.sub.3-C.sub.6-cycloalkyl, which may preferably be substituted
with 1, 2 or 3 identical or different substituents R.sup.y selected
from halogen, CN and C(O)NH.sub.2.
[0254] Most preferably, R.sup.5 is CH.sub.3, while R.sup.4 is
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-haloalkyl, or
C.sub.3-cycloalkyl, wherein the cycloalkyl group is preferably
substituted with one substituent selected from CN and C(O)NH.sub.2.
Suitable combinations of R.sup.5 and R.sup.4 may thus e.g. be
CH.sub.3/i-Pr or CH.sub.3/1-CN-cC.sub.3H.sub.4.
[0255] In another preferred embodiment of the invention, [0256]
R.sup.4 and R.sup.5 together with the carbon atom to which they are
attached form a 3- to 12-membered non-aromatic carbocycle, which
may be partially or fully substituted by R.sup.j.
[0257] In a more preferred embodiment of this embodiment, [0258]
R.sup.4 and R.sup.5 together with the carbon atom to which they are
attached form a 3- to 12-membered non-aromatic, saturated
carbocycle, which may be partially or fully substituted by R.sup.j,
wherein R.sup.j is selected from halogen, CN and C(O)NH.sub.2.
[0259] In an even more preferred embodiment of this embodiment,
[0260] R.sup.4 and R.sup.5 together with the carbon atom to which
they are attached form a 3- to 6-membered non-aromatic, saturated
carbocycle, which may be partially or fully substituted by R.sup.j,
wherein R.sup.j is selected from halogen, CN and C(O)NH.sub.2.
[0261] It is particularly preferred according to this embodiment of
the present invention that R.sup.4 and R.sup.5 together with the
carbon atom to which they are attached form a 6-membered
carbocycle, which is partially or fully halogenated, preferably
fluorinated. Thus, R.sup.4 and R.sup.5 may together represent e.g.
--CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2--.
[0262] The substituent R.sup.6 is present in the compounds of
formulae V, Va, Vb, Vc, VI and VIII and in the reagent, with which
the compound of formula IV is reacted to give the compound of
formula V.
[0263] In one preferred embodiment of the invention, R.sup.6 is
selected from H, CN and C.sub.1-C.sub.2-fluoroalkyl. More
preferably R.sup.6 is selected from H, CN, CHF.sub.2 and CF.sub.3,
and most preferably, R.sup.6 is H.
[0264] Compounds of formula V, wherein R.sup.6 is H may be referred
to as compounds of formula V.R.sup.6--H.
[0265] Compounds of formula V.R.sup.6--H and analogously
substituted compounds of formulae Va, Vb, Vc, VI and VIII are
particularly preferred according to the present invention.
[0266] Compounds of formula V.3-H.5-R.sup.2.sub.subst, wherein
R.sup.6 is H, i.e. compounds of formula
V.3-H.5-R.sup.2.sub.subst.R.sup.6--H and analogously substituted
compounds of formulae Ill, IV, Va, Vb, Vc, VI and VIII are
particularly preferred according to the present invention.
[0267] As already indicated above, a center of chirality may be
formed upon the formation of the compounds of formula V by reacting
a compound of formula IV with a reagent comprising a R.sup.6 group,
if the substituents R.sup.4 and R.sup.5 of the compound of formula
IV and R.sup.6 are different from each other. If two or more of the
three substituents R.sup.4, R.sup.5 and R.sup.6 are identical, no
center of chirality will be formed upon the formation of the
compounds of formula V. It is particularly preferred according to
the present invention that R.sup.4, R.sup.5 and R.sup.6 are
different from each other, so that a center of chirality is formed.
If a center of chirality is formed, it is preferred that the two
possible configurations of the center of chirality are formed in
equal amounts. Thus, the formation of the compounds of formula V
according to the present invention is usually not stereoselective,
but a mixture, preferably a racemic mixture, of the two possible
stereoisomers is obtained. If a center of chirality is present at
the --CR.sup.4R.sup.5R.sup.6 group of the compounds of formula V,
generic formula V is therefore preferably intended to cover a
mixture of the two possible stereoisomers. If no further centers of
chirality are present in the compound, the stereoisomers are
enantiomers, otherwise the stereoisomers may be diastereoisomers.
The same considerations also apply for generic formulae Va, Vb, Vc,
VI and VIII.
[0268] With regard to the reagent comprising the R.sup.6 group,
which is reacted with the compounds of formula IV to give the
compounds of formula V, the following is noted.
[0269] For R.sup.6 being H, it is preferred that the reagent is
present in the form of "reagent-R.sup.6", and transfers H as a
hydride. In certain situations, it can also be preferred that the
reagent transfers H as a hydrogen radical.
[0270] In one preferred embodiment of the invention, the reagent
comprising H as the R.sup.6 group is a reducing agent. Preferably,
the reducing agents are selected from [0271] (ia) ionic hydride
donors selected from the group consisting of complex hydrides of
boron and aluminum, [0272] (ib) non-ionic hydride donors selected
from the group consisting of dihydrogen, which is particularly
preferably used in combination with a metal catalyst, Hantzsch
ester, 1,4-dihydrobenzol, isopropanol, formic acid, and ammonium
formate, and [0273] (ic) electron donors, which are used in
combination with protons, wherein the electrons are donated by a
cathode or a metal selected from Li, Na, K, Mg, Zn, Fe and Al.
[0274] Ionic hydride donors are described in the following and are
particularly preferred according to the present invention.
[0275] Although the term "ionic" indicates that the "ionic hydride
donors" have an ionic structure, ionic hydride donors principally
belong to the group of reagents, which comprise R.sup.6, i.e. H,
covalently bonded, and may thus be referred to as "reagent-H",
which may react with compounds of formula IV. However, an ionic
structure is nevertheless present in ionic hydride donors because
the reagent, which comprises H covalently bonded, is itself ionic,
preferably anionic, i.e. in the form "[reagent-H].sup.-", so that
the reagent is typically provided in the form of a salt
"Ct.sup.+[reagent-H].sup.-", wherein Ct.sup.+ represents a cation,
e.g. an alkali metal cation, and "[reagent-H].sup.-" is as defined
above. Preferably, the ionic hydride donor is a negatively charged
hydrido complex of a metal, which is provided in the form of a salt
and is capable of transferring H as a hydride.
[0276] In a particular preferred embodiment of the invention, the
ionic hydride donor is selected from the group consisting of
complex hydrides of boron and aluminium.
[0277] The term "complex hydride of boron or aluminum" refers to
hydrido complexes of boron or aluminum. Thus, R.sup.6 being H may
be covalently bonded to a boron or aluminum atom to give a hydrido
complex, which is capable of transferring H as a hydride as
indicated above. Preferably, the boron or aluminum complex is
negatively charged due to the presence of four substituents, of
which one is H as the group R.sup.6, which can be transferred in
the form of a hydride, and the three remaining substituents can
independently of each other e.g. be selected from the group
consisting of H, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and
CN. Thus, the complex may be described by the formula
"[reagent-H].sup.-" defined above. Typically, the anionic hydrido
complex of boron or aluminum is combined with a cation in the form
of a salt, e.g. according to the formula
"Ct.sup.+[reagent-H].sup.-" mentioned above. The cation Ct.sup.+ is
typically an alkali metal ion, which is preferably Na.sup.+ or
Li.sup.+.
[0278] Preferred complex hydrides of boron and aluminum include
Na.sup.+[BH.sub.4].sup.-, Na.sup.+[B(CN)H.sub.3].sup.+,
Na.sup.+[BH(OAc).sub.3].sup.-, Li.sup.+[AlH.sub.4].sup.-,
Li.sup.+[AlH(Otert-Bu).sub.4].sup.-, Li.sup.+[BH.sub.4].sup.-,
Li.sup.+[BHEt.sub.3].sup.-, Li.sup.+[BH(sec-Bu).sub.3].sup.- and
the like. Complex hydrides of aluminum are usually preferred, if a
high reactivity of the reagent comprising the R.sup.6 group is
desired. Complex hydrides of boron are typically milder reducing
agents. For the purposes of the present invention, complex hydrides
of boron are usually preferred. Most preferably, the reagent
comprising R.sup.6 is Na.sup.+[BH.sub.4].sup.- or
Na.sup.+[BCNH.sub.3].sup.-, particularly preferably
Na.sup.+[B(CN)H.sub.3].sup.-. The reagent
Na.sup.+[B(CN)H.sub.3].sup.- has the following structure.
##STR00027##
[0279] Typically, Na.sup.+[B(CN)H.sub.3].sup.- is also referred to
as NaB(CN)H.sub.3 or NaBH.sub.3CN. Similarly, also the other
complex hydrides of boron and aluminium listed above are often
referred to by a molecular formula without indicating charges.
[0280] The structures of other complex hydrides of boron and
aluminum including the ones listed above are analogous.
[0281] In the following, non-ionic hydride donors are
described.
[0282] The term "non-ionic hydride donor" refers to reagents
comprising a R.sup.6 group being H, which are non-ionic and
typically belong to the group of reagents, which comprise R.sup.6,
i.e. H, covalently bonded. Preferably, the non-ionic hydride donor
is a non-charged hydrogen source, which is capable of transferring
H in the form of a hydride, and usually also transfers a proton, so
that a dihydrogen molecule is transferred in the end. If the
reagents transfer H in the form of a hydride, they may again be
considered as "reagent-H" as described above.
[0283] As used herein, the term "non-ionic hydride donor" also
covers dihydrogen because the result of a hydrogenation reaction
with dihydrogen may principally also be seen in the transfer of a
hydride and a proton. However, such a hydrogenation may of course
also take place as such that two non-charged hydrogen atoms, i.e.
hydrogen radicals, are transferred.
[0284] In a particular preferred embodiment of the invention, the
reagent comprising the R.sup.6 group is a non-ionic hydrogen donor,
which is selected from the group consisting of Hantzsch ester,
1,4-dihydrobenzol, isopropanol, formic acid, ammonium formate, and
dihydrogen.
[0285] Hantzsch ester, 1,4-dihydrobenzol, isopropanol, formic acid,
and ammonium formate are also known in the art as "transfer
hydrogenation reagents". They can be considered as hydrogen sources
as they can transfer a hydride ion and a proton. Reactions with
these transfer hydrogenation reagents can typically be carried out
metal-free, i.e. in the absence of a metal catalyst.
[0286] The reaction with dihydrogen (H.sub.2) as reducing agent is
preferably performed in combination with a metal catalyst. A
skilled person knows suitable metal catalysts to be used in
combination with dihydrogen. Examples of suitable metal catalysts
are provided further below.
[0287] In the following, the reductive cyclization, which is
performed with protons in combination with electrons provided by an
electrode or by a metal, is described.
[0288] The protons are preferably provided by protic solvents,
preferably water or an alcohol such as methanol, ethanol or
isopropanol, and the electrons are generated from an electrode
(cathode) or a suitable metal, preferably a metal selected from Li,
Na, K, Mg, Fe and Al.
[0289] For R.sup.6 being different from H, the reagent may be
present in a form, wherein R.sup.6 is covalently bonded, i.e. in
the form of "reagent-R.sup.6", or in the form of a salt with
R.sup.6 representing the anion, i.e. in the form of
"[reagent].sup.+[R.sup.6].sup.-".
[0290] In one preferred embodiment of the invention, the reagent
comprising the R.sup.6 group being different from H is an
organometallic reagent, wherein R.sup.6 is selected from
C.sub.1-C.sub.6-fluoroalkyl, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl,
C.sub.3-C.sub.6-cycloalkenyl,
C.sub.3-C.sub.6-cycloalkenyl-C.sub.1-C.sub.2-alkyl, heterocyclyl,
heterocyclyl-C.sub.1-C.sub.2-alkyl, aryl,
aryl-C.sub.1-C.sub.2-alkyl, hetaryl, hetaryl-C.sub.1-C.sub.2-alkyl,
wherein the carbon chains or cyclic moieties may be unsubstituted,
partially or fully substituted by identical or different
substituents R.sup.x. Preferably, the reagent comprising the
R.sup.6 group is an organometallic reagent, wherein R.sup.6 is
selected from C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-alkyl,
aryl, arylmethyl and allyl, and wherein R.sup.6 is particularly
preferably selected from C.sub.1-C.sub.2-fluoroalkyl, in particular
from CH.sub.2F and CF.sub.3.
[0291] Preferably, the organometallic reagent comprises a metal M
selected from Li, Mg, Cu, Zn, Si, Mn or In. Depending on the metal,
the organometallic reagent may be considered as "reagent-R.sup.6"
(e.g. M-R.sup.6) or "[reagent].sup.+[R.sup.6].sup.-" (e.g.
[M].sup.+[R.sup.6].sup.-), but should preferably be considered as
"reagent-R.sup.6" because the above listed metals are known to form
covalent bonds rather than ionic bonds with organic groups as
listed above for R.sup.6.
[0292] Preferred organometallic reagents according to the present
invention include Grignard reagents, cuprate reagents, allyl
silanes (Hosomi-Sakurai reagents) and fluoroalkyl silanes (e.g.
Ruppert's reagent).
[0293] Particularly preferably, the organometallic reagent is
Ruppert's reagent, i.e. trimethyl(trifluoromethyl)silane, which
transfers CF.sub.3 as a R.sup.6 group.
[0294] In another preferred embodiment of the invention, the
reagent comprising the R.sup.6 group being different from H is a
nucleophilic reagent of formula H--R.sup.6, M.sub.a.sup.+R.sup.6-
or % M.sub.ea.sup.2+ R.sup.6-, wherein M.sub.a is an alkaline metal
and M.sub.ae is an alkaline earth metal, and wherein R.sup.6 is
selected from CN, OR.sup.a, SR.sup.a, NR.sup.eR.sup.f, and groups
of the general formula (i)
##STR00028##
wherein R.sup.a, R.sup.e, R.sup.f, R.sup.r, R.sup.s and R.sup.t are
as defined above.
[0295] The wavy line in the groups of the general formula (i)
indicated the position, where the group (i) may be connected to H
according to formula H--R.sup.6, or may have been deprotonated to
give a salt of formula M.sub.a.sup.+R.sup.6- or % M.sub.ea.sup.2+
R.sup.6-. If the group (i) is present in deprotonated, i.e.
anionic, form, the negative charge may be delocalized over the
1,3-di(thio)carbonyl system. It is noted, however, that the carbon
atom between the two (thio)carbonyl groups will nevertheless be the
nucleophilic position of the group (i). Preferred groups (i) are
1,3-dicarbonyl compounds, which have been deprotonated in the
2-position with a suitable base, and are thus present in anionic
form in the combination with a cation, which stems from the base.
The reagent comprising group (i) as group R.sup.6 may thus
preferably be represented by the formula M.sub.a.sup.+R.sup.6- or %
M.sub.ea.sup.2+ R.sup.6-, which may both be considered as falling
under the above formula "[reagent].sup.+[R.sup.6].sup.-", and
wherein M.sub.a may e.g. be Li, K or Na, and M.sub.ea may e.g. be
Mg or Ca. It is noted that, if the reagent comprising group (i) as
group R.sup.6 falls under formula H--R.sup.6, it may be considered
as a "reagent-R.sup.6" described above with "reagent" being H.
[0296] Preferred groups OR.sup.a include C.sub.1-C.sub.4-alkoxy and
C.sub.3-C.sub.6-cycloalkoxy.
[0297] Preferred groups SR.sup.a include C.sub.1-C.sub.4-alkylthio
and C.sub.3-C.sub.6-cycloalkylthio.
[0298] Preferred groups NR.sup.eR.sup.f include
C.sub.1-C.sub.4-alkylamino, C.sub.1-C.sub.4-dialkylamino, wherein
the alkyl chains may have an identical or different length,
morpholine, piperazine and N-methylpiperazine.
[0299] For the group R.sup.6 being OR.sup.a, SR.sup.a or
NR.sup.eR.sup.f, the reagent comprising the R.sup.6 group can
either be represented by the formula H--R.sup.6, which can be
considered as falling under the above formula "reagent-R.sup.6", or
by any one of formulae M.sub.a.sup.+R.sup.6- and % M.sub.ea.sup.2+
R.sup.6-, which may both be considered as falling under the above
formula "[reagent].sup.+[R.sup.6].sup.-", and wherein M.sub.a may
e.g. be Li, K or Na, and M.sub.ea may e.g. be Mg or Ca. For the
reagent comprising OR.sup.a or SR.sup.a as R.sup.6 group, it can be
preferred that the reagent is present in the form of
M.sub.a.sup.+R.sup.6- or 1/2M.sub.ea.sup.2+R.sup.6-. For the
reagent comprising NR.sup.eR.sup.f as R.sup.6 group, it can be
preferred that the reagent is present in the form of H--R.sup.6
because H--NR.sup.eR.sup.f also has a nucleophilic reactivity, if
it is used in protonated form.
[0300] For the R.sup.6 group being CN, similar considerations
apply. Thus, the reagent comprising CN as the R.sup.6 group can
either be represented by the formula H--R.sup.6, which can be
considered as falling under the above formula "reagent-R.sup.6", or
by any one of formulae M.sub.a.sup.+R.sup.6- and % M.sub.ea.sup.2+
R.sup.6-, which may both be considered as falling under the above
formula "[reagent].sup.+[R.sup.6].sup.-", and wherein M.sub.a may
e.g. be Li, K or Na, and M.sub.ea may e.g. be Mg or Ca. If R.sup.6
is CN, the reagent comprising the R.sup.6 group is preferably HCN,
NaCN or KCN.
[0301] It is noted that it is particularly preferred for the
reagent being a nucleophilic reagent comprising the R.sup.6 group
that R.sup.6 is CN. NaCN is a particularly preferred reagent
comprising a group R.sup.6.
[0302] The following embodiments regarding the reagent comprising a
R.sup.6 group are preferred according to the present invention.
[0303] In one preferred embodiment, the R.sup.6 group of the
reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is selected from [0304] (ia) ionic
hydride donors selected from the group consisting of complex
hydrides of boron and aluminum, or [0305] (ib) non-ionic hydride
donors selected from the group consisting of dihydrogen, which is
preferably used in combination with a metal catalyst, Hantzsch
ester, 1,4-dihydrobenzol, isopropanol, formic acid, and ammonium
formate.
[0306] In another preferred embodiment, the R.sup.6 group of the
reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is selected from [0307] (ia) ionic
hydride donors selected from the group consisting of complex
hydrides of boron and aluminum, or [0308] (ib) dihydrogen, which
used in combination with a metal catalyst.
[0309] With regard to option (a), the following embodiments are
preferred.
[0310] In one preferred embodiment, the R.sup.6 group of the
reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is an alkali salt of a negatively
charged boron or aluminum complex, wherein the boron or aluminum is
substituted by four substituents, of which at least one is H, and
the three remaining substituents are independently selected from
the group consisting of H, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, and CN.
[0311] In a more preferred embodiment, the R.sup.6 group of the
reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is a sodium salt of a negatively
charged boron complex, wherein the boron is substituted by four
substituents, of which at least one is H, and the three remaining
substituents are independently selected from the group consisting
of H, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, and CN.
[0312] In a particularly preferred embodiment, the R.sup.6 group of
the reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is Na.sup.+[B(CN)H.sub.3].sup.-.
[0313] With regard to option (b), the following embodiments are
preferred.
[0314] In one preferred embodiment, the R.sup.6 group of the
reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is dihydrogen (H.sub.2), which is used
in combination with a metal catalyst.
[0315] In a more preferred embodiment, the R.sup.6 group of the
reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is dihydrogen, which is used in
combination with a metal catalyst selected from the group
consisting of Rayney-Nickel, Pd/C, Pt/C, and PtO.sub.2.
[0316] In an even more preferred embodiment, the R.sup.6 group of
the reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is dihydrogen, which is used in
combination with a metal catalyst selected from the group
consisting of Rayney-Nickel, Pd/C, Pt/C, and PtO.sub.2, and wherein
the dihydrogen is applied with a pressure, which does not exceed
100 bar, and preferably does not exceed 50 bar.
[0317] In an even more preferred embodiment, the R.sup.6 group of
the reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is dihydrogen, which is used in
combination with a metal catalyst selected from the group
consisting of Rayney-Nickel, Pd/C, Pt/C, and PtO.sub.2, and in
combination with a catalytic amount of an acid, and wherein the
dihydrogen is applied with a pressure, which does not exceed 100
bar, and preferably does not exceed 50 bar.
[0318] In an even more preferred embodiment, the R.sup.6 group of
the reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is dihydrogen, which is used in
combination with a metal catalyst selected from the group
consisting of Rayney-Nickel, Pd/C, Pt/C, and PtO.sub.2, and in
combination with a catalytic amount of an acid, which is selected
from aromatic sulfonic acids such as toluene sulfonic acid;
alkylsulfonic acids, such as methyl sulfonic acid; aromatic
carboxylic acids such as benzoic acid; alkylcarboxylic acids such
as acetic acid; haloalkylcarboxylic acids such as trifluoroacetic
acid, and mineral acids such as hydrogen chloride or sulfuric acid
in methanol, and wherein the dihydrogen is applied with a pressure,
which does not exceed 100 bar, and preferably does not exceed 50
bar.
[0319] In an even more preferred embodiment, the R.sup.6 group of
the reagent comprising the R.sup.6 group is H, and the reagent
comprising the R.sup.6 group is dihydrogen, which is used in
combination with a metal catalyst selected from the group
consisting of Rayney-Nickel, Pd/C, Pt/C, and PtO.sub.2, and in
combination with a catalytic amount of an acid, which is selected
from HCl, H.sub.2SO.sub.4, and trifluoracetic acid, and wherein the
dihydrogen is applied with a pressure, which does not exceed 100
bar, and preferably does not exceed 50 bar.
[0320] Summarizing, the reagent comprising the R.sup.6 group, which
is reacted with the compounds of formula IV to give the compounds
of formula V, may be [0321] a reducing agent, which may preferably
be an ionic hydride donor, and is particularly preferably
Na.sup.+[B(CN)H.sub.3].sup.-; or [0322] an organometallic reagent,
which may preferably be a silane, such as an allyl silane or a
fluoroalkylsilane, and is particularly preferably Ruppert's
reagent; or [0323] a nucleophilic reagent, which may preferably be
selected from HCN, or a salt, such as NaCN, or KCN, and is
particularly preferably NaCN.
[0324] In summary, the following combinations of substituents are
preferred in the compounds of formula V and its precursors or the
reagents used in the process of the present invention.
[0325] Table 1
Combination, in which R.sup.1 is H, R.sup.2 is CH.sub.3, R.sup.3 is
H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0326] Table 2
Combination, in which R.sup.1 is H, R.sup.2 is CH.sub.3, R.sup.3 is
C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0327] Table 3
Combination, in which R.sup.1 is H, R.sup.2 is CH.sub.3, R.sup.3 is
C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0328] Table 4
Combination, in which R.sup.1 is H, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0329] Table 5
Combination, in which R.sup.1 is H, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is CH.sub.3 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0330] Table 6
Combination, in which R.sup.1 is H, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0331] Table 7
Combination, in which R.sup.1 is H, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0332] Table 8
Combination, in which R.sup.1 is H, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is CH.sub.3 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0333] Table 9
Combination, in which R.sup.1 is H, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0334] Table 10
Combination, in which R.sup.1 is H, R.sup.2 is CF.sub.2H, R.sup.3
is H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0335] Table 11
Combination, in which R.sup.1 is H, R.sup.2 is CF.sub.2H, R.sup.3
is CH.sub.3 and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0336] Table 12
Combination, in which R.sup.1 is H, R.sup.2 is CF.sub.2H, R.sup.3
is C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0337] Table 13
Combination, in which R.sup.1 is H, R.sup.2 is CF.sub.2H, R.sup.3
is C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0338] Table 14
Combination, in which R.sup.1 is H, R.sup.2 is CF.sub.3, R.sup.3 is
H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0339] Table 15
Combination, in which R.sup.1 is H, R.sup.2 is CF.sub.3, R.sup.3 is
CH.sub.3 and the combination of R.sup.4 and R.sup.5 corresponds in
each case to one row of Table A
[0340] Table 16
Combination, in which R.sup.1 is H, R.sup.2 is CF.sub.3, R.sup.3 is
C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0341] Table 17
Combination, in which R.sup.1 is H, R.sup.2 is CF.sub.3, R.sup.3 is
C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0342] Table 18
Combination, in which R.sup.1 is F, R.sup.2 is CH.sub.3, R.sup.3 is
H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0343] Table 19
Combination, in which R.sup.1 is F, R.sup.2 is CH.sub.3, R.sup.3 is
C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0344] Table 20
Combination, in which R.sup.1 is F, R.sup.2 is CH.sub.3, R.sup.3 is
C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0345] Table 21
Combination, in which R.sup.1 is F, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0346] Table 22
Combination, in which R.sup.1 is F, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is CH.sub.3 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0347] Table 23
Combination, in which R.sup.1 is F, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0348] Table 24
Combination, in which R.sup.1 is F, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0349] Table 25
Combination, in which R.sup.1 is F, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is CH.sub.3 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0350] Table 26
Combination, in which R.sup.1 is F, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0351] Table 27
Combination, in which R.sup.1 is F, R.sup.2 is CF.sub.2H, R.sup.3
is H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0352] Table 28
Combination, in which R.sup.1 is F, R.sup.2 is CF.sub.2H, R.sup.3
is CH.sub.3 and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0353] Table 29
Combination, in which R.sup.1 is F, R.sup.2 is CF.sub.2H, R.sup.3
is C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0354] Table 30
Combination, in which R.sup.1 is F, R.sup.2 is CF.sub.2H, R.sup.3
is C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0355] Table 31
Combination, in which R.sup.1 is F, R.sup.2 is CF.sub.3, R.sup.3 is
H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0356] Table 32
Combination, in which R.sup.1 is F, R.sup.2 is CF.sub.3, R.sup.3 is
CH.sub.3 and the combination of R.sup.4 and R.sup.5 corresponds in
each case to one row of Table A
[0357] Table 33
Combination, in which R.sup.1 is F, R.sup.2 is CF.sub.3, R.sup.3 is
C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0358] Table 34
Combination, in which R.sup.1 is F, R.sup.2 is CF.sub.3, R.sup.3 is
C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0359] Table 35
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CH.sub.3,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0360] Table 36
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CH.sub.3,
R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0361] Table 37
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CH.sub.3,
R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0362] Table 38
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0363] Table 39
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0364] Table 40
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is C.sub.6H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0365] Table 41
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0366] Table 42
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0367] Table 43
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is C.sub.3H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0368] Table 44
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CF.sub.2H,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0369] Table 45
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CF.sub.2H,
R.sup.3 is CH.sub.3 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0370] Table 46
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CF.sub.2H,
R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0371] Table 47
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CF.sub.2H,
R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0372] Table 48
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CF.sub.3,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0373] Table 49
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CF.sub.3,
R.sup.3 is CH.sub.3 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0374] Table 50
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CF.sub.3,
R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0375] Table 51
Combination, in which R.sup.1 is CH.sub.3, R.sup.2 is CF.sub.3,
R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0376] Table 52
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CH.sub.3, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0377] Table 53
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CH.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0378] Table 54
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CH.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0379] Table 55
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0380] Table 56
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0381] Table 57
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is C.sub.6H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0382] Table 58
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0383] Table 59
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0384] Table 60
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is C.sub.3H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0385] Table 61
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CF.sub.2H, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0386] Table 62
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CF.sub.2H, R.sup.3 is CH.sub.3 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0387] Table 63
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CF.sub.2H, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0388] Table 64
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CF.sub.2H, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0389] Table 65
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CF.sub.3, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0390] Table 66
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CF.sub.3, R.sup.3 is CH.sub.3 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0391] Table 67
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CF.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0392] Table 68
Combination, in which R.sup.1 is C.sub.6H.sub.5, R.sup.2 is
CF.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0393] Table 69
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0394] Table 70
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0395] Table 71
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0396] Table 72
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0397] Table 73
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0398] Table 74
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is C.sub.6H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0399] Table 75
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0400] Table 76
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0401] Table 77
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is C.sub.3H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0402] Table 78
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0403] Table 79
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is CH.sub.3 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0404] Table 80
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0405] Table 81
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0406] Table 82
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0407] Table 83
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is CH.sub.3 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0408] Table 84
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0409] Table 85
Combination, in which R.sup.1 is C(O)OCH.sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0410] Table 86
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0411] Table 87
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0412] Table 88
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0413] Table 89
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0414] Table 90
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0415] Table 91
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is C.sub.6H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0416] Table 92
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0417] Table 93
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0418] Table 94
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is C.sub.3H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0419] Table 95
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0420] Table 96
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is CH.sub.3 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0421] Table 97
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0422] Table 98
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0423] Table 99
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0424] Table 100
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is CH.sub.3 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0425] Table 101
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0426] Table 102
Combination, in which R.sup.1 is C(O)OCH.sub.2CH.sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0427] Table 103
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0428] Table 104
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0429] Table 105
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CH.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0430] Table 106
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0431] Table 107
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0432] Table 108
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
C.sub.3H.sub.5, R.sup.3 is C.sub.6H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0433] Table 109
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is H and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0434] Table 110
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is CH.sub.3 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0435] Table 111
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
C.sub.6H.sub.5, R.sup.3 is C.sub.3H.sub.5 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0436] Table 112
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0437] Table 113
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is CH.sub.3 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0438] Table 114
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0439] Table 115
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CF.sub.2H, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0440] Table 116
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is H and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0441] Table 117
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is CH.sub.3 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0442] Table 118
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0443] Table 119
Combination, in which R.sup.1 is C(O)OC(CH.sub.3).sub.3, R.sup.2 is
CF.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0444] Table 120
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CH.sub.3, R.sup.3 is H and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0445] Table 121
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CH.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination
of R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0446] Table 122
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CH.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination
of R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0447] Table 123
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is C.sub.3H.sub.5, R.sup.3 is H and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0448] Table 124
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is C.sub.3H.sub.5, R.sup.3 is CH.sub.3 and the combination
of R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0449] Table 125
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is C.sub.3H.sub.5, R.sup.3 is C.sub.6H.sub.5 and the
combination of R.sup.4 and R.sup.5 corresponds in each case to one
row of Table A
[0450] Table 126
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is C.sub.6H.sub.5, R.sup.3 is H and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0451] Table 127
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is C.sub.6H.sub.5, R.sup.3 is CH.sub.3 and the combination
of R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0452] Table 128
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is C.sub.6H.sub.5, R.sup.3 is C.sub.3H.sub.5 and the
combination of R.sup.4 and R.sup.5 corresponds in each case to one
row of Table A
[0453] Table 129
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CF.sub.2H, R.sup.3 is H and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0454] Table 130
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CF.sub.2H, R.sup.3 is CH.sub.3 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0455] Table 131
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CF.sub.2H, R.sup.3 is C.sub.3H.sub.5 and the combination
of R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0456] Table 132
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CF.sub.2H, R.sup.3 is C.sub.6H.sub.5 and the combination
of R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0457] Table 133
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CF.sub.3, R.sup.3 is H and the combination of R.sup.4
and R.sup.5 corresponds in each case to one row of Table A
[0458] Table 134
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CF.sub.3, R.sup.3 is CH.sub.3 and the combination of
R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0459] Table 135
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CF.sub.3, R.sup.3 is C.sub.3H.sub.5 and the combination
of R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0460] Table 136
Combination, in which R.sup.1 is C(O)OCH.sub.2C.sub.6H.sub.5,
R.sup.2 is CF.sub.3, R.sup.3 is C.sub.6H.sub.5 and the combination
of R.sup.4 and R.sup.5 corresponds in each case to one row of Table
A
[0461] Table 137
Combination, in which R.sup.1 is CN, R.sup.2 is CH.sub.3, R.sup.3
is H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0462] Table 138
Combination, in which R.sup.1 is CN, R.sup.2 is CH.sub.3, R.sup.3
is C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0463] Table 139
Combination, in which R.sup.1 is CN, R.sup.2 is CH.sub.3, R.sup.3
is C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0464] Table 140
Combination, in which R.sup.1 is CN, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0465] Table 141
Combination, in which R.sup.1 is CN, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is CH.sub.3 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0466] Table 142
Combination, in which R.sup.1 is CN, R.sup.2 is C.sub.3H.sub.5,
R.sup.3 is C.sub.6H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0467] Table 143
Combination, in which R.sup.1 is CN, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is H and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0468] Table 144
Combination, in which R.sup.1 is CN, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is CH.sub.3 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0469] Table 145
Combination, in which R.sup.1 is CN, R.sup.2 is C.sub.6H.sub.5,
R.sup.3 is C.sub.3H.sub.5 and the combination of R.sup.4 and
R.sup.5 corresponds in each case to one row of Table A
[0470] Table 146
Combination, in which R.sup.1 is CN, R.sup.2 is CF.sub.2H, R.sup.3
is H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0471] Table 147
Combination, in which R.sup.1 is CN, R.sup.2 is CF.sub.2H, R.sup.3
is CH.sub.3 and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0472] Table 148
Combination, in which R.sup.1 is CN, R.sup.2 is CF.sub.2H, R.sup.3
is C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0473] Table 149
Combination, in which R.sup.1 is CN, R.sup.2 is CF.sub.2H, R.sup.3
is C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0474] Table 150
Combination, in which R.sup.1 is CN, R.sup.2 is CF.sub.3, R.sup.3
is H and the combination of R.sup.4 and R.sup.5 corresponds in each
case to one row of Table A
[0475] Table 151
Combination, in which R.sup.1 is CN, R.sup.2 is CF.sub.3, R.sup.3
is CH.sub.3 and the combination of R.sup.4 and R.sup.5 corresponds
in each case to one row of Table A
[0476] Table 152
Combination, in which R.sup.1 is CN, R.sup.2 is CF.sub.3, R.sup.3
is C.sub.3H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
[0477] Table 153
Combination, in which R.sup.1 is CN, R.sup.2 is CF.sub.3, R.sup.3
is C.sub.6H.sub.5 and the combination of R.sup.4 and R.sup.5
corresponds in each case to one row of Table A
TABLE-US-00001 TABLE A No. R.sup.4 R.sup.5 A-1 H H A-2 CH.sub.3 H
A-3 CH(CH.sub.3).sub.2 H A-4 cC.sub.3H.sub.5 H A-5 C.sub.6H.sub.5 H
A-6 CH.sub.2C.sub.6H.sub.5 H A-7 CHFCH.sub.3 H A-8
1-C(O)NH.sub.2--cC.sub.3H.sub.4 H A-9 1-CN--C.sub.3H.sub.4 H A-10
CH.sub.3 CH.sub.3 A-11 CH(CH.sub.3).sub.2 CH.sub.3 A-12
cC.sub.3H.sub.5 CH.sub.3 A-13 C.sub.6H.sub.5 CH.sub.3 A-14
CH.sub.2C.sub.6H.sub.5 CH.sub.3 A-15 CHFCH.sub.3 CH.sub.3 A-16
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.3 A-17 1-CN--C.sub.3H.sub.4
CH.sub.3 A-18 CH(CH.sub.3).sub.2 CH(CH.sub.3).sub.2 A-19
cC.sub.3H.sub.5 CH(CH.sub.3).sub.2 A-20 C.sub.6H.sub.5
CH(CH.sub.3).sub.2 A-21 CH.sub.2C.sub.6H.sub.5 CH(CH.sub.3).sub.2
A-22 CHFCH.sub.3 CH(CH.sub.3).sub.2 A-23
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH(CH.sub.3).sub.2 A-24
1-CN--C.sub.3H.sub.4 CH(CH.sub.3).sub.2 A-25 cC.sub.3H.sub.5
cC.sub.3H.sub.5 A-26 C.sub.6H.sub.5 cC.sub.3H.sub.5 A-27
CH.sub.2C.sub.6H.sub.5 cC.sub.3H.sub.5 A-28 CHFCH.sub.3
cC.sub.3H.sub.5 A-29 1-C(O)NH.sub.2--cC.sub.3H.sub.4
cC.sub.3H.sub.5 A-30 1-CN--C.sub.3H.sub.4 cC.sub.3H.sub.5 A-31
C.sub.6H.sub.5 C.sub.6H.sub.5 A-32 CH.sub.2C.sub.6H.sub.5
C.sub.6H.sub.5 A-33 CHFCH.sub.3 C.sub.6H.sub.5 A-34
1-C(O)NH.sub.2--cC.sub.3H.sub.4 C.sub.6H.sub.5 A-35
1-CN--C.sub.3H.sub.4 C.sub.6H.sub.5 A-36 CH.sub.2C.sub.6H.sub.5
CH.sub.2C.sub.6H.sub.5 A-37 CHFCH.sub.3 CH.sub.2C.sub.6H.sub.5 A-38
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.2C.sub.6H.sub.5 A-39
1-CN--C.sub.3H.sub.4 CH.sub.2C.sub.6H.sub.5 A-40 CHFCH.sub.3
CHFCH.sub.3 A-41 1-C(O)NH.sub.2--cC.sub.3H.sub.4 CHFCH.sub.3 A-42
1-CN--C.sub.3H.sub.4 CHFCH.sub.3 A-43
1-C(O)NH.sub.2--cC.sub.3H.sub.4 1-C(O)NH.sub.2--cC.sub.3H.sub.4
A-44 1-CN--C.sub.3H.sub.4 1-C(O)NH.sub.2--cC.sub.3H.sub.4 A-45
1-CN--C.sub.3H.sub.4 1-CN--C.sub.3H.sub.4 A-46 H CH.sub.2OH A-47
CH.sub.3 CH.sub.2OH A-48 CH(CH.sub.3).sub.2 CH.sub.2OH A-49
cC.sub.3H.sub.5 CH.sub.2OH A-50 C.sub.6H.sub.5 CH.sub.2OH A-51
CH.sub.2C.sub.6H.sub.5 CH.sub.2OH A-52 CHFCH.sub.3 CH.sub.2OH A-53
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.2OH A-54
1-CN--C.sub.3H.sub.4 CH.sub.2OH A-55 H CH(CH.sub.3)OH A-56 CH.sub.3
CH(CH.sub.3)OH A-57 CH(CH.sub.3).sub.2 CH(CH.sub.3)OH A-58
cC.sub.3H.sub.5 CH(CH.sub.3)OH A-59 C.sub.6H.sub.5 CH(CH.sub.3)OH
A-60 CH.sub.2C.sub.6H.sub.5 CH(CH.sub.3)OH A-61 CHFCH.sub.3
CH(CH.sub.3)OH A-62 1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH(CH.sub.3)OH
A-63 1-CN--C.sub.3H.sub.4 CH(CH.sub.3)OH A-64 H C(CH.sub.3).sub.2OH
A-65 CH.sub.3 C(CH.sub.3).sub.2OH A-66 CH(CH.sub.3).sub.2
C(CH.sub.3).sub.2OH A-67 cC.sub.3H.sub.5 C(CH.sub.3).sub.2OH A-68
C.sub.6H.sub.5 C(CH.sub.3).sub.2OH A-69 CH.sub.2C.sub.6H.sub.5
C(CH.sub.3).sub.2OH A-70 CHFCH.sub.3 C(CH.sub.3).sub.2OH A-71
1-C(O)NH.sub.2--cC.sub.3H.sub.4 C(CH.sub.3).sub.2OH A-72
1-CN--C.sub.3H.sub.4 C(CH.sub.3).sub.2OH A-73 H CH.sub.2CH.sub.2OH
A-74 CH.sub.3 CH.sub.2CH.sub.2OH A-75 CH(CH.sub.3).sub.2
CH.sub.2CH.sub.2OH A-76 cC.sub.3H.sub.5 CH.sub.2CH.sub.2OH A-77
C.sub.6H.sub.5 CH.sub.2CH.sub.2OH A-78 CH.sub.2C.sub.6H.sub.5
CH.sub.2CH.sub.2OH A-79 CHFCH.sub.3 CH.sub.2CH.sub.2OH A-80
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.2CH.sub.2OH A-81
1-CN--C.sub.3H.sub.4 CH.sub.2CH.sub.2OH A-82 H
CH(CH.sub.3)CH.sub.2OH A-83 CH.sub.3 CH(CH.sub.3)CH.sub.2OH A-84
CH(CH.sub.3).sub.2 CH(CH.sub.3)CH.sub.2OH A-85 cC.sub.3H.sub.5
CH(CH.sub.3)CH.sub.2OH A-86 C.sub.6H.sub.5 CH(CH.sub.3)CH.sub.2OH
A-87 CH.sub.2C.sub.6H.sub.5 CH(CH.sub.3)CH.sub.2OH A-88 CHFCH.sub.3
CH(CH.sub.3)CH.sub.2OH A-89 1-C(O)NH.sub.2--cC.sub.3H.sub.4
CH(CH.sub.3)CH.sub.2OH A-90 1-CN--C.sub.3H.sub.4
CH(CH.sub.3)CH.sub.2OH A-91 H 2-furyl A-92 CH.sub.3 2-furyl A-93
CH(CH.sub.3).sub.2 2-furyl A-94 cC.sub.3H.sub.5 2-furyl A-95
C.sub.6H.sub.5 2-furyl A-96 CH.sub.2C.sub.6H.sub.5 2-furyl A-97
CHFCH.sub.3 2-furyl A-98 1-C(O)NH.sub.2--cC.sub.3H.sub.4 2-furyl
A-99 1-CN--C.sub.3H.sub.4 2-furyl A-100 H 3-furyl A-101 CH.sub.3
3-furyl A-102 CH(CH.sub.3).sub.2 3-furyl A-103 cC.sub.3H.sub.5
3-furyl A-104 C.sub.6H.sub.5 3-furyl A-105 CH.sub.2C.sub.6H.sub.5
3-furyl A-106 CHFCH.sub.3 3-furyl A-107
1-C(O)NH.sub.2--cC.sub.3H.sub.4 3-furyl A-108 1-CN--C.sub.3H.sub.4
3-furyl A-109 H CH(OCH.sub.3).sub.2 A-110 CH.sub.3
CH(OCH.sub.3).sub.2 A-111 CH(CH.sub.3).sub.2 CH(OCH.sub.3).sub.2
A-112 cC.sub.3H.sub.5 CH(OCH.sub.3).sub.2 A-113 C.sub.6H.sub.5
CH(OCH.sub.3).sub.2 A-114 CH.sub.2C.sub.6H.sub.5
CH(OCH.sub.3).sub.2 A-115 CHFCH.sub.3 CH(OCH.sub.3).sub.2 A-116
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH(OCH.sub.3).sub.2 A-117
1-CN--C.sub.3H.sub.4 CH(OCH.sub.3).sub.2 A-118 H
CH.sub.2cC.sub.6H.sub.11 A-119 CH.sub.3 CH.sub.2cC.sub.6H.sub.11
A-120 CH(CH.sub.3).sub.2 CH.sub.2cC.sub.6H.sub.11 A-121
cC.sub.3H.sub.5 CH.sub.2cC.sub.6H.sub.11 A-122 C.sub.6H.sub.5
CH.sub.2cC.sub.6H.sub.11 A-123 CH.sub.2C.sub.6H.sub.5
CH.sub.2cC.sub.6H.sub.11 A-124 CHFCH.sub.3 CH.sub.2cC.sub.6H.sub.11
A-125 1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.2cC.sub.6H.sub.11
A-126 1-CN--C.sub.3H.sub.4 CH.sub.2cC.sub.6H.sub.11 A-127 H
CH.sub.2C(CH.sub.3).sub.3 A-128 CH.sub.3 CH.sub.2C(CH.sub.3).sub.3
A-129 CH(CH.sub.3).sub.2 CH.sub.2C(CH.sub.3).sub.3 A-130
cC.sub.3H.sub.5 CH.sub.2C(CH.sub.3).sub.3 A-131 C.sub.6H.sub.5
CH.sub.2C(CH.sub.3).sub.3 A-132 CH.sub.2C.sub.6H.sub.5
CH.sub.2C(CH.sub.3).sub.3 A-133 CHFCH.sub.3
CH.sub.2C(CH.sub.3).sub.3 A-134 1-C(O)NH.sub.2--cC.sub.3H.sub.4
CH.sub.2C(CH.sub.3).sub.3 A-135 1-CN--C.sub.3H.sub.4
CH.sub.2C(CH.sub.3).sub.3 A-136 H CH(CH.sub.2CH.sub.3).sub.2 A-137
CH.sub.3 CH(CH.sub.2CH.sub.3).sub.2 A-138 CH(CH.sub.3).sub.2
CH(CH.sub.2CH.sub.3).sub.2 A-139 cC.sub.3H.sub.5
CH(CH.sub.2CH.sub.3).sub.2 A-140 C.sub.6H.sub.5
CH(CH.sub.2CH.sub.3).sub.2 A-141 CH.sub.2C.sub.6H.sub.5
CH(CH.sub.2CH.sub.3).sub.2 A-142 CHFCH.sub.3
CH(CH.sub.2CH.sub.3).sub.2 A-143 1-C(O)NH.sub.2--cC.sub.3H.sub.4
CH(CH.sub.2CH.sub.3).sub.2 A-144 1-CN--C.sub.3H.sub.4
CH(CH.sub.2CH.sub.3).sub.2 A-145 H C(CH.sub.3).sub.2SCH.sub.3 A-146
CH.sub.3 C(CH.sub.3).sub.2SCH.sub.3 A-147 CH(CH.sub.3).sub.2
C(CH.sub.3).sub.2SCH.sub.3 A-148 cC.sub.3H.sub.5
C(CH.sub.3).sub.2SCH.sub.3 A-149 C.sub.6H.sub.5
C(CH.sub.3).sub.2SCH.sub.3 A-150 CH.sub.2C.sub.6H.sub.5
C(CH.sub.3).sub.2SCH.sub.3 A-151 CHFCH.sub.3
C(CH.sub.3).sub.2SCH.sub.3 A-152 1-C(O)NH.sub.2--cC.sub.3H.sub.4
C(CH.sub.3).sub.2SCH.sub.3 A-153 1-CN--C.sub.3H.sub.4
C(CH.sub.3).sub.2SCH.sub.3 A-154
CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2 A-155
CH.sub.2CH.sub.2CH.sub.2 A-156 CH.sub.2CH.sub.2CH.sub.2CH.sub.2
A-157 CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2 A-158
CH.sub.2OC(CH.sub.3).sub.2OCH.sub.2 A-159
CH.sub.2OCH.sub.2OCH.sub.2
[0478] In a preferred embodiment of the invention, the compounds of
formula V are compounds, wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H.
[0479] In another preferred embodiment of the invention, the
compounds of formula V are compounds, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, and R.sup.5 are according to any one of Tables 1
to 153 in combination with table A, entries A-1 to A-159, and
wherein R.sup.6 is CN.
[0480] In yet another preferred embodiment of the invention, the
compounds of formula V are compounds, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, and R.sup.5 are according to any one of Tables 1
to 153 in combination with table A, entries A-1 to A-159, and
wherein R.sup.6 is CHF.sub.2.
[0481] In yet another preferred embodiment of the invention, the
compounds of formula V are compounds, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, and R.sup.5 are according to any one of Tables 1
to 153 in combination with table A, entries A-1 to A-159, and
wherein R.sup.6 is CF.sub.3.
[0482] Particularly preferred are compounds of formula V, wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are according to
any one of Tables 1 to 153 in combination with table A, entries A-1
to A-159, and wherein R.sup.6 is H.
[0483] If the meanings of R.sup.4 and R.sup.5 are different from
each other and different from R.sup.6, it is again noted that the
compounds of formula V, for which the above combinations of
substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 as well
as R.sup.6 are preferred, may be present in the form of different
stereoisomers because the --CR.sup.4R.sup.5R.sup.6 group is then
chiral.
[0484] The same combinations of substituents R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 as defined in the above tables 1 to
153 in combination with table A, entries A-1 to A-159, are also
preferred for the compounds of formula IV.
[0485] Thus, in a preferred embodiment of the invention, the
compounds of formula IV are compounds, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, and R.sup.5 are according to any one of Tables 1
to 153 in combination with table A, entries A-1 to A-159.
[0486] It is again noted that the wavy lines in generic formula IV
indicate that the substituents R.sup.4 and R.sup.5 as well as the
substituents R.sup.3 and the hydrazone moiety may be present in
both possible positions, so that all possible E- and Z-isomers can
be realized.
[0487] The same combinations of substituents R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 as defined in the above tables 1 to
153 in combination with table A, entries A-1 to A-159, are also
preferred for the precursors of the compounds of formula IV, i.e.
the compounds of formula I, II and III, provided that the
substituents are present.
[0488] Thus, in one preferred embodiment of the invention, the
compounds of formula Ill are compounds, wherein R.sup.1, R.sup.2
and R.sup.3 are as defined in Tables 1 to 153.
[0489] Furthermore, in one preferred embodiment of the invention,
the compounds of formula II are compounds, wherein R.sup.4 and
R.sup.5 are as defined in Tables A-1 to A-159.
[0490] Furthermore, in one preferred embodiment of the invention,
the compounds of formula I are compounds, wherein R.sup.4 and
R.sup.5 are as defined in Tables A-1 to A-159.
[0491] As already indicated above, the compounds of formula IV are
obtainable from the compounds of formula Ill by reacting them with
compounds of formula II.
[0492] Apart from the substituents discussed above, the compounds
of formula Ill further comprise a substituent X, which represents a
leaving group. In principal, any leaving group, which is known in
the art, e.g. in the context of nucleophilic substitution
reactions, is suitable as substituent X. In the process of
preparing the compounds of formula IV as described herein, the
substituent X of the compounds of formula Ill is substituted by the
amino group of hydrazine, so that the substituent is no longer
contained in the compounds of formula IV.
[0493] In a preferred embodiment of the invention, in the compounds
of formula Ill X is halogen, OH, C.sub.1-C.sub.10-alkoxy,
C.sub.3-C.sub.10-cycloalkoxy, C.sub.1-C.sub.10-alkyl-C(O)O--,
C.sub.1-C.sub.10-alkyl-S(O).sub.2O--,
C.sub.1-C.sub.10-haloalkyl-S(O).sub.2O--, phenyl-S(O).sub.2O--,
tolyl-S(O).sub.2O--, (C.sub.1-C.sub.10-alkyloxy).sub.2P(O)O--,
C.sub.1-C.sub.10-alkylthio, C.sub.3-C.sub.10-cycloalkylthio,
C.sub.1-C.sub.10-alkyl-C(O)S--, NH.sub.2,
C.sub.1-C.sub.10-alkylamino, C.sub.1-C.sub.10-dialkylamino,
morpholino, N-methylpiperazino or
aza-C.sub.3-C.sub.10-cycloalkyl;
In a more preferred embodiment of the invention, in the compounds
of formula III X is halogen, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-dialkylamino, morpholino, N-methylpiperazino or
aza-C.sub.5-C.sub.6-cycloalkyl.
[0494] Preferably, X is halogen. As halogen, chlorine is
particularly preferred.
[0495] With regard to the C.sub.1-C.sub.4-dialkylamino groups, it
is noted that the alkyl chains may have identical or different
chain lengths. Dimethylamino and diethylamino groups are
particularly preferred according to the present invention.
[0496] Furthermore, C.sub.1-C.sub.4-alkoxy groups, in particular
C.sub.1-C.sub.2-alkoxy groups, are particularly preferred according
to the present invention.
[0497] The substituents R.sup.1, R.sup.2 and R.sup.3 of the
compounds of formula III were already discussed above.
[0498] Preferred compounds of formula III according to the present
invention are compounds, wherein R.sup.1, R.sup.2 and R.sup.3 are
as defined above in any one of tables 1 to 153, and X is any one of
Cl, OCH.sub.3, OCH.sub.2CH.sub.3, N(CH.sub.3).sub.2,
N(CH.sub.2CH.sub.3).sub.2. It is to be understood that each
combination between the substituents R.sup.1, R.sup.2 and R.sup.3
according to tables 1 to 153 and X being Cl, OCH.sub.3,
OCH.sub.2CH.sub.3, N(CH.sub.3).sub.2, N(CH.sub.2CH.sub.3).sub.2 is
suitable for the compounds of formula III according to the present
invention.
[0499] Thus, in a preferred embodiment of the invention, the
compounds of formula III are compounds, wherein R.sup.1, R.sup.2
and R.sup.3 are as defined in Tables 1 to 153, and wherein X is
Cl.
[0500] In another preferred embodiment of the invention, the
compounds of formula III are compounds, wherein R.sup.1, R.sup.2
and R.sup.3 are as defined in Tables 1 to 153, and wherein X is
OCH.sub.3.
[0501] In yet another preferred embodiment of the invention, the
compounds of formula III are compounds, wherein R.sup.1, R.sup.2
and R.sup.3 are as defined in Tables 1 to 153, and wherein X is
OCH.sub.2CH.sub.3.
[0502] In yet another preferred embodiment of the invention, the
compounds of formula III are compounds, wherein R.sup.1, R.sup.2
and R.sup.3 are as defined in Tables 1 to 153, and wherein X is
N(CH.sub.3).sub.2.
[0503] In yet another preferred embodiment of the invention, the
compounds of formula III are compounds, wherein R.sup.1, R.sup.2
and R.sup.3 are as defined in Tables 1 to 153, and wherein X is
N(CH.sub.2CH.sub.3).sub.2.
[0504] The compounds of formula II do not contain any further
substituents apart from the substituents R.sup.4 and R.sup.5, which
were already discussed above. It is again noted, however, that the
substituents R.sup.4 and R.sup.5 may preferably be selected in
accordance with Table A above.
[0505] The compounds of formula II are obtainable from the
compounds of formula I by reacting them with hydrazine.
[0506] The compounds of formula I do not contain any further
substituents apart from substituents R.sup.4 and R.sup.5, which
were already discussed above, and may particularly preferably
selected in accordance with Table A.
[0507] With regard to hydrazine as a reagent to be reacted with the
compounds of formula I in the process of the present invention, the
following is noted.
[0508] Hydrazine (also called diazane) is a compound with the
formula H.sub.2N--NH.sub.2. Although hydrazine may principally be
used in anhydrous form, it is preferred that hydrazine is used in
the form of an organic solution or that hydrazine is used in the
form of the monohydrate H.sub.2N--NH.sub.2xH.sub.2O or in the form
of an aqueous solution of said monohydrate. It is particularly
preferred that hydrazine is used in the form of the monohydrate
H.sub.2N--NH.sub.2xH.sub.2O or in the form of an aqueous solution
of said monohydrate.
[0509] If hydrazine is used in a solution in an organic solvent,
the solvent is preferably an alcohol, e.g. isopropanol, ethanol or
methanol. Preferred concentrations for alcoholic hydrazine
solutions are in the range of from 20% to 50% by weight, preferably
34% to 50% by weight of hydrazine, based on the total weight of the
solution. It is particularly preferred that hydrazine and the
alcohol are present in a weight ratio of about 1:1 in such
alcoholic solutions.
[0510] If hydrazine is used in a solution in an aqueous solvent,
the solvent is preferably water, and the concentration typically
refers to the concentration of the monohydrate of hydrazine
(H.sub.2N--NH.sub.2xH.sub.2O). Preferred concentrations for aqueous
hydrazine monohydrate solutions are in the range of 45 to 100% by
weight, preferably 60 to 100% by weight, e.g., 80 to 100% or 70 to
90% by weight of hydrazine monohydrate based on the total weight of
the solution. Preferably, hydrazine is used as 100% hydrazine
monohydrate or as an aqueous solution of hydrazine monohydrate with
a concentration of about 80 wt.-% of hydrazine monohydrate based on
the total weight of the solution.
[0511] Alternatively, hydrazine may be used in the form of a salt.
Hydrazine can easily be converted into salts by treatment with
mineral or organic acids such as sulfuric acid, hydrochloric acid
or acetic acid to give, e.g. salts of the formula
[H.sub.2N--NH.sub.3].sup.+HSO.sub.4.sup.-,
[H.sub.2N--NH.sub.3].sup.+Cl.sup.- or
[H.sub.2N--NH.sub.3].sup.+[O(C.dbd.O)CH.sub.3].sup.-, respectively.
In certain preferred embodiments, hydrazine may be used in the form
of an acetate or hydrochloride salt in the process according to the
present invention. The salt may be added to the reaction mixture as
a solid or in solution in an organic or aqueous solvent, e.g. in
methanol, ethanol, isopropanol or water.
[0512] As already indicated above, the compounds of formula V may
be present as compounds of formula Va, Vb or Vc.
[0513] In principal, the same combinations of substituents R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 as defined in the above
tables 1 to 153 in combination with table A, entries A-1 to A-159
are also preferred for the compounds of formulae Va, Vb and Vc and
the compounds, which are obtainable from the compounds of formula
Vc, namely the compounds of formulae VI and VIII. It is noted,
however, that these generic formulae are already pre-defined in
terms of the substituent R.sup.1, so that only the specific
combinations of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may be
derived from the above tables.
[0514] The compounds of formula Va, Vb and Vc fall under the
definition of the compounds of formula V, if R.sup.1 is selected as
such that R.sup.1 is CN (compound of formula Vb) or C(O)OR.sup.c
(compound of formula Va) or C(O)OH (compound of formula Vc). If
R.sup.1 in the compounds of formula V is C(O)OR.sup.c, it is
further preferred that R.sup.c is C.sub.1-C.sub.4-alkyl, e.g.
CH.sub.3, CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, or that R.sup.1 is
aryl-C.sub.1-C.sub.4-alkyl, e.g. CH.sub.2C.sub.6H.sub.5.
[0515] For the remaining substituents, the same substituent
definitions are preferred as discussed above in tables 1 to 153 in
combination with table A. Furthermore, R.sup.6 is preferably H, CN,
CHF.sub.2, or CF.sub.3.
[0516] Thus, in one preferred embodiment of the invention, the
compounds of formula Vb are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H.
[0517] Furthermore, in one preferred embodiment of the invention,
the compounds of formula Va are compounds, wherein R.sup.2,
R.sup.3, R.sup.4, and R.sup.5 are according to any one of Tables 1
to 153 in combination with table A, entries A-1 to A-159, and
wherein R.sup.6 is H, and wherein R.sup.c is CH.sub.3.
[0518] In another preferred embodiment of the invention, the
compounds of formula Va are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H, and wherein R.sup.c is CH.sub.2CH.sub.3.
[0519] In another preferred embodiment of the invention, the
compounds of formula Va are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H, and wherein R.sup.c is C(CH.sub.3).sub.3.
[0520] In another preferred embodiment of the invention, the
compounds of formula Va are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H, and wherein R.sup.c is CH.sub.2C.sub.6H.sub.5.
[0521] Moreover, in one preferred embodiment of the invention, the
compounds of formula Vc are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H.
[0522] Further to the above discussed preferred substituent
combinations, it can be preferred for the compounds of formula Va,
Vb and Vc that
[0523] R.sup.2 is CH.sub.3 or halomethyl,
[0524] R.sup.3 is H,
[0525] R.sup.4 is C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-haloalkyl,
or C.sub.3-cycloalkyl, wherein the cycloalkyl group is preferably
substituted with one substituent selected from CN and
C(O)NH.sub.2,
[0526] R.sup.5 is C.sub.1-C.sub.2-alkyl or
C.sub.3-C.sub.4-cycloalkyl,
[0527] or R.sup.4 and R.sup.5 together with the carbon atom to
which they are attached form a 6-membered carbocycle, which is
partially or fully halogenated, preferably fluorinated, and
[0528] R.sup.6 is H.
[0529] In view of the fact that the above compounds of formulae Va,
Vb and Vc are versatile reaction tools for obtaining further
pyrazole derivatives, the substituents of the compounds of formula
V are particularly preferably selected as such that R.sup.2 is
CH.sub.3, R.sup.3 is H, R.sup.6 is H and the remaining substituent
definitions are selected as indicated in one of the rows B-1 to
B-30 of Table B.
TABLE-US-00002 TABLE B R.sup.1 R.sup.4 R.sup.5 B-1 CN
CH(CH.sub.3).sub.2 CH.sub.3 B-2 CN CHFCH.sub.3 CH.sub.3 B-3 CN
1-CN--cC.sub.3H.sub.4 CH.sub.3 B-4 CN
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.3 B-5 CN
CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2 B-6 C(O)OCH.sub.3
CH(CH.sub.3).sub.2 CH.sub.3 B-7 C(O)OCH.sub.3 CHFCH.sub.3 CH.sub.3
B-8 C(O)OCH.sub.3 1-CN--cC.sub.3H.sub.4 CH.sub.3 B-9 C(O)OCH.sub.3
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.3 B-10 C(O)OCH.sub.3
CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2 B-11 C(O)OCH.sub.2CH.sub.3
CH(CH.sub.3).sub.2 CH.sub.3 B-12 C(O)OCH.sub.2CH.sub.3 CHFCH.sub.3
CH.sub.3 B-13 C(O)OCH.sub.2CH.sub.3 1-CN--cC.sub.3H.sub.4 CH.sub.3
B-14 C(O)OCH.sub.2CH.sub.3 1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.3
B-15 C(O)OCH.sub.2CH.sub.3 CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2
B-16 C(O)OC(CH.sub.3).sub.3 CH(CH.sub.3).sub.2 CH.sub.3 B-17
C(O)OC(CH.sub.3).sub.3 CHFCH.sub.3 CH.sub.3 B-18
C(O)OC(CH.sub.3).sub.3 1-CN--cC.sub.3H.sub.4 CH.sub.3 B-19
C(O)OC(CH.sub.3).sub.3 1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.3
B-20 C(O)OC(CH.sub.3).sub.3
CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2 B-21
C(O)OCH.sub.2C.sub.6H.sub.5 CH(CH.sub.3).sub.2 CH.sub.3 B-22
C(O)OCH.sub.2C.sub.6H.sub.5 CHFCH.sub.3 CH.sub.3 B-23
C(O)OCH.sub.2C.sub.6H.sub.5 1-CN--cC.sub.3H.sub.4 CH.sub.3 B-24
C(O)OCH.sub.2C.sub.6H.sub.5 1-C(O)NH.sub.2--cC.sub.3H.sub.4
CH.sub.3 B-25 C(O)OCH.sub.2C.sub.6H.sub.5
CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2 B-26 C(O)OH
CH(CH.sub.3).sub.2 CH.sub.3 B-27 C(O)OH CHFCH.sub.3 CH.sub.3 B-28
C(O)OH 1-CN--cC.sub.3H.sub.4 CH.sub.3 B-29 C(O)OH
1-C(O)NH.sub.2--cC.sub.3H.sub.4 CH.sub.3 B-30 C(O)OH
CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2
[0530] Rows B-1 to B-5 correspond to preferred compounds of formula
Vb, rows B-6 to B-25 correspond to preferred compounds of formula
Va and rows B-26 to B-30 correspond to preferred compounds of
formula Vc, which may be used in the process of the present
invention.
[0531] As already indicated above, the compounds of formula Va and
Vb can be obtained from the compounds of formula IV according the
present invention. The compounds of formula Vc are obtainable from
the compounds of formula Va or Vb. Alternatively, the compounds of
formula Vc may directly be obtained from the compounds of formula
IV according the present invention.
[0532] The compounds of formula Vc may be further converted into
compounds of formula VI according to the present invention.
[0533] Apart from the substituents discussed above, the compounds
of formula VI further comprise a substituent X.sup.1, which
represents a leaving group. In principal, any leaving group, which
is known in the art, e.g. in the context of activated carboxylic
acid derivatives, is suitable as substituent X.sup.1.
[0534] For example, X.sup.1 may be a leaving group, which is based
on a peptide coupling reagent. Suitable peptide coupling reagents
are described by Han et al. in Tetrahedron 60 (2004) 2447-2467.
[0535] In this regard, N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic
chloride (BOP--Cl) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) are preferred according to the present
invention.
[0536] Furthermore, X.sup.1 may be a leaving group selected from
active esters, azide and halogens.
[0537] In a preferred embodiment of the invention, X.sup.1 is
halogen, N.sub.3, p-nitrophenoxy, or pentafluorophenoxy.
[0538] Preferably, X.sup.1 is halogen, in particular Cl.
[0539] Thus, in one preferred embodiment of the invention, the
compounds of formula VI are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H, and wherein X.sup.1 is Cl.
[0540] In another preferred embodiment of the invention, the
compounds of formula VI are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H, and wherein X.sup.1 is N.sub.3.
[0541] In another preferred embodiment of the invention, the
compounds of formula VI are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H, and wherein X.sup.1 is p-nitrophenoxy.
[0542] In another preferred embodiment of the invention, the
compounds of formula VI are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H, and wherein X.sup.1 is pentafluorophenoxy.
[0543] The compounds of formula VI may be further converted into
compounds of formula VIII.
[0544] In the process of preparing the compounds of formula VIII as
described above, the substituent X.sup.1 of the compounds of
formula VI is substituted by the amine group of the
N-(het)arylamine of formula VII, so that the substituent is no
longer contained in the compounds of formula VIII.
[0545] However, apart from the remaining substituents discussed
above, the compounds of formula VIII further comprise the
N-(het)arylamide group, wherein the amide nitrogen atom is
substituted by R.sup.1N and the (het)aryl group comprises a
substituent U and substituents R.sup.P1, R.sup.P2 and R.sup.P3. The
same substituents are also present in the compounds of formula VII,
with which the compounds of formula VI may be reacted to give the
compounds of formula VIII.
[0546] In a preferred embodiment of the invention,
[0547] U is N or CH;
[0548] R.sup.P1, R.sup.P2, R.sup.P3 are H; and
[0549] R.sup.1N is H, C.sub.1-C.sub.2-alkyl or
C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl.
[0550] In particular, the following combinations of substituents U,
R.sup.M1, R.sup.P2, R.sup.P3 and R.sup.1N according to Table C are
preferred in the compounds of formula VII and VIII.
TABLE-US-00003 TABLE C U R.sup.P1, R.sup.P2, R.sup.P3 R.sup.1N C-1
N H H C-2 N H CH.sub.3 C-3 N H CH.sub.2CH.sub.3 C-4 N H
CH.sub.2OCH.sub.3 C-5 N H CH.sub.2OCH.sub.2CH.sub.3 C-6 N H
CH.sub.2CH.sub.2OCH.sub.3 C-7 N H CH.sub.2CH.sub.2OCH.sub.2CH.sub.3
C-8 CH H H C-9 CH H CH.sub.3 C-10 CH H CH.sub.2CH.sub.3 C-11 CH H
CH.sub.2OCH.sub.3 C-12 CH H CH.sub.2OCH.sub.2CH.sub.3 C-13 CH H
CH.sub.2CH.sub.2OCH.sub.3 C-14 CH H
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3
[0551] Thus, in a preferred embodiment of the invention, the
compounds of formula VII are compounds, wherein U, R.sup.P1,
R.sup.P2, R.sup.P3, and R.sup.1N are as defined in any one of rows
C-1 to C-14 of table C.
[0552] Furthermore, in a preferred embodiment of the invention, the
compounds of formula VIII are compounds, wherein R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are according to any one of Tables 1 to 153 in
combination with table A, entries A-1 to A-159, and wherein R.sup.6
is H, and wherein U, R.sup.P1, R.sup.P2, R.sup.P3, and R.sup.1N are
as defined in any one of rows C-1 to C-14 of table C.
[0553] As already indicated above, the present invention is also
directed to compounds of formulae Va, Vb, Vc and VI.
[0554] In one embodiment, the present invention relates to a
compound of formula Va or a salt, stereoisomer, tautomer or N-oxide
thereof
##STR00029##
[0555] wherein
[0556] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0557] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is CHFCH.sub.3,
R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0558] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-CN-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0559] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is
H; or
[0560] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 and R.sup.5
together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and R.sup.6
is H;
[0561] and wherein
[0562] R.sup.c is C.sub.1-C.sub.4-alkyl or
aryl-C.sub.1-C.sub.4-alkyl, or wherein R.sup.c together with the
C(O)O group forms a salt [C(O)O].sup.-NR.sub.4.sup.+,
[C(O)O].sup.-M.sub.a or [C(O)O].sup.-1/2M.sub.ea.sup.2+, wherein
M.sub.a is an alkali metal and M.sub.ea is an alkaline earth metal;
and wherein the substituents R at the nitrogen atom are
independently of each other selected from H,
C.sub.1-C.sub.10-alkyl, phenyl and
phenyl-C.sub.1-C.sub.4-alkyl.
[0563] If R.sup.c together with the C(O)O group forms a salt, the
salt is preferably selected from [C(O)O].sup.-NH.sub.4.sup.+,
[C(O)O].sup.-Na.sup.+, [C(O)O].sup.-K+, [C(O)O].sup.-1/2Ca.sup.2+
and [C(O)O].sup.-1/2Mg.sup.2+, and is particularly preferably
[C(O)O].sup.-Na.sup.+. If R.sup.c together with the C(O)O group
forms a salt, this is to be understood as a carboxylate salt,
wherein the negative charge is delocalized in the carboxylate group
[C(O)O].sup.-.
[0564] If R.sup.c is selected as such that the C(O)OR.sup.c group
is an ester group, it is preferred that R.sup.c is
C.sub.1-C.sub.4-alkyl or benzyl, more preferably, ethyl or
tert-butyl.
[0565] It is particularly preferred according to the invention that
R.sup.c is selected as such that the C(O)OR.sup.c group is an ester
group. In this context, C.sub.1-C.sub.4-alkyl or benzyl ester
groups are particularly preferred.
[0566] In another embodiment, the present invention relates to a
compound of formula Vb or a salt, stereoisomer, tautomer or N-oxide
thereof
##STR00030##
[0567] wherein
[0568] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0569] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is CHFCH.sub.3,
R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0570] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-CN-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0571] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is
H; or
[0572] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 and R.sup.5
together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and R.sup.6
is H.
[0573] In yet another embodiment, the present invention relates to
a compound of formula Vc or a salt, stereoisomer, tautomer or
N-oxide thereof
##STR00031##
[0574] wherein
[0575] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0576] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is CHFCH.sub.3,
R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0577] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-CN-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0578] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is
H; or
[0579] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 and R.sup.5
together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and R.sup.6
is H.
[0580] In yet another embodiment, the present invention relates to
a compound of formula VI or a salt, stereoisomer, tautomer or
N-oxide thereof
##STR00032##
[0581] wherein
[0582] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
CH(CH.sub.3).sub.2, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0583] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is CHFCH.sub.3,
R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0584] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-CN-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is H; or
[0585] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 is
1-C(O)NH.sub.2-cC.sub.3H.sub.4, R.sup.5 is CH.sub.3 and R.sup.6 is
H; or
[0586] R.sup.2 is CH.sub.3, R.sub.3 is H, R.sup.4 and R.sup.5
together are CH.sub.2CH.sub.2CF.sub.2CH.sub.2CH.sub.2, and R.sup.6
is H;
[0587] and wherein
[0588] X.sup.1 is a leaving group.
[0589] Suitable leaving groups include leaving groups, which are
known in the art in the context of activated carboxylic acid
derivatives.
[0590] For example, X.sup.1 may be a leaving group, which is based
on a peptide coupling reagent. Suitable peptide coupling reagents
are described by Han et al. in Tetrahedron 60 (2004) 2447-2467. In
this regard, N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride
(BOP--Cl) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) are preferred according to the present
invention.
[0591] Furthermore, X.sup.1 may be a leaving group selected from
active esters, azide and halogens.
[0592] Preferably, X.sup.1 is selected from halogen, N.sub.3,
p-nitrophenoxy and pentafluorophenoxy, and more preferably, X.sup.1
is halogen, and particularly preferably X.sup.1 is Cl.
[0593] As already indicated above, the process of the present
invention covers the preparation of a compound of formula V by
cyclizing a compound of formula IV by reacting it with a reagent
comprising a R.sup.6 group. Said reaction step provides for the
benefits of the present invention, namely the versatile and
convenient provision of compounds of formula V, thereby preferably
ensuring regioselectivity. Preferably, the process of the present
invention also includes the preparation of the compounds of formula
IV, so that in particular a reaction sequence of the following
steps (b) and (c) or the steps (a), (b) and (c) is covered by the
present invention:
[0594] (a) I->II:
##STR00033##
[0595] (b) II+III->IV:
##STR00034##
[0596] (c) IV->V:
##STR00035##
[0597] It is emphasized that the above reaction steps may not only
be performed separately, i.e. under isolation of the compounds of
formulae II and IV, but that the reaction steps may also be
performed in a one-pot reaction, i.e. without isolating the
compounds of formulae II and/or IV. One option is that steps (a),
(b) and (c) are combined in a one-pot reaction, e.g. by combining
the compounds of formula I with hydrazine, so that first the
compound of formula II is in situ formed, then adding the compound
of formula III to give the compound of formula IV in situ, and then
adding the reagent comprising the R.sup.6 group to give a compound
of formula V. Another option is that steps (a) and (b) are
performed in a one-pot reaction and the compound of formula IV is
isolated, and that then step (c) is performed. And yet another
option is that step (a) is performed as a first step and the
compound of formula II is isolated, and that then steps (b) and (c)
are then performed in a one-pot reaction.
[0598] Furthermore, it is emphasized that the reactions may be
performed on a technical scale. Preferably, the reactants are
converted equally well and only minor deviations in terms of yield
are observed.
[0599] As also already discussed above, the compounds of formula V
are versatile reaction tools for the preparation of pesticidally
active agents. For example, if the compounds of formula V are
compounds of formula Va or Vb, these compounds may be converted
into compounds of formula Vc. The compounds of formula Vc, which
can either be obtained from the compounds of formula Va or Vb or as
a reaction product of the above reaction step (c), can then be
further converted into compounds of formula VI. In a further
reaction step, the compounds of formula VIII may then be obtained.
Thus, the following reaction sequence comprising step (d),
preferably step (d) and step (e), and particularly preferably steps
(d), (e) and (f), may be performed subsequent to the above reaction
sequence according to the present invention.
[0600] (d) Va or Vb->Vc:
##STR00036##
[0601] (e) Vc->VI:
##STR00037##
[0602] (f) VI+VII->VIII:
##STR00038##
[0603] It is noted that also steps (e) and (f) may be performed as
a one-pot reaction so that the activated compound VI does not have
to be isolated prior to the amidation reaction.
[0604] The above reaction steps of the process of the invention
will be described hereinafter, wherein it will be referred to the
steps (a), (b), (c), (d), (e) and (f) as indicated above with step
(c) being the essential step of the process of the present
invention.
[0605] The reaction steps of the process of the invention as
described hereinafter are performed in reaction vessels customary
for such reactions, the reactions being carried out in a
continuous, semi-continuous or batchwise manner.
[0606] In general, the particular reactions will be carried out
under atmospheric pressure. The reactions may, however, also be
carried out under reduced pressure.
[0607] The temperatures and the duration times of the reactions may
be varied in broad ranges, which the person skilled in the art
knows from analogous reactions. The temperatures often depend on
the reflux temperature of the solvents. Other reactions are
preferably performed at room temperature, i.e. at about 25.degree.
C., or under ice cooling, i.e. at about 0.degree. C. The end of the
reaction can be monitored by methods known to a person skilled in
the art, e.g. thin layer chromatography or HPLC.
[0608] If not otherwise indicated, the molar ratios of the
reactants, which are used in the reactions, are in the range of
from 0.2:1 to 1:0.2, preferably from 0.5:1 to 1:0.5, more
preferably from 0.8:1 to 1:0.8. Preferably, equimolar amounts are
used.
[0609] If not otherwise indicated, the reactants can in principle
be contacted with one another in any desired sequence.
[0610] The person skilled in the art knows when the reactants or
reagents are moisture sensitive, so that the reaction should be
carried out under protective gases such as under a nitrogen
atmosphere, and dried solvents should be used.
[0611] The person skilled in the art also knows the best work-up of
the reaction mixture after the end of the reaction.
[0612] In the following, the process of the invention is described
in further detail.
[0613] The reaction conditions for step (a) of the process are as
follows.
[0614] In step (a) of the process of the invention, a compound of
formula I is reacted with hydrazine to give a compound of formula
II. Said reaction is a hydrazone formation, which can be performed
under reaction conditions known in the art. In particular, the
reaction can be carried out by a process, wherein hydrazine
monohydrate or a solution of hydrazine, is reacted with a compound
of formula I either in the absence of a solvent or in an aqueous or
organic solvent, wherein a basic or an acidic catalyst may
optionally be present.
[0615] In a preferred embodiment the reaction is conducted in the
absence of a solvent.
[0616] In a preferred embodiment the reaction is conducted in the
absence of a catalyst.
[0617] Suitable reaction temperatures for the reaction are in the
range of from 0.degree. C. to 80.degree. C., preferably from
15.degree. C. to 50.degree. C., more preferably from 20 to
25.degree. C. In certain situations it can be preferred to start at
a lower temperature of from 20 to 25.degree. C. for about 1 hour
and then heat the reaction mixture to a higher temperature of from
50 to 80.degree. C. In other situations, it can be preferred to
start at a medium temperature of from 30 to 50.degree. C. for about
1 hour and then stir the reaction mixture at a temperature of from
20 to 25.degree. C.
[0618] The overall reaction times may vary in a broad range, e.g.
from 1 hour to 3 days. It is therefore preferred that the reaction
is monitored by analytical methods and stopped after complete
conversion of the compound of formula I into formula II.
[0619] The compound of formula I is commercially available or can
be prepared by methods known in the art.
[0620] As already indicated above, hydrazine is preferably provided
in the form of the monohydrate or in the form of a solution of said
monohydrate in water. Preferred concentrations for aqueous
hydrazine monohydrate solutions are in the range of 45 to 100% by
weight, preferably 60 to 100% by weight, e.g., 80 to 100% or 70 to
90% by weight of hydrazine monohydrate based on the total weight of
the solution. Preferably, hydrazine is used as 100% hydrazine
monohydrate or as an aqueous solution of hydrazine monohydrate with
a concentration of about 80 wt.-% of hydrazine monohydrate based on
the total weight of the solution.
[0621] Preferably, hydrazine is used at least in stochiometric
amounts. Preferably, hydrazine is used in amounts in the range of
from 1.0 to 10.0 mol, preferably from 1.0 to 2.0 mol, more
preferably from 1.0 to 1.5 mol, per mol of the compound of formula
I.
[0622] For practical reasons, it is preferred that the compound of
formula I is added to hydrazine monohydrate or a solution thereof
and not vice versa, so that it is avoided that an excess of the
compound of formula I compared to hydrazine is present in the
reaction mixture upon mixing the two components.
[0623] If a solvent is present, it is preferred that the solvent is
an organic solvent, either an aprotic or a protic solvent or a
mixture thereof. Suitable aprotic solvents include aromatic
solvents, ethers, or mixtures thereof. Preferred aromatic solvents
are e.g. benzene, toluene, xylene (ortho-xylene, meta-xylene or
para-xylene), mesitylene, chlorobenzene, 1,2-dichlorobenzene,
1,3-dichlorobenzene, 1,4-dichlorobenzene, or mixtures thereof.
Preferred ethers are open-chained and cyclic ethers, in particular
diethyl ether, methyl-tert-butyl-ether (MTBE),
2-methoxy-2-methylbutane, cyclopentylmethylether, 1,4-dioxane,
tetrahydrofuran, 2-methyltetrahydrofuran, or mixtures thereof.
Protic solvents are typically preferred as solvents. Suitable
protic solvents are C.sub.1-C.sub.4-alkanols such as methanol,
ethanol, propanol and isopropanol, C.sub.2-C.sub.4-alkandiols, such
as ethylene glycol or propylene glycol, and ether alkanols such as
diethylene glycol, and mixtures thereof. Particularly preferred are
C.sub.1-C.sub.4-alkanols, e.g. methanol, ethanol, isopropanol,
butanol, or mixtures thereof, in particular ethanol.
[0624] The reaction may also be performed in the presence of an
acidic or basic catalyst. Preferred acid catalysts include HCl in
H.sub.2O, HCl in MeOH, HCl in dioxane; H.sub.2SO.sub.4,
H.sub.3PO.sub.4 and salts of H.sub.2SO.sub.4 and H.sub.3PO.sub.4;
aromatic sulfonic acids such as toluene sulfonic acid;
alkylsulfonic acids, such as methyl sulfonic acid; aromatic
carboxylic acids such as benzoic acid; alkylcarboxylic acids such
as acetic acid; salts of rare earth metals; and Lewis acids such as
BF.sub.3, BF.sub.3xOEt.sub.2, BF.sub.3xSMe.sub.2, TiCl.sub.4,
Ti(OiPr).sub.4. A preferred acid catalyst is acetic acid. Preferred
basic catalysts include BaO, CaO, MgCO.sub.3, CaCO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3 and NEt.sub.3. A preferred basic
catalyst is BaO.
[0625] The acidic or basic catalyst is preferably used in amounts
in the range of from 0.001 to 10 mol, preferably from 0.01 to 0.5
mol, more preferably from 0.02 to 0.3 mol, per mol of the compound
of formula I. For acidic catalysts, amounts in the range of from
0.05 to 0.2 mol per mol of the compound of formula I can be
preferred. For basic catalysts, amounts in the range of from 0.15
to 0.25 or from 0.2 to 0.3 mol per mol of the compound of formula I
can be preferred.
[0626] The reaction conditions for step (b) of the process of the
invention are as follows.
[0627] In step (b), a compound of formula II is reacted with a
compound of formula III to give a compound of formula IV. Said
reaction corresponds to a substitution reaction at an
.alpha.,.beta.-unsaturated carbonyl compound comprising a leaving
group in the .beta.-position with a hydrazone acting as a
nucleophile. The reaction can be performed under reaction
conditions known in the art. In particular, the reaction can be
carried out by a process, wherein the compound of formula II is
reacted with a compound of formula III either in the absence of a
solvent or in an organic solvent, wherein a basic catalyst may
optionally be present.
[0628] Suitable reaction temperatures for the reaction are in the
range of from -20.degree. C. to 50.degree. C., preferably from
15.degree. C. to 40.degree. C., more preferably from 20 to
25.degree. C. It is typically preferred that the compounds of
formulae II and III are mixed with each other at temperatures below
0.degree. C., preferably about -20.degree. C., and that the mixture
is then allowed to warm to a reaction temperature defined
above.
[0629] The overall reaction times may vary in a broad range, e.g.
from 1 hour to 1 day, preferably from 3 to 12 hours.
[0630] The compound of formula II may be provided as the crude
product of step (a), i.e. without performing any purification steps
prior to step (b), or as part of the reaction mixture obtained in
step (a), to which the compound of formula III may then be
added.
[0631] The compound of formula III is commercially available or can
be prepared by methods known in the art.
[0632] Preferably, the compound of formula III is used in amounts
in the range of from 0.1 to 10.0 mol, preferably from 0.8 to 1.5
mol, more preferably from 0.9 to 1.3 mol per mol of the compound of
formula II.
[0633] If a solvent is present, it is preferred that the solvent is
an organic solvent, either an aprotic or a protic solvent or a
mixture thereof. Suitable aprotic solvents include aromatic
solvents, ethers, or mixtures thereof. Preferred aromatic solvents
are e.g. benzene, toluene, xylene (orthoxylene, meta-xylene or
para-xylene), mesitylene, chlorobenzene, 1,2-dichlorobenzene,
1,3-dichlorobenzene, 1,4-dichlorobenzene, or mixtures thereof.
Preferred ethers are open-chained and cyclic ethers, in particular
diethyl ether, methyl-tert-butyl-ether (MTBE),
2-methoxy-2-methylbutane, cyclopentylmethylether, 1,4-dioxane,
tetrahydrofuran, 2-methyltetrahydrofuran, or mixtures thereof. A
particularly suitable open-chained ether is e.g. MTBE. Protic
solvents are typically preferred as solvents. Suitable protic
solvents are C.sub.1-C.sub.4-alkanols such as methanol, ethanol,
propanol and isopropanol, C.sub.2-C.sub.4-alkandiols, such as
ethylene glycol or propylene glycol, and ether alkanols such as
diethylene glycol, and mixtures thereof. Particularly preferred are
C.sub.1-C.sub.4-alkanols, e.g. methanol, ethanol, isopropanol,
butanol, or mixtures thereof, in particular ethanol.
[0634] In principal, the reaction can easily be performed without
having to use a catalyst. However, the reaction may also be
performed in the presence of a basic catalyst. Preferred basic
catalysts include BaO, CaO, MgCO.sub.3, CaCO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3 and NEt.sub.3.
[0635] If a basic catalyst is used, amounts in the range of from
0.01 to 2.0 mol, preferably from 1.0 to 2.0 mol, per mol of the
compound of formula II are preferred.
[0636] The reaction conditions for step (c) of the process of the
invention are as follows.
[0637] In step (c), a compound of formula IV is reacted with a
reagent comprising a R.sup.6 group to give a compound of formula V.
The reaction conditions are described hereinafter. In particular,
the reaction can be carried out by a process, wherein the compound
of formula IV is reacted with the reagent comprising the R.sup.6
group either in the presence of a solvent, wherein an acidic
catalyst or a metal catalyst may optionally be present.
[0638] The selection of the solvent depends on the type of the
reagent comprising the R.sup.6 group. In general organic solvents
including aprotic solvents, such as aromatic solvents, ethers or
mixtures thereof, and protic solvents may be used. Preferred
aromatic solvents are e.g. benzene, toluene, xylene (ortho-xylene,
meta-xylene or para-xylene), mesitylene, chlorobenzene,
1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, or
mixtures thereof. Preferred ethers are open-chained and cyclic
ethers, in particular diethyl ether, methyl-tert-butyl-ether
(MTBE), 2-methoxy-2-methylbutane, cyclopentylmethylether,
1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or mixtures
thereof. Preferred protic solvents are C.sub.1-C.sub.4-alkanols
such as methanol, ethanol, propanol and isopropanol,
C.sub.2-C.sub.4-alkandiols, such as ethylene glycol or propylene
glycol, and ether alkanols such as diethylene glycol, and mixtures
thereof. Particularly preferred are C.sub.1-C.sub.4-alkanols, e.g.
methanol, ethanol, isopropanol, butanol, or mixtures thereof.
[0639] If the reagent is reducing agent, preferably an ionic
hydride donor, protic organic solvents can be preferred. Suitable
protic solvents include C.sub.1-C.sub.4-alkanols such as methanol,
ethanol, propanol and isopropanol, C.sub.2-C.sub.4-alkandiols, such
as ethylene glycol or propylene glycol, and ether alkanols such as
diethylene glycol, and mixtures thereof. Particularly preferred are
C.sub.1-C.sub.4-alkanols, e.g. methanol, ethanol, isopropanol,
butanol, or mixtures thereof, in particular methanol, ethanol and
isopropanol. If the reducing agent is an ionic hydride donor of
higher reactivity, such as in case of Li.sup.+[AlH.sub.4].sup.-, it
can be preferred that the solvent is an aprotic organic solvent,
e.g. an ether solvent such as diethyl ether, methyl-tert-butyl
ether (MTBE), 2-methoxy-2-methylbutane, cyclopentylmethylether,
1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or mixtures
thereof. Ether solvents such as the ones listed above are also
preferred, if the reagent is a non-ionic hydride donor.
[0640] On the other hand, protic solvents as mentioned above are
again preferred, if electron donors are used in combination with
protons to act as a reducing agent because protons are required for
the in situ formation of hydrogen radicals.
[0641] If the reagent is an organometallic agent, aprotic organic
solvents are typically preferred. Suitable aprotic solvents include
aliphatic hydrocarbons, cycloaliphatic hydrocarbons, halogenated
alkanes, aromatic hydrocarbons, open-chained ethers, cyclic ethers,
esters, aliphatic or alicyclic carbonates, in particular aromatic
solvents and open-chained and cyclic ethers. Preferred aprotic
solvents are open-chained and cyclic ethers. Preferred open-chained
ethers are diethyl ether, methy-tert-butyl ether (MTBE),
2-methoxy-2-methylbutane and cyclopentylmethylether.
[0642] Preferred cyclic ethers are tetrahydrofuran,
2-methyltetrahydrofuran and 1,4-dioxane.
[0643] If the reagent is a nucleophilic reagent, both protic and
aprotic organic solvents may be used. Protic solvents such as
C.sub.1-C.sub.4-alkanols, in particular methanol, ethanol and
isopropanol, can again be preferred.
[0644] The reaction temperatures also depend on the type of the
reagent comprising the R.sup.6 group.
[0645] If the reagent is a reducing agent, the reaction
temperatures may be in the range of from -20.degree. C. to
50.degree. C., preferably from 10.degree. C. to 30.degree. C., more
preferably from 20.degree. C. to 25.degree. C. In certain
situations, it can be preferred to start the reaction at a higher
temperature of from 30.degree. C. to 50.degree. C. and then
continue the reaction at room temperature.
[0646] If the reagent is an organometallic reagent, lower reaction
temperatures of -78.degree. C. to 0.degree. C. may be suitable.
Alternatively, the reaction temperature may be in the range of from
0.degree. C. to 50.degree. C., preferably from 10.degree. C. to
30.degree. C., more preferably from 20 to 25.degree. C. In certain
situations it can be preferred to start at a lower temperature of
about -78.degree. C., -20.degree. C. or 0.degree. C. for about 1
hour and then allow the reaction mixture to warm to a temperature
of from 0.degree. C. to 25.degree. C.
[0647] If the reagent is a nucleophilic reagent, the reaction
temperatures may be in the range of from 0.degree. C. to 50.degree.
C., preferably from 10.degree. C. to 30.degree. C., more preferably
from 20 to 25.degree. C. Alternatively, it can be preferred that
the reaction mixture is heated, e.g. to a reaction temperature of
from 50.degree. C. to 80.degree. C.
[0648] The overall reaction times may vary in a broad range,
preferably from 1 hour to 4 days, e.g. from 4 hours to 8 hours,
from 10 to 18 hours, from 24 hours to 48 hours, or from 2 days to 4
days. It is therefore preferred that the reaction is monitored by
analytical methods and stopped after complete conversion of the
compound of formula IV into the compound of formula V.
[0649] The compound of formula IV can be provided as a crude
product of step (b), i.e. without performing any purification steps
prior to step (c), or as part of the reaction mixture obtained in
step (b), to which the reagent comprising the R.sup.6 group may
then be added.
[0650] The reagent comprising the R.sup.6 group is preferably used
at least in stochiometric amounts, e.g. in amounts in the range of
from 1.0 to 10.0 mol, preferably from 1.0 to 2.0 mol per mol of the
compound of formula IV. If the reagent comprises more than one
R.sup.6 groups, which may be transferred, it can also be sufficient
to use sub-stochiometric amounts, e.g. in the range of from 0.1 to
less than 1.0 mol, preferably 0.5 to less than 1.0 mol per mol of
the compound of formula IV. In principal, the reagent may therefore
be used in amounts in the range of from 0.1 to 10.0 mol per mol of
the compound of formula IV. Preferably, the reagent is used in
amounts of from 0.8 to 2.0 mol, more preferably from 1.0 to 1.5
mol, per mol of the compound of formula IV.
[0651] If the reagent comprising the R.sup.6 group is in gaseous
form, e.g. in case of dihydrogen, the reagent is typically used in
an excess by performing the reaction in an atmosphere of the
reagent comprising the R.sup.6 group. A certain pressure may be
applied, which preferably does not exceed 100 bar for practical
reasons.
[0652] The reagent comprising the R.sup.6 group may be added all at
once or portion wise. In particular for the reagent being a
reducing agent, e.g. an ionic hydride donor such as
Na.sup.+[B(CN)H.sub.3].sup.-, it is preferred that the reagent is
provided in two or three portions.
[0653] If the amount of the reagent comprising the R.sup.6 group is
used all at once, it is preferred for practical reasons that the
compound of formula IV is added to the reagent comprising the
R.sup.6 group.
[0654] Similarly, if the amount of the reagent comprising the
R.sup.6 group is used portion wise, it is preferred that the
compound of formula IV is added to the first portion of the
reducing agent. Typically, about half of the amount of the reagent
comprising the R.sup.6 group is used in this context. The mixture
is then stirred for a certain reaction time of e.g. 10 to 18 hours,
and one or two further portions of the reagent are added later on,
so that the total amount of the reagent is finally added to the
reaction mixture. The reaction mixture is then again stirred for a
certain reaction time of, e.g., 10 to 18 hours, 12 to 24 hours, or
3 to 4 days.
[0655] Preferred pH values for the reaction of the compounds of
formula IV with the reagent comprising the R.sup.6 group, e.g. an
ionic hydride donor such as Na.sup.+[B(CN)H.sub.3].sup.-, are in
the range of from 4 to 6.
[0656] In general, the reaction may be performed in the presence of
an acidic catalyst. This is particularly preferred, if the reagent
comprising the R.sup.6 group is a reducing agent or a nucleophilic
reagent. Preferred acid catalysts include HCl in H.sub.2O, HCl in
MeOH, HCl in dioxane; H.sub.2SO.sub.4, H.sub.3PO.sub.4 and salts of
H.sub.2SO.sub.4 and H.sub.3PO.sub.4; aromatic sulfonic acids such
as toluene sulfonic acid; alkylsulfonic acids, such as methyl
sulfonic acid; aromatic carboxylic acids such as benzoic acid;
alkylcarboxylic acids such as acetic acid; salts of rare earth
metals; and Lewis acids such as BF.sub.3, BF.sub.3xOEt.sub.2,
BF.sub.3xSMe.sub.2, TiCl.sub.4, Ti(OiPr).sub.4. Preferred acids
catalysts further include aromatic sulfonic acids such as toluene
sulfonic acid; alkylsulfonic acids, such as methyl sulfonic acid;
aromatic carboxylic acids such as benzoic acid; alkylcarboxylic
acids such as acetic acid; haloalkylcarboxylic acids such as
trifluoroacetic acid, and mineral acids such as hydrogen chloride
or sulfuric acid in methanol. A preferred acid catalyst is acetic
acid or HCl in MeOH. Acetic acid is particularly preferred.
[0657] The acidic catalyst is preferably used in amounts in the
range of from 0.001 to 10 mol, preferably from 1.0 to 5.0 mol, e.g.
1.0 to 2.0 mol or 2.0 to 4.0 mol, per mol of the compound of
formula IV. For acetic acid, amounts of 1.0 to 3.0 mol per mol of
the compound of formula IV are preferred, and for HCl in MeOH,
amounts of 1.0 to 5.0 mol per mol of the compound of formula IV are
preferred.
[0658] Alternatively or additionally, a metal catalyst may be
present in the reaction mixture. Suitable metal catalysts include
Cu, Pd, Pt, Ni, Fe, Rh, Ru either as the elements or in the form of
a salt, and either pure or on an inert carrier. Suitable catalysts
include Rayney-Nickel, Pd/C, Pt/C and the like. Preferred metal
catalysts are selected from the group consisting of Rayney-Nickel,
Pd/C, Pt/C, Ru/C, Rh/C, and PtO.sub.2, in particular from
Rayney-Nickel, Pd/C, Pt/C, and PtO.sub.2.
[0659] The resulting compounds of formula V, which can be obtained
according to step (c) of the process of the invention, can be
purified by methods known in the art, e.g. by distillation, if
esters of formula Va are prepared.
[0660] The reaction conditions for step (d) of the process of the
invention are as follows.
[0661] In step (d), a compound of formula Va or Vb is converted
into a compound of formula Vc. Typically, said reaction may be
understood as a hydrolysis reaction because an ester or a nitrile
is hydrolyzed to give the free acid. However, other conversion
reactions of esters or nitriles into the free acids, such as the
conversion of tert-butyl esters into the free acids by the addition
of trifluoroacetic acid, are also covered by the invention.
[0662] If the reaction is a according to step (d) is a hydrolysis
reaction, the reaction may be carried out by a process, wherein the
compound of formula Va or Vb is reacted with water e.g. in the
presence of a base or in the presence of an acid, or by a process,
wherein the compound of formula Va or Vb is reacted with a water
soluble base, preferably an oxo-base, in an aqueous solvent, or by
a process, wherein the compound of formula Va or Vb is reacted with
a hydroxide in a protic aqueous or organic solvent. Such hydrolysis
reactions can be performed according to procedures known in the
art.
[0663] It is preferred according to the present invention that step
(d) is performed by dissolving a compound of formula Va in a protic
solvent, either an aqueous solvent such as water or in a protic
organic solvent, a such as a C.sub.1-C.sub.4-alkanol, e.g.
methanol, ethanol or isopropanol, and adding a hydroxide.
[0664] Suitable hydroxides include alkali metal hydroxides such as
lithium, sodium or potassium hydroxide, and mixtures thereof.
Sodium hydroxide is particularly preferred.
[0665] It is preferred that sodium hydroxide is used in amounts of
from 1 to 10 mol, preferably from 2.0 to 6.0 mol, e.g. 2.0 to 3.0
mol or 5.0 to 6.0 mol, per mol of the compound of formula Va.
[0666] Suitable reaction temperatures may vary from 20 to
100.degree. C., e.g. from 20 to 25.degree. C. or from 50 to
100.degree. C.
[0667] The reaction times may vary from 1 hour to 2 days, e.g. from
1 to 3 hours or from 12 hours to 24 hours or from 1 to 2 days.
[0668] The conversion of compounds of formula Va into compounds of
formula Vc can be enhanced, and complete conversion can more easily
be ensured, if the alcohol, which is formed upon hydrolysis of the
compounds of formula Va, is removed from the reaction mixture, e.g.
by distillation.
[0669] The conversions of compounds of formula Vb into compounds of
formula Vc is advantageously performed in an acidic medium,
preferably in the presence of H.sub.2SO.sub.4 or in the presence of
HCl in MeOH. As intermediate compounds, iminoester compounds are
formed, which are then hydrolysed to the desired acids of formula
Vc.
[0670] The resulting compounds of formula Vc can be purified by
methods known in the art, e.g. by crystallization under suitable pH
conditions.
[0671] The reaction conditions for steps (e) and (f) of the process
are as follows.
[0672] In step (e), the compound of formula Vc is activated by
converting it into the activated acid derivative of formula VI.
[0673] Suitable peptide coupling reagents, which may be used for
introducing the leaving group X.sup.1 of the compounds of formula
VI starting from compounds of formula V, are described by Han et
al. in Tetrahedron 60 (2004) 2447-2467. In this regard,
N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP--Cl) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) are preferred according to the present
invention.
[0674] In addition to the conversion of the compounds of formula Vc
into activated acid derivatives of formula VI by means of these
peptide coupling reagents, it has also been described in the art
how leaving groups such as halogen, N.sub.3, p-nitrophenoxy and
pentafluorophenoxy can be introduced into the compounds of formula
Vc to give the corresponding compounds of formula VI. In this
regard, reference is made to WO 2009/027393 and WO 2010/034737.
[0675] The compound of formula VI may either be directly converted
into a compound of formula VIII or isolated. It is preferred,
however, that the compound of formula VI is directly converted into
the compound of formula VIII.
[0676] The coversion of compounds of formula VI into compounds of
formula VIIII by reacting the compounds of formula VI with
compounds of formula VIII has already been described in WO
2009/027393 and WO 2010/034737.
EXAMPLES
I. Characterization
[0677] The characterization can be done by coupled High Performance
Liquid Chromatography/mass spectrometry (HPLC/MS), by NMR or by
their melting points.
[0678] HPLC/MS: the following methods A), B), C) and D) have been
used, and will be referred to further below. [0679] A) Phenomenex
Kinetex 1.7 .mu.m XB-C18 100A; 50.times.2.1 mm; mobile phase: A:
water+0.1% trifluoroacetic acid (TFA); B: acetonitrile (MeCN)+0.1%
TFA; gradient: 5-100% B in 1.50 minutes; 100% B 0.20 min; flow:
0.8-1.0 mL/min in 1.50 minutes at 60.degree. C. MS-method: ESI
positive. [0680] B) The gradient was 10-80% B in 1.15 min with a
hold at 90% B for 0.4 min, 80-10% B in 0.01 min, and then hold at
10% B for 0.54 min (1.0 mL/min flow rate). Mobile phase A was
0.0375% TFA in water, mobile phase B was 0.018% TFA in MeCN. Column
temperature was 40.degree. C. The column used for the
chromatography was a 2.1.times.30 mm Halo C18 column (2.7 .mu.m
particles). MS-method: ESI positive. [0681] C) The gradient was
10-80% B in 1.15 min with a hold at 90% B for 0.4 min, 80-10% B in
0.01 min, and then hold at 10% B for 0.54 min (1.0 mL/min flow
rate). Mobile phase A was 0.0375% TFA in water, mobile phase B was
0.018% TFA in MeCN. Column temperature was 40.degree. C. The column
used for the chromatography was 2.0.times.30 mm phenomenex Luna-C18
column (3 .mu.m particles). MS-method: ESI positive. [0682] D) The
gradient was 5-95% B in 0.7 min, 95-95% B in 0.45 min, 95-5% B in
0.01 min, and then hold at 0% B for 0.44 min (1.5 mL/min flow
rate). Mobile phase A was 0.0375% TFA in water, mobile phase B was
0.018% TFA in MeCN. Column temperature was 40.degree. C. The column
used for the chromatography was a Chromolith Flash RP-18e 25-2 mm
column. MS-method: ESI positive.
[0683] .sup.1H-NMR: The signals are characterized by chemical shift
(ppm) vs. tetramethylsilane, by their multiplicity and by their
integral (relative number of hydrogen atoms given). The following
abbreviations are used to characterize the multiplicity of the
signals: m=multiplet, q=quartet, t=triplet, d=doublet and
s=singlet.
[0684] Abbreviations used are: h for hour(s), min for minute(s) and
room temperature for 20-25.degree. C.
II. Preparation Examples
Example 1 (Step (a)): 1-cyclohexylpropan-2-one hydrazone
[0685] A mixture of 1-cyclohexylpropan-2-one (10 g), hydrazine
monohydrate (4.3 g), barium oxide (2.8 g) and ethanol (100 ml) was
refluxed for 14 h. After cooling to room temperature, diethyl ether
(120 ml) was added. The mixture was filtered and the filtrate was
evaporated to give the crude title compound (9.0 g, ca. 82%
yield).
Example 2 (Step (b)): ethyl
2-[[2-(2-cyclohexyl-1-methyl-ethylidene)hydrazino]methylene]-3-oxo-butano-
ate
[0686] Crude 1-cyclohexylpropan-2-one hydrazone (9.0 g) in ethanol
(20 ml) was added to ethyl 2-(ethoxymethylene)-3-oxo-butanoate (11
g) in ethanol (80 ml) at -20.degree. C. within 40 min. After 30
min, the mixture was stirred at room temperature over night and
directly used in the next step.
Example 3 (step (c)): ethyl
1-(2-cyclohexyl-1-methyl-ethyl)-5-methyl-pyrazole-4-carboxylate
[0687] Acetic acid (4.3 ml) was added to the reaction mixture from
step 2. Sodium cyanoborohydride (2.4 g) was added portionwise
within 30 min at room temperature. After stirring over night, more
acetic acid (2.5 ml) and more sodium cyanoborohydride (1.1 g) was
added. After stirring over night, again more acetic acid (3 ml) and
more sodium cyanoborohydride (2.0 g) was added and the mixture was
stirred at 50.degree. C. for 3 h and then concentrated in vacuo.
Water (80 ml) was added to the residue, and the aqueous phase was
extracted three times with tert-butyl methyl ether. The combined
organic extracts were washed with water, dried over sodium sulfate
and concentrated in vacuo to give the crude title compound (17 g,
ca. 80% purity, ca. 84% yield over 2 steps).
Example 4 (step (d)):
1-(2-cyclohexyl-1-methyl-ethyl)-5-methyl-pyrazole-4-carboxylic
acid
[0688] A mixture of crude ethyl
1-(2-cyclohexyl-1-methyl-ethyl)-5-methyl-pyrazole-4-carboxylate (17
g, ca. 80% purity), aqueous sodium hydroxide solution (2 M, 56 ml)
and ethanol (150 ml) was stirred at room temperature for 2 d and
then concentrated in vacuo. Water was added to the residue, and the
aqueous phase was extracted three times with tert-butyl methyl
ether. Concentrated hydrochloric acid was added under ice cooling
to adjust the pH to ca. 4. The precipitate was filtered off, washed
with water, triturated with tert-butyl methyl ether and dried in
vacuo to give the title compound (5.3 g, ca. 43% yield, 30% yield
over all 4 steps). .sup.1H-NMR (d.sub.6-DMSO): 7.76 (s, 1H), 4.46
(m, 1H), 2.49 (s, 3H), 1.84 (m, 1H), 1.70 (d, 11.3 Hz, 1H),
1.66-1.43 (m, 5H), 1.31 (d, 6.6 Hz, 3H), 1.09 (m, 3H), 0.89 (m,
3H).
[0689] In accordance with the above 4-step reaction procedure for
preparing compounds of formula V.c by performing [0690] step (a) to
provide compounds of formula II (Example 1), [0691] step (b) to
provide compounds of formula IV (Example 2), [0692] step (c) to
provide compounds of formula Va (Example 3), and [0693] step (d) to
provide compounds of formula Vc (Example 4), a variety of compounds
of formula V.a and V.c have been prepared. The relevant
substituents of the compounds of formula V.c and its precursors are
listed in the following table D. Furthermore, the yields and
analytical HPLC/MS data are provided. The relevant reaction scheme
is again depicted below.
Step (a):
##STR00039##
[0694] Step (b):
##STR00040##
[0695] Step (c):
##STR00041##
[0696] Step (d):
##STR00042##
TABLE-US-00004 [0697] TABLE D yield V.a V.a V.c V.c R.sup.c X I
.fwdarw. V.a RT m/z RT m/z # R.sup.5 R.sup.4 in V.a R.sup.2 R.sup.3
in III.a [%] [min] Method [MH].sup.+ [min] Method [MH].sup.+ 1
CH.sub.3 CH(CH.sub.3)OH CH.sub.2CH.sub.3 CH.sub.3 H
OCH.sub.2CH.sub.3 55 0.846 A 227.1 0.590 A 199.2 2 CH.sub.3
CH.sub.2CH.sub.2OH CH.sub.2CH.sub.3 CH.sub.3 H OCH.sub.2CH.sub.3 12
0.870 A 227.2 n/a n/a n/a 3 CH.sub.3 1-CN--cC.sub.3H.sub.4
CH.sub.2CH.sub.3 CH.sub.3 H OCH.sub.2CH.sub.3 n/a 0.961 A 248.3 n/a
n/a n/a 4 CH.sub.3 CH(CH.sub.3)SCH.sub.2CH(CH.sub.3).sub.2
CH.sub.2CH.sub.3 CH.sub.3 H OCH.sub.2CH.sub.3 18 1.332 A 298.8 n/a
n/a n/a 5 CH.sub.3 2-furyl CH.sub.2CH.sub.3 CH.sub.3 H
OCH.sub.2CH.sub.3 5 1.064 A 249.5 n/a n/a n/a 6 CH.sub.3 2-furyl
CH.sub.2CH.sub.3 CF.sub.3 H OCH.sub.2CH.sub.3 3 1.091 A 302.8 n/a
n/a n/a 7 CH.sub.2CH.sub.2C(F.sub.2)CH.sub.2CH.sub.2
CH.sub.2CH.sub.3 CH.sub.3 H OCH.sub.2CH.sub.3 85 1.116 A 273.5
0.837 A 245.1 8 CH.sub.2SCH.sub.2CH.sub.2CH(CN) CH.sub.2CH.sub.3
CH.sub.3 H OCH.sub.2CH.sub.3 35 0.894 A 280.0 n/a n/a n/a 9
CH.sub.3 CH(OCH.sub.3).sub.2 CH.sub.2CH.sub.3 CH.sub.3 H
OCH.sub.2CH.sub.3 85 1.002 A 257.5 0.709 A 228.8 10
CH.sub.2CH.sub.2CH(OCH.sub.2C.sub.6H.sub.5) CH.sub.2CH.sub.3
CH.sub.3 H OCH.sub.2CH.sub.3 16 1.189 A 314.8 n/a n/a n/a .sup.
1.225.sup.a 11 CH.sub.3 CH.sub.2CH.sub.2CHC(CH.sub.3).sub.2
CH.sub.2CH.sub.3 CH.sub.3 H OCH.sub.2CH.sub.3 86 1.276 A 265.3
1.061 A 237.4 12 CH.sub.3 1-C(O)NH.sub.2--cC.sub.3H.sub.4
CH.sub.2CH.sub.3 CH.sub.3 H OCH.sub.2CH.sub.3 24 0.841 A 265.8
0.582 A 238.4 13 CH.sub.3 CH.sub.2cC.sub.6H.sub.11 CH.sub.2CH.sub.3
CH.sub.3 H OCH.sub.2CH.sub.3 69 1.381 A 279.2 1.129 A 251.2 14
CH.sub.3 CH.sub.2C(CH.sub.3).sub.3 CH.sub.2CH.sub.3 CH.sub.3 H
OCH.sub.2CH.sub.3 96 1.310 A 253.2 1.038 A 225.2 15 CH.sub.3
CH(CH.sub.2CH.sub.3).sub.2 CH.sub.2CH.sub.3 CH.sub.3 H
OCH.sub.2CH.sub.3 n/a 1.315 A 253.2 1.037 A 225.2 16
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CF.sub.3) CH.sub.2CH.sub.3
CH.sub.3 H OCH.sub.2CH.sub.3 38 1.284 A 305.1 1.040 A 277.1 17
CH.sub.3 CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.3
CH.sub.3 H OCH.sub.2CH.sub.3 77 1.310 A 253.2 1.046 A 225.2 18
CH.sub.3 CH(CH.sub.3)CH.sub.2OH CH.sub.2CH.sub.3 CH.sub.3 H
OCH.sub.2CH.sub.3 88 0.889 A 241.5 0.614 A 213.4 19 CH.sub.3
CH(CH.sub.3).sub.2 CH.sub.2CH.sub.3 CH.sub.3 H OCH.sub.2CH.sub.3 64
1.510 A 225.1 0.890 A 197.2 20 CH.sub.3 ##STR00043## CH.sub.2CH3
CH.sub.3 H OCH.sub.2CH.sub.3 42 1.542 .sup. 1.637.sup.a C 349.2 n/a
n/a n/a 21 CH.sub.3 ##STR00044## CH.sub.2CH.sub.3 CH.sub.3 H
N(CH.sub.3).sub.2 35 1.385 .sup. 1.431.sup.a C 293.2 1.111 .sup.
1.150.sup.a B 265.2 22 CH.sub.3 ##STR00045## CH.sub.2CH.sub.3
CH.sub.3 H N(CH.sub.3).sub.2 58 1.579 C 375.1 n/a n/a n/a 23
CH.sub.3 C(CH.sub.3).sub.2OH CH.sub.2CH.sub.3 CH.sub.3 H
N(CH.sub.3).sub.2 22 1.308 C 255.2 0.965 B 227.2 24 CH.sub.3
2-Br-2-CH.sub.3--cC.sub.3H.sub.3 CH.sub.2CH.sub.3 CH.sub.3 H
OCH.sub.2CH.sub.3 39 0.885 .sup. 0.910.sup.a D 315.1 n/a n/a n/a 25
CH.sub.2OC(CH.sub.3).sub.2OCH.sub.2 CH.sub.2CH.sub.3 CH.sub.3 H
N(CH.sub.3).sub.2 35 1.328 B 269.2 1.022 B 241.1 26 CH.sub.3
C(CH.sub.3).sub.2SCH.sub.3 CH.sub.2CH.sub.3 CH.sub.3 H
N(CH.sub.3).sub.2 33 1.328 C 271.2 1.253 B 243.2 27 CH.sub.3
1-C(O)OC(CH.sub.3).sub.3--cC.sub.3H.sub.4 CH.sub.2CH.sub.3 CH.sub.3
H N(CH.sub.3).sub.2 39 0.934 D 323.2 n/a n/a n/a 28 cC.sub.3H.sub.5
1-CH.sub.2OCH.sub.2C.sub.6H.sub.5--cC.sub.3H.sub.4 CH.sub.2CH.sub.3
CH.sub.3 H N(CH.sub.3).sub.2 44 0.947 D 369.2 n/a n/a n/a 29
cC.sub.3H.sub.5 C(CH.sub.3).sub.2CH.sub.2OCH.sub.2C.sub.6H.sub.5
CH.sub.2CH.sub.3 CH.sub.3 H N(CH.sub.3).sub.2 66 0.990 D 371.2 n/a
n/a n/a 30 CH.sub.3 ##STR00046## CH.sub.2CH.sub.3 CH.sub.3 H
N(CH.sub.3).sub.2 28 0.835 D 311.2 1.077 B 283.3 31 CH.sub.3
CH.sub.2OH C(CH.sub.3).sub.3 CH.sub.3 H N(CH.sub.3).sub.2 41 0.697
D 241.1 n/a n/a n/a 32 CH.sub.3
C(CH.sub.3)(CO.sub.2CH.sub.2CH.sub.3) C(CH.sub.3).sub.3 CH.sub.3 H
N(CH.sub.3).sub.2 31 1.063 D 468.4 n/a n/a n/a
(CH.sub.2).sub.3NHCO.sub.2C(CH.sub.3).sub.3 33 CH.sub.3
CH(CH.sub.3)OH CH.sub.2CH.sub.3 CH.sub.3 H N(CH.sub.3).sub.2 46
1.002 B 227.2 n/a n/a n/a 34 CH.sub.3 C(CH.sub.3).sub.2OH
C(CH.sub.3).sub.3 CH.sub.3 H N(CH.sub.3).sub.2 74 0.784 D 269.2 n/a
n/a n/a 35 CH.sub.3 CH(CH.sub.3)OH C(CH.sub.3).sub.3 CH.sub.3 H
N(CH.sub.3).sub.2 69 0.757 D 255.2 n/a n/a n/a .sup.amixture of two
diastereoisomers
[0698] The reaction procedure of Examples 1 to 4 refers compounds
with a substitution pattern according to entry 13 of table D.
[0699] The compounds according to the remaining entries were either
prepared analogously or according to the reaction conditions
exemplified below referring to certain entries of the above table
D. The reaction conditions exemplified below are not limited to the
entries of table D to which they refer, but were also suitable for
the preparation of other compounds disclosed in table D.
[0700] It is noted that steps (a) and (b), steps (b) and (c) were
also performed in a one-pot reaction in the preparation of certain
compounds.
[0701] The following reaction conditions for steps (a), (b), (c)
and (d) are relevant for the preparation of the compounds listed
above (abbreviations: rt=room temperature, i.e. 20 to 25.degree.
C., rfx=reflux temperature, i.e. boiling point of the solvent;
MeOH=methanol; EtOH=ethanol; AcOH=acetic acid; MTBE=methyltertbutyl
ether; eq=equivalent).
Step (a):
TABLE-US-00005 [0702] corresponds to # entry x in table D
conditions (a)-1 7 N.sub.2H.sub.4 .times. H.sub.2O (1.2 eq), BaO
(0.02 eq), I (2 g/1 eq), MeOH (2 ml), rt, rfx overnight (a)-2 13
N.sub.2H.sub.4 .times. H.sub.2O (1.2 eq), BaO (0.26 eq), EtOH (50
ml), I (10 g/1 eq), rt, rfx 14 h (a)-3 1 I (10 g/1 eq), BaO (0.26
eq), EtOH (80 ml), 10-20.degree. C., N.sub.2H.sub.4 .times.
H.sub.2O (1.2 eq), rt 1 h, 80.degree. C. overnight (a)-4 12
N.sub.2H.sub.4 .times. H.sub.2O (1 eq), AcOH (0.17 eq), I (262 g/1
eq), EtOH (2200 ml), rt 3 days (a)-5 8 N.sub.2H.sub.4 .times.
H.sub.2O (10 g/1.2 eq), EtOH (100 ml), I (262 g/1 eq), EtOH (100
ml), rt overnight (a)-6 10 I (3.6 g/1 eq), BaO (0.26 eq), EtOH (100
ml), rt, N.sub.2H.sub.4 .times. H.sub.2O (1.2 eq), rt 3 days (a)-7
19 MeOH (3.25 eq), N.sub.2H.sub.4 .times. H.sub.2O (1.28 eq), BaO
(0.02 eq), 33-47.degree. C., I (2415 g/1 eq), 25.degree. C.
overnight
Steps (a)+(b):
TABLE-US-00006 corresponds to entry x in # table D conditions (a) +
(b)-1 3 N.sub.2H.sub.4 .times. H.sub.2O (1 eq), AcOH (0.1 eq), I
(1.376 g/1 eq), EtOH (15 ml), rt overnight; III.a (6.15 g/1.2 eq),
rt overnight (a) + (b)-2 14 N.sub.2H.sub.4 .times. H.sub.2O (1.2
eq), BaO (0.26 eq), EtOH (50 ml), rt, I (5 g/1 eq), rfx overnight;
III.a (1 eq), EtOH (50 ml), -20.degree. C., II (5.5 g/1 eq), EtOH
(20 ml), 30 min -20.degree. C., rt overnight
Step (b):
TABLE-US-00007 [0703] corresponds to # entry x in table D
conditions (b)-1 9 III.a (1.1 eq), EtOH (60 ml), rt, II (12.5 g/ 1
eq), EtOH (40 ml), rt-37.degree. C., rt overnight (b)-2 1 III.a
(16.96 g/1 eq), EtOH (70 ml), 0-10.degree. C., II (9.3 g/1 eq),
EtOH (30 ml), rt overnight (b)-3 12 III.a (450 g/1.51 eq), EtOH
(3000 ml), AcOH (8.5 ml), II (221 g/1 eq), rt overnight (b)-4 19
III.a (609 g/1 eq), II (3818 g/1.09 eq) in MTBE (9.36% solution), 3
h rt-33.degree. C. overnight
Step (b)+(c):
TABLE-US-00008 corresponds to entry x in # table D conditions (b) +
(c)-1 16 III.a (0.83 g/1 eq), EtOH (15 ml), -20.degree. C., II (0.8
g/1 eq), EtOH (5 ml), -20.degree. C. 30 min, rt over 3 days, AcOH
(0.34 g/1.3 eq), 0-5.degree. C. NaB(CN)H.sub.3 (0.28 g/1 eq), rt
overnight, NaB(CN)H.sub.3 (0.25 g), AcOH (0.4 ml), 6 h 40.degree.
C., rt overnight, 20 ml isopropanol, AcOH (1.3 eq), rt,
NaB(CN)H.sub.3 (1 eq), rt overnight, NaB(CN)H.sub.3 (0.15 g), AcOH
(0.2 ml), 6 h 40.degree. C., rt overnight, NaB(CN)H.sub.3 (0.1 g),
6 h 40.degree. C., rt overnight (b) + (c)-2 17 III.a (7.12 g/1 eq),
EtOH (50 ml), rt, II (4.9 g/1 eq), EtOH (20 ml), rt overnight, AcOH
(2.61 g/1.2 eq), rt, NaB(CN)H.sub.3 (1.67 g/0.7 eq), rt over 3
days, isopropanol (100 ml), 10.degree. C., AcOH (1.2 eq),
10.degree. C., NaB(CN)H.sub.3 (0.65 eq), rt overnight,
NaB(CN)H.sub.3 (0.5 g), AcOH (0.5 ml), 6 h 40.degree. C., rt
overnight (b) + (c)-3 1 III.a (16.96 g/1 eq), EtOH (70 ml),
0-10.degree. C., II (9.3 g/1 eq), EtOH (30 ml), rt overnight, EtOH
(120 ml), AcOH (1.3 eq), 10-17.degree. C., NaB(CN)H.sub.3 (1 eq),
rt 3 days (b) + (c)-4 8 III.a (7.55 g/1 eq), EtOH (50 ml),
-20.degree. C., II (5.2 g/1 eq), EtOH (20 ml), -20.degree. C. 30
min, rt over 3 days, MeOH (100 ml), AcOH (1.3 eq), 0-5.degree. C.,
NaB(CN)H.sub.3 (2.51 g/1 eq), rt overnight, NaB(CN)H.sub.3 (1.2 g),
AcOH (1.5 ml), 6 h 40.degree. C., rt overnight, NaB(CN)H.sub.3 (1.5
g), AcOH (2 ml), 6 h 40.degree. C., rt overnight, isopropanol (100
ml), NaB(CN)H.sub.3 (1 eq), rt overnight (b) + (c)-5 15 III.a
(10.86 g/1 eq), EtOH (80 ml), -20.degree. C., II (9 g/1 eq), EtOH
(20 ml), -20.degree. C. 20 min, rt overnight, AcOH (4.53 g/1.3 eq),
NaB(CN)H.sub.3 (2.37 g/ 0.65 eq), rt overnight, 3 h 50.degree. C.,
NaB(CN)H.sub.3 (1.1 g), AcOH (2.5 ml), rt overnight, NaB(CN)H.sub.3
(2 g), AcOH (3 ml), 3 h 50.degree. C. (b) + (c)-6 13 III.a (10.86
g/1 eq), EtOH (80 ml), -20.degree. C., II (1 eq), EtOH (20 ml),
-20.degree. C. 30 min, rt overnight, AcOH (4.53 g/1.3 eq), rt,
NaB(CN)H.sub.3 (2.37 g/ 0.65 eq), rt overnight, 3 h 50.degree. C.,
NaB(CN)H.sub.3 (1.1 g), AcOH (2.5 ml), 3 h 50.degree. C., rt
overnight, NaB(CN)H.sub.3 (2 g), AcOH (3 ml), 3 h 50.degree. C. (b)
+ (c)-7 11 III.a (13.01 g/1 eq), EtOH (60 ml), rt, II (1 eq), EtOH
(20 ml), rt overnight, AcOH (5.45 g/3.64 eq), 0-5.degree. C.,
NaB(CN)H.sub.3 (1.02 g/0.65 eq), rt 3 days
Step (c):
TABLE-US-00009 [0704] corresponds to # entry x in table D
conditions (c)-1 9 IV.a (27.9 g/1 eq), isopropanol (100 ml), rt,
NaB(CN)H.sub.3 (0.6 eq), AcOH (1.2 eq), rt overnight,
NaB(CN)H.sub.3 (0.6 eq), rt overnight (c)-2 10 IV.a (1 g/1 eq),
EtOH (20 ml), rt, AcOH (2.4 eq), NaB(CN)H.sub.3 (1.2 eq), rt over 3
days (c)-3 17 IV.a (9.5 g/1 eq), isopropanol (100 ml), 10.degree.
C., NaB(CN)H.sub.3 (0.65 eq), AcOH (1.2 eq) rt overnight,
NaB(CN)H.sub.3 (0.5 g), AcOH (0.5 ml), 6 h 40.degree. C., rt
overnight (c)-4 18 IV.a (18 g/1 eq), MeOH (120 ml), AcOH (1.2 eq),
rt, NaB(CN)H.sub.3 (1 eq), rt overnight (c)-5 18 IV.a (15.7 g/1
eq), isopropanol (100 ml), AcOH (1.25 eq), rt, NaB(CN)H.sub.3 (1
eq), rt over 3 days, AcOH (2.5 ml), NaB(CN)H.sub.3 (1 g), 4 h
40.degree. C., rt overnight (c)-6 7 IV.a (1.9 g/1 eq), 0-5.degree.
C., NaB(CN)H.sub.3 (0.65 eq), AcOH (1.3 eq), rt overnight,
NaB(CN)H.sub.3 (0.3 eq), rt over 3 days (c)-7 12 IV.a (100 g/1 eq),
MeOH (1400 ml), rt, NaB(CN)H.sub.3 (2.19 eq), HCl (1N in MeOH, 1000
ml), 40.degree. C., rt overnight (c)-8 19 IV.a (889 g/1 eq), MeOH
(3000 ml), AcOH (400 g), rt-30.degree. C., NaB(CN)H.sub.3 (1.09
eq), rt overnight
Step (d):
TABLE-US-00010 [0705] corresponds to # entry x in table D
conditions (d)-1 13 V.a (17 g/1 eq), EtOH (150 ml), NaOH (2M in
H.sub.2O, 4.49 g/2.3 eq), rt overnight, NaOH (2M in H.sub.2O, 25
ml), rt 24 h (d)-2 1 V.a (15.3 g/1 eq), EtOH (80 ml), NaOH (2.5
eq), H.sub.2O (40 ml), rt over-night (d)-3 12 V.a (120 g/1 eq),
MeOH (1400 ml), NaOH (5.96 eq), H.sub.2O (58.54 eq), rtovernight
(d)-4 7 V.a (2.15 g/1 eq), EtOH 30 ml), NaOH(2M in H.sub.2O, 2.5
eq), 45.degree. C. 2.5 h (d)-5 19 NaOH (10% in H.sub.2O, 3 eq), rt,
V.a (724 g/1 eq), 1 h 95.degree. C.
* * * * *