JPH0455428B2 - - Google Patents

Description

[Detailed description of the invention] [Detailed description of the invention] The present invention provides novel sulfonylurea herbicide compounds.
classes, compositions suitable for agricultural use thereof, and
those for regulating undesirable plant growth
It is about how to use. Effective in regulating undesirable plant growth
Certain new classes of compounds are continually needed. many
Under the general circumstances of, to name a few, e.g.
Cotton, rice, corn, wheat and soybeans
to regulate the growth of weeds in useful crops such as
compounds are being searched for. in such crops
The unchecked growth of weeds causes considerable damage and
reducing profits and causing consumer prices to rise
vinegar. Under other circumstances, it regulates the growth of all plants.
A herbicide that can Completely control all plants
Locations where it is desirable to
Locations around warehouses and industrial storage areas.
There are many commercially available products for these purposes;
More effective, inexpensive and environmentally safe products
constantly in demand. “Sulfonylurea” herbicides have been used in recent years.
It is a very powerful type of herbicide discovered in
There are many structural variants of this class of herbicides.
However, they generally contain two aromatic or
is a sulfonylurea bridge connecting heteroaromatic rings.
Bridge-SO₂Contains NHCONH-. US Patent 4394506 [During the ceremony, R₂is H, F, Cl, Br, C₁−C₃Alkyl, NO₂,
S.O.₂CH₃,OCH₃, ScH₃,CF₃,N(CH₃)₂, N.H.₂
or CN, and X is H, Cl, CH₃,OCH₃,
OCH₂CH₃or OCH₂CH₂OCH₃is, and
Y is H, halogen, C₁−C_FourAlkyl, C₁−C_FourPlace
substituted alkyl, C₁−C_Fouralkoxy, alkyl
ruamino, dialkylamino, etc.] Herbicidal ortho-alkoxycarbonyls such as
Benzene sulfonamides are disclosed. South African Patent Application 81/4874 is a formula [During the ceremony, A is halogen or various other organic substituents
C being replaced by₁−C₆alkyl or substituted
or unsubstituted C₂−C₆Arkeni
is a group, X is O, S, SO or SO₂and R₁is H,
halogen, C₁−C_FiveAlkyl, C₂−C_Fivealkenyl
or YR_Fiveand R₂is H, halogen, C₁−C_Five
Alkyl, C₂−C_Fivealkenyl, C₁−C_Fourhaloal
Kill, CO₂R₆, Y.R._Five, NO₂or CONR₇R₈And
ri, and R₃and R_Fourare independent of each other,
Basic, C₁−C_FourAlkyl, C₁−C_FourAlkoxy, C₁−
C_FourAlkylthio, C₁−C_Fourhaloalkyl, halogen
or an alkoxyalkyl group having at most 4 carbon atoms.
] discloses herbicidal sulfonamides. South African patent application 82/5042 is a formula [During the ceremony, A is C₃−C₆is alkynyl, X is O, S, SO or SO₂and R₁is H, halogen, C₁−C_FiveAlkyl, C₂−C_Fivea
Lukenyl or YR_Fiveand R₂is H, halogen, C₁−C_FiveAlkyl, C₂−C_Fivea
Lukenil, C.₁−C_Fourhaloalkyl, CO₂R₆, Y.R._Five，
NO.₂or CONR₇R₈and R₃and R_Fourare, independently of each other, hydrogen, C₁−C_Foura
Lukil, C.₁−C_FourAlkoxy, C₁−C_Fouralkirchi
O, C₁−C_Fourhaloalkyl, C₁−C_Fourhaloalcoki
halogen or alkoxycarbonate having at most 4 carbon atoms
is xyalkyl] discloses herbicidal sulfonamides. South African Patent Application 82/5671 is a formula [During the ceremony, A is halogen or various other organic substituents
C being replaced by₁−C₆Alkyl group or C₂
−C₆is an alkenyl group, X is O, S, SO or SO₂and R is H, halogen, C₁−C_FiveAlkyl, C₂−C_Five
alkenyl or YR_Fiveand R₂is H, halogen, C₁−C_FiveAlkyl, C₂−C_Fivea
Lukenil, C.₁−C_Fourhaloalkyl, CO₂R₆, Y.R._Five,
NO.₂or CONR₇R₈And, R₃and R_Fourare, independently of each other, hydrogen, C₁−C_Foura
Lukil, C.₁−C_FourHaloalkoxy, halogen,
or alkoxyalkyl having at most 4 carbon atoms.
be〕 discloses herbicidal sulfonamides. South African Patent Application 82/7439 is based on the formula [During the ceremony, A is C₃−C₆Alkynyl group; halogen, C₁−C_Four
Alkoxy, C₁−C_FourAlkylthio, C₁−C_FourAl
Kirsulfinyl, C₁−C_Fouralkylsulfonyl,
C₁−C_FourHaloalkoxy, C₁−C_Fourhaloalkilch
O, C₁−C_Fourhaloalkylsulfinyl or
C₁−C_Foursubstituted by haloalkylsulfonyl
C₁−C₆an alkyl group; or one of the above substituents
C replaced by species₂−C₆is an alkenyl group,
X is O, S, SO or SO₂and R₁is hydrogen,
halogen, C₁−C_FiveAlkyl, C₂−C_Fivealkenyl
or YR₆is a group and R₂is hydrogen, halogen, C₁
−C_FiveAlkyl, C₂−C_Fivealkenyl, C₁−C_FourHalo
Alkyl, YR₆, CO₂R₇, NO₂or CONR₈R₉
and R₃is hydrogen, C₁−C_FourAlkyl, C₁−C_Fouralkoxy,
C₁−C_FourAlkylthio, C₁−C_Fourhaloalkyl, C₁
−C_FourHaloalkoxy, halogen or carbon number
at most 4 alkoxyalkyl, R_Fouris hydrogen, methyl or ethyl and R_Fiveis water
Basic, C₁−C_FourAlkyl, C₁−C₃alkoxy, meth
With oxymethyl, cyanomethyl or cyanoethyl
can be, R₆and R₇are each C₁−C_FiveAlkyl, C₂−C_Five
alkenyl or C₂−C₆is alkynyl] discloses herbicidal sulfonamides. South African patent application 84/2722 is a formula [During the ceremony, A is the formula CR₆R₇XR₈,CR₉R_TenR₁₁or CHR₇
SCQR_{twenty one}is the basis of R₁is hydrogen, halogen, nitro, cyani, C₁−C_Four
Alkyl, C₁−C_FourHaloalkyl, YR₁₄,
CONR₁₂R₁₃,NR₁₂R₁₃,SONR₁₅R₁₆, O.S.O.₂R₁₇
or COR₁₈and R₂is hydrogen, halogen, C₁−C_FourAlkyl, C₁−
C_FourAlkoxy, C₁−C_FourAlkylthio, C₁−C_Foura
Rukylsulfinyl or C₁−C_Fouralkylsul
Honil, R₃and R_Fourare independently hydrogen,
halogen, C₁−C_FourAlkyl, C₁−C_Fourhaloarchi
le, C₁−C_FourAlkoxy, C₁−C_Fourhaloalkoxy,
C₁−C_FourAlkylthio, C₁−C_Fourhaloalkylthio,
C₂−C_Fivealkoxyalkyl or NR₁₉R₂₀And
the law of nature, R₉is hydrogen, halogen, C₁−C_FourAlkyl, C₁−
C_FourAlkoxy, C₁−C_FourAlkylthio, C₁−C_Foura
Rukylsulfinyl or C₁−C_Fouralkylsul
Honil and R_Tenis hydrogen, halogen or methyl
R₁₁is base COR_{twenty four}; or cyano, nitrate
B, hydroxyl, C₁−C_FourAlkoxy, C₁−C_Four
with substituents selected from the group such as alkylthio.
mono or polysubstituted C₁−C_FourArchi
is a group, R₁₈is H,C₁−C_FourAlkoxy and various other
It is a machine base] Discloses herbicide benzenesulfonamides.
There is. South African Patent Application 83/0127 is a formula [During the ceremony, R₁is hydrogen, halogen, cyano, nitro, C₁−
C_Fourhaloalkyl, C₁−C_FourAlkyl, C₁−C_FourAl
Koxi, COR₆,NR₇R₈,S(O)_n−C₁−C_FourAl
kill or so₂R₉and R₂are H, F, Cl, Br, NO₂, C.F.₃,NR₂₀R_{twenty one},
C₁−C₂Alkyl, C₁−C₂alkoxy or S
(O)_n−C₁−C_Fouris alkyl, R₃is H, F, Cl, Br, NH₂,NO₂or
OCH₃and R₆is hydrogen, C₁−C_FourAlkyl, C₃−C_Fivealkenyl
Oxy, C₃−C_FiveAlkynyloxy, C₁−C_FourHalo
Alkyl, C₁−C_FiveAlkylthio, phenoxy,
Benzyloxy, NR_TenR₁₁or unsubstituted or
is 1-3 halogen atoms or C₁−C₃Al
C substituted by koxy₁−C_FiveIt is alkoxy
the law of nature, R₁₈is hydrogen, C₁−C₃alkyl or C₁−C₃Al
Koxi, m is 0, 1 or 2 and Y is C₁−
C₃Alkyl, C₁−C₃haloalkyl, C₁−C₃Al
Coxi, C.₁−C₃Haloalkoxy, C₂−C₃Arco
xyalkyl, C₁−C₃alkylthio, halogen
or NR₁₆R₁₇] discloses herbicidal sulfonamides. Now general or selective pre-emergence or germination
Acts as a post-herbicide or as a plant growth regulator
Discover new herbicidal compounds and compositions that
I put it out. The compounds of the invention have the formula [During the ceremony, R is H or CH₃and R₁is C₁−C₃is alkyl, R₂is Ra or Rb, Ra is C₁−C₆Alkoxy, C₁−C₈alkirchi
O, C₁−C₈Alkylsulfinyl, C₁−C₈Al
Killsulfonyl, C₃−C₆alkenyloxy, C₃
−C₆Alkynyloxy, C₃−C₆alkenylthio,
C₃−C₆alkenylsulfinyl, C₃−C₆Arche
Nylsulfonyl, C₃−C₆Alkynylthio, C₃−
C₆Alkynylsulfinyl, C₃−C₆Alkynyl
Sulfonyl, OCH₂CH₂OCH₃,OCH₂CH₂
SCH₃,OCH₂CH₂S(O)CH₃,OCH₂CH₂S.O.₂
CH₃; substituted with 1-3 F, Cl or Br atoms
C₂−C₆Alkyl; CH₂F.CHF₂;C₁−C₂
Alkoxy, C₁−C₂Alkylthio, C₁−C₂Al
Kirsulfinyl or C₁−C₂alkylsul
C substituted with Honyl₁−C_FourAlkyl; OCF₂H,
OCH₂CH₂F.OCH₂CHF₂,OCH₂C.F.₃,OCH₂
CH₂Cl, S-cyclohexyl, S-C₆H_Fiveor
SCH₂C₆H_Fiveand Rb is C₁−C₃Alkyl, cyclopropyl, C₁−
C₃Alkoxy, C₁−C₃Alkylthio, C₁−C₃a
Rukylsulfinyl, C₁−C₃Alkylsulfony
allyl, allyloxy, allylthio, allylsulfy
nil, allylsulfonyl, propargyloxy,
propargylthio, propargyl sulfinyl,
Propargyl sulfonyl, OCF₂H,OCH₂CH₂
F.OCH₂CHF₂,OCH₂C.F.₃,OCH₂CH₂Cl;ma
or substituted with 1-3 F or Cl atoms
C₁−C₃Alkyl; or OCH₃Or SCH₃in
replaced C₁−C₂is alkyl, X is CH₃,OCH₃, O.C.₂H_Five, Cl, Br or OCF₂
H, Y is C₁−C₂Alkyl, C₁−C₂alkoxy,
O.C.F.₂H, O CH₂CH₂F.OCH₂CHF₂,OCH₂
C.F.₃,NHC H₃or N(CH₃)₂and Z is CH or N, However, as a condition, 1 When X is Cl or Br, Z is CH
Yes, and Y is C₁−C₂Alkoxy, NHCH₃or N
(CH₃)₂and 2 Ra is SCH₃, then R is H;
R₁is CH₃and X is OCH₃and Y is
OCH₃, and Z is CH, 3 Ra is OCH₃, then R is H;
R₁is CH₃and X is OCH₃and Y is CH₃
, and Z is N, 4 X and/or Y are OCF₂When it is H,
R₂is Rb, 4A Both X and Y are OCF₂If it's not H
Ki, R₂is Ra, 5 X or Y is OCF₂When H, Z is
CH, and 6 X or Y is OCF₂When H, the other
is CH₃,OCH₃or OCF₂It is H] compounds, and their agriculturally suitable salts.
It is a kind. Relatively high herbicide activity, relatively large plant growth
of modulator activity and/or relatively favorable synthesis.
Preferred compounds for ease of use are:
be: (1) R₂is Ra, and Ra is CH₃O, CH₃
S, CH₃S.O.₂,C₃−C₆alkenyloxy, C₃−
C₆Alkynyloxy, C₃−C₆alkenylthio,
C₃−C₆alkenylsulfinyl, C₃−C₆Al
Kenylsulfonyl, C₃−C₆Alkynylsulf
inil, C₃−C₆Alkynylsulfonyl; 1-
C substituted with three F, Cl or Br atoms₂
−C₆Alkyl; CH₂F.CHF₂;C₁−C₂Arco
Kishi, C₁−C₂Alkylthio, C₁−C₂alkyl
Sulfinyl or C₁−C₂Alkyl sulfo
C substituted with nyl₁−C_FourAlkyl; OCH₂CH₂
OCH₃,OCH₂CH₂SCH₃,OCH₂CH₂S(O)
CH₃,OCH₂CH₂S.O.₂CH₃,OCF₂H,OCH₂
CH₂F.OCH₂CHF₂,OCH₂C.F.₃or OCH₂
CH₂Cl, Compounds of formula. (2) R is H; Compounds of preferred item (1). (3) Ra is CH₃O, CH₃S, CH₃S.O.₂,C₃−C_Foura
Lukenyloxy, C₃−C_Fouralkenylthio, C₃
−C_Fouralkenylsulfinyl, C₃−C_FourArche
Nylsulfonyl; 1-3 F or Cl atoms
C replaced with₂−C₃Alkyl; CH₂F,
CHF₂;C₁−C₂Alkoxy, C₁−C₂alkirchi
O, C₁−C₂Alkylsulfinyl or C₁
−C₂C substituted with alkylsulfonyl₁−C₂
Alkyl; OCHF₂,OCH₂CH₂F.OCH₂C.F.₃
or OCH₂CH₂Cl, Compounds of preferred item (2). (4) R₁is CH₃or CH₂CH₃and X is CH₃,OCH₃or Cl and Y is
CH₃,OCH₃,C₂H_Fiveor OC₂H_Fiveis, Compounds of preferred item (3). (5) Ra is allyloxy, allylthio, propal
Gyloxy, propargylthio, CH₂F,
OCHF₂,OCH₂CH₂F.CH.₃S or CH₃S.O.₂
is, Compounds of preferred item (4). (6) R₂is Ra, and Ra is C₂−C₆Alcoki
C, C₂−C₈Alkylthio, C₂−C₈Archilus
Ruhonyl, C₁−C₈Alkylsulfinyl, S
-Cyclohexyl, S-C₆H_Fiveor SCH₂C₆
H_Fiveis, Compounds of formula. (7) R is H; Compounds of preferred item (6). (8) Ra is C₂−C_FourAlkoxy, C₂−C_Fouralkirchi
O, C₂−C_FourAlkylsulfonyl or C₁−C_Four
is alkylsulfinyl, Compounds of preferred item (7). (9)R₁is CH₃or C₂H_Fiveand X is CH₃,
OCH₃or Cl and Y is CH₃,
OCH₃,C₂H_Fiveor OC₂H_Fiveis, Compounds of preferred item (8). (10) Ra is C₂−C₃Alkoxy, C₂−C₃alkirchi
O or C₁−C₃is alkylsulfinyl, Compounds of preferred item (9). (11) R₂is Rb, and Rb is C₁−C₂Archi
Le, cyclopropyl, C₁−C₂Alkoxy, C₁
−C₃thioalkyl, C₁−C₃alkyl sulfui
Nil, C.₁−C₃Alkylsulfonyl, CF₃,Professional
pargyloxy, propargylthio, propal
Gyl sulfinyl, propargyl sulfonyl,
O.C.F.₂H,OCH₂CH₂F.OCH₂CHF₂,OCH₂
C.F.₃,OCH₂CH₂Cl; or OCH₃or
SCH₃C replaced with₂is an alkyl, Compounds of formula. (12) R is H; R₁is C₁−C₂is alkyl, Rb is C₁−C₂Alkyl, C₁−C₂alkoxy,
C₁−C₂Alkylthio, OF₃or OCF₂In H
ri, and Y is CH₃or OCH₃is, Preferred compounds: (13) Rb is CH₃,OCH₃,OCH₂CH₃or CF₃in
be, Compounds of preferred item (12). (14) R₂is Rb, and Rb is propyl, propyl
Lopyroxy, allyloxy, allylthio, a
Lylsulfinyl, allylsulfonyl, CH₃
OCH₂,C.H.₃SCH₂,C.H.₂F.CHF₂;1-3 pieces
C substituted with F atom of₂−C₃Alkyl; also
is C substituted with 1-3 C1 atoms₁−C₃Al
It's a kill, Compounds of formula. (15) R is H; R₁is C₁−C₂is alkyl, Rb is CH₂F or CH₂CH₂F and so
te Y is CH₃or OCH₃is, Compounds of preferred item (14). Highest herbicide activity, greatest plant growth regulation
agent activity and/or the most favorable ease of synthesis.
Particularly suitable for: 2
-[[(4,6-dimethoxypyrimidin-2-yl)
Aminocarbonyl]Aminosulfonyl]-4-(Metal
Chilthio)benzoic acid methyl ester, melting point 201−
202℃. 4-methoxy-2-[[(4-methoxy-6-methy
-1,3,5-triazin-2-yl)amino
Methyl carbonyl]aminosulfonyl]benzoate
Ester, melting point 190-192°C. 2-[[[4-(difluoromethoxy)-6-methoxy
cypyrimidin-2-yl]-aminocarbonyl]
Methyl ammonosulfonyl]-4-ethoxybenzoate
ester, melting point 195-196°C. The present invention can also be used as a pre- or post-emergent herbicide.
or as plant growth regulators.
and how to use the compositions thereof.
It is something. Synthesis Compounds of the formula are shown in Reaction Schemes 1 to 3 and 14.
Can be manufactured by one or more of the following methods:
Ru. As shown in Reaction Scheme 1, a compound of formula
is an appropriately substituted sulfonylisocyanate of formula (1).
nate to a suitable amino or methylamino of formula (2)
It can be produced by reacting with a heterocycle. A is
[Formula], and R, R₁,R₂X, Y and Z are as defined above. This reaction can be performed, for example, in dichloromethane 1,2-di
Chloroethane, tetrahydrofuran or acetate
in an inert aprotic organic solvent such as a nitrile.
Best performed at temperatures between 20° and 85°C. Attachment
The addition order is not strict, but sulfonyliso
Stirred solution of cyanate or its reaction solvent
It is often easy to add to amine suspensions where
It is a flight. In some cases, the desired product is present in the reaction solvent.
Insoluble at room temperature and pure from there
crystallizes in a certain form. Raw materials that are soluble in the reaction solvent
The products are isolated upon evaporation of the solvent. The evaporation residue is then treated with e.g. 1-chlorobutane or
is triturated with a solvent such as ethyl ether and
For example, 1,2-dichloroethane
A mixture of chlorobutane, 1-chlorobutane and heptane
or by recrystallizing from silica gel
By the above chromatography, compounds of formula
Can be purified. Many of the compounds of the formula are shown in reaction formula 2.
It can be manufactured by a process in which A, R, R₁Oyo
BiR₂is as defined above. The reaction shown in Reaction Equation 2 is based on the reaction of Equation (3).
Nylcarbamates are expressed as aminoheterocycles of formula (2) and about
Approximately 30 minutes to 24 hours at a temperature of 20-100℃
This is carried out by making contact over a period of time.
The product is isolated by evaporation of the reaction solvent and
It is purified by the above method. The phenyl carbamates of formula (3) were introduced in January 1982.
European patent application 818102824 issued on the 27th
(Publication No. 44808) or South African Patent Application
The method described in 825042 or the specialty of this technology
They can be produced by home-known variations thereof. On the other hand, many of the compounds of the formula are shown in reaction formula 3.
A, R₁oh
and R₂is as defined in the previous term.
and R is H. The reaction of reaction formula 3 is based on South African patent application 830441.
equimolar amounts by a method similar to that described in
The sulfonamide of formula (4) is replaced by the heterocyclic phenylene of formula (5).
1,8-diazabisi in an equimolar amount as carbamate
Kuro [5.4.0] Existence of Undece-7-en (DBU)
This can be carried out by contacting the person in the presence of the person. Equation (5)
South African patent application for phenyl carbamate
825671 and South African patent application 825045.
or as known to those skilled in the art.
It can be produced by a modified method of et al. Some compounds of the formula R₂is OH or
It can be prepared from compounds of the formula SH. Unsubstituted and substituted alco of formula (4a)
xy, alkenyloxy and alkynyloxy
One or more types of benzenesulfonamide intermediate products
It can be produced by the following general method. As shown in reaction scheme 4, a very useful
The general method starts from phenol (6). [During the ceremony, R₁is as defined above, and R₃teeth
C₁−C₆Alkyl, C₃−C₆alkenyl, C₃−C₆a
Lukinil, CF₂H, CH₂CH₂F.CH.₂CHF₂,
CH₂CH₂OCH₃,C.H.₂CH₂SCH₃,C.H.₂C.F.₃,C.H.₂
CH₂Cl, M₁is Na or K, X₁is Cl, Br, I, [formula] [Formula] [Formula] O (R₃)₂BF _Four,or [Formula]. ] For example dichloromethane or N,N-dimethyl
A suitable polar non-propylene such as formamide (DMF)
4-Hydroxy-2-nitrobene in rotonic solvents
A solution or suspension of zozoic acid (6) at least
2 equivalents of e.g. N,N-diisopropylethyl acetate
the presence of a suitable base such as amine or potassium carbonate
4 to 16 below and at temperatures between 20 and 155℃
Over time, at least 2 equivalents of R₃X₁(7)
(Reaction formula 4a). The solvent is miscible with water.
If so, then evaporate it and extract the residue.
Extract in lomethane. Dilute the product solution with sodium carbonate
Wash with aqueous solution of potassium or potassium and aqueous hydrochloric acid.
and then apply a suitable drying agent such as magnesium sulfate.
Dry on desiccant. filtrate and evaporate the solvent.
(8) remains in semi-purified form. recrystallize it
Chromatography on chromatography or silica gel columns
It can be further purified by b. Necessary a
alkylating agents, alkenylating agents and alkynylation
Agent R₃X₁(7) is known or known in the art
It can be manufactured by various methods. R₃is R₁ester (8) if not the same as
water and e.g. ethanol or p-dioxa
20 to 100 in a mixture of a suitable organic co-solvent such as
for 4 to 16 hours at temperatures between
At least 1 equivalent of sodium or potassium hydroxide
(Reaction formula 4b). The reaction mixture is then concentrated with salt
Acidify with acid. The product is separated in crystalline form.
If so, collect it. If not, water soluble
Extract the liquid with ether. The ether solution is diluted with sodium sulfate.
Dry over thorium, filter, and evaporate the solvent.
to give carboxylic acid (10). Convert carboxylic acid (10) to ester (12)
A solution of it in pyridine was prepared by J.H. Brieusta.
(Brewster) and C.J. Cio-
tti), Jr.J.Am.Chem.Soc.,1955,77, 6214
p-Toluenesulfonylchlora according to the general process
id and R₁Process sequentially with OH (11). On the other hand, carboxylic acid (10) was prepared by C.A. Bühler
(Buehler) and D.E. Pearson (Pearson).
Survey of Organic Synthesis, Wheelie Inn
Terscience, New York, 1970, 802−807
Excess R as noted by p.₁OH11 and
For example, by using a strong acid catalyst such as hydrogen chloride,
It can also be converted to tel (12) (Scheme 4c). Nitrobenzene (12) was prepared by C.A. Bühler and
and D.E. Pearson (cited in p. 413-414).
By the use of iron in acetic acid as described by
or platinum sulfide as a catalyst and F.S. Dauber
(Dovel) and H. Greenfield
(Greenfield)J.Am.Chem.Soc.,87, 2767
(1965) by hydrogenation using the conditions of
(13) (reaction formula 4d). Existing
Other substituents are latent to hydrogenation or hydrolysis.
Platinum sulfide is used as a catalyst when it is not physically sensitive.
Palladium can also be used instead. Aniline (13) is H. Meerwein (Mee)
−rwein), G. Dittmer, R.
Gollner, K. Hafner, F. Mehner
Mensch, O. Steinfoort
(Steinfort)Chem.Ber. 90, 841 (1957) General
Converted to sulfonyl chloride (14) using a standard process.
(reaction equation 4e). Hydrolysis of the product during the binding step
dichlorometh as a cosolvent to limit the solution.
It is advantageous to use Finally, add 2 equivalents of sulfonyl chloride (14) to
−30 ~ in dichloromethane solution using Monia
Amination to give 4a at temperatures between –10°C.
(reaction formula 4b). On the other hand, many of the sulfonamides (4a) are reactive
2,4-dihydro by the process shown in formula 5
It can be produced starting from xybenzoic acid (15). (g) (14)NH₃ ――――→(4a) [In the ceremony, M₁,R₁and X₁is defined above
It is as if there is, and R₃is C₁−C₆Alkyl, CH₂CH₂F.CH.₂
CHF₂,C.H.₂CH₂OCH₃,C.H.₂C.F.₃,C.H.₂CH₂Cl,
C.F.₂H or Penzil]. Phenol (15) in anhydrous solution of 2 equivalents of sodium
methanol, ethanol or amyl alcohol
Add to medium solution. R slightly more than 1 equivalent₃X₁(7)
and heat the mixture to reflux for 4 to 24 hours.
Ru. The solvent was removed in vacuo and the residue was dissolved in 1N hydrochloric acid and
and ether. ether phase with sulfuric acid
Dry over sodium and filter. Aete
Evaporating the phenol (16) leaves the phenol (16) (reaction
Equation 5a). Carboxylic acid (16) was prepared by C.A. Buehler and
In D.E. Pearson (cited above, pp. 802-807)
Excess R as described above₁OH and
Esters (17) with strong acids such as hydrogen chloride
(Scheme 5b). Phenol (17) by M.S. Newman
(Newman) and H.A. Karnes.J.
The thiocarbamate ( 18 ) (reaction formula 5c). Meanwhile, a mixture of phenol (17), at least 1 equivalent of dimethylthiocarbamoyl chloride, at least 1 equivalent of triethylamine ( _Et3N ), and a catalytic amount of 4-dimethylaminopyridine (DMAP) was dissolved in dichloromethane from 1 to 7
Heat to reflux for 1 day. Reaction mixture 1N
Wash with hydrochloric acid and 10% aqueous sodium hydroxide, then dry over magnesium sulfate and filter. Evaporation of the solvent leaves the crude product (18), which can be purified by chromatography on silica gel or by recrystallization if it is crystalline. The thiocarbamate (18) can be converted to its isomer (19) by heating according to the general procedure of MS Newman and HA Carnes (cited above) (Scheme 5d). To a solution of (19) in anhydrous R ₁ OH (11) is added slightly more than 1 equivalent of NaOR ₁ (20). The solvent is removed in vacuo and the residue is partitioned between dichloromethane and water. Soak the aqueous phase with dichloromethane, 12N
Acidify with hydrochloric acid and extract with dichloromethane. The dichloromethane extract is dried over sodium sulfate and filtered. Evaporation of the solvent leaves the thiol (21) (Scheme 5e). At least 3 equivalents of hydrogen peroxide are added to a mixture of thiol (21) and at least 1 equivalent of sodium formate in formic acid at a rate such that the temperature is maintained between 40 and 50°C. The reaction mixture is then heated to 45-55°C for 1-5 hours. Excess peroxide is destroyed using sodium sulfide and the solvent is evaporated. The residue was added to excess thionyl chloride and a catalytic amount of N,N-dimethylformamide (DMF)
Add. The mixture is heated to reflux for 8-24 hours, then the solvent is evaporated. The residue is partitioned between water and ether. The ethereal solution is washed with aqueous sodium bicarbonate, dried over magnesium sulfate and filtered. Evaporation of the solvent leaves the sulfonyl chloride (14) (Scheme 5f). Finally, the sulfonyl chloride (14) is aminated as previously described for Scheme 4f to give the sulfonamide (4a) (Scheme 5g). Many of the sulfonamides (4a) can be produced starting from 6-hydroxysaccharin (22) by the process shown in Reaction Scheme 6. (b) (23) HCl ――――――――――→ /R ₁ OH (11) (4a) (d) (24) R ₃ X ₁ (7) ――――――――→ Base ( _4a ) [wherein _{R 1} and is _C1 - _C6 alkyl, _C3 - _C6 alkenyl, _C3
-C6 alkynyl, _CF2H , _{CH2CH2F , CH2}
CHF ₂ , CH ₂ CF ₃ , CH ₂ CH ₂ Cl, CH ₂ CH ₂ OCH ₃ or CH ₂ CH ₂ SCH ₃ ]. 6-Hydroxysacchulin (22) was prepared by C. Finzi and M. Colonna , Atti.
accad. Lincei. Classe, sci. fis. , mat. nat. , 1937 ,
26, 19 ( Chem. Abst. 1938 , 32 , 3762). On the other hand, R ₁ =CH ₃ ,
(4a) in which R ₃ =C ₆ H ₅ CH ₂ can be prepared by the process described by Reaction Scheme 5. A solution of this sulfonamide in dichloromethane was added to 1 equivalent of 1,8
- treatment with diazabicyclo[5.4.0]undec-7-ene (DBU). The solvent is evaporated, the residue is dissolved in a minimum amount of water and acidified with concentrated hydrochloric acid to precipitate 6-benzyloxysaccharin.
This is dissolved in ethanol containing palladium catalyst. Mixture until hydrogen absorption stops.
Hydrogenate at 20-40°C and 1-10 psi. Filtration and evaporation of the solvent afforded 6-hydroxysacchulin (22). In the method described by reaction scheme 6a,
6-Hydroxysacchulin (22) is added to a solution of 2 equivalents of sodium in anhydrous methanol, ethanol or amyl alcohol. A little more than 1 equivalent of R ₃ X ₁ (7) is added and the mixture is heated to reflux for 4-24 hours. The solvent is removed in vacuo and the residue is dissolved in a minimum amount of water. Acidify it with concentrated hydrochloric acid. If the product crystallizes, collect it, wash with dilute hydrochloric acid, and dry. If it does not crystallize, the aqueous mixture is extracted with dichloromethane. The dichloromethane phase is dried over sodium sulfate and filtered.
Evaporation of the solvent leaves sacculin (23) (Scheme 6a). A solution or suspension of saccharin (23) in R ₁ OH (11) is saturated with hydrogen chloride. Mixture 65−
Heat to 80°C for 1-6 hours. Evaporate the solvent and hydrogen chloride. The residue is dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and filtered. Evaporation of the solvent gives the sulfonamide (4a) (Scheme 6b). On the other hand, satsucalin (22) is converted into (23) in reaction formula 6b.
ring opening to give the sulfonamide (24) using conditions previously described for the conversion of (4a) from
(Equation 6c). A solution of the sulfonamide (24) in anhydrous methanol, ethanol, amyl alcohol, or a suitable aprotic solvent such as N,N-dimethylformamide is added to one equivalent of sodium or potassium methoxide, ethoxide, or tertiary-butoxide. , then the alkylating agent R ₃ X ₁ (7) is added. The mixture is kept at 20-80°C for 1-8 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and diluted with _Na2
Dry over _SO4 and filter. Evaporation of the solvent gives the sulfonamide (4a) (reaction formula
6d). Sulfonamides of formula (4b) can be produced by the method shown in Reaction Scheme 7. (h) (32) R ₄ X ₁ (28) ――――――――→ Base (4d) [wherein M ₁ , _{R 1} and , _X2 is F, Cl, Br or I, and _R4 is _C1 - _C6 alkyl, _C3 - _C6 alkenyl, _{C3
−C6alkynyl} , _cyclohexyl , _C6H5 or
CH ₂ C ₆ H ₅ ]. Hydroxysacchucalin (22) was prepared using dimethylthiocarbamoyl chloride and 1,4-diazabicyclo[2.2.2] according to the general procedure of MS Newman and HA Carnes (cited above) or variations thereof known to those skilled in the art. ] Conversion to thiocarbamate (25) using octane (DABCO) in N,N-dimethylformamide (Scheme 7a). The thiocarbamate (25) is converted to its isomer (25) by heating according to the general procedure of MS Newman and HA Carnes (ibid.) or variations thereof known to those skilled in the art (reaction scheme 7b). Add slightly more than 2 equivalents of sodium methoxide to the solution of (26) in anhydrous methanol. mixture
Heat to 60-70°C for 0.5-1 hour. The solvent is removed in vacuo and the residue is partitioned between dichloromethane and water. The aqueous phase is washed with dichloromethane and acidified with concentrated hydrochloric acid. If saccharin (27) crystallizes, collect it, rinse with dilute hydrochloric acid, and dry. If it does not crystallize, the aqueous phase is extracted with dichloromethane. The dichloromethane extract is dried over sodium sulfate and filtered. Evaporation of the solvent leaves saccharin (27) (Scheme 7c). Mercaptan (27) is added to a solution in 2 equivalents of anhydrous methanol, ethanol or amyl alcohol. Add a little more than 1 equivalent of R ₄ X ₁ (28),
The mixture is then heated to reflux for 1-8 hours. The necessary alkylating agents, alkenylating agents, and alkynylating agents R ₄ X ₁ (28) are known in the art or can be prepared by a variety of methods known in the art. The solvent is removed in vacuo and the residue is dissolved in a minimum amount of water. Acidify it with concentrated hydrochloric acid.
If saccharin (29) crystallizes, collect it, wash with cold dilute hydrochloric acid, and dry.
If it does not crystallize, the aqueous mixture is extracted with dichloromethane. The dichloromethane phase is dried over sodium sulfate and filtered. When the solvent is evaporated, saccharin (29) remains (reaction formula
7d). On the other hand, in many cases, halosatucalin (30) is prepared using at least 2 equivalents of the corresponding thiolate of formula (31) in a polar aprotic solvent such as N,N-dimethylformamide at 20-100°C. Saccharin (29) can also be produced by processing for 24 hours. The reaction is worked up by evaporation of the solvent. The residue is dissolved in a minimum amount of water and acidified with concentrated hydrochloric acid. If saccharin (29) crystallizes, it will pass. If not, the aqueous solution is extracted with dichloromethane and the solvent is evaporated, leaving sacculin (29) (Scheme 7e). The necessary precursor halosatucalins of formula (30) are:
It can be prepared by converting the corresponding 4-halo-2-nitrobenzoic acid to 2-(amino-sulfonyl)-4-halobenzoic acid using a method similar to that described in Scheme 4. These precursors follow the general procedure already described for the preparation of 6-benzyloxysacculin.
Treatment with DBU results in ring closure to the corresponding saccharins of formula (30). Satucalin (29) can then be ring-opened to the sulfonamide (32) using the conditions already described for the conversion of (23) to (4a) in Scheme 6(b). (Reaction formula 7g). The thiol (32) is then converted from (24) to (4a) in equation 6d.
Conversion to (4b) is carried out using the methods already described for the conversion to (Scheme 7h). Many sulfonamides of formula (4b), where R ₁ and R ₂ are as defined above,
It can also be prepared by the same synthetic steps as described for R ₁ =R ₄ =CH ₃ in Examples 9-15. Sulfonamides of formula (4c) can be produced by the method shown in Reaction Scheme 8. [wherein R ₁ is as defined above and R ₅ is C ₁ -C ₃ alkyl, cyclopropyl, CH ₂
F, CHF ₂ , OCF ₂ H, OCH ₂ CH ₂ F, OCH ₂
CHF ₂ , OCH ₂ CF ₃ , OCH ₂ CH ₂ Cl, 1 to 3 F
or _C2 - _C6 alkyl substituted with Cl, or _C1 - _C2 alkoxy, _C1 - _C4 alkyl substituted with Cl, Br or I, and _R6 is _CH3 or _{C2H5 .} Yes, _R7 is _C1 - _C3 alkyl, cyclopropyl, _CH2
F, CHF ₂ , OCF ₂ H, OCH ₂ CH ₂ F, OCH ₂
CHF ₂ , OCH ₂ CF ₃ , OCH ₂ CH ₂ Cl, 1 to 3 F
or C ₂ -C ₆ alkyl substituted with Cl atom,
or _{C1 - C4} alkyl substituted with _C1 -C2 alkoxy or _C1 - _C2 alkylthio, and _M2 is Na or K. ]. The starting nitrobenzenes (33) are known in the art or can be prepared by a variety of methods known in the art. Some of these methods produce coupling products obtained from the reaction of Zyfnierk plates with appropriate halides (for details, see G.
Nitration (for details see G. Posner, “Substitution Reactions with Organocopper Reagents”, Organic Reactions , vol. 22 , W. G. Dauben, ed., Wiley, New York, 1975). .Lehmann, H. Eichmann's "Generation of Carbon-Nitrogen Bonds",
Preparative Organic Chemistry, G. Hilgetag, A. Martini ed., Willie-Interscience, New York.
1972). Another method involves Friedel-Crafts acylation of benzene with the appropriate acid halide or anhydride (for details see Friedel -Crafts acylation in G. A. Ohler,
Crafts and Related Reactions, -vol., Wiley-Interscience, New York.
1963-1965), followed by reductive removal of the carbonyl oxidation (for details see C. Bischoff, PG Dietrich;
"Generation of carbon-hydrogen bonds" by E. HO¨ft and D. Murowski,
Preparative Organic Chemistry, G. Hilgetag, A. Martini ed., Wiley-Interscience, New York, 1972) and then nitration. Yet another method is GA Boswell (Boswe11), Jr., WC Ripka (Ripka), RM
Scribner, CW Tullock, “Fluorination with Sulfur Tetrafluoride” and CM Sharts, WA Sheppard, “Modern Methods for the Production of Monofluoroaliphatic Compounds,” Organic Reactions , 21 Volume, W.
G. Dauben ed, Willey, New York, 1974
The conversion of appropriate 4-nitrobenzyl alcohols, altehydes or ketones to their mono- or difluoroalkyl congeners using the conditions described by . Nitrobenzene (33) is (12) in reaction formula 4d.
is reduced to aniline using the conditions already described for the conversion to (13) (reaction equation
8a). Aniline (34) is treated with at least one equivalent of acetic anhydride in a suitable solvent such as benzene,
Then heat to reflux for 8-24 hours. The reaction mixture is cooled and if acetanilide (35) crystallizes, it is collected and dried. If it does not crystallize, the benzene solution is washed with 1N hydrochloric acid and aqueous sodium bicarbonate solution, dried over magnesium sulfate and filtered. When the solvent is evaporated, acetanilide (35) remains (reaction formula
8b). Acetanilide (35) is then nitrated to give nitroacetanilide (36) (Scheme 8c) using the general conditions described by G. Lehmann and H. Eichmann (cited above). A slurry of acetanilide (36) in 1N hydrochloric acid is heated to reflux until all solids are dissolved. The solution is then made slightly basic using sodium bicarbonate and extracted with dichloromethane. The dichloromethane extract is dried over sodium sulfate and filtered. Evaporation of the solvent leaves aniline (37) (Scheme 8d). The substituent R ₅ of aniline (37) cannot contain an alkylthio group because the nitric acid used in the reaction shown by reaction scheme 8c can also act as an oxidizing agent. However, R ₅ can be any other substituent possible for R ₇ as long as it does not contain an alkylthio group. In these cases, the reaction shown by Scheme 8e is omitted and the aniline (39) used in Scheme 8f is prepared as aniline (37). On the other hand, when R ₇ contains an alkylthio group, the alkylthio-containing aniline is converted from a homologue aniline (37) having an R ₅ substituent containing a substitutable halogen atom at the position where the alkylthio group is substituted. (39) is manufactured. To effect the substitution of a halogen by an alkylthio group, a solution of the halide (35) in a suitable solvent such as N,N-dimethylformamide is treated with slightly more than 1 equivalent of the appropriate sodium or potassium alkylthiolate (38). do. Heat the mixture to 20-100℃
-Keep for 8 hours. The solvent is then evaporated and the residue is partitioned between water and dichloromethane. Dry the dichloromethane solution over sodium sulfate,
And pass. After evaporation, the thio compound (39) remains (Scheme 8e). Aniline (39) was then diazotized and G.
Sandmeyer reaction following the general experimental procedure of T. Morgan and EA Coulson, J. Chem. Soc. 1929 , 2551, gives the nitrile (40) (Scheme 8f). A suspension of nitrile (40) in 75-80% aqueous sulfuric acid
Heat to 95-100°C for 2-5 hours. Then 1.5-2.5 equivalents of sodium nitrite are added in portions at a temperature of 80-100° C. over a period of 1-2 hours. Heating was continued for another 0.5-1 hour, then the mixture was cooled and
Then pour over the excess ice. If the carboxylic acid (41) crystallizes, collect it and rinse with ice water.
and dry. If it does not crystallize,
The aqueous mixture is extracted with dichloromethane. Extract the dichloromethane solution with 10% sodium carbonate solution. The aqueous extract is acidified using concentrated hydrochloric acid. If the carboxylic acid (41) then crystallizes, it is collected, rinsed with ice water, and dried. If it does not crystallize, the aqueous solution is extracted with ether. The ether extract is dried over magnesium sulfate and filtered. Evaporation of the solvent leaves carboxylic acid (41) (reaction formula 8g). By using the method described above, carboxylic acid (41) can be converted to sulfonamide (4c) (Scheme 8h). The sulfonamides of formula (4c) in which R ₇ is C ₁ -C ₂ alkylsulfinyl or C ₁ -C ₄ alkyl substituted with an alkylsulfonyl group are represented by reaction formula 9.
(see below) for the preparation of sulfinyl sulfonamides of formula (4d, n=1) and sulfonylsulfonamides of formula (4d, n=2). So, R ₇ is C ₁
They can be prepared by oxidation with peracids of the corresponding sulfonamides of formula (4c) which are _{C1 - C4} alkyl substituted with a -C2 alkylthio group. The sulfinyl sulfonamides of formula (4d, n=1) and the sulfonylsulfonamides of formula (4d, n=2) are the corresponding thiosulfonamides of formula (4b) as shown in Reaction Scheme 9. It can be manufactured from [where R ₁ and R ₄ are as defined above and n is 1 or 2]. In order to produce sulfinyl sulfonamides of formula (4d, n=1), one equivalent of e.g.
A solution of a peracid such as chloroperoxybenzoic acid in an inert solvent such as dichloromethane is added to a stirred solution of the appropriate thiosulfonamide (4b) in an inert solvent such as a mixture of dichloromethane and tetrahydrofuran at 0-5°C. The mixture is then warmed to 20-40°C. When subjected to thin layer chromatography on the sulfonamide (4b) to be oxidized, the mixture was washed with 5% aqueous sodium sulfite, saturated aqueous sodium bicarbonate, water and brine, then dried ( _MgSO4 ). . The solvent was then evaporated leaving a sulfinyl sulfonamide of formula (4d, n=1). To prepare sulfonylsulfonamides of formula (4d, n=2), more than 2 equivalents (and only 2 equivalents when R ₄ is alkenyl or alkynyl) of a peracid such as 3-chloroperoxybenzoic acid can be used. For example, a solution in an inert solvent such as 1,2-dichloroethane is prepared with 1-5 mol % of e.g.
4-thiobis(6-tert-butyl-m-
a suitable thiosulfonamide (4b) in an inert solvent such as 1,2-dichloroethane containing a free radical initiator such as cresol).
Add to the stirred mixture. Heat the mixture to 50-80°C. When thin layer chromatography shows that the thiosulfonamide (4b) and the intermediate sulfinylsulfonamide (4d, n=1) are consumed, the mixture is cooled and diluted with tetrahydrofuran. to maintain sulfonamide solubility. Using the same process method already described for the preparation of sulfinyl sulfonamides (4d, n=1), the formula (4d, n=1)
2) Sulfonylsulfonamides are obtained. Sulfonylisocyanates (1) are prepared from the corresponding sulfonamides (4) by one of two general methods: Reaction formula 10 (4) CH ₃ (CH ₂ ) ₃ NCO ―――――――――――――→ COCl ₂ catalyst (1) [wherein R ₁ and R ₂ are defined above and (4) is (4a), (4b), (4c) or (4d)] The sulfonamide (4) and the alkyl isocyanate (e.g. n-butyl isocyanate) in the presence or absence of a catalytic amount of 1,4-diaza[2.2.2]bicyclooctane (DABCO);
Then heat to 135-140℃. After 5-60 minutes, add phosgene to the heated mixture until the temperature reaches 133-135°C.
Heat slowly at a speed maintained between When phosgene consumption has ceased, the mixture is cooled and filtered to remove insoluble material. Finally, the solvent, alkyl isocyanate and excess phosgene are evaporated leaving the sulfonylisocyanate (1). If desired, the alkyl isocyanate-sulfonamide adduct can be prepared and isolated prior to reaction with phosgene. In this case, the sulfonamide (4), the alkyl isocyanate and the anhydrous base (e.g. K ₂ CO ₃ ) are combined in a polar aprotic solvent (e.g. acetone, butanone or acetonitrile).
and heat to reflux for 1-6 hours. The reaction mixture is then diluted with water and the PH is adjusted to about 3 using an acid (eg HCl, H ₂ SO ₄ ). The adduct is filtered, dried and then reacted with phosgene as described above. This process change is
It is particularly useful when the sulfonamide (4) has a high melting point and low solubility in phosgenated solvents. Sulfonylisocyanates (1) can also be produced by the following method. (b) (42) COCl ₂ −−−−−−−−→ Pyridine catalyst (1) [wherein R ₁ and R ₂ are as defined above, and (4) is (4a) , (4b), (4c) or (4d)] The sulfonamide (4) is heated to reflux in excess thionyl chloride. The reaction is continued until the sulfonamide protons can no longer be detected in the proton magnetic resonance spectrum. Typically 16 hours to 5 days is sufficient for complete conversion to thionylamide (42) (Scheme 11a). The thionyl chloride is evaporated and the residue is dissolved in an inert solvent (e.g. toluene) containing at least 1 equivalent (typically 2-3 equivalents) of phosgene.
Process with. A catalytic amount of pyridine (typically 0.1
60-140°C, preferably 80-100°C. Isocyanate(1)
Conversion to is generally substantially complete within 15 minutes to 3 hours (Scheme 11b). The mixture is then cooled, filtered and the solvent is evaporated leaving the sulfonylisocyanate (1). Multicyclic amines of formula (2) below are known, disclosed in this application, or can be prepared by methods obvious to those skilled in the art. For details on the synthesis and reaction of 2-amino and 2-methylaminopyrimidines (2.Z=CH), see Chemistry of Heterocyclic Compounds ,
See Volume 16, Willey-Interscience, New York (1962). 2-amino- and 2-methylamino-s-triazines (2.Z=N)
For details on the synthesis and reaction of The
Chemistry of Heterocyclic Compounds, 13
Vol., Wiley-Interscience, New York (1959), U.S. Pat. No. 3,154,537 to FC Schaefer and FC Schaefer and KR.
Huffman's J.Org.Chem . 28 , 1812 (1963). Heterocyclic amines in which X or Y is OCF ₂ H can be prepared as described in US Pat. No. 4,478,635. In some cases, the heterocycles of formula (2) are easier to prepare when R is H than when R is _CH3 . Many heterocycles (2, R=CH ₃ ) can be prepared from the corresponding heterocycles (2, R=H) by one or more of the following two methods. [wherein A is as defined above]. In this method, a solution or slurry of the appropriate heterocycle (2, R=H) in a suitable aprotic solvent (eg, tetrahydrofuran, dioxane, glyme) is treated with 2 equivalents of sodium hydride at 0-30°C. After gas evolution had ceased, the reaction mixture was treated with 1 equivalent of dimethyl carbonate and 20−30
Stirring for 8-24 hours at <0>C gives a suspension of the sodium salt (43) (Scheme 12a). The reaction mixture containing (43) was treated with at least 2 equivalents of iodomethane and then heated to 60−80 °C.
Heat for 8-24 hours. The mixture is cooled, filtered and the solvent is evaporated. Extraction of the residue in dichloromethane, washing with water and evaporation of the solvent yielded N-methyl carbamate (44, R=
CH ₃ ) remains (Equation 12b). The carbamate (44, R=CH ₃ ) is dissolved in anhydrous alcohol-free chloroform saturated with propylene gas. Slightly more than 1 equivalent (typically 1.1-1.2 equivalents) of iodotrimethylsilane is added and the stirred solution is heated to 50-60°C for 2-4 hours. Cool the mixture and add 2 equivalents of methanol. The solvent is evaporated and the residue is extracted in methanol. The mixture is carefully neutralized with 10% sodium methoxide in methanol, then the solvent is evaporated. Tritify the residue with ice water. If a precipitate forms, filter it, rinse with ice water and dry (2R=
CH ₃ ). If no precipitate forms, the solution is saturated with sodium chloride and extracted with ethyl acetate. When the solvent is evaporated, the heterocycle (2, R
=CH ₃ ) remains (reaction formula 12c). On the other hand, the two-step process described below can be used in many cases. [wherein A is as defined above] A solution of the amine (2, R=H) in concentrated hydrochloric acid is treated with a sodium nitrite solution and the chloro compound (45) is dissolved in an acidic solution in the usual manner. (Scheme 13a). A representative process is Bee and Rose's J.Chem.Soc.C. 1966 , 2031
The case where Z=CH and X=Y=OCH ₃ is described in . The heterocycle (45) is then dissolved in a suitable inert solvent (e.g. tetrahydrofuran, glyme or diglyme).
at temperatures between 20° and 80°C in
Treat with an equivalent amount of methylamine (Scheme 13b).
The reaction mixture is then cooled and filtered. Evaporation of the solvent leaves (2, R=CH ₃ ) contaminated with a small amount of CH ₃ NH ₃ ⁺ Cl ⁻ salt. The product can be purified by trituration with ice water or by dissolution in dichloromethane, then washed with a little water, dried and the solvent evaporated. Other purification methods can be performed by recrystallization or column chromatography on silica gel. As a variant of the above process, in which the sulfonamides of formula (4a) and (4b) are completely formed before the formation of the urea bridge of the compounds of formula, many compounds of formula a It can be produced by the method described in 14. [wherein R ₁ , X, X ₁ , Y and Z are as defined above, W is O or S, and when W is O, R ₈ is C ₁ -C ₆ alkyl ,
_C3 - _C6 alkenyl, _C3 - _C6 alkynyl, _CH2
CH ₂ F, CH ₂ CHF ₂ , CH ₂ CH ₂ Cl, CH ₂ CH ₂ OCH ₃
or CH ₂ CH ₂ SCH ₃ , and when W is S, R ₈ is C ₁ -C ₆ alkyl,
_C3 - _C6 alkenyl or _C3 - _C6 alkynyl,
cyclohexyl, or CH ₂ C ₆ H ₅ ]. In this method, a solution of a suitable compound of formula (46) in a polar solvent, such as a mixture of acetonitrile and N,N-dimethylformamide, is treated with 2 equivalents of a strong base, such as sodium methoxide, followed by 1 Treat with slightly more than an equivalent amount of a suitable alkylating agent, alkenylating agent or alkynylating agent (47). The mixture is kept at 20-60°C for 2-24 hours. Then pour the mixture into excess hydrochloric acid. If the compound of formula a crystallizes, it will pass. Otherwise, the aqueous mixture is extracted with dichloromethane and the solvent is evaporated leaving a compound of formula a. The appropriate sulfonamides of formula (24) (W=O) or (23) (W=S) are prepared by preparing the appropriate sulfonamides of formula (5,
Compounds of formula (46) are prepared by coupling with heterocyclic phenyl carbamates of R=H). The following examples further illustrate the synthesis of the invention. Example 1 Methyl 4-ethoxy-2-hydroxybenzoate Hydrogen chloride was dissolved in 4-ethoxy-2-hydroxybenzoic acid (10.10 g, 0.554 mol) in methanol (2000 g, 0.554 mol).
ml) into a stirred solution until the solution is saturated. The solution was heated to reflux for 3 days, then cooled to 15°C. This caused the product to crystallize. The crystals were collected, rinsed with methanol and hexane and dried. Methyl 4-ethoxy-2-hydroxybenzoate was obtained in the form of a pale amber solid (49.3 g) melting at 77-78°C. PMR (CDCl ₃ , 90MHz): δ 11.90 (slightly broadened s, 1H, OH); 7.76 (d, 1H, H ortho to CO ₂ CH ₃ ); 6.35-6.55 (m, 2H, other aryl H); 4.06 (q, 2H, OCH ₂ CH ₃ ); 3.89
(s, 3H, OCH ₃ ); 1.41 (t, 3H, OCH ₂ CH ₃ ).
IR (Nujol); 3130 (wide, W, OH): 1668 (s, C
=O)cm ^-1 . Further product was obtained by reprocessing the mother liquor. Example 2 2-[(dimethylamino)thioxomethoxy]-
Methyl 4-ethoxybenzoate triethylamine (76.6 ml, 0.550 mol) was added to 4
-Methyl ethoxy-2-hydroxybenzoate (49.3 g, 0.251 mol), 4-dimethylaminopyridine (3.06 g, 0.025 mol) and dimethylthiocarbamoyl chloride (54.4 g, 0.440 mol)
was added via syringe to a stirred solution of . The reaction solution was heated to reflux for 3 days and then left at room temperature overnight. Add it to hydrochloric acid (1N,
3 x 300 ml), then dried (MgSO ₄ ),
And it passed. Rotary evaporation of the solvent left the crude product (95.2 g) as a brown oil. This was applied to a column of silica gel and eluted with 2:1 and then 1:1 hexane-ether. The fraction containing the product (Rf=0.43, 1:
Rotary evaporation of 1 (hexane-ether, UV light) gave the partially purified product (60.2 g) as a yellow solid. Further purification was achieved by another column chromatography using a larger silica gel to sample ratio. Finally, the twice chromatographed product (48.7 g, including 7.4 g from another similar experiment) was washed with boiling methanol (3
ml/g). After cooling in an ice bath, the crystals were collected, rinsed with ice-cold methanol, and dried. Methyl 2-[(dimethylamino)thioxomethoxy]-4-ethoxybenzoate is 77-
It was obtained in the form of large white prisms (46.1 g) that melted at 79°C. PMR (CDCl ₃ , 200MHz): δ7.96 (d, 1H, CO ₂
H ortho to CH ₃ ); 7.81 (dd, 1H,
Para H) for OCSN; 6.62 (d, 1H,
para H) for OCSN; 4.08 (g, 2H, OCH ₂
CH ₃ ); 3.81 (s, 3H, CO ₂ CH ₃ ); 3.47 (s, 3H,
NCH ₃ ); 3.40 (s, 3H, NCH ₃ ); 1.42 (t, 3H,
_{OCH2CH3 )} . IR (Nujol): 1715cm ^-1 (vs, C=
O). Example 3 2-[(dimethylamino)carbonylthio]-4
-Methyl ethoxybenzoate 2-[(dimethylamino)thioxomethoxy]-
Methyl 4-ethoxybenzoate (28.3g, 0.100mol) was heated to 220<0>C under nitrogen for 1.5 hours. Thin layer chromatography (6:3:1 _CH3Cl2 - _hexane -ether, UV) shows a very weak spot (starting material) at an Rf of 0.63 and a very strong spot (product) at an Rf of 0.35. showed that. In this case, the crude product was used in the reaction step without further identification or purification. The crude product from a similar but smaller scale experiment was chromatographed on a silica gel column using 4:1 ether-hexane as pre-elution. Rotary evaporation of the fraction containing the product (Rf=0.40, same solvent, UV light) gave an oil that slowly crystallized. This was dissolved in a small amount of dichloromethane, diluted with 1-chlorobutane, seeded and rotary evaporated. The residue was collected, rinsed with hexane, and dried. Methyl 2-[(dimethylamino)-carbonylthio]-4-ethoxybenzoate is 65-
It was obtained in the form of white prisms that melted at 67°C. PMR (CDCl ₃ , 200MHz): δ7.93 (d, 1H, CO ₂
H ortho to CH ₃ ); 7.16 (d, 1H,
Ortho H) for SCON; 6.89 (dd, 1H,
Para H for SCON); 4.08 (q, 2H, OCH ₂
CH ₃ ); 3.84 (s, 3H, CO ₂ CH ₃ ); 3.09 (wide s,
6H, N(CH ₃ ) ₂ ); 1.42 (t, 3h, OCH ₂ CH ₃ ). IR
(Nujol): 1730 (s, ester C=O); 1680 (s,
Carbonyl C=O) cm ^-1 . Example 4 Methyl 4-ethoxy-2-mercaptobenzoate Methanolic sodium methoxide (4.9M,
22.4 ml, 0.11 mol) of methyl 2-[(dimethylamino)carbonylthio]-4-ethoxybenzoate (crude, approximately 28.3 g, 0.10 mol) in methanol (100
ml) solution by syringe under nitrogen. The reaction mixture was heated to reflux for 30 minutes, then cooled using a water bath. Rotary evaporation produced a solid. This was partitioned between dichloromethane (100ml) and water (100ml). The aqueous layer was dichloromethane (3 x 40
ml), acidified to PH<1 with concentrated hydrochloric acid, then extracted with dichloromethane (3 x 40 ml). These dichloromethane extracts were combined, dried (Na ₂ SO ₄ ) and filtered. Rotary evaporate,
Methyl 4-ethoxy-2-mercaptobenzoate is produced in the form of an oil (18.4 g), and when it is left to stand, 42-
A crystalline solid was formed that melted at 44°C. PMR (CDCl ₃ , 200MHz): δ7.97 (d, 1H, CO ₂
H ortho to CH ₃ ); 6.78 (H ortho to d, 1H, SH); 6.64 (H para to dd, 1H, SH); 5.06 (s, 1H, SH); 4.05 (2H,
OCH ₂ CH ₃ ); 3.88 (s, 3H, CO ₂ CH ₃ ); 1.42 (t,
3H, _{OCH2CH3 )} . IR (Nujol): 1686 (vs, C=
O) cm ^-1 . Example 5 Methyl 2-(chlorosulfonyl)-4-ethoxybenzoate Hydrogen peroxide (30%, 9.79M, 30.7 ml, 300 mmol) was dissolved in methyl 4-ethoxy-2-mercaptobenzoate (18.2 g, 85.7 mmol). and sodium formate (11.7 g, 172 mmol) for formic acid (171.4
ml) was added dropwise to the stirred solution. By using an ice bath, the internal temperature was kept at 40−50 °C during the first half of the hydrogen peroxide addition.
°C and kept at 45-50 °C during the second half of the addition. After the addition is complete and the exothermic reaction has ended, the mixture is heated to 45 ml.
Heated to -55°C for 2 hours. Excess hydrogen peroxide was destroyed with sodium sulfate, the solution was filtered, and the solvent was rotary evaporated. The residue was slurried in toluene and rotary evaporated. The process was repeated to give the sulfonic acid sodium salt as a moist white crystalline solid (21.7 g). The sulfonic acid sodium salt was added in portions to stirred thionyl chloride (150 ml, 2.1 mmol) without further purification or identification. Anhydrous N,N-dimethylformamide (1.0 ml, 13 mmol) was added slowly and the reaction mixture was heated to reflux overnight. The reaction mixture was then rotary evaporated. The residue was dissolved in ether (100 ml) and ice water (100 ml).
ml). Water layer with ether (2 x 50
ml). The combined ether solution was mixed with water (50 ml), saturated aqueous sodium bicarbonate solution (2 x 50
ml), dried ( _MgSO4 ) and filtered. Rotary evaporation of the solvent left methyl 2-(chlorosulfonyl)-4-ethoxybenzoate as a pale orange oil (22.5 g) which crystallized upon puking. The crystalline solid melted at 45-48°C. PMR ( _CDCl3 , 200MHz): δ7.76 (d, 1H, _CO2
H ortho to CH ₃ ); 7.65 (d, 1H, SO ₂ Cl
7.21 (dd, 1H, para H to SO ₂ Cl); 4.16 (q, 2H, OCH ₂ CH ₃ );
3.96 (s, 3H, CO ₂ CH ₃ ); 1.48 (t, 3H, OCH _2
CH3 ). IR (Nujol): 1722 (vs, C=O) cm ^-1 . Example 6 Methyl 2-(aminosulfonyl)-4-ethoxybenzoate Liquefied ammonia (4.4 ml, 180 mmol) was dissolved in 2-
Added to a stirred solution of methyl (chlorosulfonyl)-4-ethoxybenzoate (221 g, 79.3 mmol) in dichloromethane (221 ml) at -70°C. The reaction mixture was warmed to -10°C and kept at this temperature for 30 minutes. The mixture was then poured into water (221ml).
Additional water and dichloromethane were used for rinsing, and tetrahydrofuran (approximately 40 ml) was also added. The layers were shaken, separated and the aqueous layer was extracted with dichloromethane (2 x 221ml). The combined dichloromethane solutions were washed with water (221 ml) and the wash water was back extracted with dichloromethane (approx. 120 ml). The combined dichloromethane solutions were dried (Na ₂ SO ₄ ) and filtered. Rotary evaporation of the solvent left the crude product as a slightly off-white crystalline solid (18.1 g). This was dissolved in hot methanol (approximately 200ml) and heated. The solution was boiled to a volume corresponding to 3 ml/g methanol. After seeding and cooling using an ice bath, the crystals were collected, rinsed with ice-cold methanol and hexane, and dried. 2-(Aminosulfonyl)-4-ethoxybenzoic acid (15.3 g) was obtained as white needles melting at 146-148°C. PMR ( _CDCl3 , 200mHz): δ7.91 (d, 1H, _CO2
H ortho to CH ₃ ); 7.68 (d, 1H, SO ₂
H ortho to _NH2 ); 7.04 (dd, 1H, _SO2
para H for NH ₂ ); 5.91 (wide s, 2H,
NH ₂ ); 4.14 (q, 2H, OCH ₂ CH ₃ ); 3.95 (s,
3H, CO ₂ CH ₃ ); 1.45 (t, 3H, OCH ₂ CH ₃ ). IR
(Nujol): 3348 (m, NH); 3241 (m, NH);
1692(s,C=O)cm ^-1 . Example 7 4-ethoxy-2-(isocyanatosulfonyl)
Methyl benzoate Methyl 2-(aminosulfonyl)-4-ethoxybenzoate (7.56 g, 29.2 mmol), n-butyl isocyanate (3,29 ml, 29.2 mmol) and 1,4-diaza[2.2.2]bicyclooctane ( 0.13 g, 1.2 mmol) in mixed xylene.
Heat to reflux for 10 minutes. Phosgene was then added at a rate such that the internal temperature was above 133°C.
When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporate,
4-ethoxy-2-(isocyanatosulfonyl)
Methyl benzoate was given as a cloudy yellow oil (8.2g). This was used immediately without further purification or identification. Example 8 Methyl 2-[[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminocarbonyl]aminosulfonyl]-4-ethoxybenzoate 4,6-dimethoxy-1,3,5 -To a slurry of triazin-2-amine (0.46 g, 2.9 mmol) in dry dichloromethane (5 ml) was added methyl 4-ethoxy-2-(isocyanatosulfonyl)benzoate (crude, approximately 1.2 g, 4.2 mmol) in dichloromethane (5 ml). 5 ml) of the solution was added. reaction mixture
Heated to reflux for 1.5 hours, during which time the solids dissolved.
A new solid formed upon stirring at room temperature overnight.
Rotary evaporation of the solvent left the crude product as a white solid (1.5 g). Warm this 1,2-
15:1, 10:1 and finally 7:1 dissolved in dichloroethane and on a column of silica gel, all containing 2 ml/acetic acid as eluent.
Chromatographed using 1 dichloromethane-ether. The appropriate fractions were diluted with toluene and rotary evaporated to give a solid. This was dissolved in a minimum amount of hot dichloromethane, diluted with 1-chlorobutane and rotary evaporated to give a crystalline solid. This was slurried in hexane, collected, rinsed with 1:11-chlorobutane-hexane and hexane, and dried. The product is
White crystalline powder (0.98
g) was obtained. PMR (CDCl ₃ , 200MHz): δ12.15 (slightly expanded s, 1H, SO ₂ NHCO); 7.89 (d, 1H,
H) 7.77 (d, 1H, CO ₂ ortho to SO ₂ NH)
H ortho to _CH3 ); 7.45 (slightly extended s, 1H, CONH−Het); 7.11 (dd, 1H,
para H for SO ₂ NH); 4.17 (q, 2H,
OCH ₂ CH ₃ ); 4.12 (s, 6H, Het−OCH ₃ ); 3.90
(s, 3H, CO ₂ CH ₃ ); 1.46 (t, 3H, OCH _2
CH3 ). IR (Nujol): 1730 (vs, Ester C=
O); 1715 (s, urea C=O) cm ^-1 . Example 9 4-(Methylthio)-2-nitrobenzoic acid 4-amino-2-nitrobenzoic acid (20.0 g,
110 mmol) in aqueous sulfuric acid (32.8 ml H ₂ O + 24.0
ml of concentrated H ₂ SO ₄ ). The stirred mixture was heated until all the aniline was dissolved and then thrown into an ice bath to precipitate the anilinium salt in a suspension of very small crystals. A portion of aqueous sodium nitrite (8.8 g, 128 mmol in 18.4 ml _H2O ) was then added over 1 hour to the stirred reaction mixture maintained at -5 to 0<0>C. The diazotization mixture is then cooled in an ice bath in portions with sodium hydroxide (24.4 g, 610 mmol), methanethiol (33.6 ml, 605 mmol),
It was poured into a mixture of cupric sulfate (17.6 g, 110 mmol) and sodium acetate (55.2 g, 673 mmol) in 140 ml of water. The addition was exothermic and involved significant gas evolution. A suspension of brown-yellow solid formed. The mixture was heated to 60°C and then allowed to cool to room temperature. Dichloromethane (200ml) and tetrahydrofuran (20ml) were added with stirring. Concentrated hydrochloric acid was added to bring the pH below 1. The mixture was filtered through Celite and additional dichloromethane was used for rinsing. The layers were separated and the aqueous layer was extracted with dichloromethane (2x50ml). The combined dichloromethane solutions were dried (Na ₂ SO ₄ ) and
It was aspirated through Celite. The solvent was rotary evaporated. Dissolve the residue in a minimum amount of acetone,
Diluted with toluene and evaporated. The process was repeated and crude 4-(methylthio)-2-nitrobenzoic acid remained as an orange solid (20.4 g) melting at 165-168°C. This was used in the next step without further purification. PMR (DMSO- _d6 , 200MHz): δ13.6 (very wide s, 1H, _CO2H ); 7.83 (d, 1H, H ortho to _CO2H ); 7.76 (d, 1H, NO H ortho to ₂ ); 7,58 (dd, 1H, H para to NO ₂ ); 2.58 (s, 3H, SCH ₃ ). IR (Nujol):
2800 (very wide, m, OH); 1675 (s, C=O)
cm ^-1 . Example 10 Methyl 4-(methylthio)-2-nitrobenzoate 4-(methylthio) kept at 5°C under nitrogen
p-Toluenesulfone chloride (43.6 g, 229 mmol) was added to a stirred solution of -2-nitrobenzoic acid (24.4 g, 11 mmol) in dry pyridine (265 ml).
added. After 1 hour, dry methanol (6.2 ml, 153 mmol) was added with continued cooling using an ice bath. After the exotherm subsided, another portion of methanol (4.1 ml, 101 mmol) was added and the ice bath was removed. The reaction solution was stirred at room temperature for 1 hour and then poured into an ice bath (1060ml). Ether (530ml) was added with stirring and the layers separated. The aqueous layer was extracted with ether (2 x 530ml). Add the combined ether solution to 10% sodium hydroxide solution (2 x 530ml)
Washed with water, dried (MgSO ₄ ) and filtered.
The solvent was rotary evaporated. The residue was extracted in toluene, which was then rotary evaporated. This process was repeated again to give a dark brown oil. This oil was chromatographed on a silica gel column using a mixture of hexane and ether (first 2:1 and then 3:2) as the eluent. Evaporation of the fraction containing the product (Rf=0.38, UV, 2:1 hexane-ether) left a yellow solid. Add this to the minimum amount of 1
- Dissolved in chlorobutane, diluted to saturation with hexane and seeded. After the crystallization was completed, the mixture was evaporated. The residue was slurried in hexane, rinsed with hexane, and dried. Methyl 4-(methylthio)-2-nitrobenzoate was obtained as pale yellow needles (11.6 g) melting at 57-59°C. PMR (CDCl ₃ , 200MHz): δ7.71 (d, 1H, CO ₂
H ortho to CH ₃ ); 7.55 (d, 1H, NO ₂
7.41 (dd, 1H, para H to NO ₂ ); 3.90 (s, 3H, CO ₂ CH ₃ ); 2.56
(s, 3H, SCH ₃ ), IR (Nujol): 1709 (vs, C=
O) cm ^-1 . Example 11 Methyl 2-amino-4-(methylthio)benzoate Methyl acetate on 4-(methylthio)-2-nitrobenzoate (11.3 g, 49.7 mmol) and 5% platinum sulfide on carbon catalyst (0.7 g) (40 ml) mixture was hydrogenated at 750 psi and 75° C. until hydrogen suction ceased. Passing the mixture through Celite and rotary evaporation of the liquid solvent yielded 2-
Methyl amino-4-(methylthio)benzoate is 57
Pale brown crystalline solid (8.7 g) melting at -59°C
It remained in shape. PMR ( _CDCl3 , 200MHz): δ7.74(d, 1H, _CO2
H ortho to _CH3 ); 6.50 (dd, 1H, _NH2
para H); 6.44 (ortho H to dd, 1H, NH ₂ ): 5.75 (wide s, 2H, NH ₂ ); 3.85
(s, 3H, CO ₂ CH ₃ ); 2.46 (s, 3H, SCH ₃ ). IR
(Nujol): 3422 (m, NH); 3312 (m, NH);
1650(s,C=O)cm ^-1 . Example 12 2-(chlorosulfonyl)-4-(methylthio)
Methyl benzoate was added to a stirred aqueous sulfuric acid solution (7.2 ml concentrated H ₂ SO ₄ + 51.6 ml H ₂ O) maintained at -5 to 0°C.
A solution of methyl 2-amino-4-(methylthio)benzoate (12.8 g, 64.9 ml) in glacial acetic acid (6.4 ml) and aqueous sodium nitrite (4.9 g, 7.8 ml H2 ₎
71 mmol) portions in O were added in alternating portions. The diazotization mixture was then mixed with cupric chloride dihydrate (5.5 g, 32 mmol), concentrated hydrochloric acid (13.0 ml) and liquefied sulfur dioxide (5.5 ml, 129 mmol) in glacial acetic acid (51.6 ml) and dichloromethane (64.6 ml). ml) was poured portionwise into the mixture at 0°C. Using a dry ice filled dewar condenser,
The coupling mixture was heated to reflux for 45 minutes. The reaction mixture was then poured into water (approximately 400 ml) and another portion of dichloromethane (approximately 60 ml) was used for rinsing. The layers were shaken and separated and the aqueous layer was extracted with dichloromethane (3 x 50ml). The combined dichloromethane solutions were washed with water (approximately 100 ml).
Water (25ml) was added to the dichloromethane solution and sodium bicarbonate was added with vigorous stirring until effervescence ceased. The mixture was diluted with water (approximately 40ml) and the layers were separated. The dichloromethane layer was washed with water (approximately 2 x 60ml) and dried ( _MgSO4 ). The solvent was rotary evaporated to give the crude 2-
Methyl (chlorosulfonyl)-4-(methylthio)benzoate was provided in the form of a yellow semi-solid (10.0 g).
This was used immediately in the next reaction step without further purification or identification. Example 13 2-(aminosulfonyl)-4-(methylthio)
Methyl benzoate liquefied ammonia (1.7 ml, 68 mmol) in 2-
Added to a stirred solution of methyl (chlorosulfonyl)-4-(methylthio)benzoate (10 g, 36 mmol) in dichloromethane (100 ml) at -70°C. The reaction mixture was warmed to -10°C and kept at this temperature for 10 minutes. The mixture was then poured into water (100ml).
Additional water and dichloromethane were used for rinsing. The layers were shaken, separated and the aqueous layer was extracted with dichloromethane (2 x 50ml). The combined dichloromethane solutions were washed with water (100ml), dried (Na ₂ SO ₄ ) and passed through Celite.
Rotary evaporation of the solvent left the crude product as a solid (9.0 g). This was dissolved in dichloromethane and suspended on silica gel (27g). The material was chromatographed on a column of silica gel using dichloromethane-hexane-ether (6:3:1 then 6:2:2) as eluent. Rotary evaporation of the appropriate fractions left a solid. This was dissolved in dichloromethane, diluted with hexane and rotary evaporated to give a crystalline solid.
Slurry this in hexane, collect, 1:11
-Chlorobutane-hexane and rinsed with hexane and dried. 2-(aminosulfonyl)-
Methyl 4-(methylthio)benzoate at 123-125℃
It was obtained in the form of a white crystalline powder (6.7 g) which melted at . PMR ( _CDCl3 , 200MHz): δ7.97 (d, 1H, _SO2
H ortho to _NH2 ); 7.82 (d, 1H, _CO2
H ortho to CH ₃ ); 7.39 (dd, 1H, SO ₂
para H for NH ₂ ): 5.86 (s, 2H, NH ₂ );
3.97 (s, 3H, CO ₂ CH ₃ ); 2.56 (s, 3H,
_SCH3 ). IR (Nujol): 3322 (m, NH ₂ ); 3245 (m,
_NH2 ): 1700 (s, C=O) cm ^-1 . Example 14 Methyl 2-(isocyanatosulfonyl)-4-(methylthio)benzoate 2-(aminosulfonyl)-4-(methylthio)
Methyl benzoate (5.23 g, 20.0 mmol), n-
Butyl isoanate (2.25 ml, 20.0 mmol) and 1,4-diaza[2.2.2]bicyclooctane (0.09 g, 0.8 mmol) in mixed xylene (50 ml)
The medium solution was heated to reflux for 10 minutes. Phosgene was then added at a rate such that the internal temperature remained above 133°C. When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporation gave methyl 2-(isocyanatosulfonyl)-4-(methylthio)benzoate to a yellow oil (6.4 g).
It was given in form. This was used immediately without further purification or identification. Example 15 2-[[(4,6-dimethoxypyrimidine-2-
yl)aminocarbonyl〕aminosulfonyl〕
Methyl -4-(methylthio)benzoate 4,6-dimethoxy-1,3-pyrimidine-2
- To a slurry of the amine (0.36 g, 2.32 mmol) in dry dichloromethane (4 ml) was added 2-(isocyanatosulfonyl)-4-(methylthio)benzoic acid (crude, approximately 0.95 g, 3.3 ml) in dichloromethane (5 ml).
ml) solution was added. The reaction mixture was heated to reflux for 2.5 hours, during which time new solid formed. A new solid formed upon standing at room temperature overnight. The mixture was diluted with a 1:11-chlorobutane-hexane solution (9 ml) and the solid was collected and 1-
Rinse with chlorobutane and hexane and dry. The product was obtained in the form of a white crystalline powder (0.92 g) melting at 201-202°C. PMR (CDCl ₃ , 200MHz): δ12.57 (slightly expanded s, 1H, SO ₂ NHCO): 8.20 (d, 1H,
H ortho to SO ₂ NH); 7.66 (d, 1H,
H ortho to CO ₂ CH ₃ ); 7.43 (dd, 1H,
para H to SO ₂ NH); 7.18 (slightly expanded s, 1H, CONH−Het); 5.79 (s, 1H,
Het 5-H); 4.01 (s, 6H, Het-OCH ₃ );
3.87 (s, 3H, CO ₂ CH ₃ ); 2.58 (s, 3H,
_SCH3 ). IR (Nujol): 1721 (vs. Ester C=
O): 1698 (s, urea, C=O) cm ^-1 . Example 16 Methyl 2-[[[[4-(difluoromethoxy)-6-methoxypyrimidin-2-yl]aminocarbonyl]aminosulfonyl]-4-ethoxybenzoate 4-difluoromethoxy-6-methoxy-pyrimidine-2- To a slurry of amine (0.56 g, 2.92 mmol) in dry dichloromethane (5 ml) was added 4-
Added to a solution of methyl ethoxy-2-(isocyanatosulfonyl)benzoate (crude, approximately 5.6 ml) in dichloromethane (5 ml). The reaction mixture was heated to reflux for 3 hours, during which time the solid dissolved. After stirring for 12 hours at room temperature, a new solid formed. The crude reaction mixture was run on a column of silica gel, 40:1, 20:1, all containing 2 ml of acetic acid as eluent.
1 and finally 10:1 dichloromethane-ether. The appropriate fractions were diluted with toluene and rotary evaporated to give a solid. The solid was slurried in hexane, collected, washed with butyl chloride, 1:1 butyl chloride-hexane, hexane, and air dried. The product was a white crystalline solid that melted at 195-196°C. PMR (CDCl ₃ , 200MHz): δ12.02 (wide s,
1H); 7.91 (d, 1H); 7.78 (d, 1H); 7.52 (t,
1H); 7.34 (wide s, 1H); 7.09 (dd, 1H); 5.97
(s, 1H); 4.17 (q, 2H); 4.12 (s, 3H); 3.87
(s, 3H); 1.46 (t, 3H). IR (Nujol): 1722
(vs, C=O) cm ^-1 . Using the above steps and examples, Table -
We were able to produce the following compounds. [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] ] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] ] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] ] [Table] [Table] [Table] [Table] [Table] [Table] [Table] Useful agricultural tone of prepared compounds can be manufactured in normal methods. They are powders, granules, tablets,
Includes suspensions, emulsions, wettable powders, concentrated emulsions, etc. Many of these can be applied directly. The spray preparations can be bulked up in a suitable medium and used in spray volumes of a few liters to a few hundred liters/ha. High strength compositions are primarily used as intermediates for further formulation. Generally speaking, the preparation comprises about 0.1% to 99% by weight of active ingredient, and a) about 0.1% to 99% by weight of surfactant.
20% and b) about 1 to 99.9% of a solid or liquid diluent. More particularly, the preparation will contain these ingredients in approximately the following proportions: * Active ingredient + surfactant or rare
At least one diluent = 100% by weight
Of course, lower or higher amounts of active ingredient than those listed may be present depending on the intended use and physical properties of the compound. A high proportion of surface-active to active ingredients is particularly desirable and is achieved by incorporation into the formulation or by mixing in a tank. Typical solid diluents are described in “Handbook of Insecticide” by Watkins et al.
"Dust Diluents and Carriers", 2nd edition, Dorland Books, Caldwell, N.
J.), but other solids, natural and synthetic, may also be used. Adsorptive diluents are also suitable for wettable powders and powder concentrates. Representative liquid diluents and solvents are described in "Solvents guide" by Marsden, 2nd edition, Intersience, NY, 1950. Solubility below 0.1% is suitable for concentrated suspensions; concentrated solutions are preferably stable to phase separation at 0°C. “McCutcheon′s D. etergents and
Emulsifiers Annual”, Allured Publ. Corp., NJ, and by Sisely and Wood.
“Encyclopedia of Surface Active Agents”
Chemical Publ.Co.Inc., N.
Y.), 1964, indicates surface activity and its recommended uses. All preparations may contain small amounts of additives to reduce foaming, caking, corrosion, microbial growth, etc. Methods for producing such compositions are well known.
Solutions are prepared by simply mixing the components. Finely divided solid compositions are produced by mixing and commonly grinding using a hammer mill or fluid energy mill. Suspensions are made by wet milling (see Littler, US Pat. No. 3,060,084). Granules and tablets may be produced by spraying the active substance onto preformed granular carriers or by agglomeration methods. References, by J.E. Brownig,
“Agglomeration”, Chemical Engineering, 12
Monthly issue, 147 pages (1967), and Perry.
Author, Chemical Engineer's Handbook, 4th edition,
pp. 8-59, McGraw-Hill, Inc.
Hill, NY), 1963. For further literature on preparation techniques see, for example: HM Loux, US Pat. No. 3,235,361
No. 6, column 6, line 16 to column 7, line 19, and Examples 10 to 41. RW Luckenbaugh, U.S. Patent No. 3,309,192, column 5, line 43 to column 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138,
~140, 162~164, 166, 167, 169~182. H. Gysin and E. Knusli,
U.S. Pat. No. 2,891,855, column 3, line 66 to column 5, line 17 and Examples 1-4. GC Klingman, “Weed
Contral as a Science”, John Wiley and Sons.Inc.
NY), 1961, pp. 81-96. “Weed Control Handbook” by JD Fryer and SA Evans, 5th edition, Blackwell Scientific.
Publications (Blackwell Scientific
Publications, Oxford), 1968, pp. 101-103. The disclosures of the above-mentioned documents are incorporated herein by reference. In the following examples, all parts are by weight unless otherwise indicated. Example 17 Wettable powder 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 80% Sodium alkylnaphthalene sulfonate 2% Sodium lignin sulfonate 2% Synthetic amorphous silica 3% Kaolinite 13% The above ingredients were mixed and ground with a hammer mill to determine the average particle size. Reduced to 50 microns or less. The material was remixed, passed through a No. 50 US standard sieve, and packaged. Example 18 Wettable powder 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 50% Sodium alkylnaphthalene sulfonate 2% Low viscosity methyl cellulose 2% Diatomaceous earth 46% The above ingredients were mixed and coarsely ground with a hammer mill.
It was then ground in an air mill to produce particles essentially all less than 10 microns in diameter. The product was remixed and packaged. Example 19 Granule Wettable powder of Example 17 5% attapulgite particles (US standard sieve No. 20-40;
0.84~0.42mm) A slurry of wettable powder containing 95% solids and 25% solids,
The surface of the attapulgite particles was sprayed in a double cone mixer. The particles were dried and packaged. Example 20 Extruded tablet 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 25% Anhydrous sodium sulfate 10% Crude calcium lignin sulfonate 5% Sodium alkylnaphthalene sulfonate 1% Calcium/magnesium bentonite 59% The above ingredients were mixed and processed in a hammer mill, then approx. Moistened with 12% water. This mixture was extruded into cylinders with a diameter of about 3 mm, which were cut into tablets with a length of 3 mm. It could be used directly after drying, or the dried tablets could be crushed and passed through a No. 20 US standard sieve (0.84 mm opening). The particles were packaged and circulated under the sieve for use with particles that fit through a No. 40 US standard sieve (0.42 mm opening). Example 21 Oily suspension 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 25% Polyoxyethylene sorbitol hexaoleate 5% Higher aliphatic hydrocarbon oil 70% The above ingredients were ground together in a sand mill to reduce solid particles to less than about 5 microns. The resulting suspension was applied directly, preferably after bulking up with oil or emulsifying in water. Example 22 Wettable powder 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 20% Sodium alkylnaphthalene sulfonate 4% Sodium lignin sulfonate 4% Low viscosity methylcellulose 3% Attapulgite 69% The above components were thoroughly mixed. Grind in a hammer mill to produce particles essentially all below 100 microns, remix the material, and pass through a U.S. standard sieve.
No. 50 (opening 0.3 mm) and packaged. Example 23 Low strength granules 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 1% N,N-dimethylformamide 9% Attapulgite particles (US standard sieve No. 20-40)
The 90% active ingredient was dissolved in the solvent and the solution was sprayed onto the dust removal particles in a double cone mixer.
The mixer was operated briefly after spraying of the solution was completed and the granules were then packaged. Example 24 Aqueous suspension 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 40% Polyacrylic acid thickener 0.3% Dodecylphenol polyethylene glycol ether 0.5% Disodium phosphate 1% Monosodium phosphate 0.5% Polyvinyl alcohol 1.0% Water 56.7% The above ingredients were mixed and placed in a sand mill. The particles were milled together to produce particles essentially all of which were less than 5 microns in size. Example 25 Solution 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
- (Methylthio)benzoic acid methyl ester 5% water 95% The salt was added directly to water with stirring to produce a solution, which was packaged for subsequent use. Example 26 Low strength granules 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 0.1% attapulgite particles (US standard sieve No. 20-40)
The 99.9% active ingredient was dissolved in the solvent and the solution was sprayed onto the dust removal particles in a double cone mixer.
After spraying the solution was completed, the material was warmed to allow the solution to evaporate. The material was naturally cooled and packaged. Example 27 Granules 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 80% Wetting agent 1% Crude lignin sulfonate (containing 5-20% natural sugar) 10% Attapulgite clay 9% The above ingredients were mixed and ground and passed through a No. 100 screen. . This material was then added to a fluidized bed granulator, the air flow was adjusted to gently fluidize the material, and a fine mist of water was sprayed onto the fluidized material. Fluidization and atomization continued until particles of the desired size range were produced. Spraying was stopped but fluidization was continued with optional heating until the water content was reduced to the desired level, generally below 1%. The material was then removed, sieved to the desired size range, generally 14-100 (1410-149 microns), and packaged for use. Example 28 High strength thickener 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 99% Silica aerogel 0.5% Synthetic amorphous silica 0.5% The above ingredients were mixed and ground in a hammer mill to ensure that essentially all of the
0.3 mm) was produced. This thickener can be further formulated if necessary. Example 29 Wettable powder 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 90% Sodium dioctyl sulfosuccinate 0.1% Synthetic finely divided silica 9.9% The above ingredients were mixed and ground in a hammer mill to produce particles essentially all below 100 microns. The material was passed through a US Standard Sieve No. 50 screen and then packaged. Example 30 Wettable powder 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
- (Methylthio)benzoic acid methyl ester 40% Sodium ligninsulfonate 20% Montmorillonite clay 40% The above ingredients were thoroughly mixed and coarsely ground in a hammer mill, then ground in an air mill until essentially all Particles with dimensions below 10 microns were produced. The material was remixed and then packaged. Example 31 Oily suspension 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 35% Mixture of polyalcohol carboxylic acid esters and oil-soluble petroleum sulfonates 6% Xylene 59% The above ingredients were combined and ground together in a sand mill until essentially all Particles less than 5 microns were produced. The product could be used directly, spread in oil or emulsified in water. Example 32 Powder 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 10% Attapulgite 10% Pyrophyllite 80% The active ingredient was mixed with attapulgite and then passed through a hammer mill to produce particles substantially all of which were 200 microns or less. The powder concentrate was mixed with the powdered pyrophyllite until homogeneous. Example 33 Concentrated emulsion 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4
-(Methylthio)benzoic acid methyl ester 20% Chlorobenzene 74% Sorbitan monostearate and its polyoxyethylene condensate 6% The above ingredients are combined and stirred to produce a solution, which is emulsified in water for application. I was able to do that. Example 34 Wettable powder 4-methoxy-2-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]aminosulfonylbenzoic acid methyl ester 80% Alkylnaphthalenesulfonic acid Sodium 2% Sodium Lignosulfonate 2% Synthetic Amorphous Silica 3% Kaolinite 13% The above ingredients are mixed, hammer milled until all solids are essentially 50 microns or less, remixed, and Packaged. Example 35 Wettable powder 2-[[[[4-(difluoromethoxy)-6-methoxypyrimidin-2-yl]aminocarbonyl]aminosulfonyl]-4-ethoxybenzoic acid methyl ester 50% Sodium alkylnaphthalenesulfonate 2% Low viscosity methyl cellulose 2% Diatomaceous earth 46% Mix the above ingredients, coarsely grind with a hammer mill,
It was then ground in an air mill to produce particles essentially all below 10 microns in diameter. The product was remixed and packaged. Example 36 Granules Wettable powder of Example 9 5% attapulgite particles (US standard sieve No. 20-40;
0.84-0.42 mm) 95% A slurry of the wettable powder containing 25% solids was sprayed onto the surface of the attapulgite particles with stirring in a double cone mixer. dry the particles;
And packaged. Applications Test results show that the compounds of the invention are highly active pre- or post-emergent herbicides or plant growth regulators. They are used to pre-emergence weeds in areas where complete eradication of all vegetation is expected, such as around fuel storage tanks, around ammunition depots, industrial storage areas, parking lots, amphitheaters, around billboards, highways and railway areas. and/or exhibit broad utility for post-emergence control. Additionally, some of the compounds are useful for selectively controlling weeds in crops such as wheat, barley, and cotton. The compounds can also be used to improve plant growth. The rate of use of the compounds of the invention will depend on their use as selective or systemic herbicides, the coexisting crop species, the weed species to be controlled, the weather and climate, the formulation chosen,
Determined by many factors including application method, amount of foliage present, etc. Generally speaking, the compounds are approximately
Should be used in amounts of 0.05-10Kg/ha. In this case, lower doses in the above range are used when applied to light soils and/or soils with low organic matter content, when selectively controlling weeds, or when only short-term persistence is required. Ru. The compounds of the invention can also be used in combination with other commercially available herbicides, such as those of the triazine, triazole, uracil, urea, amide, diphenyl ether, carbamate and bipyridylium types. The herbicidal properties of this compound have been demonstrated in a number of greenhouse tests. The test method and results are as follows. Test A: Digitaria sp., Echinochloa crusgalli, Avenafatua, Cassia tora, Bromus socalimus, Cassia obtusifolia, Ipomoea
Sp. Pre-emergence treatments were carried out using chemicals dissolved in non-toxic solvents. At the same time, these crops and weed species were treated with soil/foliar applications. At the time of treatment, plants ranged in height from 2 to 18 cm. Treated and control plants were kept in the greenhouse for 16 days and all species were compared to the control and the response to treatment was visually assessed. Table 1
The evaluation method summarized in is based on a scale from 0 (no drop) to 10 (maximum drop). The accompanying letter symbols have the following meanings. B = Burn C = Yellowing/Destruction D = Defoliation E = Germination inhibition G = Growth retardation H = Formation effects U = Abnormal pigmentation and 6Y = Abscessed buds or flowers - = Not tested [Table] [Table] [Table] Cheatgrass − − −
− − − −
− −
[Table] [Table] Cheatgrass − − −
−

Test B After germination Two round bottom pots (diameter 25 cm x depth 12.5 cm) were filled with woodstone sandy loam soil. blackgrass (Alopecurus myosuroides) in one pot;
Sugar beet, Cyperus rotundus
tubers, Digitaria sanguinalis, Cassia obtusifolia, Sida spinosa, Datura stramonium, Abutilon theophrasti, and Setaria faberii. In other pots, add wheat, cotton, rice, corn, soybeans, oats (Avena fatua), and
pensylvanicum), morning glory (Ipomoea
hederacae), Sorghum
halepense) and Golden Millet (Echinochloa
crusgalli). Let the transplants grow for about 14 days,
Chemicals dissolved in non-phytotoxic solvents were then sprayed post-emergence. Before germination Two round-bottom pots (diameter 25 cm x depth 12.5 cm) were filled with woodstone sandy loam soil. Black grass, sugar beet, Japanese mullet root in one pot,
I planted crabgrass, black pot, teaweed, morning glory, velvet leaf, and red foxtail. In another pot, add wheat, cotton,
Rice, maize, soybean, oat, Japanese fir, morning glory, japanese grass, and rice millet were planted. Two pans were pre-sprayed with chemicals dissolved in non-phytotoxic solvents. Treated plants and controls were kept in the greenhouse for 28 days, then all treated plants were compared to controls and plant responses were visually assessed. Response evaluation is based on a scale of 0 to 10, where 0 = no effect and 10 = complete control. The type of response was indicated by a letter symbol as described for Test 1. Datushiyu (-) means no test. Response evaluations are shown in Table 2. [TABLE] [TABLE] [TABLE] [TABLE] [TABLE] [TABLE] TEST C Two 10-inch diameter polyethylene liner-lined plastic pans were filled with formulated Falsington silt loam soil. In one pot, add wheat (Triticum aestivum), barley (Hordeum vulgare), and oats (Avena).
fatua), Bromussecalinus,
Black grass (Alopecurus myosuroides),
Seeds of annual bluegrass (Poa annua), green foxtail (Setariaviridis), rapeseed (Brassica napus) and Italian ryegrass (Lolium multiflorum) were planted. In another pot, Russian chittle (Salsola kali), Speedwell (Veronica persica), Kochia (Kochia)
scoparia), Capsellabursa
-pastoris), Matricaria inodora, grass straw (Gallium aparine), black nightshade (Solanum nigrum) and wild buckweed (Polygonum convolvulus). The above two pots were treated before germination. At the same time, two pots in which the above plants were growing were treated after germination. The height of the plants at the time of treatment ranged from 1 to 15 cm, depending on the plant type. The compound was diluted in a non-phytotoxic solvent and sprayed onto the top of the pan. Untreated controls and solvent only were also included for comparison. All treatments were kept in a greenhouse for 20 days, after which treatments were compared to controls and the effects were visually evaluated. The recorded data are shown in Table 3. [Table] [Table]

Claims (1)

[Claims] 1 formula [wherein R is H or _CH3 , _R1 is _C1 - _C3 alkyl, _R2 is Ra or Rb, Ra is _C1 - _C6 alkoxy, _C1 - _C8 alkylthio, _C1 - _C8 alkylsulfinyl, _C2 - _C8 alkylsulfonyl, _C3 - _C6 alkenyloxy, _C3
-C6 alkynyloxy, _{C3 -C6} alkenylthio,
_C3 - _C6 alkenylsulfinyl, _C3 - _C6 alkenylsulfonyl, _C3 - _C6 alkynylthio, _C3-
C6 alkynylsulfinyl, _C3 - _C6 alkynylsulfonyl, OCH ₂ CH ₂ OCH ₃ , OCH ₂ CH ₂
SCH ₃ , OCH ₂ CH ₂ S(O)CH ₃ , OCH ₂ CH ₂ SO _2
CH3 ; C2- _C6 alkyl substituted with 1 to 3 F, _C1 or Br atoms; _CH2F , _CHF2 ; C1 _{- C2
C1} -C4 alkyl substituted with alkoxy, C1 _{- C2} alkylthio, _C1 - _C2 alkylsulfinyl or _{C1 - C2} alkylsulfonyl; _OCF2H ,
OCH ₂ CH ₂ F, OCH ₂ CHF ₂ , OCH ₂ CF ₃ , OCH _2
CH2C1 ,S-cyclohexyl or S- _C6H5 , and Rb is _C1 - _{C3 alkyl} , cyclopropyl,
_C1 - _C3 alkoxy, _C1 - _C3 alkylthio, _C1-
C ₃ alkylsulfinyl, C ₁ -C ₃ alkylsulfonyl, allyloxy, allylthio, allylsulfinyl, allylsulfonyl, propargyloxy, propargylthio, propargyl sulfinyl, propargyl sulfonyl, OCF ₂ H, OCH ₂
CH ₂ F, OCH ₂ CHF ₂ , OCH ₂ CF ₃ , OCH ₂ CH ₂
C1; or C1- _C3 alkyl substituted with ₁ to 3 F or C1 atoms; or _OCH3 or
_{C1 - C2} alkyl substituted with _SCH3 , and X is _CH3 , _OCH3 , _OC2H5 , C1, Br or
_OCF2H , Y is _C1 - _C2 alkyl, _C1 - _C2 alkoxy,
OCF ₂ H, OCH ₂ CH ₂ F, OCH ₂ CHF ₂ , OCH _2
CF3 , _NHCH3 or N( _CH3 ) ₂ , Z is CH or N, provided that when 1X is C1 or Br, Z is CH and Y is _C1 - _C2 alkoxy, NHCH ₃ or N(CH ₃ ) ₂ , and when 2 Ra is SCH ₃ , R is H;
R ₁ is CH ₃ , X is OCH ₃ , and Y is
OCH ₃ and Z is CH; 3 When Ra is OCH ₃ , R is H;
R ₁ is CH ₃ , X is OCH ₃ and Y is CH ₃
and Z is N and 4 X and/or Y are OCF ₂ H,
R ₂ is Rb, 4A When neither X nor Y is OCF ₂ H, R ₂ is Ra, 5 When X or Y is OCF ₂ H, Z is
and when 6 X or Y is OCF ₂ H, the other is CH ₃ , OCH ₃ or OCF ₂ H] and agriculturally suitable salts thereof. 2 R ₂ is Ra, and Ra is CH ₃ O, OCH ₃
S, _C3 - _C6 alkenyloxy, _C3 - _C6 alkynyloxy, _C3 - _C6 alkenylthio, _C3 - _C6 alkenylsulfinyl, _C3 - _C6 alkenylsulfonyl, _C3 - _C6 alkynyl Sulfinyl, _C3 - _C6
Alkynylsulfonyl; C2- _C6 alkyl substituted with 1 to 3 F, _C1 or Br atoms; _CH2
F, _CHF2 ; _C1 - _C2 alkoxy, _C1 - _C2 alkylthio, _C1 - _C2 alkylsulfinyl or _{C1
C1 - C4 alkyl} substituted with _-C2 alkylsulfonyl; _{OCH2CH2OCH3 , OCH2CH2SCH3 ,}
OCH ₂ CH ₂ S(O)CH ₃ , OCH ₂ CH ₂ SO ₂ CH ₃ ,
OCF ₂ H, OCH ₂ CH ₂ F, OCH ₂ CHF ₂ , OCH ₂ CF ₃
or OCH ₂ CH ₂ C1. 3. The compound according to claim 2, wherein R is H. 4 Ra is _CH3O , _CH3S , _{C3 -} C4alkynyloxy, _{C3 -} C4alkenylthio, _{C3 -} C4alkenylsulfinyl, _{C3 -} C4alkenylsulfonyl; 1 to 3 Substituted with F or C1 atom
C2 _{- C3} alkyl; _CH2F , _CHF2 ; C substituted with _C1 - _C2 alkoxy, _C1 - _C2 alkylthio, _C1 - _C2 alkylsulfinyl or _C1 - _C2 alkylsulfonyl ₁ −C ₂ alkyl; OCHF ₂ , OCH ₂
The compound according to claim 3, which is CH ₂ F, OCH ₂ CF ₃ or OCH ₂ CH ₂ C1. 5 R ₁ is CH ₃ or CH ₂ CH ₃ , X is CH ₃ ,
OCH ₃ or C1, and Y is CH ₃ ,
The compound according to claim 4, which is OCH ₃ , C ₂ H ₅ or OC ₂ H ₅ . 6 Ra is allyloxy, allylthio, propargyloxy, propargylthio, CH ₄ F,
The compound according to claim 5, which is OCHF ₂ , OCH ₂ CH ₂ F or CH ₃ S. 7 _R2 is Ra, and Ra is _C2 - _C6 alkoxy, _C2 - _C8 alkylthio, _C2 - _C8 alkylsulfonyl, _C1 - _C8 alkylsulfinyl, S-cyclohexyl or _{SC6H 5.} The compound according to claim 1, which is 8. The compound according to claim 7, wherein R is H. 9. The compound according to claim 8, wherein Ra is _C2 - _C4 alkoxy, _C2 - _C4 alkylthio, _C2 - _C4 alkylsulsul or _C1 - _C4 alkylsulfinyl. 10 R ₁ is CH ₃ or C ₂ H ₅ , X is CH ₃ , OCH ₃ or C1, and Y is
The compound according to claim 9, which is CH ₃ , OCH ₃ , C ₂ H ₅ or OC ₂ H ₅ . 11. The compound according to claim 10, wherein 11 Ra is _C2 - _C3 alkoxy, _C2 - _C3 alkylthio or _C1 - _C3 alkylsulfinyl. 12 _R2 is Rb, and Rb is _C1 - _C2 alkyl, cyclopropyl, _C1 - _C2 alkoxy, _C1-
C3 thioalkyl, _C1 - _C3 alkylsulfinyl,
C ₁ -C ₃ alkylsulfonyl, CF ₃ , propargyloxy, propargylthio, propargyl sulfinyl, propargyl sulfonyl, OCF ₂ H,
OCH ₂ CH ₂ F, OCH ₂ CHF ₂ , OCH ₂ CF ₃ , OCH ₂
The compound according to claim 1, which is _C2 alkyl substituted with _CH2C1 ; or _OCH3 or _SCH3 . 13 R is H, R ₁ is C ₁ -C ₂ alkyl, Rb is C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C _{1
-C2alkylthio} , _CF3 or _OCF2H ,
The compound according to claim 12, wherein Y is _CH3 or _OCH3 . 14 Rb is CH ₃ , OCH ₃ , OCH ₂ CH ₃ or CF ₃
The compound according to claim 13, which is 15 R ₂ is Rb, and Rb is propyl, propyloxy, allyloxy, allylthio, allylsulfinyl, allylsulfonyl, CH _3
OCH2 , _CH3SCH2 , _CH2F , _CHF2 ; _C2 -C3 alkyl substituted with 1 to _{3 F} atoms; or 1
2. A compound according to claim 1 which is _C1 - _C3 alkyl substituted with ~3 C1 atoms. 16 R is H, R ₁ is C ₁ -C ₂ alkyl, Rb is CH ₂ F or CH ₂ CH ₂ F, and Y is CH ₃ or OCH ₃ , Claim 15 Compounds described in Section. 17 2-[[(4,6-dimethoxypyrimidine-
2-yl)aminocarbonyl]aminosulfonyl]-4-(methylthio)benzoic acid methyl ester. 18 4-methoxy-2-[[(4-methoxy-6
-methyl-1,3,5-triazin-2-yl)
The compound according to claim 1, which is aminocarbonyl]aminosulfonyl]benzoic acid methyl ester. 19 2-[[[4-(difluoromethoxy)-6-
The compound according to claim 1, which is methoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4-ethoxybenzoic acid methyl ester. 20 formula [wherein R is H or _CH3 , _R1 is _C1 - _C3 alkyl, _R2 is Ra or Rb, Ra is _C1 - _C6 alkoxy, _C1 - _C8 alkylthio, _C3 - _C6 alkenyloxy, _C3 - _C6 alkynyloxy, _C3 - _C6 alkenylthio, _C3 - _C6 alkenylsulfinyl, _C3 - _C6 alkenylsulfonyl, _C3 - _C6 alkynylthio, _C3 - _C6 alkynylsulfinyl, ₃ - _C6 alkynylsulfonyl,
OCH ₂ CH ₂ OCH ₃ , OCH ₂ CH ₂ SCH ₃ , OCH ₂ CH ₂
S(O) _{CH3 , OCH2CH2SO2CH3} ; _{C2 - C6} alkyl substituted with 1 to 3 F, C1 or Br _atoms ; _CH2F , _CHF2 ; _C1 - _C2 Alkoxy, C ₁ −
C 1 -C 4 alkyl substituted with C ₂ alkylthio, C ₁ -C ₂ alkylsulfinyl or C _{1 -C 2} alkylsulfonyl; _{OCH 2 CH 2} F, OCH ₂ CHF ₂ ,
OCH ₂ CH ₂ C1, S-cyclohexyl or S-C _6
H5 and Rb is _C1 - _C3 alkyl, cyclopropyl, _C1 - _C3 alkoxy, _C1 - _C3 alkylthio,
C ₁ -C ₃ alkylsulfinyl, C ₁ -C ₃ alkylsulfonyl, allyloxy, allylthio, allylsulfinyl, allylsulfonyl, propargyloxy, propargylthio, propargyl sulfinyl, propargyl sulfonyl, OCF ₂ H,
OCH ₂ CH ₂ F, OCH ₂ CHF ₂ , OCH ₂ OF ₃ , OCH ₂
or C1 _{- C3 alkyl substituted with 1 to 3 F or C1 atoms; or C1-C2 alkyl substituted} with _OCH3 or _SCH3 , _and X is _CH3 , OCH ₃ , OC ₂ H ₅ , C1, Br or
_OCF2H , Y is _C1 - _C2 alkyl, _C1 - _C2 alkoxy,
OCF ₂ H, OCH ₂ CH ₂ F, OCH ₂ CHF ₂ , OCH _2
CF3 , _NHCH3 or N( _CH3 ) ₂ , Z is CH or N, provided that when 1X is C1 or Br, Z is CH and Y is _C1 - _C2 alkoxy, NHCH ₃ or N(CH ₃ ) ₂ , and when 2 Ra is SCH ₃ , R is H;
R ₁ is CH ₃ , X is OCH ₃ , and Y is
OCH ₃ and Z is CH; 3 When Ra is OCH ₃ , R is H;
R ₁ is CH ₃ , X is OCH ₃ , Y is CH ₃
and Z is N and 4 X and/or Y are OCF ₂ H,
R ₂ is Rb, 4A When neither X nor Y is OCF ₂ H, R ₂ is Ra, 5 When X or Y is OCF ₂ H, Z is
and 6 when X or Y is OCF ₂ H, the other is CH ₃ , OCH ₃ or OCF ₂ H] or an agriculturally suitable salt thereof as an active ingredient. An agent suitable for agricultural use for regulating undesirable plant growth. 21. The drug according to claim 20, further comprising at least one of a surfactant or a solid or liquid diluent. 22 R ₂ is Ra, and Ra is CH ₃ O, CH ₃
S, _C3 - _C6 alkynyloxy, _C3 - _C6 alkynyloxy, _C3 -C6 alkenylthio, _C3 - _{C6 alkenylsulfinyl} , _C3 - _C6 alkenylsulfonyl, _C3 - _C6 alkynyl Sulfinyl, _C3 - _C6
Alkynylsulfonyl; _C2 - _C6 alkyl substituted with 1 to 3 F.C1 or Br atoms; _CH2F ,
_CHF2 ; _C1 - _C2 alkoxy, _C1 - _C2 alkylthio, _C1 - _C2 alkylsulfinyl or _{C1-
C1 - C4 alkyl} substituted with C2 _{alkylsulfonyl} ; _{OCH2CH2OCH3 , OCH2CH2SCH3 ,}
OCH ₂ CH ₂ S(O)CH ₃ , OCH ₂ CH ₂ SO ₂ CH ₃ ,
A patent containing an effective amount of a compound according to claim 20 which is OCH ₂ CH ₂ F, OCH ₂ CHF ₂ or OCH ₂ CH ₂ C1 and at least one of a surfactant or a solid or liquid diluent. The drug according to claim 20. 23. A medicament according to claim 21, containing an effective amount of a compound according to claim 21, in which 23 R is H and at least one surfactant or a solid or liquid diluent. 24 Ra is CH ₃ O, CH ₃ S, C ₃ -C ₄ alkenyloxy, C ₃ -C ₄ alkenylthio, C ₃ -C ₄ alkenylsulfinyl, C ₃ -C ₄ alkenylsulfonyl; 1 to 3 Substituted with F or C1 atom
C2 _{- C3} alkyl; _CH2F , _CHF2 ; C substituted with _C1 - _C2 alkoxy, _C1 - _C2 alkylthio, _C1 - _C2 alkylsulfinyl or _C1 - _C2 alkylsulfonyl _{1 -C2} alkyl; containing an effective amount _of a compound according to claim ₂₃ which is _OCH2CH2F or _OCH2CH2C1 and at least one surfactant or solid or liquid diluent. The drug according to claim 23. 25 R ₁ is CH ₃ or CH ₂ CH ₃ and X is
CH ₃ , OCH ₃ or C1, and Y is CH ₃ ,
OCH ₃ , C ₂ H ₅ or OC ₂ H ₅ and an effective amount of a compound according to claim 24 and at least one of a surfactant or a solid or liquid diluent. 2
The drug described in Section 4. 26 Ra is allyloxy, allylthio, propargyloxy, propargylthio, CH ₂ F,
Claim 25 containing an effective amount of a compound according to Claim 25 which is OCH ₂ CH ₂ F or CH ₃ S and at least one surfactant or a solid or liquid diluent. drug. 27 Effective amount and surface of the compound of claim 20, wherein R ₂ is Ra and Ra is C ₂ -C ₆ alkoxy, C ₂ -C ₈ alkylthio, S-cyclohexyl or SC ₆ H ₅ 21. Medicament according to claim 20, containing at least one active agent or a solid or liquid diluent. 28. A medicament according to claim 27 containing an effective amount of a compound according to claim 27, wherein R is H and at least one surfactant or a solid or liquid diluent. 29. A patent containing an effective amount of a compound according to claim 27, wherein Ra is _C2 - _C4 alkoxy or _C2 - _C4 alkylthio, and at least one surfactant or solid or liquid diluent. The drug according to claim 27. 30 R ₁ is CH ₃ or C ₂ H ₅ , X is CH ₃ ,
OCH ₃ or C1, and Y is CH ₃ , C ₂ H ₅
or OC ₂ H ₅ Claim 2 containing an effective amount of a compound according to Claim 29 and at least one of a surfactant or a solid or liquid diluent.
The drug described in item 9. 31 A patent containing an effective amount of a compound according to claim 30, wherein Ra is _C2 - _C3 alkoxy or _C2 - _C3 alkylthio, and at least one surfactant or solid or liquid diluent. The drug according to claim 30. 32 _R2 is Rb, and Rb is _C1 - _C2 alkyl, cyclopropyl, _C1 - _C2 alkoxy, _C1-
C3 thioalkyl, _C1 - _C3 alkylsulfinyl,
C ₁ -C ₃ alkylsulfonyl, CF ₃ , propargyloxy, propargylthio, propargyl sulfinyl, propargyl sulfonyl, OCF ₂ H,
or OCH ₂ CH ₂ F, _{OCH 2} CHF ₂ , OCH ₂ CH _{2 C1 ;} or a surfactant or 21. Medicament according to claim 20, containing at least one solid or liquid diluent. 33 R is H, R ₁ is C ₁ -C ₂ alkyl, Rb is C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C _{1
-C2alkylthio} , _CF3 or _OCF2H ,
and Claim 3 containing an effective amount of the compound of Claim 32, wherein Y is _CH3 or _OCH3 , and at least one surfactant or solid or liquid diluent.
The drug described in Section 2. 34 Rb is CH ₃ , OCH ₃ , OCH ₂ CH ₃ or CF ₃
34. A medicament according to claim 33 containing an effective amount of a compound according to claim 33 and at least one of a surfactant or a solid or liquid diluent. 35 R ₂ is Rb, and Rb is propyl, propyloxy, allyloxy, allylthio, allylsulfinyl, allylsulfonyl, CH _3
OCH2 , _CH3SCH2 , _CH2F , _CHF2 ; _C2 -C3 alkyl substituted with 1 to _{3 F} atoms; or 1
A patent containing an effective amount of a compound according to claim 20 which is _C1 - _C3 alkyl substituted with ~3 C1 atoms and at least one surfactant or solid or liquid diluent. The drug according to claim 20. 36 R is H, R ₁ is C ₁ -C ₂ alkyl, Rb is CH ₂ F or CH ₂ CH ₂ F, and Y is CH ₃ or OCH ₃ , Claim 35 Claim 3 containing an effective amount of a compound as described in Claim 3 and at least one surfactant or a solid or liquid diluent.
The drug described in item 5. 37 2-[[(4,6-dimethoxypyrimidine-
2-yl)aminocarbonyl]aminosulfonyl]-4-(methylthio)benzoic acid methyl ester and at least one surfactant or solid or liquid diluent. drug. 38 4-methoxy-2-[[(4-methoxy-6
-methyl-1,3,5-triazin-2-yl)
21. Medicament according to claim 20, containing an effective amount of aminocarbonyl]aminosulfonyl]benzoic acid methyl ester and at least one surfactant or solid or liquid diluent. 39 2-[[[4-(difluoromethoxy)-6-
Claim 20 containing an effective amount of methoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4-ethoxybenzoic acid methyl ester and at least one surfactant or solid or liquid diluent. drug.