CA2033346A1 - Heterocyclic compounds - Google Patents
Heterocyclic compoundsInfo
- Publication number
- CA2033346A1 CA2033346A1 CA002033346A CA2033346A CA2033346A1 CA 2033346 A1 CA2033346 A1 CA 2033346A1 CA 002033346 A CA002033346 A CA 002033346A CA 2033346 A CA2033346 A CA 2033346A CA 2033346 A1 CA2033346 A1 CA 2033346A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- signifies
- methyl
- oxo
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract The invention is concerned with compounds of the formula I
wherein R1, R2, R3, R4, R5, R6, R7, n and X
have the significances given in the description, as well as enol ethers and salts thereof and their manufacture.
The compounds have herbicidal properties and are accordingly suitable as active ingredients of weed control compositions. The invention is also concerned with weed control compositions containing one or more of such substances as well as the use of the substances or compositions for the control of weeds. Certain starting materials, which also have herbicidal activity, and their production are also described.
wherein R1, R2, R3, R4, R5, R6, R7, n and X
have the significances given in the description, as well as enol ethers and salts thereof and their manufacture.
The compounds have herbicidal properties and are accordingly suitable as active ingredients of weed control compositions. The invention is also concerned with weed control compositions containing one or more of such substances as well as the use of the substances or compositions for the control of weeds. Certain starting materials, which also have herbicidal activity, and their production are also described.
Description
~ ~` ` 2 ~ 3 ~
PS/5-18386/ROC 2071 :. .
.
Ele~ero~yclic compowlds :
: ~' The presen~ invention is conce~ned with heterocyclic compounds, namely 3-aryluracils of the general formula R ~N~O R2 : ~ ~.
R~x~C~ 4) ~;
wherein Rl signifies hydrogen, Cl_4-alkyl, Cl 4-halo- .
alkyl, C2 5-alkenyl or C3_5-alkYnYl, ~ :
R2 signifies hydrogen, Cl 4-alkyl, Cl 4-halo- ; .
alkyl, Cl 4-alkoxy-cl-4-alkyl~ cl_4-alkoXY
-Cl 4-alkoxY-C1 4-alkyl~ C2_s-CYanalkYl~ ~ :
C2 5-carboxyalkyl, Cz 5-alkoxycarbonyl~
-Cl 4-alkyl, C2 5-haloalkoxycaLbonyl-C1 4-1-4 Y 2-5 y arbonyl -Cl 4-alkyl. C2 5-alkoxycarbonyl-C2 5--alkoxycarbonyl-Cl 4-alkyl, C -cyclo- :~
alkyloxycarbonyl-Cl 4-alkyl, carbamoyl-Cl 4- .
-alkyl, mono(Cl 4-alkyl)carbamoyl-C1 4-alkyl, di(Cl 4-alkyl)carbamoyl-C1 4-alkyl, C3 or 4-alkenyl~ C3 or 4~halalkenYl~
cinnamyl, C3 O~ 4-alkynyl o~ C3 or 4-halo-alkynyl, R and R each independently signify hydrogen, ::.
halogen, C1 4-alkyl ol phenyl, 35 R5 fiignifies hydrogen, fluorine or chlo~ine, 3 3 ~
PS/5-18386/ROC 2071 :. .
.
Ele~ero~yclic compowlds :
: ~' The presen~ invention is conce~ned with heterocyclic compounds, namely 3-aryluracils of the general formula R ~N~O R2 : ~ ~.
R~x~C~ 4) ~;
wherein Rl signifies hydrogen, Cl_4-alkyl, Cl 4-halo- .
alkyl, C2 5-alkenyl or C3_5-alkYnYl, ~ :
R2 signifies hydrogen, Cl 4-alkyl, Cl 4-halo- ; .
alkyl, Cl 4-alkoxy-cl-4-alkyl~ cl_4-alkoXY
-Cl 4-alkoxY-C1 4-alkyl~ C2_s-CYanalkYl~ ~ :
C2 5-carboxyalkyl, Cz 5-alkoxycarbonyl~
-Cl 4-alkyl, C2 5-haloalkoxycaLbonyl-C1 4-1-4 Y 2-5 y arbonyl -Cl 4-alkyl. C2 5-alkoxycarbonyl-C2 5--alkoxycarbonyl-Cl 4-alkyl, C -cyclo- :~
alkyloxycarbonyl-Cl 4-alkyl, carbamoyl-Cl 4- .
-alkyl, mono(Cl 4-alkyl)carbamoyl-C1 4-alkyl, di(Cl 4-alkyl)carbamoyl-C1 4-alkyl, C3 or 4-alkenyl~ C3 or 4~halalkenYl~
cinnamyl, C3 O~ 4-alkynyl o~ C3 or 4-halo-alkynyl, R and R each independently signify hydrogen, ::.
halogen, C1 4-alkyl ol phenyl, 35 R5 fiignifies hydrogen, fluorine or chlo~ine, 3 3 ~
RS signifies hydrogen, halogen or C~ 4-alkyl, R7 signifies Cl_4-alkyl or, where R iB not Cl 4-haloalkyl, also Cl 4-haloalkyl, n 6ignifies zero or 1 and 5 X ~ignifies oxygen or sulphur, and the enol e~hers of those compounds of formula I in which Rl signifies Cl ~-alkyl, C2 5-alkenyl or C3 5-alkynyl as well as sal~s of those compounds of formula I in which Rl signifies hydrogen, R2 signifies hydrogen and/or R2 signifies C~ 5-carboxyalkyl.
The above-mentioned enol ethers are thus the compounds of the formula R7 1/ ;-:
~ N ~ OR R2 R~R~X~ 4)n Ia Wherein R2, R3, R4 R5 R6 R7 d have the significances given above and Rl signifies C 25 Cl 4-alkyl~ C~ 5-alkenyl or C3 ~-alkynyl.
The compounds in accordance with the invention, namely the compounds of formula I and their enol ethers and salts, have herbicidal activity and are suitable as active 30 ingredien~s of weed control compositions. Accordingly, the :
invention also embraces weed control compositions which contain compounds in accordance with the invention as active ingredients, a proces6 for the manufacture of these compounds as well as the use of the compounds or ~ -compositions for the control of weeds.
2~333L?!~
.~ `
In formula I above "halogen~ embraces fluorine, chlorine, bromine or iodine. The alkyl, alkenyl and alkynyl residues can be stcaigh~-chain or branched, and ,~
this also applies to the or each alkyl, alkenyl or alkynyl ~ ~;
5 part of larger groups such as alkoxyalkoxyalkyl. A halo-alkyl, haloalkenyl or haloalkynyl group can have one or more (similar or different) halogen atoms, and this also apelies to haloal~yl as pa~t of a larger group such as haloalkoxycacbonylalkyl. Depending on the number of carbon lO atoms therein, the alkenyl and alkynyl ~esidues can have more than one double bond and t~iple bond, respectively.
C The salts of the compounds of formula I are especially alkali metal salts, e.g. sodium and potassium salts;
15 alkaline ear~h metal salts, e.g. calcium and magnesium salts: ~ammonium salts, i.e. unsubstituted ammonium salts and mono- or multiply-substituted ammonium salts, e.g. ;~
triethylammonium and methylammonium salts, as well as salts with other organic basest e.g. with pyridine.
The presence of at least one asymmetLic carbon atom in the compounds I and in their enol ethers Ia means that the compounds can occur in optically isomeric forms. Geometric isomerism can also occur when an aliphatic C=C or C=N
C double bond is present. Moceover, keto-enol tautomerism 25 [-NH-CO~-N=C(OH)-] can occur in those compounds of formula I in which R signifies hydrogen. Formula I is ~
intended to embrace all of these possible isomeric forms ~-as well as mixtures thereof.
An interesting group of compounds in accordance with the invention comprises those compounds of formula I in which R signifies hydrogen OL Cl 4-alkyl, R
signifies hydrogen, Cl 4-alkyl, Cl_4 hal a y Cl ~-alkoxy-Cl 4-alkyl, C2 5-cyanoalkyl, C2 5--alkoxycarbonyl-Cl ~-alkyl, carbamoyl-Cl 4-alkyl, ~ ~333~i~
di(Cl 4-alkyl.)ca~bamoyl-C1 4-alkyl, C~ or 4-alkenyl, cinnamyl or C3 0~ 4-alkynyl, R3 and R each independently signify hydrogen o~ Cl 4-alkyl, R
signifies hydrogen or fluorine, R6 ~ignifies hydrogen or halogen, R signifies Cl 4-alkyl or Cl 4-haloalkyl, n signifies zero or 1 and X ~ignifies oxygen or sulphur, a~ well as ~he enol ethe~s of those compounds of formula I
in which R ~ignifie~ Cl 4-alkyl.
Independently of each othe~ R preferably signifies ~t~aigh~-chain Cl 4-alkyl, e6pecially methyl, or Cl 4--haloalkyl, especially difluoromethyl; R prefe~ably gnif ieS Cl_4-alkYl~ Cl 4-alkOxy-cl 4-alkyl, ~ -alkenyl. C3 0~ 4-alkynYl, Cl_4 halo y -C3 or 4-haloalkenyl or C3 0 4-haloalkynYl. especially the first, second, third or fourth of such groups; R
and R each preferably signify hydrogen or Cl 4-alkyl, especially hydrogen: R5 preferably signifies hydrogen or fluorine: RS preferably signifies hydrogen, fluorine, chlorine, bromine or methyl, especially hydrogen: R7 pLeferably signifies Cl 4-alkyl, especially Cl 3-alkyl such as methyl or ethyl, or Cl 4-fluoroalkyl, especially trifluoromethyl or pentafluoroethyl: and n preferably signifies zero when X signifies sulphur or n preferably signifies 1 when X ~ignifies oxygen.
Preferred individu~l compounds of formula I are:
:
6-Ethyl-3-~4-allyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazin-6-yl~-5-bromo-1-methyl-2,4(1H,3H)-pyrimidine-dione, :
The above-mentioned enol ethers are thus the compounds of the formula R7 1/ ;-:
~ N ~ OR R2 R~R~X~ 4)n Ia Wherein R2, R3, R4 R5 R6 R7 d have the significances given above and Rl signifies C 25 Cl 4-alkyl~ C~ 5-alkenyl or C3 ~-alkynyl.
The compounds in accordance with the invention, namely the compounds of formula I and their enol ethers and salts, have herbicidal activity and are suitable as active 30 ingredien~s of weed control compositions. Accordingly, the :
invention also embraces weed control compositions which contain compounds in accordance with the invention as active ingredients, a proces6 for the manufacture of these compounds as well as the use of the compounds or ~ -compositions for the control of weeds.
2~333L?!~
.~ `
In formula I above "halogen~ embraces fluorine, chlorine, bromine or iodine. The alkyl, alkenyl and alkynyl residues can be stcaigh~-chain or branched, and ,~
this also applies to the or each alkyl, alkenyl or alkynyl ~ ~;
5 part of larger groups such as alkoxyalkoxyalkyl. A halo-alkyl, haloalkenyl or haloalkynyl group can have one or more (similar or different) halogen atoms, and this also apelies to haloal~yl as pa~t of a larger group such as haloalkoxycacbonylalkyl. Depending on the number of carbon lO atoms therein, the alkenyl and alkynyl ~esidues can have more than one double bond and t~iple bond, respectively.
C The salts of the compounds of formula I are especially alkali metal salts, e.g. sodium and potassium salts;
15 alkaline ear~h metal salts, e.g. calcium and magnesium salts: ~ammonium salts, i.e. unsubstituted ammonium salts and mono- or multiply-substituted ammonium salts, e.g. ;~
triethylammonium and methylammonium salts, as well as salts with other organic basest e.g. with pyridine.
The presence of at least one asymmetLic carbon atom in the compounds I and in their enol ethers Ia means that the compounds can occur in optically isomeric forms. Geometric isomerism can also occur when an aliphatic C=C or C=N
C double bond is present. Moceover, keto-enol tautomerism 25 [-NH-CO~-N=C(OH)-] can occur in those compounds of formula I in which R signifies hydrogen. Formula I is ~
intended to embrace all of these possible isomeric forms ~-as well as mixtures thereof.
An interesting group of compounds in accordance with the invention comprises those compounds of formula I in which R signifies hydrogen OL Cl 4-alkyl, R
signifies hydrogen, Cl 4-alkyl, Cl_4 hal a y Cl ~-alkoxy-Cl 4-alkyl, C2 5-cyanoalkyl, C2 5--alkoxycarbonyl-Cl ~-alkyl, carbamoyl-Cl 4-alkyl, ~ ~333~i~
di(Cl 4-alkyl.)ca~bamoyl-C1 4-alkyl, C~ or 4-alkenyl, cinnamyl or C3 0~ 4-alkynyl, R3 and R each independently signify hydrogen o~ Cl 4-alkyl, R
signifies hydrogen or fluorine, R6 ~ignifies hydrogen or halogen, R signifies Cl 4-alkyl or Cl 4-haloalkyl, n signifies zero or 1 and X ~ignifies oxygen or sulphur, a~ well as ~he enol ethe~s of those compounds of formula I
in which R ~ignifie~ Cl 4-alkyl.
Independently of each othe~ R preferably signifies ~t~aigh~-chain Cl 4-alkyl, e6pecially methyl, or Cl 4--haloalkyl, especially difluoromethyl; R prefe~ably gnif ieS Cl_4-alkYl~ Cl 4-alkOxy-cl 4-alkyl, ~ -alkenyl. C3 0~ 4-alkynYl, Cl_4 halo y -C3 or 4-haloalkenyl or C3 0 4-haloalkynYl. especially the first, second, third or fourth of such groups; R
and R each preferably signify hydrogen or Cl 4-alkyl, especially hydrogen: R5 preferably signifies hydrogen or fluorine: RS preferably signifies hydrogen, fluorine, chlorine, bromine or methyl, especially hydrogen: R7 pLeferably signifies Cl 4-alkyl, especially Cl 3-alkyl such as methyl or ethyl, or Cl 4-fluoroalkyl, especially trifluoromethyl or pentafluoroethyl: and n preferably signifies zero when X signifies sulphur or n preferably signifies 1 when X ~ignifies oxygen.
Preferred individu~l compounds of formula I are:
:
6-Ethyl-3-~4-allyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazin-6-yl~-5-bromo-1-methyl-2,4(1H,3H)-pyrimidine-dione, :
3 r3,4-dihyd~o-7-fluo~o-3-oxo-4-(2-propynyl)-ZH-1,4- .. ~ .
-benzoxazin-6-yl]-1-methyl-6-(n-p~opyl)-2,4(lH,3H)- - .
-py~imidinedione, : ~-6-ethyl-3-[3,4-dihydro-7-f 1UOrO-4-iSOpf opyl-3-oxo-ZH--1,4-benzoxazin-6-yl~-1-methyl-2,4(lH,3H)-pyrimidinedione, "": ~' ;
.
~ ~ 2~3~
s .
. . .
6-ethyl-3-[4-sec.butyl-3,~-dihydro-7-fluoro-3-oxo-2H--1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl~3-[3,4-dihydro-7-fluoro-4-(1-methoxyethyl)-3--oxo-ZH~ -benzoxazin-6-yl]-1-methyl-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-t3,4-dihydro-7-fluoro-4-(1-methoxypropyl)-3- , :
-oxo-2H-l~-benzoxazin-6-yl3-1-methyl-2,4(1H,3H)~
-py~imidinedione, 6-ethyl-3-[4-allyl-3,4-dihydro-7-fluoro 3-oxo-2H-1,4-10-benzoxazin-6-yl]-1-me~hyl-2,4(1H,3H)-pyrimidinedione, ~ ;
6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methyl-Z-c -propenyl3-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-Z,4-~lH,3H)-pyrimidinedione, 6-ethyl-3-~3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)--2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidine-dione, 6-ethyl-3-t3,4-dihydro-7-fluoro-4-(1-methyl-2--propynyl)-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4 -(lH,3H)-pyrimidinQdione, 206-e~hyl-3-~6-fluoro-3-isopropyl-2-oxo-5-benzo- -thiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-sec.butyl-6-fluoro-2-oxo-5-benzo-thiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methoxyethyl)-2-oxo-5-benzo- ~ -~hiazolinyl~-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-~6-fluoro-3-(1-methoxypropyl)-2-oxo-5-benzo~
thiazolinyl]-l-methyl-~,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-allyl-6-fluoro-2-oxo-5-benzothiazolinyl]--l-methyl-2.4(lH.3H)-pyrimidinedione, 306-ethyl-3-[6-fluoro-3-(1-methyl-2-propenyl)-2-oxo-5--benzothiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-Z-oxo-3-(2-propinyl)-5-benzo-thiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione and 6-ethyl-3-~6-fluoro-3-(1-methyl-2-propinyl)-2-oxo-5--benzothiaæolin~l]-l-methyl-2,4(1H,3H)-pyrimidinedione.
;~
".
:
: .
3 ~ ~ ~
Representatives of compounds of formula I are:
Those compounds I in which R and R7 each signiy methyl, R , R and R each signify hydrogen, R
signifies fluorine, n signifies 1, X signifie~ oxygen and R signifies ethyl, n propyl, Z-fluoroethyl, methoxy-methyl, 2-methoxyethyl, methoxycarbonylmethyl, l-methoxy-carbonyl-ethyl, 2-methoxycarbonyl-ethyl~ cyclopentyloxy-carbonylmethyl, carbamoylmethyl, dimethylcarbamoylmethyl, 3,3-dichloro-2-propenyl, cinnamyl or 3-chloro-Z-propynyl, 3-r3~4-dihydro-7-fluoro-3-oxo-4-(2-propynyl~-2H-l~4-g -benzoxazin-6-yl~-1,5,6-t~imethyl-2,4(lH,3H~-pyrimidine-dione, 3-[3,4-dihydro-2,2-dimethyl-7-fluoro-3-oxo-4-(2-15 -propynyl)-2H-1,4-benzoxazin-6-yl]-1,6-dimethyl--2,4(1H,3H)-pyLimidinedione, 3-[2-ethyl-3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)--2H-1,4-benzoxazin-6-yl]-1,6-dimethyl-2,4-(lH,3H)--pyrimidinedione, 3-[3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin--6-yl]-1,6-dimethyl-2,4(1H,3H)-pyrimidinedione, 3-[7-chloro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4--benzoxazin-6-yl]-1,6-dimethyl~2;4(lH,3H)-pyrimidinedione, -those compounds I in which R signifies difluoro-methyl, R3, R4 and R each signify hydrogen, R
signifie~ fluorine. R signifies methyl, n signifies 1, ~-X signifies oxygen and R signifies ethyl, ~-propyl, allyl or peopargyl, 6-ethyl-1-difluoromethyl-3-[3,4-dihydro-7-fluoro-3-30 -oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-2,4(1H,3H)- ;
-pyrimidinedione, l-difluoromethyl-3-[3,4-dihydro-7-fluoro-2-methyl-3--oxo-4-(2-propynyl)-2H-1,4-benzoxaæin-6-yl]-6-methyl--2,4(1H,3H)-pyrimidinedione, those com~ounds I in which R signifies methyl, R , R and R eaFh si~nify hyd~ogen, R signifies ..
, . , . ,, , , . ... ., ~,,.. .. ,.; . . . . .
2~333~i~3 _ 7 _ 7 ~:
fluorine, R signifies trifluoromethyl, n signifies 1, X
signifies oxygen and R signifies ethyl, n-propyl, n-bu~yl, carbamoylmethyl, allyl or ~-chloro-2-proeynyl, : .
those compounds I in which Rl siqnifies methyl, R , R , R and R eaGh signify hydrogen, R
signifies trifluoromethyl, n signifies 1, X ~ignifies ~:
oxygen and R signifies ethyl, n-eropyl, 2-fluoroethyl, methoxymethyl, 2-methoxyethyl, cyanome~hyl, methoxy-carbonylmethyl, l-methoxycarbonyl-ethyl, 2-methoxy-1 carbonyl-ethyl, cyclopentyloxycarbonylmethyl, carbamoyl-methyl, dimethylcarbamoylmethyl, allyl, 3,3-dichloro-2--propenyl, cinnamyl, l-methyl-2-propynyl or 3-chloro-2--propynyl, . ::
3-[3,4-dihydro-2-methyl-3-oxo-4-(Z-propynyl)-2H-1,4--benzoxazin-6-yl]-1-methyl-6-trifluoromethyl--2,4-flH,3H)--pyrimidinedione, ''' 3-L7-chloro-3~i4-dihydLo-3-oxo-4-(2-propynyl)-2H-l~4--benzoxazin-6-yl1-1-methyl-6-trifluoromethyl-2~4tlH,3H)- , ..
-pyrimidinedione, those compounds I in which R signifies methyl, ::
R, R . R and R each signify hydrogen, R
signifies pentafluoroethyl, n signifies 1, X signifies oxygen and R signifies n-propyli allyl or peopargyl, those compounds I in which R signifies methyl, R , R and R each signify hydrogen, R signifies : : .
25 fluorine, R signifies pentafluoroethyl, n signifies 1, ~- , X siignifies oxygen and R signifies allyl or propargyl, as well as the corresponding 1,4-benzthiazine derivatives (the above individual compounds of formula I
in which the oxygen atom (X) is re~laced by a sulphur atom) those compounds I in which R and R each signify methyl, R signifies fluorine, R signifies hydrogen, ,~ -n signifies zero, X signifies oxygen and R signifies ethyl, 2-fluoroethyl, 2-methoxyethyl, cyanomethyl, methoxycarbonylmethyl, l-methoxycarbonyl-ethyl, 2-methoxy-'' ' "' . .' , , , . ~ . ' . ~ ' ' ' ''i ' ' ' '' ' ' ' " ' ' carbonyl-ethy.l, cyclopentyloxycarbonylmethyl, carbamoyl-methyl, dimethylcarbamoylmethyl, 3,3-dichloro-2-propenyl, cinnamyl or 3-chloro-2-propynyl, 3-[6-fluoro-2-oxo-3-(2-p~opynyl)-5-benzoxazolinyl]--1,5,6-trimethyl-2,4(1H,3H)-pyrimidinedione, 1,6-dimethyl-3-t2-oxo-3-(2-propynyl)-5-ben20xazolinyl]--2,4(1H,3H)-pyrimidin~dione, 3-[6-chloro-2-oxo-3-(2-propynyl)-5-benzoxazolinyl]--1,6-d;methyl-2,4(1H,3H)-pyrimidinedione, those compound~ I in which Rl signifies difluoro-methyl, R signifies fluorine, R signifie~ hydrogen, R ~ignifies methyl, n signifie~ zero, X signifie6 oxygen and R signifies ethyl, n-propyl, allyl or propargylJ ' ~ ~, lS 6-ethyl-1-difluoromethyl-3-~6-fluoro-2-oxo-3-(2--propynyl~-5-benzoxazolinyl]-2,4~1H,3H)-eyrimidinedione, ~ :
l-difluoromethyl-3-t6-fluoro-2-oxo-3-~2-propynyl)-5- ~. :
-benzoxazolinyl]-6-methyl-2,4(1H,3H)-pyrimidinedione, .: :
those compounds I in which R signifies methyl, R : ::
signifies fluorine, R signifies hydcoge~, R
signifies trifluoromethyl, n signifies zero, X ~ignifies -~
: oxygen and R ~ignifies ethyl, n-propyl, n-butyl, :~
carbamoylmethyl, allyl or 3-chloro-2-propynyl, those compounds I in which R signifies methyl, R
and R each signify hydrogen, R ~ignifies trifluoro-methyl, n signifies zero, X signifies oxygen and R .:~
~ignifies ethyl, n-propyl, 2-fluoroethyl, methoxymethyl, : 5 2-methoxyethyl, cyanomethyl, methoxycarbonylmethyl, l-methoxycarbonyl-ethyl, 2-methoxycarbonyl-ethyl, cyclo-pentyloxycarbonylmethyl, carbamoylmethyl, dimethyl-carbamoylmethyl, allyl, 3,3-dichloro-Z-propenyl, cinnamyl, l-methyl-2-propynyl or 3-chloro-2-propynyl, 3-~6-chloro-2-oxo-3-(2-propynyl)-5-benzoxazolinyl]-1- ~ :
-methyl-6-triEluoromethyl-2,4(1H,3H)-pyrimidinedione, 1-methyl-3-[2-oxo-3-(2-p~opynyl)-5-benzoxazolinylJ-6- .
-trifluoromethyl-2,4(lH,3H)-pyrimidinedione, .
those compounds I in which Rl signifies methyl, R5 and R each signify hydcogen, R7 signifies penta-fluoroe~hyl, n signifies zero, X signifies oxygen and R
signifies n-propyl, allyl or propargyl, those compounds I in which R signifies methyl, R
signifies fluorine, R signifies hydrogen, R
signifies pentafluoroethyl, n signifies zero, X signifies oxygen and R signifies allyl or propargyl, as well as the corresponding benz~hiazoline deriva~ives (the above individual benzoxazolines of formula I in which the oxygen atom (X) is replaced by a sulphur atom).
The process in accordance with ~he invention for the ~ ~:
manufacture of the compounds of formula I and their enol ethers as well as salts comprises a) for th0 manufacture of those compounds of formula I in which R signifies hydrogen and R signifies hydrogen, :.
fluorine or Cl 4~alkyl as well as, if desired, of metal 20 salts of these compounds, subjecting a compound of the ~; .
general formula ',;
C 25 J ~1 ~ 4)n wherein R2, R3, R4, R5, R , n and X have the significances given above, R signifies hydrogen, fluoLine or Cl 4-alkyl and ,.,.. .. , .. , .. . , . , .. ". . " , . . . .. . . . .
:
~--' ` 2~ 3~ ~
R8 signifies lower-alkyl, ~referably Cl 4-alkyl, to a cyclization under basic conditions and, if desired, converting a metal salt of the uracil derivative of formula I which may be obtained into the acidic form -:
5 (R = hyd~ogen) by treatment with an acid.
b) for the manufacture of those compounds of focmula I in which Rl signifies hyd~ogen, R ~ignifies hydrogen, fluorine o~ Cl 4 alkyl and R signi~ies Cl 4-alkyl 10 as well as of salts of the compound6 of fo~mula I, subjecting a csmpound of the gene~al formula C r~x~ --R4 n 20 whe l e i n R2, R3, R , R5, R , n and X have the - significances given above, R ~ignifies Cl 4-alkyl and 25 R signifies lowe~ alkyl, preferably Cl 4-alkyl, to a cyclization under basic conditions and, if desired, ~:
conve~ting a metal salt of the uracil derivative of formula I which may be obtained into the acidic form (R = hyd~ogen) by treatment with an acid, c) for the manufacture of those compounds of formula I in which R signifies Cl 4-alkyl, Cl 4-haloalkyl, C2 5-alkenyl or C3 5-alkynyl, subjecting a u~acil . :
derivative of t~e gene~al fo~mula R ~ N ~ 0 2 R6~R~X~ --R4 ) n wherein RZ, R3, R4 R5 R6 R7 have the significances given above, to an alkylation with an appropriate alkylating agent containing a Cl ~-alkyl. C2_5-alkenYl or C3_5--alkynyl group, d) for the manufacture of tho6e compounds of formula I in which R signifies hydrogen, cleaving off the protecting group R in a uracil derivative of the general formula , :
~ 1 - . ' . 7 1 ~ 0 R10 R' ~ ~j/ ~R
wherein Rl, R3, R4 R5 R6 R7 have the ~iignificances given above and R signifies ~ :
a protecting group, for example i~iopropyl or tert.butyl, e) for the manufactu~e of those compounds of formula I in which R is different from hydrogen, appropriately alkylating a uracil derivative of the general formula " r~ ~ ~ "
~ ~ - 12 - 2~33~
Rl ~ , . R ~ ~1 S R~X~ ~ R4 )n wherein Rl, R3, R4 R5 ~6 R7 have the significances given above, " ' "'~, f) for the manufacture of those compounds of formula I in which R signifies chlorine, bromine or iodine, chlorinating, brominating or iodinating a uracil derivative of the general formula R
R ~ I ~ R2 c R ~ ~ ~ R4)n ~ ~
. :
whe r e i n Rl, ~2 E~3 R4 R5 R~
have the significances qiven above, . : ~:
g) for the manufacture of the enol ethers of formula Ia, treating a pyrimidinone derivative of the general formula . - - .
- .
: ~ .
- 13 - 2~33~
,.
R ~ H a l R 2 ~ X~ ~ ~4 ) n , ~ ~
. :
~ ' wherein ~;
R2, R3. R4 R5 R6 R7 n and X h significances given above :. .
and : :
Hal signifies chlorine or bromine, 1' -with an alkanol, alkenol or alkynol R OH in the ;~
presence of an organic base or with the corresponding alcohola~e, alkenolate or alkynolate of the general formula :
Rl ' ~ V
~ 20 : whe~ein Rl has the significance given above and . ~ signifies one equivalent of a metal ion, C and, if desired, converting a thus-obtained compound of formula I in which R signifies hydrogen, R signifies hydrogen and/or R signifies C2 5-carboxyalkyl in~o a salt.
The cyclization according to process variant a) can be carried out conveniently by treating the compound of formula II in an inert protic organic solvent such as an alcohol, e.g. methanol, ethanol or isopropanol; an inert aprotic organic solvent such as an aliphatic or cyclic ether, e.g. l,Z-dimethoxyethane, tetrahydrofuran or ,,,,. ," ,,~, "1,'",,","',',1 ;,',,,~',',',,',",.,,, ~',;'" ~,',, ',.' ,, ., ', :~ "; . .',,,,~ ~, . ' .. ' ' ', . ,',, : . .,. ' :,,,' .: ,... ., ' '........ : ' 3~ 3 dioxan, or an aromatic, e.g. benzene or toluene: an inert aprotic, ~olar organic i~olvent, e.g. dime~hylfocmamide or -dimethyl sulphoxide, whereby such solvents can be used, if desiced, in a two-phase mixture with a hydrocarbon, e.g.
n-hexane or toluene, or water with a base at temperatures 5 between -78CC and the reflux temperature of the reaction mixture. As bases there ~referably come into consideration sodium alcoholates, alkali metal hydroxide~, especially sodium hydroxide and potassium hydroxide, alkali metal carbonates, especially sodium carbonate and potasEiium 10 carbonate, and sodium hydcide. When sodium hydride is used as the base, the solvent i5 preferably an aliphatic or g cyclic ether, dimethylformamide or dimethyl sulphoxide, whereby any of these solvents can be used in admixture with toluene.
After completion of the cyclization the product, when one of the above-mentioned bases is used, is present in the fo~m of the corresponding alkali metal salt. This can be isolated and purified in a manner known per se or the 20 mixture can be acidified in order to isolate the respective compound of formula I itself. A mineral acid ;~
such as hydcochloric acid oc a stLong organic acid such as acetic acid or p-toluenesulphonic acid is preferably used for this purpose.
According to process variant b) the compound of formula III can be cyclized conveniently in an e6sentially anhydrous inert protic organic solvent such as an alcohol, especially a lower alcohol, e.g. methanol or ethanol, in 30 the presence of a base such as an alkali metal alcoholate, especially the corresponding alcoholate, i.e. methylate or ethylate, of sodium at temperatures between 0C and 70C, prefecably in the temperature eange of 10C to 30C.
Alternatively, for example, the compound III can be ~;~
cyclized in an essentially anhyd~ous inert aprotic organic : .' ., , , . : ~ ! . ,, ; , ! ' solvent such as e.g. dimethylformamide, N-methyl- ~ ~-pyrrolidone, tetramethylurea or hexamethylphosphoric acid triamide in the presence of a metal hydride as the base, e.g. sodium hydride or potassium hydride, at temperatures between 0C and 70C, preferably 10C to 30C.
.
As in the case of process variant a), af~er completion , -of the cyclization the pLoduct, when one of the above- ; ;
-mentioned bases is used, is present in the form of the corresponding alkali me~al salt. This can likewise be isolated and purified in a manner known per ie or the mixture can be acidified in order to isolate the respective compound of formula I itself.
In process variant c) the term "alkylation" refers to the substitution of the hydrogen atom of the N -atom of the uracil nucleus with a Cl 4~alkyl, Cl 4-haloalkyl, C2 5-alkenyl or C3 5-alkynyl group. As the alkylation agent there is conveniently used a Cl 4-alkyl, C2 5--alkenyl or C3 5-alkynyl halide, especially the respective chloride or bromide, or sulphate or a multiply--halogenated Cl 4-alkane such as, for example, chloi~o-difluoromethane or a mono- or multiply-halogenated alkene such as, for example, tetrafluoroethene. -~
The alkylation is conveniently carried out in the preience of an inert, protic organic solvent such as a lower alkanol, e.g. ethanol, optionally in admixture with water: an inert, aprotic organic solvent such as an aliphatic or cyclic ether, e.g. 1,2-dimethoxyethane, tetrahydro~uran or dioxan; a ketone, e.g. acetone or butan-2-one; or an inert, aprotic, polar organic solvent, e.g. dimethylformamide, dimethyl sulphoxide or aceto-nitrile, as well as in the presence of a base such as ;
sodium hydride, an alkali metal hydroxide, especially sodium or potassium hydroxide, an alkali metal alcoholate, - - , i . - : , , ., , , ,, , , ,, ", , ^' 2 ~ 3 ~ x '~
'. ..
especially sodium alcoholate, or an alkali metal carbonate or bicarbonate, especially sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, at temperature~ between 0C and the reflux temperature of the reaction mixture, preferably at room tem~eratuee, or, in the case of the substitution of the hydrogen atom of the -atom with a Cl 4-haloal~yl group, preferably at temperatures between 50C and 100C. In a preferred embodiment, the uracil derivative of formula 1' is treated fiestly wi~h the base such as sodium hydride, ~odium ethanolate or sodium carbonate in the solvent and, a~ter a short reaction time, treated with the halide in the same solvent. In a further embodiment, the uracil derivative I' is Leacted with a dialkyl sul~hate in the presence of an alkali metal carbonate, especially sodium carbonate or potassium carbonate, in the solven~, e.g. acetone, at ~-reflux temeerature. De~ending on the solvent which is used, ~he reaction has generally finished wi~hin a relatively short time or aftar a few hours. After working-up the reaction mixture the desired end product can be separated from starting materials which may remain and/or byploducts according to methods known per se, e.g.
column chromatography and/or fractional crystallization. ~;
The cleavage of the protecting group R10 on the nitrogen atom of the o~azolinone, thiazolinone or 3,4-dihydro-3-oxo-2H-1,4-oxa/thiazine ring according to process variant d) is conveniently effected by the action of a strong, essentially anhydrous, inorganic acid such as, for example, sulphuric acid or oLthophosphoric acid.
Normally, the acid serves not only as the ~eagent, but also as the solvent, so that no additional solvent is required. The reaction is preferably carried out at temperatures between 80C and 160~C, preferably in the temperature range of 120C to 150C.
. . ! . ' ' . ' ' : . ', ' : , . ', . ': ' , , i ~ . . ' . . ' ~ - 17 - ~333~
Process variant e) involves the substitution of the hyd~ogen atom attached to the heterocyclic nitrogen atom wi~h a C -al~Yl, Cl 4-haloalkyl~ Cl-4-alk y 1-4 1-4 ~lk~Y-cl ~-alkoxy-c alkyl C2 5-cyanoalkyl, C2 5-carboxyalkyl, C2 5-alkoxy-5 carbonyl-Cl 4-alkyl, C2_5-haloalko~yca~bonyl Cl_4 -alkyl, Cl 4-alkoxy-C2 5-alkoxycarbonyl-C1 4-alkyl, C2 5-alkoxycarbonyl-C2 5-alkoxycarbonyl-C1 4-alkyl, C4 7-cycloalkyloxycarbonyl-C1 4-alkyl, carbamoyl--Cl 4-alkyl, mono(Cl 4 alkyl)carbamoyl-Cl 4-alkyl, di(Cl_4-alkyl)carbamoyl-Cl_4 alkyl, C3 or 4 Y
C3 4-haloalkenyl, cinnamyl, C3 or 4-alkynyl o~
C3 or 4-haloalkynyl group. This 'lalkylationll can be carried out using a respective halide, especially chloride ,~
ol bromide, analogously ~o prccess variant c). Where a uracil derivative of formula I"' in which R signifies hydrogen is used, process variant c) can of course also come into play and respective mixed alkylation products are formed. Aftec working-up the reaction mixture the desired end product can be liberated from any remaining starting materials and from byproducts according to methods known per se, e.g. column chromatography and/or fractional crystallization.
The chlorination or bromination according to process va~iant f) is conveniently carried out by means of elemental chlorine or sulphuryl chloride or elemental b~omine or sulphuryl bromide in the presence of an inert organic solvent such as acetic acid or a chlorinated aliphatic hydrocarbon, e.g. methylene chloride, chloroform or carbon tetrachloride, and in a temperature range of O~C
to 60C, preferably at room temperature. Moreover, the reaction can be effected with the aid of an acid-binding agent, for which purpose sodium acetate and tertiary amines such as triethylamine, dimethylaniline and pyridine are especially preferred acid-binding agenSs.
.
~33~
- 18 - ~
: . . ' The iodination according to this proce6s variant is conveniently effec~ed using elemental iodine as the iodinating agent and a low-boiling aliphatic carboxylic ~cid such a~ acetic acid as the solvent and at temperatures between about 0C and about 110C, preferably at room tempelature. Mo~eover, i~ has been found to be convenient to carly out the reaction in the presence of an acid such as fuming nitric acid. In o~der to eliminate ;~
excess iodine, saturated aqueous sodium bisulphite solution can be added after completion of the reaction.
Where in this process variant a u~acil derivative of formula I"'l in which R and/or R signifies an unsaturated aliphatic g~oup such as alkenyl or alkynyl is used, it can happen that not only the unoccupied S-position of the uracil nucleus i~ halogenated, but also the mentioned unsaturated aliphatic gcoup is halogenated, e.g. allyl to 2,3-dib~omopropyl. Such two different kinds of halogenated products also belong ~o the scope of the 20 compounds I. After working-up the reaction mixture the ;~
desiled end product can be liberated from any simulta- ~-neously manufactured halogenation products according to methods known per se, e.g. column chromatography and fractional crystallization, or two or more desi~ed halogenation products can be isolated.
: .
In process variant g) the term "metal ion" stands e6pecially for an alkali metal ion, e.g. the sodium or potassium ion, or an alkaline earth metal ion, e.g. the calcium or magnesium ion. The sodium ion is the prefelled metal ion. Where the alkanol, alkenol or alkynol R OHi - is used, pyridine is the e~pecially suitable organic base.
.. . .
The reaction is conveniently effected in an excess of ' -the corresponding hydroxy compound R OH as the diluent and at temperatures between 0C and 50C, preferably at ~oom temperature.
:.''. ''.
' .
` ` 2~33~
Insofar as they are not manufac~ured directly by the above-described cyclization which is carried out under basic conditions, the desired salts of the compounds of formula I in which Rl signifies hydrogen, R signifies hydrogen and/or R signifies Cz 5-carboxyalkyl can also be manufactured from ~hese compounds I in a mannec known per se such as, for example, by dissolving the compound of formula I in a solution of a respective inorganic or organic base. The ~alt formation i6 generally effected within a ~hort time at ~oom tempera~ure. In one embodiment the sodium salt is manufactured by dissolving the uracil derivative I in aqueous sodium hydroxide solution at room temperature, with equivalent amounts of the uracil derivative and of sodium hydroxide being used.
The solid salt can then be isolated by precipitation with a suitable inert solvent or by evaporation of the solvent.
A furthec embodiment comp~ises introducing an aqueous solution of an alkali metal salt of the uracil derivative I into an aqueous solution of a salt which has a metal ion other than an alkali metal ion, whereby the second metal salt of the uracil derivative is manufactured. This embodiment is generall~ used for the manufacture of uracil metal salts which are insoluble in water.
The resulting compounds of formula I, enol ethers as well as salts can be isolated and pucified according to methods known per se. Further, the sequence in which a possible combination of process variants c)-f~ will be conveniently carried out in order to avoid possible undesired concurrent reactions will be familiaL to a person skilled in the art.
Insofar as no planned synthesis for the isolation of pure isomers is carried out, the product can result as a mixture of two or moee isomers. The isomers can be , ... . . . . , ~ . ~ :
;;. : : ,: : , .. . .. . ..... . .... . ..... .. ...
., , , . . ., ., , . , ; .:., ~ : .... , . :
^: : 2~3~
.- 20 -separated according to methods known per ~e. If de8ired, pure optically active i~omers can also be manufactuLed, for example, by synthesis from eorresponding optically active staEting materials.
The ~ta~ting matPrials of focmula II are novel and can be produced in a manner known pe~ se. e.g. in accordance with Reaction Scheme 1 hereinafter ~me~hods aa) and bb)~
in which R2, R3 R4 R5 R6~ ~7 7~ 8 n and X have the significances given above: .
, , , ., ,~ , ; ~:; ...
~ -~..
': .,' ' .
- :
.
::: :, '' '~.'.
- ~ :
Reaction Scheme 1 aa) ~ 0 R 7 D H 2 N ~
R ~--c - O R H N~ ~c ~ 4 ) n \ ~''. ' -VI \ VI I
-7 ~ 7 H o \~ R
R~ HN~ N~0 R 5~ X ~ ~ R 4 ) n I I
C 25 ~;~
b~ ) / R
R X ll-oR9 OC~ ~\C~ R3 IX
V I I I
" , ' :~ : ,~. ..
,.: .,: ~ , .: -~ , , ., :
3 ~ 1~
Method aa3 is conveniently carried out by reacting the compounds of fo~mulae VI and VII with each other in an essen~ially anhydrous diluent and in the presence of an acidic catalyst at an elevated temperature. As diluents there especially come into consideration organic solvents which form azeotcopes with water, such as aromatics, e.g.
benzene, toluene and xylenes; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetra-chloride and chlorobenzene; and aliphatic and cyclic -ethers such as 1,2-dimethoxyethane, tetrahydrofuran and dioxan, and as acidic catalysts there e~pecially come into consideration strong mineral acids such as sulphuric acid ~ and hydrochloric acid; organic acids such as p-toluene-sulphonic acid: phosphorus-containing acids such as orthophosphoric acid and polyphosphoric acid; and acidic cation exchangers such as "Amberlyst 15" (Fluka). The reaction is generally carried out in a temperature range of about 70C to 120C, preferably at the reflux temperature of the reaction mixture. Under these reaction conditions the desired rapid removal of the water which is formed in the reaction is achieved.
The ~eaction according to method bb) is conveniently effected in the presence of an essentially anhydrous aprotic organic solvent such as an aliphatic-or cyclic ether, e.g. diethyl ether, 1,2-dimethoxyethane, tetrahyd~ofuran or dioxan, an aliphatic or aromatic hydrocarbon, e.g. n-hexane, benzene. toluene or a xylene:
or a halogenated, aliphatic hydrocarbon, e.g. methylene chloride, chloroform, carbon tetrachlo~ide or 1,2-dichloroe~hane, as well as optionally in the presence of a base, especially an organic tertiary base such as triethylamine or pyridine, whereby the latter can serve not only as the solvent but also as the base, or a metal hydride ~uch as sodium hydride or potassium hydride. The reaction temperatures are preferably in the range of about ... . .
;~ ` - 23 - ~3 -80C to 50C, with the reaction being caIried out particularly at temperatures between -30C and room temperature.
The sta~ting mateIials of focmulae III are also novel.
These can be produced by reacting a compound of the general formula 7~
R ~ 0 R2 ~ ~ X~ ~ R4 n wherein R , R , R4 R5 R6' R7' have the significances given above, with a lower alkyl carbamate of the general focmula wherein R has the significance given above.
This reaction is conveniently effected in an essentially anhyd~ous inert aprotic organic solvent in the presence of an acidic catalyst. The reaction mixture is heated at the boiling temperature until water has foImed and this is removed continuously from the reaction mixture. As solvents there especially come into consideration organic solvents which form azeotropes with water, such as aromatics, e.g. benzene, toluene and xylenes; and halogenated hydrocaLbons, e.g. chloroform~
carbon tetrachloride and chlorobenzene, and as acidic 2~3~
.. .... ...
catalysts there especially come into consideration organic acids, e.g. toluene-4-~ulphonic acid; mineral acids, e.g.
sulehuric acid, orthophosphoric acid and polyphospho~ic acid; and cation exchangecs, e.g. "Ambeelyst 15" (Fluka).
- The heating is generally ca~ried out in a temperature Lange of about 70C to 120C, preferably at the reflux temperature of the reaction mixture. Under these reaction condi~ions the desired rapid removal of the water which is formed in the reaction is achieved.
Those uracil derivatives of formulae I', I", I"' and I"" which are used as starting mateLials in process variants c) to f) are a sub-group of compounds of formula I which can be produced in accordance with process variant a) or b) and, in the appropriate case, also in 1 accordance with one or more of processes c) to f)0 : :'.
The starting materials of formula IV are novel and can be produced by halogenating the corresponding uracil derivatives of general formula I' given above. In the 20 halogenation there is used as the halogenating agent ~.
especially thionyl chloride, phosphorus pentachloride or phosphorus oxychloride or, respectively, phosphorus pentabromide or phosphoryl bromide. If desired, a mixture of phosphorus pentachloride and phosphorus oxychloride or 25 of phosphorus pentabromide and phosphoryl bromide is used, -~
whereby an excess of phosphorus oxychloride or phosphoryl bromide can serve as the diluent. The chlorination or bromination can be carried out in the presence of an inert diluent, especially an aprotic organic solvent such as an aliphatic or aromatic hydrocarbon, e.g. n-hexane, benzene, toluene or a xylene; a halogenated aliphatic hydrocarbon, e.g. methylene chloride, chloroform or 1,2-dichloroethane;
a halogenated aromatic hydrocarbon, e.g. chlorobenzene, or a tertiary amine, e.g. N,N-dimethylaniline, but this is not necessary when phosphorus oxychloride or phosphoryl 3 ~
bromide is used as the halogenating agent. When thionyl chloride is used as the halogenating agentO it ha~ been found to be convenient to add a catalytic amount of dimethylformamide. The reaction temperatures generally lie between 0C and the reflux temperature of the reaction mixture, preferably between 80C and 120C.
The urea derivatives of formula YII which are used as starting materials in method aa) are novel and can be produced by reacting an amine of the general formula R~(~ ~ R4 n whecein R , R , R , R , n and X have the significances given above, at room te~perature with isocyanic acid in aqueous acetic acid or an aromatic isocyanate of formula IX [see Reaction Scheme 1, method bb)] with ammonia in an inert solvent, e.g. diethyl ether. The production of aromatic ureas is gene~ally known and is described in many literature ~ou~Ges.
The isocyanates of formula IX which are used as ~tarting materials in method bb) and for the production of the urea derivatives VII are also novel and can be produced by treating an amine of formula XII with phosgene. The reaction is conveniently effected in ethyl acetate as the solvent and at temperatures between room temperatuLe and the reflux temperature of the reaction 3S mixture. Also in this case, the production of aromatic - 26 - 2~33~
isocyanates is generally ~nown and is described in many instances in the literature.
The staeting materials of formula X used for the production of the compounds of formula III are also novel.
They can be p~oduced, for example, in accordance with Reaction Scheme 2 hereinafter rmethods cc) ~ dd) and ee)] :~
in which R2, R3, R4 R5 R6' R7' R8 ~ have the significances given above and R signifies hydLogen or Cl 4-alkyl and R signifies hydrogen or Cl 3-alkyl: .
C
~: ~
"'~
- 27 - ~ ~ 3 ~
Reaction Scheme 2 cc) R
R 11 C H = C _ o 2 ~/N~0 5 R6 CH-C=O RSJ~J~X~ ~ R n 'XIII XII
R C H 2~C ,~ O I :
R5CH ~ ~ i~ 4)n dd ) 7/
R ~55 C) R 2 X
R 6~ C - OR 8 ~ H 2 N \~ ~ 3 VI 5~/~ x,~c ~ R4 ) n \ XII
R ~0 R
2 5 R 6~N~
R 5l~0~X~ ~ R 4 n ee) X
~¦~CH3 + ~ R ~
3 5X I ~,~ C H 3 ~I R 0 \~ I H IR . j , H 2 C~ ~ ~ \~ ~ 3 sJ~\x~c ~ 4 )n - 2 8 - 2d 0 3 3 3 L7t ~i Method cc) ii6 conYeniently car~ied out by reacting the amine of formula XII with the diketene of formula XIII in the presence of an ap~otic solvent such as an a~omatic hydrocarbon, e.g. benzene or toluene, at temperatu~es in the ~ange of about 20 to 50C. Moreover, a basic cataly~, e.g. 4-pyrIolidino-pyridine, is ad~antageously used.
.: .
The ~eaction according ~o method dd) is conveniently -effected under an exces~ of the compound of fo~mula VI at temperatu~es between about 60C and the reflux temperature of th~ reaction mixture. The methyl este~ VI (R is methyl) is advantageously used. -. . .
Method ee) is conveniently effected in an aprotic ~olvent such as an aromatic hydrocarbon, e.g. toluene or a xylene, at tempe~atu~es between 100C and 140C.
The remaining starting mate~ials and, respec~ively, reagents, namely of formulae V, VI, VIII, XI, XII, XIII
and XIV, are either known or can be produced according to methods known per se, see, for example, Houben-Weyl Methoden der organischen Chemie, volume VII/2a, p. 492, and volume VIII, p. 563, J.A.C.S. 69, 1819 (1947), J. o~g.
Chem. 36, 37 (1971), J.A.C.S. 75 315~ (1953) and J. Org. ;
Chem. 48, 724 (1983) [compounds VI]: J. Org. Chem. 14, 807 ~-(1949), Helv. Chim. Ac~a Z5, 1311 (19~2), J. Org. Chem.
21, 1358 (1956) and J. OLg. Chem. 49, 4780 (1984) [compounds VIII]; Japanese Patent Publication No. 221,677 ~
(1987), Eu~opean Patent Publication No. 170.191 and -~ , 218.972 tcompounds XIIJ, Houben-Weyl Methoden de~
o~ganischen Chemie, volume VIIJ4, pp. 226-263 and J.A.C.S.
69, 2446 (1947) tcompounds XIII~; and J. O~g. Chem. 43~ --Z087 (1972) [compounds XIV].
The compounds of fo~mula I as well as theiI enol ethers and salts (he~einafte~ collectively refe~ed ~o as - 29 _ 2 ~ 3 3 ~
compounds in accordance with the invention or active substances) have he~bicidal properties and are suitable fo~ the control of weeds, including weed grasses, inter alia Abutilon theophrasti, Agropyron repens, Alopecurus myosuroides, Amaran~hus retroflexus, Avena fatua, Bromus inermis, Cassia obtusifolia, Chenopodium album, Chrysanthemum segetum, Cyperus esculentu~, Datura stramonium, Digitaria sanguinalis, Echinochloa crus-galli, Galium aparine, Ipomoea purpurea, Matricaria chamomilla, Poa annua, Setaria faberii, Sinapis arvensis, Sorghum halepense, Stellaria media and Xanthium pennsylvanicum, in diverse crops, for example in cotton, rice, maize, wheat and soya crops. ~oreover, the compounds are not only pre-emergence herbicides, but also post-emergence herbicides.
The novel starting material~ of formulae II, III, IV, VII, IX and X also have herbicidal properties and can be used for the control of weeds in a similar manner to the compounds I.
In practice, a concentration of 0.01 to 6.0 kg of compound in accordance with the invention/ha, preferably 0.05 to 2.0 kg of compound in accordance with the ~ -invention/ha, is sufficient to achieve the desired herbicidal effect.
Furthermore, the compounds can be used for the control of undesired plant growth, e.g. in potatoes, cotton, sunflowers, seed vegetables and aguatic weeds. They can he used, for example, as desiccants to facilitate the harvesting of potatoes and cotton.
The weed control composition in accordance with the invention contains an effective amount of at least one compound of formula I, as defined above, or an enol ether ..
~ 2~3~3~
or salt thereof as well as focmulation adjuvants. The -composition conveniently contains at least one of the following focmulation adjuvants: solid carrier substances:
solvents or dispersion media: tensides (wetting and emulsifying agents); dispersing agents (without tenside action); and stabilizers. With the use of these and other adjuvants these compounds, namely the herbicidally ac~ive substances, can be converted into the usual formulations such as du6ts, powders, granulates, solutions~ emulsions, suspensions, emulsifiable concentrates, pastes and the like.
' The co~pounds. of formula I and their enol ethers are generally insoluble in water, whereas the salts, especially the alkali metal salts and ammonium salts, are geneLally soluble in water, and can be formulated according to methods which are usual for water-insoluble or water soluble compounds using the respective formulation adjuvants. The manufacture of the compositions can be carried out in a manner known per se, e.g. by mixing the lespective active ingredient with solid carrier substances, by dissolution or sus~ension in suitable solvents or dispersion media, if necessary using tensides as we~ting or emulsifying agents and/or dispersing agents, by diluting pre-prepared emulsifiable concentrates with solvents or dispersion media etc.
As solid carrier substances there essentially come ;
into consideration: natural mineral substances such as chalk, dolomite, limestone, aluminas and silicic acid and salts thereof (for example siliceous earth, kaolin, - bentonite, talc, attapul~ite and montmorillonite):
synthetic mineral substances such as highly dispersible 8ilicic acid, aluminium oxide and silicates: organic substances such as cellulose, starch, urea and synthetic resins: and fertilizers such as phosphates and nitrates, - 31 - ~333~;~
whereby such carrier substances can be present e.g. as powders or as granulates.
As solvents or dispersion media there essentially come 5 into consideration: aromatics such as benzene, toluene, xylenes and alkylnaphthalenes: chlorinated aromatics and chlorinated aliphatic hydrocarbon6 such as chlorobenzenes, chloroe~hylenes and methylene chloride; aliphatic hydro-carbons such as cyclohexane and paraffins, e.g. petroleum 10 fractions; alcohols such as butanol and glycol, as well as their ethers and esters; ketones such as acetone, methyl g ethyl ketone, methyl isobutyl ketone and cyclohexanone:
and strongly polar solvents or dispersion media ~uch as dimethylformamide, N-methylpyrrolidone and dimethyl 15 sulphoxide, such solvents preferably having flash points of at least 30C and boiling points of at least 50C, and water. Among the solvents oc dispersion media there also come into consideration so-called liquified gaseous ~ -extenders or carrier substances, which are those products which ace gaseous at room temperatULe and under normal pressure. Examples of such products are especially aerosol ~-propellants such as halogenated hydrocarbons, e.g. ~
dichlorodifluoromethane. If the weed control composition --in accordance with the invention is present in the form of - ~ ;
a pressurized pack, then a solvent is conveniently used in addition to the propellant.
The tensides (wetting and emulsifying agents) can be non-ionic compounds such as condensation products of fatty 3 acids, fatty alcohols or fatty-substituted phenols with ~ ~ ;
ethylene oxide; fatty acid esters and ethers of sugars or polyvalent alcohols: the products which are obtained from su~ars or polyvalent alcohols by condensation with ethylene oxide; block pol~mers of ethylene oxide and propylene oxide: or alkyldimethylamine oxides.
- 32 - ~333~ :
The tensides can al80 he anionic compounds such as ~oaps: fatty sulphate esters, e.g. dodecyl 60dium sulphate, octadecyl sodium sulphate and cetyl sodium sulphate; alkyl sulphonates, aryl sulphonates and fatty-aromatic sulphonates such as alkylbenzenesulphonates, e.g.calcium dodecylbenzenesulphonate, and butyl naphthalene-sulphona~es: and more complex fatty ~ulphonates, e.g. the amide condensation p~oducts of oleic acid and N-methyl-taurine and the sodium sulphonate of dioctyl succinate.
Finally, the ten~ides can be cationic compounds ~uch as alkyldimethylbenzylammonium chlorides, dialkyldimethyl-~- ammonium chlolides, alkyltrimethylammonium chlorides and ethoxylated quaternary ammonium chlorides.
As dispersing agents (without tenside action) there essentially come into consideration: lignin, sodium and ammonium salts of lignin sulphonic acids, sodium salts of maleic anhydride-dii60butylene copolymers, sodium and ammonium salts of sulphonated polycondensation products of naphthaiene and formaldehyde, and sulphite lyes.
- As dispersing agents, which are e pecially suitable as thickening or anti-settling agents, there can be used e.g.
methylcellulose, carboxymethylcellulose, hydroxyethyl-25 cellulose, polyvinyl alcohol, alginates, caseinates and , blood albumin.
Examples of suitable stabilizers are acid-binding agents, e.g. epichlorohydrin, phenyl glycidyl ether and soya epoxides; antioxidants, e.g. gallic acid esters and butylhydroxytoluene; W-absorbecs, e.g. substituted benzo-phenone~, diphenylacrylonitrile acid esters and cinnamic acid esters; and deactivators, e.g. salts of ethylene-~îaminotetraacetic acid and polyglycols.
'' ' '', :, ' ':'' ~ . '~ ; ' " ,' ' ;: ,"', .,' :' ' _ 33 _ 2~3~
The weed control compositions in accordance with the invention can contain, in addition to the active ingredien~s in accordance with the invention, synergists and other active ingredients, e.g. insecticides, acaricides, fungicides, plant growth regulators and fertili2ers. Such combination compositions are suitable for intensifying the activity or for broadening the spectrum of activity.
The weed control compositions in accordance with the invention generally contain between 0.01 and 95 weight percent, p~eferably between 0.5 and 75 weight percent, of one or more compo~nds in accordance with the invention as the active ingredient(s). They can be pcesen~ e.g. in a -~
form which is suitable for storage and transport. In such formulations, e.g. emulsifiable concentrates, the active ingredient concentration is normally in the higher range, preferably between 1 and 50 weight percent, especially between 10 and Z0 weight percent. These formulations can then be diluted, e.g. with the same or different inert substances, to give active ingredient concentrations which are suitable for practical use, i.e. preferably about 0.01 -~
to 10 weight percent, especially about 0.5 to 5 weight percen~. The active ingredient concentrations can, however, also be smaller or greater.
', ~ :
As mentioned above, the manufacture of thP weed control compositions in accordance with the in~ention can be carried out in a manner known per se.
For the manufacture of pulverous preparations the active ingredient, i.e. at least one compound in accordance with the invention, can be mixed with a solid carrier substance, e.g. by grinding together: or the solid carcier substance can be impregnated with a solution or suspension of the active ingredient and then the solvent ,.
_ 34 _ ~3~3~
or dispecsion medium can be removed by evaporation, heating oc sucking-off under reduced pressure. By adding tensides or di~persing agents such pulverous preparations can be made readily wettable with water, 60 that they can be converted into aqueous suspensions which are suitable e.g. as spray com~ositions.
The active ingredient can also be mixed with a tenside and a solid carrier substance to form a wettable powder which is dispersible in water or it can be mixed with a ~ -solid pre-granulated carrier substance to form a product in ~he focm of a granulate.
'' '.
When desiced, the active ingredient can be dissolved in a wateE-immiscible solvent such as, for example, a high-boiling hydrocarbon, which conveniently contains dissolved emulsifying agent, so that the solution becomes self-emulsifying upon addi~ion to water. Alternatively, the active ingredient can be mixed with an emulsifying ~
agent and the mixture can then be diluted with water to ~ ' the desired concentration. Moreover, the active ingredient can be dissolved in a solvent and thereaf~er the solution can be mixed with an emulsifying agent. Such a mixture can likewise be diluted with water to the desired concentration. In this manner there are obtained emulsifiable concentrates or ready-for-use emulsionF.
, .
The use of the weed cont~ol compositions in accordance with the invention, which forms a further object of the pcesent invention, can be carried out according to usual application methods such as spc-inkling, spraying, dusting, watecing or scattering. The method in accocdance with the invention fo~ the control of weeds comprises treating the locus to be protected against weeds and/or the weeds with ;~
a compound in accocdance with the invention or with a weed control composition in acco~dance with the invention.
- - - - . . . - . ~ - : - . . . . . .-- - : . . . . .
, ,, , .. ", . .
_ 35 _ 2~3~3~
The following Exameles serve to illustrate the invention in more detail.
I. Manufacture of the compounds of formula _ (and II) and, respectivelY, of the enol_ethers of the ~ompounds I: -~
Example 1 .. ~:' :'' A solution of 18.51 g of ethyl 3-amino-4,4,4--trifluorocrotonate in 50 ml of dime~hylformamide is added ~-dropwise while stirring at 0C during 30 minutes to 4.41 g g of a 55% sodium hydride dispersion in 100 ml of dimethyl- -formamide and the mixture is stirred at room tempera~ure for 2 hours. The reaction mixtu~e is thPn cooled to 55C
and ~reated during 3 minutes while stirring with a solution of 25.10 g of 6-fluoro-5-isocyanato-3-(2--propynyl)-2-benzothiazolinone in 200 ml of dimethyl-formamide/toluene (1:1). In so doing, the temperature of -the reaction mixture rises to -15C and the mixture is subsequently stirred at room temperature foc one hour. The thus-formed intermediate 5-{3-~2-(ethoxycarbonyl)-1- ~ --trifluoromethyl-vinyl]ureido?-6-fluoro-3-(2-pLopynyl)--2-benzothiazolinone is not isolated. -gr . . : ,, The mixture is concentrated to 200 ml at 55C under reduced pressure and the residue is poured into a mixture of 700 ml of water and 11 ml of concentrated hydEochloric acid. The aqueous mixture is then extcacted with 300 ml of ethyl acetate, the insoluble constituents are filtered off, the organic phase is separated. this phase is washed twice with 400 ml of water each time and dried over anhydrous sodium sulphate. The solution is brought to crystallization by evaporation and the crystals are fil~ered off under suction and dissolved at 50C in 1 1 of ethyl acetate. Insoluble constituents are filtered off and - 36 - ~333~
the filtrate is evaporated until a viscous oil has formed, the cesidue is dissolved in 700 ml of diethyl ether and the solution is ~reated with charcoal and concentrated to 150 ml. The solution is ~iubsequently brought to crystal-lization with n-hexane while stircing and cooling at 0C.
Finally, the crystals are filtered off unde~ suction, washed with diethyl ethertn-hexane (1:1) and dried.
In this manner there is obtained 3-[6-fluoro-2-oxo-3--(2-propynyl)-5-ben%othiazolinyl]-6-trifluoromethyl--2,4(1H,3H)-pyrimidinedione, m.p. 224-2Z7C.
Exam~le 2 Analogously to the procedure described in Example 1, starting from ethyl 3-amino-4,4,4-trifluorocrotonate and 3,4-dihydro-7-fluoro-6-i~ocyanato-3-oxo-4-(2-pLopynyl)-2H--1,4-benzoxazine theLe is obtained 6-{3-[2-(ethoxy-carbonyl)-l-trifluoromethyl-vinyl~ureido}-3,4-dihydro-7--fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine (not isolated) and, after cyclization of this benzoxazine, there is obtained 3-[3,4-dihydro-7-fluoro-3-oxo-4-(2--propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl--2,4(1H,3H)-pyrimidinedione, H-NMR (CDCl~, 60 MHz):
7.29 ppm (d, lH), 6.99 ppm (d, lH), 6.31 ppm (s, lH), 4.85-4.61 ppm (m, 4H), 2.35 ppm tt, lH); mass spectrum:
m/e 393(20), M .
ExamDle 3 Analogously to the procedure described in Example 1, starting from ethyl 3-amino-4,4,4-trifluorocrotonate and 3,4-dihydro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4--benzoxazine there is obtained 6-{3-[2-(ethoxycarbonyl)--1-trifluo~omethyl-vinyl]ureido}-3,4-dihydro-3-oxo-4--(2-propynyl)-2H-1,4-benzoxazine (not isolated) and, after . .
j~`` 2~333~$ :
_ cyclization of this benzoxazine. there is obtained 3-r3,4-dihydro-3-oxo-4-(Z-propynyl)-2H-1,4-benzoxazin-6-yl]-6--t~ifluoromethyl-2,4-(lH,3H)-pyrimidinedione, m.p. >250C. ~ -ExamPle 4 A suspension of 8.Z g of 5-[3-ethoxycacbonylamino)-2- ;~
-butenoylamino]-6-fluoro-3-(2-propynyl)-2-benzothiazolinone to 100 ml of methanol i~ trea~ed while stirring at 50C
with 11.5 ml of a ZN sodium methylate solution and the reaction mixture is ~tirred for 15 minutes. The solution which thus results is then ~tirred for 30 minutes, concentrated to 20 ml under reduced pressure and the residue is poured into a fiolution of 20 ml of 2N hydro-chloric acid in 500 ml of water. The resulting precipitateis filtered off under suction, washed with water and dried. In this manner there are obtained 6.1 g of 3-[6--fluoro-2-oxo-3-(2-propynyl)-~-benzothiazolinyl]-6-methyl- :.
-2,4(1H,3H~-pyrimidinedione, m.p. ~250C.
Examples 5-34 The corresponding compound of formula II is in each case cyclized analogously to the procedure described in ;
Example 4 in order to manufacture the compounds of formula I listed in Tables la and lb hereinafter.
:::
C H 3\~N~0 R 2 .
~/ ~ \~ 3 " ,,,, ,.
..
:: .
2~33~
-Table la - .
2 - 3 4 , _ _ E~ample ~ ca R n ~ Physi r al dnta _ _ _ _ . ~ ~ __ _ CH2C_CH CH2 1 O lH-NMR (CDC13, 100 MHz): 7.08 ppm ~d, lH), 6.90 ppm (d, lH), 5.58 ppm (s, lH), 4.69-4.64 ppm (m, 4H), 2.33 ppm (t, lH), 2.18 ppm (s, 3X); m.p.
-benzoxazin-6-yl]-1-methyl-6-(n-p~opyl)-2,4(lH,3H)- - .
-py~imidinedione, : ~-6-ethyl-3-[3,4-dihydro-7-f 1UOrO-4-iSOpf opyl-3-oxo-ZH--1,4-benzoxazin-6-yl~-1-methyl-2,4(lH,3H)-pyrimidinedione, "": ~' ;
.
~ ~ 2~3~
s .
. . .
6-ethyl-3-[4-sec.butyl-3,~-dihydro-7-fluoro-3-oxo-2H--1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl~3-[3,4-dihydro-7-fluoro-4-(1-methoxyethyl)-3--oxo-ZH~ -benzoxazin-6-yl]-1-methyl-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-t3,4-dihydro-7-fluoro-4-(1-methoxypropyl)-3- , :
-oxo-2H-l~-benzoxazin-6-yl3-1-methyl-2,4(1H,3H)~
-py~imidinedione, 6-ethyl-3-[4-allyl-3,4-dihydro-7-fluoro 3-oxo-2H-1,4-10-benzoxazin-6-yl]-1-me~hyl-2,4(1H,3H)-pyrimidinedione, ~ ;
6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methyl-Z-c -propenyl3-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-Z,4-~lH,3H)-pyrimidinedione, 6-ethyl-3-~3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)--2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidine-dione, 6-ethyl-3-t3,4-dihydro-7-fluoro-4-(1-methyl-2--propynyl)-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4 -(lH,3H)-pyrimidinQdione, 206-e~hyl-3-~6-fluoro-3-isopropyl-2-oxo-5-benzo- -thiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-sec.butyl-6-fluoro-2-oxo-5-benzo-thiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methoxyethyl)-2-oxo-5-benzo- ~ -~hiazolinyl~-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-~6-fluoro-3-(1-methoxypropyl)-2-oxo-5-benzo~
thiazolinyl]-l-methyl-~,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-allyl-6-fluoro-2-oxo-5-benzothiazolinyl]--l-methyl-2.4(lH.3H)-pyrimidinedione, 306-ethyl-3-[6-fluoro-3-(1-methyl-2-propenyl)-2-oxo-5--benzothiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-Z-oxo-3-(2-propinyl)-5-benzo-thiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione and 6-ethyl-3-~6-fluoro-3-(1-methyl-2-propinyl)-2-oxo-5--benzothiaæolin~l]-l-methyl-2,4(1H,3H)-pyrimidinedione.
;~
".
:
: .
3 ~ ~ ~
Representatives of compounds of formula I are:
Those compounds I in which R and R7 each signiy methyl, R , R and R each signify hydrogen, R
signifies fluorine, n signifies 1, X signifie~ oxygen and R signifies ethyl, n propyl, Z-fluoroethyl, methoxy-methyl, 2-methoxyethyl, methoxycarbonylmethyl, l-methoxy-carbonyl-ethyl, 2-methoxycarbonyl-ethyl~ cyclopentyloxy-carbonylmethyl, carbamoylmethyl, dimethylcarbamoylmethyl, 3,3-dichloro-2-propenyl, cinnamyl or 3-chloro-Z-propynyl, 3-r3~4-dihydro-7-fluoro-3-oxo-4-(2-propynyl~-2H-l~4-g -benzoxazin-6-yl~-1,5,6-t~imethyl-2,4(lH,3H~-pyrimidine-dione, 3-[3,4-dihydro-2,2-dimethyl-7-fluoro-3-oxo-4-(2-15 -propynyl)-2H-1,4-benzoxazin-6-yl]-1,6-dimethyl--2,4(1H,3H)-pyLimidinedione, 3-[2-ethyl-3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)--2H-1,4-benzoxazin-6-yl]-1,6-dimethyl-2,4-(lH,3H)--pyrimidinedione, 3-[3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin--6-yl]-1,6-dimethyl-2,4(1H,3H)-pyrimidinedione, 3-[7-chloro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4--benzoxazin-6-yl]-1,6-dimethyl~2;4(lH,3H)-pyrimidinedione, -those compounds I in which R signifies difluoro-methyl, R3, R4 and R each signify hydrogen, R
signifie~ fluorine. R signifies methyl, n signifies 1, ~-X signifies oxygen and R signifies ethyl, ~-propyl, allyl or peopargyl, 6-ethyl-1-difluoromethyl-3-[3,4-dihydro-7-fluoro-3-30 -oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-2,4(1H,3H)- ;
-pyrimidinedione, l-difluoromethyl-3-[3,4-dihydro-7-fluoro-2-methyl-3--oxo-4-(2-propynyl)-2H-1,4-benzoxaæin-6-yl]-6-methyl--2,4(1H,3H)-pyrimidinedione, those com~ounds I in which R signifies methyl, R , R and R eaFh si~nify hyd~ogen, R signifies ..
, . , . ,, , , . ... ., ~,,.. .. ,.; . . . . .
2~333~i~3 _ 7 _ 7 ~:
fluorine, R signifies trifluoromethyl, n signifies 1, X
signifies oxygen and R signifies ethyl, n-propyl, n-bu~yl, carbamoylmethyl, allyl or ~-chloro-2-proeynyl, : .
those compounds I in which Rl siqnifies methyl, R , R , R and R eaGh signify hydrogen, R
signifies trifluoromethyl, n signifies 1, X ~ignifies ~:
oxygen and R signifies ethyl, n-eropyl, 2-fluoroethyl, methoxymethyl, 2-methoxyethyl, cyanome~hyl, methoxy-carbonylmethyl, l-methoxycarbonyl-ethyl, 2-methoxy-1 carbonyl-ethyl, cyclopentyloxycarbonylmethyl, carbamoyl-methyl, dimethylcarbamoylmethyl, allyl, 3,3-dichloro-2--propenyl, cinnamyl, l-methyl-2-propynyl or 3-chloro-2--propynyl, . ::
3-[3,4-dihydro-2-methyl-3-oxo-4-(Z-propynyl)-2H-1,4--benzoxazin-6-yl]-1-methyl-6-trifluoromethyl--2,4-flH,3H)--pyrimidinedione, ''' 3-L7-chloro-3~i4-dihydLo-3-oxo-4-(2-propynyl)-2H-l~4--benzoxazin-6-yl1-1-methyl-6-trifluoromethyl-2~4tlH,3H)- , ..
-pyrimidinedione, those compounds I in which R signifies methyl, ::
R, R . R and R each signify hydrogen, R
signifies pentafluoroethyl, n signifies 1, X signifies oxygen and R signifies n-propyli allyl or peopargyl, those compounds I in which R signifies methyl, R , R and R each signify hydrogen, R signifies : : .
25 fluorine, R signifies pentafluoroethyl, n signifies 1, ~- , X siignifies oxygen and R signifies allyl or propargyl, as well as the corresponding 1,4-benzthiazine derivatives (the above individual compounds of formula I
in which the oxygen atom (X) is re~laced by a sulphur atom) those compounds I in which R and R each signify methyl, R signifies fluorine, R signifies hydrogen, ,~ -n signifies zero, X signifies oxygen and R signifies ethyl, 2-fluoroethyl, 2-methoxyethyl, cyanomethyl, methoxycarbonylmethyl, l-methoxycarbonyl-ethyl, 2-methoxy-'' ' "' . .' , , , . ~ . ' . ~ ' ' ' ''i ' ' ' '' ' ' ' " ' ' carbonyl-ethy.l, cyclopentyloxycarbonylmethyl, carbamoyl-methyl, dimethylcarbamoylmethyl, 3,3-dichloro-2-propenyl, cinnamyl or 3-chloro-2-propynyl, 3-[6-fluoro-2-oxo-3-(2-p~opynyl)-5-benzoxazolinyl]--1,5,6-trimethyl-2,4(1H,3H)-pyrimidinedione, 1,6-dimethyl-3-t2-oxo-3-(2-propynyl)-5-ben20xazolinyl]--2,4(1H,3H)-pyrimidin~dione, 3-[6-chloro-2-oxo-3-(2-propynyl)-5-benzoxazolinyl]--1,6-d;methyl-2,4(1H,3H)-pyrimidinedione, those compound~ I in which Rl signifies difluoro-methyl, R signifies fluorine, R signifie~ hydrogen, R ~ignifies methyl, n signifie~ zero, X signifie6 oxygen and R signifies ethyl, n-propyl, allyl or propargylJ ' ~ ~, lS 6-ethyl-1-difluoromethyl-3-~6-fluoro-2-oxo-3-(2--propynyl~-5-benzoxazolinyl]-2,4~1H,3H)-eyrimidinedione, ~ :
l-difluoromethyl-3-t6-fluoro-2-oxo-3-~2-propynyl)-5- ~. :
-benzoxazolinyl]-6-methyl-2,4(1H,3H)-pyrimidinedione, .: :
those compounds I in which R signifies methyl, R : ::
signifies fluorine, R signifies hydcoge~, R
signifies trifluoromethyl, n signifies zero, X ~ignifies -~
: oxygen and R ~ignifies ethyl, n-propyl, n-butyl, :~
carbamoylmethyl, allyl or 3-chloro-2-propynyl, those compounds I in which R signifies methyl, R
and R each signify hydrogen, R ~ignifies trifluoro-methyl, n signifies zero, X signifies oxygen and R .:~
~ignifies ethyl, n-propyl, 2-fluoroethyl, methoxymethyl, : 5 2-methoxyethyl, cyanomethyl, methoxycarbonylmethyl, l-methoxycarbonyl-ethyl, 2-methoxycarbonyl-ethyl, cyclo-pentyloxycarbonylmethyl, carbamoylmethyl, dimethyl-carbamoylmethyl, allyl, 3,3-dichloro-Z-propenyl, cinnamyl, l-methyl-2-propynyl or 3-chloro-2-propynyl, 3-~6-chloro-2-oxo-3-(2-propynyl)-5-benzoxazolinyl]-1- ~ :
-methyl-6-triEluoromethyl-2,4(1H,3H)-pyrimidinedione, 1-methyl-3-[2-oxo-3-(2-p~opynyl)-5-benzoxazolinylJ-6- .
-trifluoromethyl-2,4(lH,3H)-pyrimidinedione, .
those compounds I in which Rl signifies methyl, R5 and R each signify hydcogen, R7 signifies penta-fluoroe~hyl, n signifies zero, X signifies oxygen and R
signifies n-propyl, allyl or propargyl, those compounds I in which R signifies methyl, R
signifies fluorine, R signifies hydrogen, R
signifies pentafluoroethyl, n signifies zero, X signifies oxygen and R signifies allyl or propargyl, as well as the corresponding benz~hiazoline deriva~ives (the above individual benzoxazolines of formula I in which the oxygen atom (X) is replaced by a sulphur atom).
The process in accordance with ~he invention for the ~ ~:
manufacture of the compounds of formula I and their enol ethers as well as salts comprises a) for th0 manufacture of those compounds of formula I in which R signifies hydrogen and R signifies hydrogen, :.
fluorine or Cl 4~alkyl as well as, if desired, of metal 20 salts of these compounds, subjecting a compound of the ~; .
general formula ',;
C 25 J ~1 ~ 4)n wherein R2, R3, R4, R5, R , n and X have the significances given above, R signifies hydrogen, fluoLine or Cl 4-alkyl and ,.,.. .. , .. , .. . , . , .. ". . " , . . . .. . . . .
:
~--' ` 2~ 3~ ~
R8 signifies lower-alkyl, ~referably Cl 4-alkyl, to a cyclization under basic conditions and, if desired, converting a metal salt of the uracil derivative of formula I which may be obtained into the acidic form -:
5 (R = hyd~ogen) by treatment with an acid.
b) for the manufacture of those compounds of focmula I in which Rl signifies hyd~ogen, R ~ignifies hydrogen, fluorine o~ Cl 4 alkyl and R signi~ies Cl 4-alkyl 10 as well as of salts of the compound6 of fo~mula I, subjecting a csmpound of the gene~al formula C r~x~ --R4 n 20 whe l e i n R2, R3, R , R5, R , n and X have the - significances given above, R ~ignifies Cl 4-alkyl and 25 R signifies lowe~ alkyl, preferably Cl 4-alkyl, to a cyclization under basic conditions and, if desired, ~:
conve~ting a metal salt of the uracil derivative of formula I which may be obtained into the acidic form (R = hyd~ogen) by treatment with an acid, c) for the manufacture of those compounds of formula I in which R signifies Cl 4-alkyl, Cl 4-haloalkyl, C2 5-alkenyl or C3 5-alkynyl, subjecting a u~acil . :
derivative of t~e gene~al fo~mula R ~ N ~ 0 2 R6~R~X~ --R4 ) n wherein RZ, R3, R4 R5 R6 R7 have the significances given above, to an alkylation with an appropriate alkylating agent containing a Cl ~-alkyl. C2_5-alkenYl or C3_5--alkynyl group, d) for the manufacture of tho6e compounds of formula I in which R signifies hydrogen, cleaving off the protecting group R in a uracil derivative of the general formula , :
~ 1 - . ' . 7 1 ~ 0 R10 R' ~ ~j/ ~R
wherein Rl, R3, R4 R5 R6 R7 have the ~iignificances given above and R signifies ~ :
a protecting group, for example i~iopropyl or tert.butyl, e) for the manufactu~e of those compounds of formula I in which R is different from hydrogen, appropriately alkylating a uracil derivative of the general formula " r~ ~ ~ "
~ ~ - 12 - 2~33~
Rl ~ , . R ~ ~1 S R~X~ ~ R4 )n wherein Rl, R3, R4 R5 ~6 R7 have the significances given above, " ' "'~, f) for the manufacture of those compounds of formula I in which R signifies chlorine, bromine or iodine, chlorinating, brominating or iodinating a uracil derivative of the general formula R
R ~ I ~ R2 c R ~ ~ ~ R4)n ~ ~
. :
whe r e i n Rl, ~2 E~3 R4 R5 R~
have the significances qiven above, . : ~:
g) for the manufacture of the enol ethers of formula Ia, treating a pyrimidinone derivative of the general formula . - - .
- .
: ~ .
- 13 - 2~33~
,.
R ~ H a l R 2 ~ X~ ~ ~4 ) n , ~ ~
. :
~ ' wherein ~;
R2, R3. R4 R5 R6 R7 n and X h significances given above :. .
and : :
Hal signifies chlorine or bromine, 1' -with an alkanol, alkenol or alkynol R OH in the ;~
presence of an organic base or with the corresponding alcohola~e, alkenolate or alkynolate of the general formula :
Rl ' ~ V
~ 20 : whe~ein Rl has the significance given above and . ~ signifies one equivalent of a metal ion, C and, if desired, converting a thus-obtained compound of formula I in which R signifies hydrogen, R signifies hydrogen and/or R signifies C2 5-carboxyalkyl in~o a salt.
The cyclization according to process variant a) can be carried out conveniently by treating the compound of formula II in an inert protic organic solvent such as an alcohol, e.g. methanol, ethanol or isopropanol; an inert aprotic organic solvent such as an aliphatic or cyclic ether, e.g. l,Z-dimethoxyethane, tetrahydrofuran or ,,,,. ," ,,~, "1,'",,","',',1 ;,',,,~',',',,',",.,,, ~',;'" ~,',, ',.' ,, ., ', :~ "; . .',,,,~ ~, . ' .. ' ' ', . ,',, : . .,. ' :,,,' .: ,... ., ' '........ : ' 3~ 3 dioxan, or an aromatic, e.g. benzene or toluene: an inert aprotic, ~olar organic i~olvent, e.g. dime~hylfocmamide or -dimethyl sulphoxide, whereby such solvents can be used, if desiced, in a two-phase mixture with a hydrocarbon, e.g.
n-hexane or toluene, or water with a base at temperatures 5 between -78CC and the reflux temperature of the reaction mixture. As bases there ~referably come into consideration sodium alcoholates, alkali metal hydroxide~, especially sodium hydroxide and potassium hydroxide, alkali metal carbonates, especially sodium carbonate and potasEiium 10 carbonate, and sodium hydcide. When sodium hydride is used as the base, the solvent i5 preferably an aliphatic or g cyclic ether, dimethylformamide or dimethyl sulphoxide, whereby any of these solvents can be used in admixture with toluene.
After completion of the cyclization the product, when one of the above-mentioned bases is used, is present in the fo~m of the corresponding alkali metal salt. This can be isolated and purified in a manner known per se or the 20 mixture can be acidified in order to isolate the respective compound of formula I itself. A mineral acid ;~
such as hydcochloric acid oc a stLong organic acid such as acetic acid or p-toluenesulphonic acid is preferably used for this purpose.
According to process variant b) the compound of formula III can be cyclized conveniently in an e6sentially anhydrous inert protic organic solvent such as an alcohol, especially a lower alcohol, e.g. methanol or ethanol, in 30 the presence of a base such as an alkali metal alcoholate, especially the corresponding alcoholate, i.e. methylate or ethylate, of sodium at temperatures between 0C and 70C, prefecably in the temperature eange of 10C to 30C.
Alternatively, for example, the compound III can be ~;~
cyclized in an essentially anhyd~ous inert aprotic organic : .' ., , , . : ~ ! . ,, ; , ! ' solvent such as e.g. dimethylformamide, N-methyl- ~ ~-pyrrolidone, tetramethylurea or hexamethylphosphoric acid triamide in the presence of a metal hydride as the base, e.g. sodium hydride or potassium hydride, at temperatures between 0C and 70C, preferably 10C to 30C.
.
As in the case of process variant a), af~er completion , -of the cyclization the pLoduct, when one of the above- ; ;
-mentioned bases is used, is present in the form of the corresponding alkali me~al salt. This can likewise be isolated and purified in a manner known per ie or the mixture can be acidified in order to isolate the respective compound of formula I itself.
In process variant c) the term "alkylation" refers to the substitution of the hydrogen atom of the N -atom of the uracil nucleus with a Cl 4~alkyl, Cl 4-haloalkyl, C2 5-alkenyl or C3 5-alkynyl group. As the alkylation agent there is conveniently used a Cl 4-alkyl, C2 5--alkenyl or C3 5-alkynyl halide, especially the respective chloride or bromide, or sulphate or a multiply--halogenated Cl 4-alkane such as, for example, chloi~o-difluoromethane or a mono- or multiply-halogenated alkene such as, for example, tetrafluoroethene. -~
The alkylation is conveniently carried out in the preience of an inert, protic organic solvent such as a lower alkanol, e.g. ethanol, optionally in admixture with water: an inert, aprotic organic solvent such as an aliphatic or cyclic ether, e.g. 1,2-dimethoxyethane, tetrahydro~uran or dioxan; a ketone, e.g. acetone or butan-2-one; or an inert, aprotic, polar organic solvent, e.g. dimethylformamide, dimethyl sulphoxide or aceto-nitrile, as well as in the presence of a base such as ;
sodium hydride, an alkali metal hydroxide, especially sodium or potassium hydroxide, an alkali metal alcoholate, - - , i . - : , , ., , , ,, , , ,, ", , ^' 2 ~ 3 ~ x '~
'. ..
especially sodium alcoholate, or an alkali metal carbonate or bicarbonate, especially sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, at temperature~ between 0C and the reflux temperature of the reaction mixture, preferably at room tem~eratuee, or, in the case of the substitution of the hydrogen atom of the -atom with a Cl 4-haloal~yl group, preferably at temperatures between 50C and 100C. In a preferred embodiment, the uracil derivative of formula 1' is treated fiestly wi~h the base such as sodium hydride, ~odium ethanolate or sodium carbonate in the solvent and, a~ter a short reaction time, treated with the halide in the same solvent. In a further embodiment, the uracil derivative I' is Leacted with a dialkyl sul~hate in the presence of an alkali metal carbonate, especially sodium carbonate or potassium carbonate, in the solven~, e.g. acetone, at ~-reflux temeerature. De~ending on the solvent which is used, ~he reaction has generally finished wi~hin a relatively short time or aftar a few hours. After working-up the reaction mixture the desired end product can be separated from starting materials which may remain and/or byploducts according to methods known per se, e.g.
column chromatography and/or fractional crystallization. ~;
The cleavage of the protecting group R10 on the nitrogen atom of the o~azolinone, thiazolinone or 3,4-dihydro-3-oxo-2H-1,4-oxa/thiazine ring according to process variant d) is conveniently effected by the action of a strong, essentially anhydrous, inorganic acid such as, for example, sulphuric acid or oLthophosphoric acid.
Normally, the acid serves not only as the ~eagent, but also as the solvent, so that no additional solvent is required. The reaction is preferably carried out at temperatures between 80C and 160~C, preferably in the temperature range of 120C to 150C.
. . ! . ' ' . ' ' : . ', ' : , . ', . ': ' , , i ~ . . ' . . ' ~ - 17 - ~333~
Process variant e) involves the substitution of the hyd~ogen atom attached to the heterocyclic nitrogen atom wi~h a C -al~Yl, Cl 4-haloalkyl~ Cl-4-alk y 1-4 1-4 ~lk~Y-cl ~-alkoxy-c alkyl C2 5-cyanoalkyl, C2 5-carboxyalkyl, C2 5-alkoxy-5 carbonyl-Cl 4-alkyl, C2_5-haloalko~yca~bonyl Cl_4 -alkyl, Cl 4-alkoxy-C2 5-alkoxycarbonyl-C1 4-alkyl, C2 5-alkoxycarbonyl-C2 5-alkoxycarbonyl-C1 4-alkyl, C4 7-cycloalkyloxycarbonyl-C1 4-alkyl, carbamoyl--Cl 4-alkyl, mono(Cl 4 alkyl)carbamoyl-Cl 4-alkyl, di(Cl_4-alkyl)carbamoyl-Cl_4 alkyl, C3 or 4 Y
C3 4-haloalkenyl, cinnamyl, C3 or 4-alkynyl o~
C3 or 4-haloalkynyl group. This 'lalkylationll can be carried out using a respective halide, especially chloride ,~
ol bromide, analogously ~o prccess variant c). Where a uracil derivative of formula I"' in which R signifies hydrogen is used, process variant c) can of course also come into play and respective mixed alkylation products are formed. Aftec working-up the reaction mixture the desired end product can be liberated from any remaining starting materials and from byproducts according to methods known per se, e.g. column chromatography and/or fractional crystallization.
The chlorination or bromination according to process va~iant f) is conveniently carried out by means of elemental chlorine or sulphuryl chloride or elemental b~omine or sulphuryl bromide in the presence of an inert organic solvent such as acetic acid or a chlorinated aliphatic hydrocarbon, e.g. methylene chloride, chloroform or carbon tetrachloride, and in a temperature range of O~C
to 60C, preferably at room temperature. Moreover, the reaction can be effected with the aid of an acid-binding agent, for which purpose sodium acetate and tertiary amines such as triethylamine, dimethylaniline and pyridine are especially preferred acid-binding agenSs.
.
~33~
- 18 - ~
: . . ' The iodination according to this proce6s variant is conveniently effec~ed using elemental iodine as the iodinating agent and a low-boiling aliphatic carboxylic ~cid such a~ acetic acid as the solvent and at temperatures between about 0C and about 110C, preferably at room tempelature. Mo~eover, i~ has been found to be convenient to carly out the reaction in the presence of an acid such as fuming nitric acid. In o~der to eliminate ;~
excess iodine, saturated aqueous sodium bisulphite solution can be added after completion of the reaction.
Where in this process variant a u~acil derivative of formula I"'l in which R and/or R signifies an unsaturated aliphatic g~oup such as alkenyl or alkynyl is used, it can happen that not only the unoccupied S-position of the uracil nucleus i~ halogenated, but also the mentioned unsaturated aliphatic gcoup is halogenated, e.g. allyl to 2,3-dib~omopropyl. Such two different kinds of halogenated products also belong ~o the scope of the 20 compounds I. After working-up the reaction mixture the ;~
desiled end product can be liberated from any simulta- ~-neously manufactured halogenation products according to methods known per se, e.g. column chromatography and fractional crystallization, or two or more desi~ed halogenation products can be isolated.
: .
In process variant g) the term "metal ion" stands e6pecially for an alkali metal ion, e.g. the sodium or potassium ion, or an alkaline earth metal ion, e.g. the calcium or magnesium ion. The sodium ion is the prefelled metal ion. Where the alkanol, alkenol or alkynol R OHi - is used, pyridine is the e~pecially suitable organic base.
.. . .
The reaction is conveniently effected in an excess of ' -the corresponding hydroxy compound R OH as the diluent and at temperatures between 0C and 50C, preferably at ~oom temperature.
:.''. ''.
' .
` ` 2~33~
Insofar as they are not manufac~ured directly by the above-described cyclization which is carried out under basic conditions, the desired salts of the compounds of formula I in which Rl signifies hydrogen, R signifies hydrogen and/or R signifies Cz 5-carboxyalkyl can also be manufactured from ~hese compounds I in a mannec known per se such as, for example, by dissolving the compound of formula I in a solution of a respective inorganic or organic base. The ~alt formation i6 generally effected within a ~hort time at ~oom tempera~ure. In one embodiment the sodium salt is manufactured by dissolving the uracil derivative I in aqueous sodium hydroxide solution at room temperature, with equivalent amounts of the uracil derivative and of sodium hydroxide being used.
The solid salt can then be isolated by precipitation with a suitable inert solvent or by evaporation of the solvent.
A furthec embodiment comp~ises introducing an aqueous solution of an alkali metal salt of the uracil derivative I into an aqueous solution of a salt which has a metal ion other than an alkali metal ion, whereby the second metal salt of the uracil derivative is manufactured. This embodiment is generall~ used for the manufacture of uracil metal salts which are insoluble in water.
The resulting compounds of formula I, enol ethers as well as salts can be isolated and pucified according to methods known per se. Further, the sequence in which a possible combination of process variants c)-f~ will be conveniently carried out in order to avoid possible undesired concurrent reactions will be familiaL to a person skilled in the art.
Insofar as no planned synthesis for the isolation of pure isomers is carried out, the product can result as a mixture of two or moee isomers. The isomers can be , ... . . . . , ~ . ~ :
;;. : : ,: : , .. . .. . ..... . .... . ..... .. ...
., , , . . ., ., , . , ; .:., ~ : .... , . :
^: : 2~3~
.- 20 -separated according to methods known per ~e. If de8ired, pure optically active i~omers can also be manufactuLed, for example, by synthesis from eorresponding optically active staEting materials.
The ~ta~ting matPrials of focmula II are novel and can be produced in a manner known pe~ se. e.g. in accordance with Reaction Scheme 1 hereinafter ~me~hods aa) and bb)~
in which R2, R3 R4 R5 R6~ ~7 7~ 8 n and X have the significances given above: .
, , , ., ,~ , ; ~:; ...
~ -~..
': .,' ' .
- :
.
::: :, '' '~.'.
- ~ :
Reaction Scheme 1 aa) ~ 0 R 7 D H 2 N ~
R ~--c - O R H N~ ~c ~ 4 ) n \ ~''. ' -VI \ VI I
-7 ~ 7 H o \~ R
R~ HN~ N~0 R 5~ X ~ ~ R 4 ) n I I
C 25 ~;~
b~ ) / R
R X ll-oR9 OC~ ~\C~ R3 IX
V I I I
" , ' :~ : ,~. ..
,.: .,: ~ , .: -~ , , ., :
3 ~ 1~
Method aa3 is conveniently carried out by reacting the compounds of fo~mulae VI and VII with each other in an essen~ially anhydrous diluent and in the presence of an acidic catalyst at an elevated temperature. As diluents there especially come into consideration organic solvents which form azeotcopes with water, such as aromatics, e.g.
benzene, toluene and xylenes; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetra-chloride and chlorobenzene; and aliphatic and cyclic -ethers such as 1,2-dimethoxyethane, tetrahydrofuran and dioxan, and as acidic catalysts there e~pecially come into consideration strong mineral acids such as sulphuric acid ~ and hydrochloric acid; organic acids such as p-toluene-sulphonic acid: phosphorus-containing acids such as orthophosphoric acid and polyphosphoric acid; and acidic cation exchangers such as "Amberlyst 15" (Fluka). The reaction is generally carried out in a temperature range of about 70C to 120C, preferably at the reflux temperature of the reaction mixture. Under these reaction conditions the desired rapid removal of the water which is formed in the reaction is achieved.
The ~eaction according to method bb) is conveniently effected in the presence of an essentially anhydrous aprotic organic solvent such as an aliphatic-or cyclic ether, e.g. diethyl ether, 1,2-dimethoxyethane, tetrahyd~ofuran or dioxan, an aliphatic or aromatic hydrocarbon, e.g. n-hexane, benzene. toluene or a xylene:
or a halogenated, aliphatic hydrocarbon, e.g. methylene chloride, chloroform, carbon tetrachlo~ide or 1,2-dichloroe~hane, as well as optionally in the presence of a base, especially an organic tertiary base such as triethylamine or pyridine, whereby the latter can serve not only as the solvent but also as the base, or a metal hydride ~uch as sodium hydride or potassium hydride. The reaction temperatures are preferably in the range of about ... . .
;~ ` - 23 - ~3 -80C to 50C, with the reaction being caIried out particularly at temperatures between -30C and room temperature.
The sta~ting mateIials of focmulae III are also novel.
These can be produced by reacting a compound of the general formula 7~
R ~ 0 R2 ~ ~ X~ ~ R4 n wherein R , R , R4 R5 R6' R7' have the significances given above, with a lower alkyl carbamate of the general focmula wherein R has the significance given above.
This reaction is conveniently effected in an essentially anhyd~ous inert aprotic organic solvent in the presence of an acidic catalyst. The reaction mixture is heated at the boiling temperature until water has foImed and this is removed continuously from the reaction mixture. As solvents there especially come into consideration organic solvents which form azeotropes with water, such as aromatics, e.g. benzene, toluene and xylenes; and halogenated hydrocaLbons, e.g. chloroform~
carbon tetrachloride and chlorobenzene, and as acidic 2~3~
.. .... ...
catalysts there especially come into consideration organic acids, e.g. toluene-4-~ulphonic acid; mineral acids, e.g.
sulehuric acid, orthophosphoric acid and polyphospho~ic acid; and cation exchangecs, e.g. "Ambeelyst 15" (Fluka).
- The heating is generally ca~ried out in a temperature Lange of about 70C to 120C, preferably at the reflux temperature of the reaction mixture. Under these reaction condi~ions the desired rapid removal of the water which is formed in the reaction is achieved.
Those uracil derivatives of formulae I', I", I"' and I"" which are used as starting mateLials in process variants c) to f) are a sub-group of compounds of formula I which can be produced in accordance with process variant a) or b) and, in the appropriate case, also in 1 accordance with one or more of processes c) to f)0 : :'.
The starting materials of formula IV are novel and can be produced by halogenating the corresponding uracil derivatives of general formula I' given above. In the 20 halogenation there is used as the halogenating agent ~.
especially thionyl chloride, phosphorus pentachloride or phosphorus oxychloride or, respectively, phosphorus pentabromide or phosphoryl bromide. If desired, a mixture of phosphorus pentachloride and phosphorus oxychloride or 25 of phosphorus pentabromide and phosphoryl bromide is used, -~
whereby an excess of phosphorus oxychloride or phosphoryl bromide can serve as the diluent. The chlorination or bromination can be carried out in the presence of an inert diluent, especially an aprotic organic solvent such as an aliphatic or aromatic hydrocarbon, e.g. n-hexane, benzene, toluene or a xylene; a halogenated aliphatic hydrocarbon, e.g. methylene chloride, chloroform or 1,2-dichloroethane;
a halogenated aromatic hydrocarbon, e.g. chlorobenzene, or a tertiary amine, e.g. N,N-dimethylaniline, but this is not necessary when phosphorus oxychloride or phosphoryl 3 ~
bromide is used as the halogenating agent. When thionyl chloride is used as the halogenating agentO it ha~ been found to be convenient to add a catalytic amount of dimethylformamide. The reaction temperatures generally lie between 0C and the reflux temperature of the reaction mixture, preferably between 80C and 120C.
The urea derivatives of formula YII which are used as starting materials in method aa) are novel and can be produced by reacting an amine of the general formula R~(~ ~ R4 n whecein R , R , R , R , n and X have the significances given above, at room te~perature with isocyanic acid in aqueous acetic acid or an aromatic isocyanate of formula IX [see Reaction Scheme 1, method bb)] with ammonia in an inert solvent, e.g. diethyl ether. The production of aromatic ureas is gene~ally known and is described in many literature ~ou~Ges.
The isocyanates of formula IX which are used as ~tarting materials in method bb) and for the production of the urea derivatives VII are also novel and can be produced by treating an amine of formula XII with phosgene. The reaction is conveniently effected in ethyl acetate as the solvent and at temperatures between room temperatuLe and the reflux temperature of the reaction 3S mixture. Also in this case, the production of aromatic - 26 - 2~33~
isocyanates is generally ~nown and is described in many instances in the literature.
The staeting materials of formula X used for the production of the compounds of formula III are also novel.
They can be p~oduced, for example, in accordance with Reaction Scheme 2 hereinafter rmethods cc) ~ dd) and ee)] :~
in which R2, R3, R4 R5 R6' R7' R8 ~ have the significances given above and R signifies hydLogen or Cl 4-alkyl and R signifies hydrogen or Cl 3-alkyl: .
C
~: ~
"'~
- 27 - ~ ~ 3 ~
Reaction Scheme 2 cc) R
R 11 C H = C _ o 2 ~/N~0 5 R6 CH-C=O RSJ~J~X~ ~ R n 'XIII XII
R C H 2~C ,~ O I :
R5CH ~ ~ i~ 4)n dd ) 7/
R ~55 C) R 2 X
R 6~ C - OR 8 ~ H 2 N \~ ~ 3 VI 5~/~ x,~c ~ R4 ) n \ XII
R ~0 R
2 5 R 6~N~
R 5l~0~X~ ~ R 4 n ee) X
~¦~CH3 + ~ R ~
3 5X I ~,~ C H 3 ~I R 0 \~ I H IR . j , H 2 C~ ~ ~ \~ ~ 3 sJ~\x~c ~ 4 )n - 2 8 - 2d 0 3 3 3 L7t ~i Method cc) ii6 conYeniently car~ied out by reacting the amine of formula XII with the diketene of formula XIII in the presence of an ap~otic solvent such as an a~omatic hydrocarbon, e.g. benzene or toluene, at temperatu~es in the ~ange of about 20 to 50C. Moreover, a basic cataly~, e.g. 4-pyrIolidino-pyridine, is ad~antageously used.
.: .
The ~eaction according ~o method dd) is conveniently -effected under an exces~ of the compound of fo~mula VI at temperatu~es between about 60C and the reflux temperature of th~ reaction mixture. The methyl este~ VI (R is methyl) is advantageously used. -. . .
Method ee) is conveniently effected in an aprotic ~olvent such as an aromatic hydrocarbon, e.g. toluene or a xylene, at tempe~atu~es between 100C and 140C.
The remaining starting mate~ials and, respec~ively, reagents, namely of formulae V, VI, VIII, XI, XII, XIII
and XIV, are either known or can be produced according to methods known per se, see, for example, Houben-Weyl Methoden der organischen Chemie, volume VII/2a, p. 492, and volume VIII, p. 563, J.A.C.S. 69, 1819 (1947), J. o~g.
Chem. 36, 37 (1971), J.A.C.S. 75 315~ (1953) and J. Org. ;
Chem. 48, 724 (1983) [compounds VI]: J. Org. Chem. 14, 807 ~-(1949), Helv. Chim. Ac~a Z5, 1311 (19~2), J. Org. Chem.
21, 1358 (1956) and J. OLg. Chem. 49, 4780 (1984) [compounds VIII]; Japanese Patent Publication No. 221,677 ~
(1987), Eu~opean Patent Publication No. 170.191 and -~ , 218.972 tcompounds XIIJ, Houben-Weyl Methoden de~
o~ganischen Chemie, volume VIIJ4, pp. 226-263 and J.A.C.S.
69, 2446 (1947) tcompounds XIII~; and J. O~g. Chem. 43~ --Z087 (1972) [compounds XIV].
The compounds of fo~mula I as well as theiI enol ethers and salts (he~einafte~ collectively refe~ed ~o as - 29 _ 2 ~ 3 3 ~
compounds in accordance with the invention or active substances) have he~bicidal properties and are suitable fo~ the control of weeds, including weed grasses, inter alia Abutilon theophrasti, Agropyron repens, Alopecurus myosuroides, Amaran~hus retroflexus, Avena fatua, Bromus inermis, Cassia obtusifolia, Chenopodium album, Chrysanthemum segetum, Cyperus esculentu~, Datura stramonium, Digitaria sanguinalis, Echinochloa crus-galli, Galium aparine, Ipomoea purpurea, Matricaria chamomilla, Poa annua, Setaria faberii, Sinapis arvensis, Sorghum halepense, Stellaria media and Xanthium pennsylvanicum, in diverse crops, for example in cotton, rice, maize, wheat and soya crops. ~oreover, the compounds are not only pre-emergence herbicides, but also post-emergence herbicides.
The novel starting material~ of formulae II, III, IV, VII, IX and X also have herbicidal properties and can be used for the control of weeds in a similar manner to the compounds I.
In practice, a concentration of 0.01 to 6.0 kg of compound in accordance with the invention/ha, preferably 0.05 to 2.0 kg of compound in accordance with the ~ -invention/ha, is sufficient to achieve the desired herbicidal effect.
Furthermore, the compounds can be used for the control of undesired plant growth, e.g. in potatoes, cotton, sunflowers, seed vegetables and aguatic weeds. They can he used, for example, as desiccants to facilitate the harvesting of potatoes and cotton.
The weed control composition in accordance with the invention contains an effective amount of at least one compound of formula I, as defined above, or an enol ether ..
~ 2~3~3~
or salt thereof as well as focmulation adjuvants. The -composition conveniently contains at least one of the following focmulation adjuvants: solid carrier substances:
solvents or dispersion media: tensides (wetting and emulsifying agents); dispersing agents (without tenside action); and stabilizers. With the use of these and other adjuvants these compounds, namely the herbicidally ac~ive substances, can be converted into the usual formulations such as du6ts, powders, granulates, solutions~ emulsions, suspensions, emulsifiable concentrates, pastes and the like.
' The co~pounds. of formula I and their enol ethers are generally insoluble in water, whereas the salts, especially the alkali metal salts and ammonium salts, are geneLally soluble in water, and can be formulated according to methods which are usual for water-insoluble or water soluble compounds using the respective formulation adjuvants. The manufacture of the compositions can be carried out in a manner known per se, e.g. by mixing the lespective active ingredient with solid carrier substances, by dissolution or sus~ension in suitable solvents or dispersion media, if necessary using tensides as we~ting or emulsifying agents and/or dispersing agents, by diluting pre-prepared emulsifiable concentrates with solvents or dispersion media etc.
As solid carrier substances there essentially come ;
into consideration: natural mineral substances such as chalk, dolomite, limestone, aluminas and silicic acid and salts thereof (for example siliceous earth, kaolin, - bentonite, talc, attapul~ite and montmorillonite):
synthetic mineral substances such as highly dispersible 8ilicic acid, aluminium oxide and silicates: organic substances such as cellulose, starch, urea and synthetic resins: and fertilizers such as phosphates and nitrates, - 31 - ~333~;~
whereby such carrier substances can be present e.g. as powders or as granulates.
As solvents or dispersion media there essentially come 5 into consideration: aromatics such as benzene, toluene, xylenes and alkylnaphthalenes: chlorinated aromatics and chlorinated aliphatic hydrocarbon6 such as chlorobenzenes, chloroe~hylenes and methylene chloride; aliphatic hydro-carbons such as cyclohexane and paraffins, e.g. petroleum 10 fractions; alcohols such as butanol and glycol, as well as their ethers and esters; ketones such as acetone, methyl g ethyl ketone, methyl isobutyl ketone and cyclohexanone:
and strongly polar solvents or dispersion media ~uch as dimethylformamide, N-methylpyrrolidone and dimethyl 15 sulphoxide, such solvents preferably having flash points of at least 30C and boiling points of at least 50C, and water. Among the solvents oc dispersion media there also come into consideration so-called liquified gaseous ~ -extenders or carrier substances, which are those products which ace gaseous at room temperatULe and under normal pressure. Examples of such products are especially aerosol ~-propellants such as halogenated hydrocarbons, e.g. ~
dichlorodifluoromethane. If the weed control composition --in accordance with the invention is present in the form of - ~ ;
a pressurized pack, then a solvent is conveniently used in addition to the propellant.
The tensides (wetting and emulsifying agents) can be non-ionic compounds such as condensation products of fatty 3 acids, fatty alcohols or fatty-substituted phenols with ~ ~ ;
ethylene oxide; fatty acid esters and ethers of sugars or polyvalent alcohols: the products which are obtained from su~ars or polyvalent alcohols by condensation with ethylene oxide; block pol~mers of ethylene oxide and propylene oxide: or alkyldimethylamine oxides.
- 32 - ~333~ :
The tensides can al80 he anionic compounds such as ~oaps: fatty sulphate esters, e.g. dodecyl 60dium sulphate, octadecyl sodium sulphate and cetyl sodium sulphate; alkyl sulphonates, aryl sulphonates and fatty-aromatic sulphonates such as alkylbenzenesulphonates, e.g.calcium dodecylbenzenesulphonate, and butyl naphthalene-sulphona~es: and more complex fatty ~ulphonates, e.g. the amide condensation p~oducts of oleic acid and N-methyl-taurine and the sodium sulphonate of dioctyl succinate.
Finally, the ten~ides can be cationic compounds ~uch as alkyldimethylbenzylammonium chlorides, dialkyldimethyl-~- ammonium chlolides, alkyltrimethylammonium chlorides and ethoxylated quaternary ammonium chlorides.
As dispersing agents (without tenside action) there essentially come into consideration: lignin, sodium and ammonium salts of lignin sulphonic acids, sodium salts of maleic anhydride-dii60butylene copolymers, sodium and ammonium salts of sulphonated polycondensation products of naphthaiene and formaldehyde, and sulphite lyes.
- As dispersing agents, which are e pecially suitable as thickening or anti-settling agents, there can be used e.g.
methylcellulose, carboxymethylcellulose, hydroxyethyl-25 cellulose, polyvinyl alcohol, alginates, caseinates and , blood albumin.
Examples of suitable stabilizers are acid-binding agents, e.g. epichlorohydrin, phenyl glycidyl ether and soya epoxides; antioxidants, e.g. gallic acid esters and butylhydroxytoluene; W-absorbecs, e.g. substituted benzo-phenone~, diphenylacrylonitrile acid esters and cinnamic acid esters; and deactivators, e.g. salts of ethylene-~îaminotetraacetic acid and polyglycols.
'' ' '', :, ' ':'' ~ . '~ ; ' " ,' ' ;: ,"', .,' :' ' _ 33 _ 2~3~
The weed control compositions in accordance with the invention can contain, in addition to the active ingredien~s in accordance with the invention, synergists and other active ingredients, e.g. insecticides, acaricides, fungicides, plant growth regulators and fertili2ers. Such combination compositions are suitable for intensifying the activity or for broadening the spectrum of activity.
The weed control compositions in accordance with the invention generally contain between 0.01 and 95 weight percent, p~eferably between 0.5 and 75 weight percent, of one or more compo~nds in accordance with the invention as the active ingredient(s). They can be pcesen~ e.g. in a -~
form which is suitable for storage and transport. In such formulations, e.g. emulsifiable concentrates, the active ingredient concentration is normally in the higher range, preferably between 1 and 50 weight percent, especially between 10 and Z0 weight percent. These formulations can then be diluted, e.g. with the same or different inert substances, to give active ingredient concentrations which are suitable for practical use, i.e. preferably about 0.01 -~
to 10 weight percent, especially about 0.5 to 5 weight percen~. The active ingredient concentrations can, however, also be smaller or greater.
', ~ :
As mentioned above, the manufacture of thP weed control compositions in accordance with the in~ention can be carried out in a manner known per se.
For the manufacture of pulverous preparations the active ingredient, i.e. at least one compound in accordance with the invention, can be mixed with a solid carrier substance, e.g. by grinding together: or the solid carcier substance can be impregnated with a solution or suspension of the active ingredient and then the solvent ,.
_ 34 _ ~3~3~
or dispecsion medium can be removed by evaporation, heating oc sucking-off under reduced pressure. By adding tensides or di~persing agents such pulverous preparations can be made readily wettable with water, 60 that they can be converted into aqueous suspensions which are suitable e.g. as spray com~ositions.
The active ingredient can also be mixed with a tenside and a solid carrier substance to form a wettable powder which is dispersible in water or it can be mixed with a ~ -solid pre-granulated carrier substance to form a product in ~he focm of a granulate.
'' '.
When desiced, the active ingredient can be dissolved in a wateE-immiscible solvent such as, for example, a high-boiling hydrocarbon, which conveniently contains dissolved emulsifying agent, so that the solution becomes self-emulsifying upon addi~ion to water. Alternatively, the active ingredient can be mixed with an emulsifying ~
agent and the mixture can then be diluted with water to ~ ' the desired concentration. Moreover, the active ingredient can be dissolved in a solvent and thereaf~er the solution can be mixed with an emulsifying agent. Such a mixture can likewise be diluted with water to the desired concentration. In this manner there are obtained emulsifiable concentrates or ready-for-use emulsionF.
, .
The use of the weed cont~ol compositions in accordance with the invention, which forms a further object of the pcesent invention, can be carried out according to usual application methods such as spc-inkling, spraying, dusting, watecing or scattering. The method in accocdance with the invention fo~ the control of weeds comprises treating the locus to be protected against weeds and/or the weeds with ;~
a compound in accocdance with the invention or with a weed control composition in acco~dance with the invention.
- - - - . . . - . ~ - : - . . . . . .-- - : . . . . .
, ,, , .. ", . .
_ 35 _ 2~3~3~
The following Exameles serve to illustrate the invention in more detail.
I. Manufacture of the compounds of formula _ (and II) and, respectivelY, of the enol_ethers of the ~ompounds I: -~
Example 1 .. ~:' :'' A solution of 18.51 g of ethyl 3-amino-4,4,4--trifluorocrotonate in 50 ml of dime~hylformamide is added ~-dropwise while stirring at 0C during 30 minutes to 4.41 g g of a 55% sodium hydride dispersion in 100 ml of dimethyl- -formamide and the mixture is stirred at room tempera~ure for 2 hours. The reaction mixtu~e is thPn cooled to 55C
and ~reated during 3 minutes while stirring with a solution of 25.10 g of 6-fluoro-5-isocyanato-3-(2--propynyl)-2-benzothiazolinone in 200 ml of dimethyl-formamide/toluene (1:1). In so doing, the temperature of -the reaction mixture rises to -15C and the mixture is subsequently stirred at room temperature foc one hour. The thus-formed intermediate 5-{3-~2-(ethoxycarbonyl)-1- ~ --trifluoromethyl-vinyl]ureido?-6-fluoro-3-(2-pLopynyl)--2-benzothiazolinone is not isolated. -gr . . : ,, The mixture is concentrated to 200 ml at 55C under reduced pressure and the residue is poured into a mixture of 700 ml of water and 11 ml of concentrated hydEochloric acid. The aqueous mixture is then extcacted with 300 ml of ethyl acetate, the insoluble constituents are filtered off, the organic phase is separated. this phase is washed twice with 400 ml of water each time and dried over anhydrous sodium sulphate. The solution is brought to crystallization by evaporation and the crystals are fil~ered off under suction and dissolved at 50C in 1 1 of ethyl acetate. Insoluble constituents are filtered off and - 36 - ~333~
the filtrate is evaporated until a viscous oil has formed, the cesidue is dissolved in 700 ml of diethyl ether and the solution is ~reated with charcoal and concentrated to 150 ml. The solution is ~iubsequently brought to crystal-lization with n-hexane while stircing and cooling at 0C.
Finally, the crystals are filtered off unde~ suction, washed with diethyl ethertn-hexane (1:1) and dried.
In this manner there is obtained 3-[6-fluoro-2-oxo-3--(2-propynyl)-5-ben%othiazolinyl]-6-trifluoromethyl--2,4(1H,3H)-pyrimidinedione, m.p. 224-2Z7C.
Exam~le 2 Analogously to the procedure described in Example 1, starting from ethyl 3-amino-4,4,4-trifluorocrotonate and 3,4-dihydro-7-fluoro-6-i~ocyanato-3-oxo-4-(2-pLopynyl)-2H--1,4-benzoxazine theLe is obtained 6-{3-[2-(ethoxy-carbonyl)-l-trifluoromethyl-vinyl~ureido}-3,4-dihydro-7--fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine (not isolated) and, after cyclization of this benzoxazine, there is obtained 3-[3,4-dihydro-7-fluoro-3-oxo-4-(2--propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl--2,4(1H,3H)-pyrimidinedione, H-NMR (CDCl~, 60 MHz):
7.29 ppm (d, lH), 6.99 ppm (d, lH), 6.31 ppm (s, lH), 4.85-4.61 ppm (m, 4H), 2.35 ppm tt, lH); mass spectrum:
m/e 393(20), M .
ExamDle 3 Analogously to the procedure described in Example 1, starting from ethyl 3-amino-4,4,4-trifluorocrotonate and 3,4-dihydro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4--benzoxazine there is obtained 6-{3-[2-(ethoxycarbonyl)--1-trifluo~omethyl-vinyl]ureido}-3,4-dihydro-3-oxo-4--(2-propynyl)-2H-1,4-benzoxazine (not isolated) and, after . .
j~`` 2~333~$ :
_ cyclization of this benzoxazine. there is obtained 3-r3,4-dihydro-3-oxo-4-(Z-propynyl)-2H-1,4-benzoxazin-6-yl]-6--t~ifluoromethyl-2,4-(lH,3H)-pyrimidinedione, m.p. >250C. ~ -ExamPle 4 A suspension of 8.Z g of 5-[3-ethoxycacbonylamino)-2- ;~
-butenoylamino]-6-fluoro-3-(2-propynyl)-2-benzothiazolinone to 100 ml of methanol i~ trea~ed while stirring at 50C
with 11.5 ml of a ZN sodium methylate solution and the reaction mixture is ~tirred for 15 minutes. The solution which thus results is then ~tirred for 30 minutes, concentrated to 20 ml under reduced pressure and the residue is poured into a fiolution of 20 ml of 2N hydro-chloric acid in 500 ml of water. The resulting precipitateis filtered off under suction, washed with water and dried. In this manner there are obtained 6.1 g of 3-[6--fluoro-2-oxo-3-(2-propynyl)-~-benzothiazolinyl]-6-methyl- :.
-2,4(1H,3H~-pyrimidinedione, m.p. ~250C.
Examples 5-34 The corresponding compound of formula II is in each case cyclized analogously to the procedure described in ;
Example 4 in order to manufacture the compounds of formula I listed in Tables la and lb hereinafter.
:::
C H 3\~N~0 R 2 .
~/ ~ \~ 3 " ,,,, ,.
..
:: .
2~33~
-Table la - .
2 - 3 4 , _ _ E~ample ~ ca R n ~ Physi r al dnta _ _ _ _ . ~ ~ __ _ CH2C_CH CH2 1 O lH-NMR (CDC13, 100 MHz): 7.08 ppm ~d, lH), 6.90 ppm (d, lH), 5.58 ppm (s, lH), 4.69-4.64 ppm (m, 4H), 2.33 ppm (t, lH), 2.18 ppm (s, 3X); m.p.
6 CH2CH=CH2 CH2 1 O H-N~R (CDCl3, 400 MHz): 9.89 ppm (s, lH), 6.98 ppm (d, lH), 6.82 ppm (d, lH), 5.83 ppm (m, lH), 5.66 ppm (s, lH), 5.22 ppm (m, 2H), 4.69 ppm (s, 2H), 4.52 ppm, (m, 2H) 2.14 ppm (d, 2H), 1.69 ppm ~s, lH~; m.p.
.
2 l 7 C2H5 CH(CH3) 1 0 M.p. 147-149C
.
2 l 7 C2H5 CH(CH3) 1 0 M.p. 147-149C
8 CH2C-CH CH(CH3) 1 0 M.p. 227-230C
3 9 CH3 _ Zero S ~.p. >260~C
C2H5 _ Zero S ~.p. ~260C
3 11 CH2CH=CH2 _ Zero S ~-P. >250C
12 CH(CH3)2 _ Zero S M.p. 193-195-C
13 nC3H7 _ Zero S M.p. ~Z50C
:, -, ~ j: , , . . ,, : .. : . . ,. , .,, ., . .. :.
,. , ", . ", , , "; . : .- .
";,:, . . . , , , , : , ~
. ; , ", ~ . '~' ' . :
. .,, : , , : ; j ~. , ;. :: , , , s ;.' ~ :~ .: ' , .
:
3 3 ~
- 39 - .
-Table la (continued) - :
_ ..~ ,.
E~ample R2 CR3R4 n ~ Physical data l l _ _ 14 CH(CH3)2 _ Zero 0 M.p. >250C
CH3 _ Zero 0 ~.p. >250C i-16 3 7 _ Zero O M.p. ~250C : ~ :
17 CH20CH3_ Zero 0 ~.p. >250C ~:-1( ~18 CH2COOC2H5 _ Zero 0 M.p. 213-215C :. :. .
19 CH2CH=CH2 _ Zero 0 ~.p. >250C -: :
C 20 CH C-CH _ Zero 0 M.p. >250C
21 H CH2 1 0 ~.p. >220C
1 ' 2 2 CH2 C - CH CH2 S p . 144-147-c :
;''~'' ~
:`. ' ., ':
~
: . .;
; ~, ~. ' '1" ~
: ' ' .
: : .
,~ . .
- 40 - :~
R H, o 2 . :
\ / ~ R
F ~ X ~ ~4 n ;
Table lb ~. .
_ 3 4 . . . . ..
:~ Example : CR R n X ~ Physi~al data ' : ::
_ _ , : ~ 23 15 CH(CH3)2 _ Zero S C2H5 ~P- 237-238C :
24 CH2CH=CH2CH2 1 C2H5 M.p. 193-200C
: ; 25 CH2CH=CI~2CH2 1 0 3 7 M.p. 157-161C .~: -:~ 26 CH2C-CH CH2 1 C2H5 ¦ ~'P' 240C
¦ twith decomposition~
27 20 CH2C-CH CH2 1 0 nC3H7 M.p. 238-239C
28 CH(CH3)2 CH2 1 C2H5 ~'P- 208-2100C ~ -:: 29 CH(~H3)C-CHCH2 1 0 C2H5 Mass spectrum m~e 357(89~ M
( 30 CH(CH3)C2H5CH2 1 0 C2H5 . :
. 31 25 3 3 CH2 1 0 C2H5 32 CH(OCH3)C2Hs CH2 1 0 C2H5 33 CH(CH3)CH=CH2 CH2 1 0 C2H5 34 CH2CH.CH2 ~ero S C2L5 ~ , 2 ~ ~ C~
- 41 - ~
:. . ' ' .
... .. .
Examæle 35 -" ,' A suspension of 6.45 g of 6-[3-tethoxycarbonylamino)--2-pentenoylamino]-3,4-dihydro-7-fluoro-3-oxo-4-(2--propynyl)-2H-1,4 benzox~zine and 3.22 g of ~odium methylate in 6.5 ml of methanol is ~tirred at 62C for 4 hours. The ~olution which thu~ results is left to ~tand at room temperature for 64 hours and ~ubsequently poured into a ~olution of 15 ml of 2N hydrochloric acid in 400 ml Of water. The ~esulting precipitate i~ filtered off under ~uction, washed with water and recry~tallized from ace~one/n-hexane. In this manner there is obtained 6-ethyl-3-[3,~-dihyd~o-7-fluoro-3-oxo-4-(2-p~opynyl)-2H--1,4-benzoxazin-6-yl]-2,4(1H,3H)-pyrimidinedione, m.p.
240C twith decomposition).
Example 36 -, :,.' ' Analogously to the procedure described in Example 35, ~;
by cyclizing 6-[3-(ethoxycarbonylamino~-2-pen~enoylamino]--4-allyl-3,4-dihyd~o-7-fluoro-3-oxo-2H-1,4-benzoxazine there is obtained 6-ethyl-3-~4-allyl-3,4-dihydlo-7-fluoro- , ,~
-3-oxo-2H-1,4-benzoxazin-6-yl)-2.4(1H,3H)-pyrimidinedione, m.p. 197-200C.
~ 25 ExamDle 37 Analogously to the procedure described in Example 35, by cyclizing 5-[3-(ethoxyca~bonylamino)-2-pentenoylamino]-30 -6-fluoro-3-(n-propyl)-2-benzothiazolinone there i~ ~-obtained 6-ethyl-3-~6-fluoro-2-oXo-3-(n-propyl)-5-benzo-thiazolinyl]-2,~(1H~3~)-pyrimidinedione. m.p. >250C.
ExamPle 38 :
A mixture of 27.50 g of 3-[6-fluoro-2-oxo-3-(2--p~opynyl)-5-benzothiazolinyl~-6-tLifluoromethyl-~ ~ .
. .
~33~
-2,4(1H,3H)-pyrimidinedione ~see Example 1), 10.80 g of dimethyl sulphate and 9.08 g of sodium ca~bonate in 250 ml of acetone i8 heated at the boiling temperature while stirring for 1.5 hours. After cooling the ~olid 5 constituent is filtered off under ~uction and washed with acetone. The filtlate is then evaporated to dryness under reduced pcessure~ the residue is dissolved in 350 ml of ethyl acetate and the solution is washed three times with r 300 ml of water each time. Subsequently, the organic phase 10 is dried ovec anhydLous sodium sulphate and evaporated to dryness under reduced presSu!e~ and the resinous residue is purified by chroma~ography on 1.5 g of silica gel using ethyl acetate/n-hexane (1:3) as the eluent. The first fraction is recrystallized from ethyl ace~ate/diethyl 15 ether (1:1), whereby there is obtained 6-fluoro-5-~Z--methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-3-(2--propynyl~-2-benzothiazolinone, m.p. 191-192C. The 2nd fraction is recrystallized from diethyl ether/n-hexane (1:1) and there is thus obtained 3-~6-fluoro-2-oxo-3-(Z-20 -propynyl) 5-benzo~hiazoiinyl]-l-methyl-6-trit`luorometh -2,4(1H,3H)-pyrimidinedione, m.p. 190-192C.
' ExamPles 39-72 C 25 The corresponding uracil derivative of formula I' is in each case methylated with dimethyl sulphate analogously to the procedure described in Example 38 in order to manu~acture the l-methyluracils (and in one case also the enol ether) listed in Table 2 hereinafter.
CH
~7 ¦ ~ o R2 R ~ N ~ OCH3 2 ~N ~ N ~0 ~ 1~ N ~f~O
R5 ~ X~ ~ R4 n R ~ X~ ~ R4)n I""' Ia' , " , , ., ~ . , , . : - . , ::
, , . , , ,, , ., . . , ,. . , . ,:
, , , ,. , , : , .: , ~ , . . . . :
: ... ... .. .
~ .: ' , : , .. .. .
: ' ' , ; ,: ,~ :
3 ~
.
Table 2 _ . _ _ _ . . _ ' E~ample E~mple No. Pormula: R2 CR3R4 R5 R7 n X Physical ~ :
of the st~tin~ I"' or data material I' Ia' ___ . .. . _ _ 39 2 I""' CH2C-CH CHz F CF3 1 O lH-NMR
(CDC13, 400 ~Hz): 7.06 ppm ~d, lH), 6.93 ppm (d, lH), ( , 6.38 ppm ~s, lH), 4.69 ppm ~s, 2H), 4.64 ppm ~q, 2H), 3.57 ppm ~t, . 3H), 2.29 ppm ~t, lH) l 3 1""' CH2C_CH CH2 H CF3 1 0 H.p. 216-217C
41 3 la' CH2C_CH CHz H CF3 1 0 ~.p. 218-220C
42 5 I""' CH2C-CH CH2 F CH3 1 0 lH_NHR
~CDC13, 400 ~Hz): 7.05 ppm -~d, lH), 6.90 ppm ~d, lH), ~ :
2( ) 5.75 ppm ~s, lH), 4.67 ppm ~s, 2H), 4.64 ppm (d, 2H), 3.40 ppm ~s, 3H), 2.32 ppm ~d, 3H), 2.27 ppm ~t, lH) C 43 2 6 I""' CH2CH=CH2 CH2 F CH3 1 0 lH-NHR
~CDC13, 100 ~Hz): 6.88 ppm (d, lH), 6.81 ppm (d, lH), ' 5.82 ppm ~m, ~ .
lH), 5.72 ppm ~d, lH), 5.23 3 ppm ~m, 2H), -4.67 ppm (s, 2H), 4.50 ppm ~m, 2H), 3.44 ppm ~s, 3H), : :
2 31 ppm ~d, .
44 7 I""' c2~5 CH~CH3) F C~l3 0 H.p. 211-213C
. ~ ; ....... _ . :. '' . . . .. ,, : .,... : " : ;. ,, 3 3 ~
- Table 2 (continued) . _ __ . _ _ E~ample E~ample No. R2 CR3R4 RS a7 n X Physic~l ays o~ the starting data for~ula ~terial I' .
. _ _ _ _. ~ .~
8 CH2C-CH CH(CH3) F CH3 1 1 H.p, 219-222C
46 9 CH3 .- F CH3 Zero S M.p. 255-257C
417O10 C2H5 _ F CH3 Zero S M.p. 235-236C
48 11 CH2CH=CH2 _ F CH3 Zero S M.p. 210-211C
49 12 CH(CH3)2 _ F CH3 Zero S H.p. 214-216C : .
S0 13 nC3H7 F CH3 Zero S M.p. 222-223C
5~526J35 CH2C-CHCHz F C2H5 1 0 M.p. 230C (with .
decomposition) 52 24J36 CH2CH=CH2 CH2 F CzH5 1 0 M.p. 172-174C
53 37 ~ nC3H7 _ F C2H5 Zero S M.p. 101-102C
54 14 CH~cH3)2 , - F CH3 Zero 0 M.p. 143-145C
5~ 15 CH3 _ F CH3 Zero 0 n. p . 228-231C
56 16 nC3G7 _ F CH3 Zero 0 M.p. 155-157C
57 17 CH20CH3 _ F CH3 Zero 0 ~.p. 200-202C
58 18 CH2C00c?H5 _ F CH3 Zero 0 M.p. 167-169C
5~5 19 CHzCH=CHz _ F CH3 Zero 0 M.p. 164-166C
CHz-CH _ F CH3 Zero 0 M.p. 182-184C
61 l02 CH2CNCH2 F CH3 1 0 M.p. ~230C
62 22 CH2C-CHCH2 F CH3 1 S M.p. 214-217C
633023 CH(CH3)2 _ F C2H5 Zero S M.p. 176-178C
64 25 CH2cH=cH2 C~2 F nC3H7 1 0 n . p . 146-147C
27 CH2C-CH CH2 F nC3H7 1 0 M.p. 192-193C
66 28 CHtCH3)2 CH2 F C2H5 1 0 M~ss spectrum:
. _ ~/e 361(67~ ~+
, ' ' ': ,. ' .' ' ' ; , . ,, : .' ;
, : ~:. . .. .. .
,, ,, . !. : ~
- 45 - ~33 Table Z (continued~
.
_ _ _ _ Ex~pl0 Example No. R2 CR3R4 R5 R7 n X Physical ~a~ways of the startinB
dat~
for~ula ~aterial I' .
~ . __ _ .
67 29 CUICH3)C-CHCH2 F C2H5 l O ~ass spectrum:
m/e 371(98) ~+
60~ 30 CH~cH3)c2HsCH2 F C2H5 1 O .. .. .
69 31 CH(CH3)OCH3CH2 F C2H5 1 O
C 70 32 ~ CH(OCH3)C2H5 CH2 F C2H5 1 O
71 33 CH(CHj)CH=CH2 CH2 F C2H5 1 ; :
72 34 CH2cH=cH2 _ F C2H5 Zero S
lg - _ _ ' ',,; ;' ~0 ~ ' c '' 2 5 ;:
:
~'.. :' .: ..
,~' ~'''' :
" ~.
: .
, , . ,, . ~ , ,.,. ,, ,,: :, ., , . .. .. ~, ;:, . . .
:"" . , , , .,, , , , . , ~ . . . , , . , , , , ; ~ , ,: . : , .. :
,....... , . . . , ,. , .: . . ~ , " ~ . . ..
- 46 - ~3 E~ample 73 A solution of 6.1 g of 3-~6~~1uoro-2-oxo-3-(Z--propynyl)-5-benzothiazolinyl]-6 methyl-Z,4(lH,3H)--pycimidinedione (see Example 4) in 50 ml of dimethyl-formamide is added while stirring to a suspension of 0.8 g of a 55% sodium hydride dispersion in 25 ml of dimethyl-formamide. Aftel the hydrogen evolution has finished the mixture is treated with 2.8 g of dimethyl sulphate and stirred fo~ one hour. Thereafter, the reaction mixture is poured in~ 500 ml of water, the agueous mixture is extracted three times with 100 ml of ethyl acetate each time and the org~nic phase is dLied ovec anhydcous sodium sulphate. The solvent is subsequently distilled off under reduced pressure and the thus-obtained residue (7.2 g) is purified by chromatography on a column of 350 g of aluminium oxide (Brockmann I) using methylene chloride/
n-hexane (3:1) as the eluent. The ficst frac~ion (1.5 g) is recrystallized from ethyl acetate, whereby there is 20 obtained 1.6-dimethyl-3-[6-fluoco-2-oxo-3-(l,Z-pcopane-dienyl)-5-benzothiazolinyl]-2,4(1H,3H)-pyrimidinedione.
m.p. >250C. By further elution of the column with methylene chloride/ethyl acetate t3:1) there is obtained the second fraction (4.7 g) which is recrystallized from C 25 ethyl acetate. In this manner there is obtained 1,6-dimethyl-3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzo-thiazolinyl]-2,4(1H,3H)-pyrimidinedione, m.p. 180-181C.
ExamPle 74 A ~olution of 0.16 ml of ~romine in 5 ml of acetic acid is added while stirring at room temperature within 15 minutes to a solution of 1.0 g of 3-t3,4-dihYdro-7--fluoro-2-methyl-3-oxo-4-(2-propynyl)-2~-1,4-benzoxazin-35 -6-yl]-1,6-dimethyl-2,4(1H,3H)-pycimidinedione tsee Example 45) in 7 ml of acetic acid and the mixture is "
stirred at ~oom temperature for 30 minutes. The mixture is then concentrated under reduced pressure, the lesidue is taken up in ethyl acetate, the solution is washed with ~- ;
dilute, aqueou~ sodium bicarbonate solution, the organic phase i~ dried o~er anhydrous ~odium 6ulphate and concentrated to drynes~. In thi~ manner there i~ obtained ~ -5-bromo-~-[3,4-dihydro-7-îluoro-2-1nethyl-3-oxo-4-(2--propynyl)-2H~1,4-benoxazin-6-yl]-1,6-dimethyl-2,4(1H,3H)--pyrimidinedione, m.p. 182-187~C.
ExamPles 75-77 The coeresponding uracil derivative of formula I"" is in each case brominated analogously to the procedure de~cribed in Exam~le 74 in order to manufacture the 5-bromouracils listed in Table 3 hereinafter.
.:
~ ~ ~ ~ ~2 B ~ ~ ~ 3 ~' 25 Table 3 ..
Example Example No. R2 CR3R4 R7 Physical ; :
of the start- . data in~ materials _ _ ____ _ ~
44 C2H5 CHCH3 CH3 ~'P- 219-2200C ~ :
76 52 CH2CH=CH2 CH2 C2H5 M.p. 215-219C
. 3577 52 CH2CH3rCH28r CH2 C2H5 N.p. 124-123C
'.' ,, ~ . , ' ' , ,'. ,~ ',. . . .
~33~ -, ExamPle 78 A solution of 1.08 g of sodium methylate in 10 ml of methanol i8 added at 20C while stiLring to a solution of 57.65 g of 6-r2-chloro-6-oxo-4-trifluoromethyl-1(6H)-rimidinyl]-4-(2-eLopynyl)-2H-l~4-benzoxazin-3(4E~)-one in 300 ml of absolute methanol. A suspension fo~ms during 15 minutes and the tempera~ure rises to 30C. The reaction mixture is concentrated at 40-50C under reduced pressure and the residue is dissolved in 500 ml of ethyl acetate.
The organic phase is washed twice with 200 ml of wa~er each time, dried over anhydrous sodium sulphate and evaporated to dr~ness undeL reduced pressure. The crystal-line residue is stirred with 20 ml of diethyl ether, cooled to 0C and treated wi~h 100 ml of n-hexane. The crystals are filte~ed off under suction and dried at 50C
under reduced pressure. In this manner there is obtained 6-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pylimidinyl]--4-(2-propynyl)--2H-1,4-benzoxazin-3(4H)-one, m.p.
218-2Z0C.
Example 79 34.94 g of 1,6-dimethyl-3-(6-fluoro-3-isopropyl-2-oxo--5-benzothiazolinyl)-2,4(1H,3H)-pyrimidinedione (see Example 49) are dissolved in 200 ml of concentrated sulphuLic acid while stirring and gassing with nitrogen and the solution is heated to 150C for 45 minutes. The reaction mixture is cooled to 25C and poured on to 1 kg of ice, and the precipitated product is filtered off under suction and washed neutral with water. The filter cake is suspended in 500 ml of ethyl acetate at 60C, the suspension is concentrated to 250 ml, the product, after cooling, is filtered off under suction, the filtrate is back-wash~d with ethyl acetate and dried at 50C undeL
reduced p~essure. In this manner there is obtained . ,, ~, .. . . " . , ., .. : . . . . . , . , , : . , : .:
- 49 - ~
'.'.:
1,6-dime~hyl 3-(6-fluoro-2-oxo-5-ben~othiazolinyl)-2 D 4' (lH,3H)-py~imidinedione, m.p. >250C.
., Example 80 ~ nalogou~ly to the p~ocedure described in Example ?g, star~ing from 6-ethyl-3-(6-fluoro-3-isopropyl-2-oxo-5 -benzothiazolinyl)-l-methyl-2,4-(lE~,3H)-pyrimidinedione ~
(see Example 50) the~e is obtained 6-e~hyl-3-(6-fluoro~
10-oxo-$-benzothiazolinyl)-1-me~hyl-2,4(1H"3H)-pyrimidino-dione, m.p. ~25QC.
- , ExamPle 8 153.07 g of 1,6-dime~hyl-3-(6-fluoro-2-oxo-5-benzo- ~;
thiazollnyl)-2,4(1H,3H)-pyrimidinedione (see Example 7 and 0.48 g of a 55% sodium hydride dispersion are Sti~
at 25C for l hour in 50 ml of absolute dimethylformàm~
Subsequently, 1.02 g of chloroacetamide are added and~
mixture is stirred at 50C for 6 hours. The reaction mixture is cooled and tleated with 400 ml o water. ~h~
precipitated product is filterecl of~' under suction, with water and the filter cake is su~pended in 200-ml~
ethyl acetate at 60C. The suspension is concentrated ;t O ~ ' ' about 50 ml, cooled to 25C, the solid is filtered off under suction and dried at 50C. In this manner there obtained 3-(3-carbamoylmethyl-6-fluoro-2-oxo-5-benzo--thiazolinyl)-1,6-dimethyl-2,4tlH,3H)-pyrimidinedione >260C.
Examples 82-101 The corresponding uracil derivative of folmula I'^' is in each case t~eated with the cor~esponding alkylatinc3 agent analogously to the procedure described in Exampl~? c~
in order to manufacture ehe compounds of formula I listed in Table 4 hereinafeer.
' ''' ' " ;, '', " ',~ ' , :' ";" . ;" ' ~' ` ''' .
2 ~ 3 3 3 ~ ~
R~l~l~fO R2 b~N~
. . , Table 4 ._ _ _ ~ample E~ample No. ~2 R7 Physical data of the st~rt-ng material : 82 79 isoc4Hg CH3 ~-P- 168-171C
5 83 79 sec.CqHg CH3 U.p. 135-137DC
t; 84 80 sec.C4Hg C2Hs ~.p. 150-152C
79 CHF2 CH3 ~.p. 206-208C
86 79 CF2CHF? CH3 ~.p. 156-158C
:-, 0 87 79 CH20CH3 CH3 H.p. 243-245C
~:: 88 80 CH20C~3 C2H5 U.p. 198-200C
,! ~ . 89 80 CH(CH3)0CH3 C2H5 M.p. 221-222C
~ 5 90 80 CH(OCH3)C2Hs C2H$ ~.p. 232-234C
:~ 91 80 CH(CH3)0c2H5 C2Hs M.p. 216-218C
92 79 CH2CN CH3 H.p. ?47-250~C
93 79 CH2COOC2H5 CH3 ~.p. 193-195C
0 94 79 CH2coN(cH3)2 CH3 n.p. 257-258C
79 CH2C~CH3)=CH2 CH3 M.p. 203-205C
96 79 CH(CH3)CH=cH2 CH3 M.p. 148-178~C
97 80 CHtCH3)CH=cH2 C2H5 M.p. 124-134C
.~ 5 98 79 Cinnamyl CH3 N.p. 125-160C
:~ 99 80 CH2C-CH C2H5 M.p. >250C
100 79 CH~CH3)C-CH CH3 M.p. lB4-186C
101 80 _ CH(CH3)C_CH C2H5 M.p. 177-179C
, ;"
-Exam~le lo?
Analogously to the proceduLe described in Example 81, by alkylating 3-(3,4-dihydro-7-fluoro-3-oxo-2H-1~4--benzoxazin-6-yl)-6-methyl-2,4(lH,3H) -pyl imidinedione (see Example 21) with chloroacetonitrile there is obtained 3-(2-cyano~ethyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazin-6-yl)-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p. >230C.
, II. Production of ~he com~ounds of formula IX ~inter-mediates in the manufacture of the compounds of formula I):
Example 103 A solution of 22.5 g of 5-amino-6-fluoro-3-(2--propynyl)-2-benzothiazolinone in 35~ ml of ethyl acetate is added dcopwise at 30OC during 2 hours while stirring to a solu~ion of 60.0 g of phosgene in 300 ml of ethyl acetate. The resulting suspension i6 stirred at 50C for 2 hours and subsequently heated slowly to the boiling point. The clear solution is then evaporated to dryness and there is thus obtained as the residue 6-fluoro-5--isocyanato-3-(2-propynyl)-2-benzothiazolinone, yellow crystals. This product serves, inter alia, as the ~ta~ting material in the manufacture of 3-[6-fluoro-2-oxo-3-(2-~propynyl)-5-benzothiazolinyl]-6-trifluoromethyl-2,4-(lH,3H)-pyrimidinedione (see Example 1).
Example 104 6-Amino-3,4-dihydro-7 fluoro-3-oxo-4-(2-propynyl)-zH
-1,4-benzoxazine is treated with phosgene analogously to the procedure described in Example 103 in order to produce the 3,4-dihydro-7-fluoro-6-isocyanato-3-oxo-4-(2-; ~ ; ' ' ' ~' , ', "' ' . . ,,: ,. ' , ' ' , , , , :: , , ,, :. . . .
~ 2~3~
5z -propynyl)-ZH-1,4-benzoxazine which is used as the starting material in Example 2. H-NMR (CDC13, 60 MHz): 7.02 ppm (d, lH), 5.88 ppm (d, lH), 4.88-4.60 ppm (m, 4H), 2.35 ppm (t, lH~.
Example 105 6-Amino-3,4-dihydro--3-oxo-4-(2-propynyl)-2H-1,4--benzoxazine is treated with phosgene analogously to the p~ocedure described in Example 103 in order to produce the 3,4-dihydro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4--benzoxazine which is used as the starting material in Example 3. H-NMR (CDC13, 400 M~z): 6.9B-6.92 ppm (m, 2H), 6.79 ppm (q, lH), 4.66 ppm (d, 2H), 4.63 ppm (s, 2H), 2.31 ppm (t, lH).
III. Production_of the compounds of formulae X and III
intermediates in the manu~Eacture of the compounds of formula IL:
Example 106 ::
~ ~ .
A sus~ension of 4.7 g of 5-amino-6-fluoro-3-~2--propynyl)-2-benzothiazolinone, 1.93 g of diketene and 0.05 g of 4-eyrrolidinop~ridine in 250 ml of benzene is stirred at room temperature for 30 minu~es and .:. -subsequently held at 50C for 30 minutes. In this manner ~.:
there is obtained a solu~ion of 5-acetoacetylamino-6--fluoro-~-(2-propynyl)-2-benzothiazolinone which is used as such in the next ~eaction step without isolation of the pr oduCt-: :
The above clear solution is heated to the boiling : :
point under a water separator for Z.5 hours with 2.B5 g of ::
ethyl carbamate and 0.2 g of p-toluenesulphonic acid mo~ohydrate. Subsequently, the mixture is again treated ~ .
, ':" ' '~ ' .
~ ~ 3 3 ~ ~ ~.3 with 0.2 g o~ p-toluenesulphonic acid monohydrate and heated for a further 2.5 hours. The reaction mixture is evaporated to dryness under reduced pressure. The --thus-obtained crude eroduct (11.7 g) i~ suspended with 50 ml of diethyl ether, the insoluble portion is filtered off under suction and dried. In this manner there are ~ -obtained 8.2 g of 5-r3-ethoxycarbonylamino)-2-butenoyl-amino]-6-fluoro-3-(2-propynyl)-2-benzothiazolinone, m.p.
about 167-169C. This product serves, inter alia, as the starting material in the manufacture of 3-~6-fluoro-2-oxo--3-(2-pro~ynyl~-5-benzothiazolinyl]-6-methyl-2,4(1H,3H)--pyrimidinedione (see Example 4).
: - -Example 107-134 Analogously to the pcocedure described in Example 106, the corresponding amine of formula XII is reacted with the corresponding diketene in order to produce the correspond-ing compound of formula X' which, in ~urn, is reacted with ethyl carbamate in order to produce the compounds offormula III listed in Tables 5a and 5b hereinafter. In these Tables there are given in each case both inter-mediates tformula X"' or X"" and, reseectively, III' or III") as well as the respective end product I to which the corresponding intermediate of formula III' or III" leads by ~ing closure.
s .
. . . .. . ~ . . . . " . , , . , - . .... .. . . . .. .
2~333~
-- 5~1 --~J ~4 n ~ ~ ~ 4 ) y - F
X' `~
Table 5a ~ :"
__ _ . . _ _ . . :
Physic~l d~ta Example E~ample No. R2 (CR3R4) n X
of the end . Compound X"' Compound III' ~:
product I :
_ _. . ,',-l~i!P 5 CH2C--CH CH2 1 O -~not isolated) (-not isolated) : ~
108 6 CH2CH=CH2 CH2 1 0 .. H.p. 175-177C ~ :
109 7 C2H5 CH~CH3) 1 0 .- ~.p. 192-194C
110 8 CH2C-CH CH(CH3) 1 0 .. H.p. 171-173C
111 9 CH3 _ Zero S H.p. 150-151C M.p. 250-251C : :-. -112 10 C2H5 _ Zero S H.p. 118-120C H.p. 195-197C - -1~35 11 CH2CH=CH2 _ 2ero S H.p. 113-115C H.p. 194-196C
114 12 CH(CH3)2 _ Zero S H.p. 166-167~C H.p. 186-187C : : .
115 13 nC3H7 _ Zero S ~.p. 116-117C H.p. 203-205C `: .116 14 CH(CH3)2 _ Zero 0 H.p. 167-169C H.p. 186-188C
117 lS CH3 _ Zero 0 H.p. 137-139C ~.p. 200-202C
~0 16 3 7 _ Zero 0 H.p. 105-107C ~.p. 159-160C
119 17 CH20CH3 Zero 0 H.p. 126-128C H.p. 181-183C :.
120 18 CH2COOC2H5 _ Zero 0 H.p. 143-145C H.p. 184-185C .
121 19 CH2CH=CH2 _ Zero 0 H.p. 106-107C ~.p. 149-151C
122 20 CH2C=CH Zero 0 p. 114-116C H. p. 199-200C
~:
" '' '~' ' :' . ,~ .
.: :' ,~
:
Table 5a ~continued) ___ _ _ _ _Physical data EYam~le E~ample No. R2 ~CR3R4) n X _ . _ of the end Compound ~"' Compound III' product I
~_ _ _ - . , _ . __ ~ _ ,'., ' .
123 21 H CH2 1 O H.p. ~230C . lH-N~RtCDC13, . 200 ~Hz): 11.50 pp~
. ~s,lH), 10.66 ppm C (s,lH~, 9.62 ppm . . ~s,lH), 7.56 ppm (d,lH), 6.96 ppm (d lH) 5 30 ppm .
~s,2H), 4.30 ppm ~q,2H), 2.26 ppm ~s,3H), 1.22 ppm ~t,3H) : :
420 22 2 CH2 1 S -(not isolated) H.p. 185-188C
6; 2 5 i:
.::
.:
; ~ :
3~ . .
. : ~ . ,, - , . ~, ,: ,-R O
2 R 7 ~ ~ COOC 2 H 5 R 2 ~N~ ~R ~ ~C HN~x~ F~4)D
X " " I I I "
Table 5b -' . ~ _ ~ _ _ _ ~
~ Physical data .i : Example Example No. R2 .(CR R ) n ~ R7 . H
of the end Co~pound X"" Compound III"
~pduct I
_ . _ _ _ . _ _ ~
,., 123 23 CH(CH3)2 _ 2ero S C2H5H.p. 167-168C ~.p. 150-152C
124 24 CH2CH=CH2 CH2 1 C2~l5 -(not isolated) M.p. 109-1154C .
125 25 CH2CH=CH2 CH2 1 0 nC3H7 -(not isolated) ~.p. ~6-884C :: .. ~
126 2~ CH C-CH CH2 1 C2H5 ~'P' 113-1150C ~.p. 132-133C
: 127 27 CH2C-CH CH2 1 0 nC3H7 ~,p, 88-93C H.p. 143-147C ..
128 28 CH~CH2)2 CH2 1 C2H5 -(not isolated) -(not isolated) ~ .
129 29 CH~CH3)C-CH CH2 1 C2H5 H.p. 110-114C -(not isolatedj ~-130 30 ~ H3~C2H5 CH2 1 0 C2H5 C131 31 CH(CH3)0CH3 CH2 1 0 C2H5 . .
132 ~25 CH~OCH3)C2H5 CH2 1 0 C2H5 . ~ .
133 33 CH~CH3)CH=CH2 CH2 1 0 C2H5 134 34 CH2CH=CH2 _ Ze~o S C2H5 . _ . _ .. ..... ~ ,, ~___ ,`'~
:
'. ;''~'',, !" . '.; , '~ , , . ' '' ' ~3~
Example 135 A solution of 11.0 g of 2,2-dimethyl-5-propionyl-1,3--dioxane-4,6-dione in 50 ml of toluene is added dropwi~e 5 at 30C during 15 minutes while ~tirring to a solution of 12.2 g of 6-amino-3,4-dihydro-7~fluoro-3-oxo-4-(2--propynyl)-2H-1,4-benzoxazine in 100 ml of ~oluene. The reaction mixture (still a solution) i5 stirred a~ 124C
for 4 hours and thereafter left to stand at room temperature for about 16 hours. Then, the precipitated crystal~ are separa~ed and dried.
.` :.
In this manner there is ob~ained 3,4-dihydro-7-fluoro--3-oxo-4-(2-propynyl)-6-propioacetylamino-2H-1,4-15-benzoxazine, m.p. 113-115C.
A suspension of the above intermediate, 6.14 g of ~ -ethyl carbamate and 0.2 g of p-toluenesulphonic acid monohydrate in 260 ml of benzene is heated at the boiling temperature under a water separator for 2.5 hours.
Subsequently, the mixture is again treated with 0.2 g of ~-p-toluenesulphonic acid monohydrate and heated for a further 2.5 hours. The reaction mixture is evaporated to dryness under reduced pressure, whereby 25.5 g of crude C 25 product are obtained. This is suspended with 200 ml of ethyl acetate, washed with 300 ml of water and crystal- -lized from ethyl acetate. In this manner there are obtained 7.2 g of 6-t3-(ethoxycarbonylamino)-2-pentenoyl-amino]-3,4-dihydro-7-fluoro-3~oxo-4-(2-propynyl)-2H-1,4-30 -benzoxazine, m.p. 133C (with decomposition). This product serves as the starting material in the manufacture of 6-ethyl-3-t3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)--2H-1,4-benzoxazin-6-yl]-2,4(lH,3H)-pyrimidinedione tsee Example 35).
,'.: ' .
, ", . , . .. , , . , . ., , ,. ,.. ~ .,. , .. . .. . .,.. ,. ., ;., . :
: , . ,., ,.. ,,, ., , ,. ... ~., ... . . . : ..
- 58 - ~33~
Example 136 Analogously to the procedure described in Example 47, 4-allyl-6-amino-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazine is reacted wi~h 2,2-dimethyl-5-~ropionyl-1,3--dioxane-4,6-dione in ocder to produce 4-allyl-3,4--dihydro-7-fluoro-3-oxo-6-propioacetylamino-2H-1,4--benzoxazine, mass spe~tcum (m/e): 3ZO(s5), M , and this can be reacted with ethyl carbama~e in order to produce the 6-[3-tethoxycarbonylamino)-2-pentenoylamino]-4-allyl--3,4-dihydro-7-fluoro-3-oxo-2H-1,4-benzoxazine, m.p. 115C
C (with decomposition), which is used as the starting ma~erial in Example ~6. ~
..
Example 137 ; ;
Analogously to the procedure described in Example 135, 5-amino-6-fluoro-3-(n-propyl)-2-benzothiazolinone is reacted with Z,2-dimethyl-5-propionyl-1,3-dioxane-4,6--dione in order to produce 6-fluoro-5-propioacetylamino-3--(n-propyl)-2-benzothiazolinone, ~.p. 87-88C, and this can then be reacted with ethyl carbamate in order to produce the 5-[3-(ethoxycarbonylamino)-2-pentenoylamino]--6-fluoro-3-(n-propyl)-2-benzothiazolinone, m.p.
25 174-175C, which is used as the starting material in Example 37.
. ~ ..
IV. Pcoduction of the com~ounds of formula IV: ~
. , .
Example 138 16.61 g of pyridine are added at 25C while stirring to a suspension of 25.55 g of 3-[3,4-dihydro-3-oxo-4-(2--propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-35 -2,4(1H,3H)-pyrimidinedione (see Example 3) and 32.13 g of phosphorus oxychloride in 250 ml of toluene. The reaction ~ f~ r mixture is heated to 100C for 6 hours, cooled to 25~C and poured on to 500 g of ice. Subsequently, the aqueous mixture is extracted three times with 150 ml of ethyl ace~ate each time and the organic phase is washed neutral with water, dried over anhydrous sodium sulphate and evaporated to dcyness under reduced pre~sure. The resinous product is purified by chromatography on a silica gel column with ethyl acetate/n-hexane (1:3) as th~ eluent.
Finally, the product i8 recrystallized from diethyl ethert n-hexane. In this manner there is ob~ained 6-~2-chloro-6--oxo-4-trifluoromethyl-1(6H~-pyrimidinyl~-4-(2-propynyl)-f -2~-1,4-benzoxazin-3(4H)-one, m.p. 143-145C (see , . .
Example 78).
V. Formulation Exam~le:
ExamPle 139 For the manufacture of a 50% spray powder, the ingredients listed hereinafter are mixed with one another:
: .
Compound in accordance with the invention (active ingredient) 50 g Silicic acid, hydrated (carrier material, milling aid) 5 g Sodium lauLyl sulphate (wett;ng agent~ 1 g Sodium lignosulphonate (dispersing agent) 2 g Kaolin (carrier material) 42 q 100 g Subsequently, the mixture is finely milled using a pinned disc mill or comearable milling aggregate.
Upon stirring in water the resulting spray powder give~ a fine ~uspen6ion which i~ suitable as a ready-for--use spray liquor.
3 9 CH3 _ Zero S ~.p. >260~C
C2H5 _ Zero S ~.p. ~260C
3 11 CH2CH=CH2 _ Zero S ~-P. >250C
12 CH(CH3)2 _ Zero S M.p. 193-195-C
13 nC3H7 _ Zero S M.p. ~Z50C
:, -, ~ j: , , . . ,, : .. : . . ,. , .,, ., . .. :.
,. , ", . ", , , "; . : .- .
";,:, . . . , , , , : , ~
. ; , ", ~ . '~' ' . :
. .,, : , , : ; j ~. , ;. :: , , , s ;.' ~ :~ .: ' , .
:
3 3 ~
- 39 - .
-Table la (continued) - :
_ ..~ ,.
E~ample R2 CR3R4 n ~ Physical data l l _ _ 14 CH(CH3)2 _ Zero 0 M.p. >250C
CH3 _ Zero 0 ~.p. >250C i-16 3 7 _ Zero O M.p. ~250C : ~ :
17 CH20CH3_ Zero 0 ~.p. >250C ~:-1( ~18 CH2COOC2H5 _ Zero 0 M.p. 213-215C :. :. .
19 CH2CH=CH2 _ Zero 0 ~.p. >250C -: :
C 20 CH C-CH _ Zero 0 M.p. >250C
21 H CH2 1 0 ~.p. >220C
1 ' 2 2 CH2 C - CH CH2 S p . 144-147-c :
;''~'' ~
:`. ' ., ':
~
: . .;
; ~, ~. ' '1" ~
: ' ' .
: : .
,~ . .
- 40 - :~
R H, o 2 . :
\ / ~ R
F ~ X ~ ~4 n ;
Table lb ~. .
_ 3 4 . . . . ..
:~ Example : CR R n X ~ Physi~al data ' : ::
_ _ , : ~ 23 15 CH(CH3)2 _ Zero S C2H5 ~P- 237-238C :
24 CH2CH=CH2CH2 1 C2H5 M.p. 193-200C
: ; 25 CH2CH=CI~2CH2 1 0 3 7 M.p. 157-161C .~: -:~ 26 CH2C-CH CH2 1 C2H5 ¦ ~'P' 240C
¦ twith decomposition~
27 20 CH2C-CH CH2 1 0 nC3H7 M.p. 238-239C
28 CH(CH3)2 CH2 1 C2H5 ~'P- 208-2100C ~ -:: 29 CH(~H3)C-CHCH2 1 0 C2H5 Mass spectrum m~e 357(89~ M
( 30 CH(CH3)C2H5CH2 1 0 C2H5 . :
. 31 25 3 3 CH2 1 0 C2H5 32 CH(OCH3)C2Hs CH2 1 0 C2H5 33 CH(CH3)CH=CH2 CH2 1 0 C2H5 34 CH2CH.CH2 ~ero S C2L5 ~ , 2 ~ ~ C~
- 41 - ~
:. . ' ' .
... .. .
Examæle 35 -" ,' A suspension of 6.45 g of 6-[3-tethoxycarbonylamino)--2-pentenoylamino]-3,4-dihydro-7-fluoro-3-oxo-4-(2--propynyl)-2H-1,4 benzox~zine and 3.22 g of ~odium methylate in 6.5 ml of methanol is ~tirred at 62C for 4 hours. The ~olution which thu~ results is left to ~tand at room temperature for 64 hours and ~ubsequently poured into a ~olution of 15 ml of 2N hydrochloric acid in 400 ml Of water. The ~esulting precipitate i~ filtered off under ~uction, washed with water and recry~tallized from ace~one/n-hexane. In this manner there is obtained 6-ethyl-3-[3,~-dihyd~o-7-fluoro-3-oxo-4-(2-p~opynyl)-2H--1,4-benzoxazin-6-yl]-2,4(1H,3H)-pyrimidinedione, m.p.
240C twith decomposition).
Example 36 -, :,.' ' Analogously to the procedure described in Example 35, ~;
by cyclizing 6-[3-(ethoxycarbonylamino~-2-pen~enoylamino]--4-allyl-3,4-dihyd~o-7-fluoro-3-oxo-2H-1,4-benzoxazine there is obtained 6-ethyl-3-~4-allyl-3,4-dihydlo-7-fluoro- , ,~
-3-oxo-2H-1,4-benzoxazin-6-yl)-2.4(1H,3H)-pyrimidinedione, m.p. 197-200C.
~ 25 ExamDle 37 Analogously to the procedure described in Example 35, by cyclizing 5-[3-(ethoxyca~bonylamino)-2-pentenoylamino]-30 -6-fluoro-3-(n-propyl)-2-benzothiazolinone there i~ ~-obtained 6-ethyl-3-~6-fluoro-2-oXo-3-(n-propyl)-5-benzo-thiazolinyl]-2,~(1H~3~)-pyrimidinedione. m.p. >250C.
ExamPle 38 :
A mixture of 27.50 g of 3-[6-fluoro-2-oxo-3-(2--p~opynyl)-5-benzothiazolinyl~-6-tLifluoromethyl-~ ~ .
. .
~33~
-2,4(1H,3H)-pyrimidinedione ~see Example 1), 10.80 g of dimethyl sulphate and 9.08 g of sodium ca~bonate in 250 ml of acetone i8 heated at the boiling temperature while stirring for 1.5 hours. After cooling the ~olid 5 constituent is filtered off under ~uction and washed with acetone. The filtlate is then evaporated to dryness under reduced pcessure~ the residue is dissolved in 350 ml of ethyl acetate and the solution is washed three times with r 300 ml of water each time. Subsequently, the organic phase 10 is dried ovec anhydLous sodium sulphate and evaporated to dryness under reduced presSu!e~ and the resinous residue is purified by chroma~ography on 1.5 g of silica gel using ethyl acetate/n-hexane (1:3) as the eluent. The first fraction is recrystallized from ethyl ace~ate/diethyl 15 ether (1:1), whereby there is obtained 6-fluoro-5-~Z--methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-3-(2--propynyl~-2-benzothiazolinone, m.p. 191-192C. The 2nd fraction is recrystallized from diethyl ether/n-hexane (1:1) and there is thus obtained 3-~6-fluoro-2-oxo-3-(Z-20 -propynyl) 5-benzo~hiazoiinyl]-l-methyl-6-trit`luorometh -2,4(1H,3H)-pyrimidinedione, m.p. 190-192C.
' ExamPles 39-72 C 25 The corresponding uracil derivative of formula I' is in each case methylated with dimethyl sulphate analogously to the procedure described in Example 38 in order to manu~acture the l-methyluracils (and in one case also the enol ether) listed in Table 2 hereinafter.
CH
~7 ¦ ~ o R2 R ~ N ~ OCH3 2 ~N ~ N ~0 ~ 1~ N ~f~O
R5 ~ X~ ~ R4 n R ~ X~ ~ R4)n I""' Ia' , " , , ., ~ . , , . : - . , ::
, , . , , ,, , ., . . , ,. . , . ,:
, , , ,. , , : , .: , ~ , . . . . :
: ... ... .. .
~ .: ' , : , .. .. .
: ' ' , ; ,: ,~ :
3 ~
.
Table 2 _ . _ _ _ . . _ ' E~ample E~mple No. Pormula: R2 CR3R4 R5 R7 n X Physical ~ :
of the st~tin~ I"' or data material I' Ia' ___ . .. . _ _ 39 2 I""' CH2C-CH CHz F CF3 1 O lH-NMR
(CDC13, 400 ~Hz): 7.06 ppm ~d, lH), 6.93 ppm (d, lH), ( , 6.38 ppm ~s, lH), 4.69 ppm ~s, 2H), 4.64 ppm ~q, 2H), 3.57 ppm ~t, . 3H), 2.29 ppm ~t, lH) l 3 1""' CH2C_CH CH2 H CF3 1 0 H.p. 216-217C
41 3 la' CH2C_CH CHz H CF3 1 0 ~.p. 218-220C
42 5 I""' CH2C-CH CH2 F CH3 1 0 lH_NHR
~CDC13, 400 ~Hz): 7.05 ppm -~d, lH), 6.90 ppm ~d, lH), ~ :
2( ) 5.75 ppm ~s, lH), 4.67 ppm ~s, 2H), 4.64 ppm (d, 2H), 3.40 ppm ~s, 3H), 2.32 ppm ~d, 3H), 2.27 ppm ~t, lH) C 43 2 6 I""' CH2CH=CH2 CH2 F CH3 1 0 lH-NHR
~CDC13, 100 ~Hz): 6.88 ppm (d, lH), 6.81 ppm (d, lH), ' 5.82 ppm ~m, ~ .
lH), 5.72 ppm ~d, lH), 5.23 3 ppm ~m, 2H), -4.67 ppm (s, 2H), 4.50 ppm ~m, 2H), 3.44 ppm ~s, 3H), : :
2 31 ppm ~d, .
44 7 I""' c2~5 CH~CH3) F C~l3 0 H.p. 211-213C
. ~ ; ....... _ . :. '' . . . .. ,, : .,... : " : ;. ,, 3 3 ~
- Table 2 (continued) . _ __ . _ _ E~ample E~ample No. R2 CR3R4 RS a7 n X Physic~l ays o~ the starting data for~ula ~terial I' .
. _ _ _ _. ~ .~
8 CH2C-CH CH(CH3) F CH3 1 1 H.p, 219-222C
46 9 CH3 .- F CH3 Zero S M.p. 255-257C
417O10 C2H5 _ F CH3 Zero S M.p. 235-236C
48 11 CH2CH=CH2 _ F CH3 Zero S M.p. 210-211C
49 12 CH(CH3)2 _ F CH3 Zero S H.p. 214-216C : .
S0 13 nC3H7 F CH3 Zero S M.p. 222-223C
5~526J35 CH2C-CHCHz F C2H5 1 0 M.p. 230C (with .
decomposition) 52 24J36 CH2CH=CH2 CH2 F CzH5 1 0 M.p. 172-174C
53 37 ~ nC3H7 _ F C2H5 Zero S M.p. 101-102C
54 14 CH~cH3)2 , - F CH3 Zero 0 M.p. 143-145C
5~ 15 CH3 _ F CH3 Zero 0 n. p . 228-231C
56 16 nC3G7 _ F CH3 Zero 0 M.p. 155-157C
57 17 CH20CH3 _ F CH3 Zero 0 ~.p. 200-202C
58 18 CH2C00c?H5 _ F CH3 Zero 0 M.p. 167-169C
5~5 19 CHzCH=CHz _ F CH3 Zero 0 M.p. 164-166C
CHz-CH _ F CH3 Zero 0 M.p. 182-184C
61 l02 CH2CNCH2 F CH3 1 0 M.p. ~230C
62 22 CH2C-CHCH2 F CH3 1 S M.p. 214-217C
633023 CH(CH3)2 _ F C2H5 Zero S M.p. 176-178C
64 25 CH2cH=cH2 C~2 F nC3H7 1 0 n . p . 146-147C
27 CH2C-CH CH2 F nC3H7 1 0 M.p. 192-193C
66 28 CHtCH3)2 CH2 F C2H5 1 0 M~ss spectrum:
. _ ~/e 361(67~ ~+
, ' ' ': ,. ' .' ' ' ; , . ,, : .' ;
, : ~:. . .. .. .
,, ,, . !. : ~
- 45 - ~33 Table Z (continued~
.
_ _ _ _ Ex~pl0 Example No. R2 CR3R4 R5 R7 n X Physical ~a~ways of the startinB
dat~
for~ula ~aterial I' .
~ . __ _ .
67 29 CUICH3)C-CHCH2 F C2H5 l O ~ass spectrum:
m/e 371(98) ~+
60~ 30 CH~cH3)c2HsCH2 F C2H5 1 O .. .. .
69 31 CH(CH3)OCH3CH2 F C2H5 1 O
C 70 32 ~ CH(OCH3)C2H5 CH2 F C2H5 1 O
71 33 CH(CHj)CH=CH2 CH2 F C2H5 1 ; :
72 34 CH2cH=cH2 _ F C2H5 Zero S
lg - _ _ ' ',,; ;' ~0 ~ ' c '' 2 5 ;:
:
~'.. :' .: ..
,~' ~'''' :
" ~.
: .
, , . ,, . ~ , ,.,. ,, ,,: :, ., , . .. .. ~, ;:, . . .
:"" . , , , .,, , , , . , ~ . . . , , . , , , , ; ~ , ,: . : , .. :
,....... , . . . , ,. , .: . . ~ , " ~ . . ..
- 46 - ~3 E~ample 73 A solution of 6.1 g of 3-~6~~1uoro-2-oxo-3-(Z--propynyl)-5-benzothiazolinyl]-6 methyl-Z,4(lH,3H)--pycimidinedione (see Example 4) in 50 ml of dimethyl-formamide is added while stirring to a suspension of 0.8 g of a 55% sodium hydride dispersion in 25 ml of dimethyl-formamide. Aftel the hydrogen evolution has finished the mixture is treated with 2.8 g of dimethyl sulphate and stirred fo~ one hour. Thereafter, the reaction mixture is poured in~ 500 ml of water, the agueous mixture is extracted three times with 100 ml of ethyl acetate each time and the org~nic phase is dLied ovec anhydcous sodium sulphate. The solvent is subsequently distilled off under reduced pressure and the thus-obtained residue (7.2 g) is purified by chromatography on a column of 350 g of aluminium oxide (Brockmann I) using methylene chloride/
n-hexane (3:1) as the eluent. The ficst frac~ion (1.5 g) is recrystallized from ethyl acetate, whereby there is 20 obtained 1.6-dimethyl-3-[6-fluoco-2-oxo-3-(l,Z-pcopane-dienyl)-5-benzothiazolinyl]-2,4(1H,3H)-pyrimidinedione.
m.p. >250C. By further elution of the column with methylene chloride/ethyl acetate t3:1) there is obtained the second fraction (4.7 g) which is recrystallized from C 25 ethyl acetate. In this manner there is obtained 1,6-dimethyl-3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzo-thiazolinyl]-2,4(1H,3H)-pyrimidinedione, m.p. 180-181C.
ExamPle 74 A ~olution of 0.16 ml of ~romine in 5 ml of acetic acid is added while stirring at room temperature within 15 minutes to a solution of 1.0 g of 3-t3,4-dihYdro-7--fluoro-2-methyl-3-oxo-4-(2-propynyl)-2~-1,4-benzoxazin-35 -6-yl]-1,6-dimethyl-2,4(1H,3H)-pycimidinedione tsee Example 45) in 7 ml of acetic acid and the mixture is "
stirred at ~oom temperature for 30 minutes. The mixture is then concentrated under reduced pressure, the lesidue is taken up in ethyl acetate, the solution is washed with ~- ;
dilute, aqueou~ sodium bicarbonate solution, the organic phase i~ dried o~er anhydrous ~odium 6ulphate and concentrated to drynes~. In thi~ manner there i~ obtained ~ -5-bromo-~-[3,4-dihydro-7-îluoro-2-1nethyl-3-oxo-4-(2--propynyl)-2H~1,4-benoxazin-6-yl]-1,6-dimethyl-2,4(1H,3H)--pyrimidinedione, m.p. 182-187~C.
ExamPles 75-77 The coeresponding uracil derivative of formula I"" is in each case brominated analogously to the procedure de~cribed in Exam~le 74 in order to manufacture the 5-bromouracils listed in Table 3 hereinafter.
.:
~ ~ ~ ~ ~2 B ~ ~ ~ 3 ~' 25 Table 3 ..
Example Example No. R2 CR3R4 R7 Physical ; :
of the start- . data in~ materials _ _ ____ _ ~
44 C2H5 CHCH3 CH3 ~'P- 219-2200C ~ :
76 52 CH2CH=CH2 CH2 C2H5 M.p. 215-219C
. 3577 52 CH2CH3rCH28r CH2 C2H5 N.p. 124-123C
'.' ,, ~ . , ' ' , ,'. ,~ ',. . . .
~33~ -, ExamPle 78 A solution of 1.08 g of sodium methylate in 10 ml of methanol i8 added at 20C while stiLring to a solution of 57.65 g of 6-r2-chloro-6-oxo-4-trifluoromethyl-1(6H)-rimidinyl]-4-(2-eLopynyl)-2H-l~4-benzoxazin-3(4E~)-one in 300 ml of absolute methanol. A suspension fo~ms during 15 minutes and the tempera~ure rises to 30C. The reaction mixture is concentrated at 40-50C under reduced pressure and the residue is dissolved in 500 ml of ethyl acetate.
The organic phase is washed twice with 200 ml of wa~er each time, dried over anhydrous sodium sulphate and evaporated to dr~ness undeL reduced pressure. The crystal-line residue is stirred with 20 ml of diethyl ether, cooled to 0C and treated wi~h 100 ml of n-hexane. The crystals are filte~ed off under suction and dried at 50C
under reduced pressure. In this manner there is obtained 6-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pylimidinyl]--4-(2-propynyl)--2H-1,4-benzoxazin-3(4H)-one, m.p.
218-2Z0C.
Example 79 34.94 g of 1,6-dimethyl-3-(6-fluoro-3-isopropyl-2-oxo--5-benzothiazolinyl)-2,4(1H,3H)-pyrimidinedione (see Example 49) are dissolved in 200 ml of concentrated sulphuLic acid while stirring and gassing with nitrogen and the solution is heated to 150C for 45 minutes. The reaction mixture is cooled to 25C and poured on to 1 kg of ice, and the precipitated product is filtered off under suction and washed neutral with water. The filter cake is suspended in 500 ml of ethyl acetate at 60C, the suspension is concentrated to 250 ml, the product, after cooling, is filtered off under suction, the filtrate is back-wash~d with ethyl acetate and dried at 50C undeL
reduced p~essure. In this manner there is obtained . ,, ~, .. . . " . , ., .. : . . . . . , . , , : . , : .:
- 49 - ~
'.'.:
1,6-dime~hyl 3-(6-fluoro-2-oxo-5-ben~othiazolinyl)-2 D 4' (lH,3H)-py~imidinedione, m.p. >250C.
., Example 80 ~ nalogou~ly to the p~ocedure described in Example ?g, star~ing from 6-ethyl-3-(6-fluoro-3-isopropyl-2-oxo-5 -benzothiazolinyl)-l-methyl-2,4-(lE~,3H)-pyrimidinedione ~
(see Example 50) the~e is obtained 6-e~hyl-3-(6-fluoro~
10-oxo-$-benzothiazolinyl)-1-me~hyl-2,4(1H"3H)-pyrimidino-dione, m.p. ~25QC.
- , ExamPle 8 153.07 g of 1,6-dime~hyl-3-(6-fluoro-2-oxo-5-benzo- ~;
thiazollnyl)-2,4(1H,3H)-pyrimidinedione (see Example 7 and 0.48 g of a 55% sodium hydride dispersion are Sti~
at 25C for l hour in 50 ml of absolute dimethylformàm~
Subsequently, 1.02 g of chloroacetamide are added and~
mixture is stirred at 50C for 6 hours. The reaction mixture is cooled and tleated with 400 ml o water. ~h~
precipitated product is filterecl of~' under suction, with water and the filter cake is su~pended in 200-ml~
ethyl acetate at 60C. The suspension is concentrated ;t O ~ ' ' about 50 ml, cooled to 25C, the solid is filtered off under suction and dried at 50C. In this manner there obtained 3-(3-carbamoylmethyl-6-fluoro-2-oxo-5-benzo--thiazolinyl)-1,6-dimethyl-2,4tlH,3H)-pyrimidinedione >260C.
Examples 82-101 The corresponding uracil derivative of folmula I'^' is in each case t~eated with the cor~esponding alkylatinc3 agent analogously to the procedure described in Exampl~? c~
in order to manufacture ehe compounds of formula I listed in Table 4 hereinafeer.
' ''' ' " ;, '', " ',~ ' , :' ";" . ;" ' ~' ` ''' .
2 ~ 3 3 3 ~ ~
R~l~l~fO R2 b~N~
. . , Table 4 ._ _ _ ~ample E~ample No. ~2 R7 Physical data of the st~rt-ng material : 82 79 isoc4Hg CH3 ~-P- 168-171C
5 83 79 sec.CqHg CH3 U.p. 135-137DC
t; 84 80 sec.C4Hg C2Hs ~.p. 150-152C
79 CHF2 CH3 ~.p. 206-208C
86 79 CF2CHF? CH3 ~.p. 156-158C
:-, 0 87 79 CH20CH3 CH3 H.p. 243-245C
~:: 88 80 CH20C~3 C2H5 U.p. 198-200C
,! ~ . 89 80 CH(CH3)0CH3 C2H5 M.p. 221-222C
~ 5 90 80 CH(OCH3)C2Hs C2H$ ~.p. 232-234C
:~ 91 80 CH(CH3)0c2H5 C2Hs M.p. 216-218C
92 79 CH2CN CH3 H.p. ?47-250~C
93 79 CH2COOC2H5 CH3 ~.p. 193-195C
0 94 79 CH2coN(cH3)2 CH3 n.p. 257-258C
79 CH2C~CH3)=CH2 CH3 M.p. 203-205C
96 79 CH(CH3)CH=cH2 CH3 M.p. 148-178~C
97 80 CHtCH3)CH=cH2 C2H5 M.p. 124-134C
.~ 5 98 79 Cinnamyl CH3 N.p. 125-160C
:~ 99 80 CH2C-CH C2H5 M.p. >250C
100 79 CH~CH3)C-CH CH3 M.p. lB4-186C
101 80 _ CH(CH3)C_CH C2H5 M.p. 177-179C
, ;"
-Exam~le lo?
Analogously to the proceduLe described in Example 81, by alkylating 3-(3,4-dihydro-7-fluoro-3-oxo-2H-1~4--benzoxazin-6-yl)-6-methyl-2,4(lH,3H) -pyl imidinedione (see Example 21) with chloroacetonitrile there is obtained 3-(2-cyano~ethyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazin-6-yl)-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p. >230C.
, II. Production of ~he com~ounds of formula IX ~inter-mediates in the manufacture of the compounds of formula I):
Example 103 A solution of 22.5 g of 5-amino-6-fluoro-3-(2--propynyl)-2-benzothiazolinone in 35~ ml of ethyl acetate is added dcopwise at 30OC during 2 hours while stirring to a solu~ion of 60.0 g of phosgene in 300 ml of ethyl acetate. The resulting suspension i6 stirred at 50C for 2 hours and subsequently heated slowly to the boiling point. The clear solution is then evaporated to dryness and there is thus obtained as the residue 6-fluoro-5--isocyanato-3-(2-propynyl)-2-benzothiazolinone, yellow crystals. This product serves, inter alia, as the ~ta~ting material in the manufacture of 3-[6-fluoro-2-oxo-3-(2-~propynyl)-5-benzothiazolinyl]-6-trifluoromethyl-2,4-(lH,3H)-pyrimidinedione (see Example 1).
Example 104 6-Amino-3,4-dihydro-7 fluoro-3-oxo-4-(2-propynyl)-zH
-1,4-benzoxazine is treated with phosgene analogously to the procedure described in Example 103 in order to produce the 3,4-dihydro-7-fluoro-6-isocyanato-3-oxo-4-(2-; ~ ; ' ' ' ~' , ', "' ' . . ,,: ,. ' , ' ' , , , , :: , , ,, :. . . .
~ 2~3~
5z -propynyl)-ZH-1,4-benzoxazine which is used as the starting material in Example 2. H-NMR (CDC13, 60 MHz): 7.02 ppm (d, lH), 5.88 ppm (d, lH), 4.88-4.60 ppm (m, 4H), 2.35 ppm (t, lH~.
Example 105 6-Amino-3,4-dihydro--3-oxo-4-(2-propynyl)-2H-1,4--benzoxazine is treated with phosgene analogously to the p~ocedure described in Example 103 in order to produce the 3,4-dihydro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4--benzoxazine which is used as the starting material in Example 3. H-NMR (CDC13, 400 M~z): 6.9B-6.92 ppm (m, 2H), 6.79 ppm (q, lH), 4.66 ppm (d, 2H), 4.63 ppm (s, 2H), 2.31 ppm (t, lH).
III. Production_of the compounds of formulae X and III
intermediates in the manu~Eacture of the compounds of formula IL:
Example 106 ::
~ ~ .
A sus~ension of 4.7 g of 5-amino-6-fluoro-3-~2--propynyl)-2-benzothiazolinone, 1.93 g of diketene and 0.05 g of 4-eyrrolidinop~ridine in 250 ml of benzene is stirred at room temperature for 30 minu~es and .:. -subsequently held at 50C for 30 minutes. In this manner ~.:
there is obtained a solu~ion of 5-acetoacetylamino-6--fluoro-~-(2-propynyl)-2-benzothiazolinone which is used as such in the next ~eaction step without isolation of the pr oduCt-: :
The above clear solution is heated to the boiling : :
point under a water separator for Z.5 hours with 2.B5 g of ::
ethyl carbamate and 0.2 g of p-toluenesulphonic acid mo~ohydrate. Subsequently, the mixture is again treated ~ .
, ':" ' '~ ' .
~ ~ 3 3 ~ ~ ~.3 with 0.2 g o~ p-toluenesulphonic acid monohydrate and heated for a further 2.5 hours. The reaction mixture is evaporated to dryness under reduced pressure. The --thus-obtained crude eroduct (11.7 g) i~ suspended with 50 ml of diethyl ether, the insoluble portion is filtered off under suction and dried. In this manner there are ~ -obtained 8.2 g of 5-r3-ethoxycarbonylamino)-2-butenoyl-amino]-6-fluoro-3-(2-propynyl)-2-benzothiazolinone, m.p.
about 167-169C. This product serves, inter alia, as the starting material in the manufacture of 3-~6-fluoro-2-oxo--3-(2-pro~ynyl~-5-benzothiazolinyl]-6-methyl-2,4(1H,3H)--pyrimidinedione (see Example 4).
: - -Example 107-134 Analogously to the pcocedure described in Example 106, the corresponding amine of formula XII is reacted with the corresponding diketene in order to produce the correspond-ing compound of formula X' which, in ~urn, is reacted with ethyl carbamate in order to produce the compounds offormula III listed in Tables 5a and 5b hereinafter. In these Tables there are given in each case both inter-mediates tformula X"' or X"" and, reseectively, III' or III") as well as the respective end product I to which the corresponding intermediate of formula III' or III" leads by ~ing closure.
s .
. . . .. . ~ . . . . " . , , . , - . .... .. . . . .. .
2~333~
-- 5~1 --~J ~4 n ~ ~ ~ 4 ) y - F
X' `~
Table 5a ~ :"
__ _ . . _ _ . . :
Physic~l d~ta Example E~ample No. R2 (CR3R4) n X
of the end . Compound X"' Compound III' ~:
product I :
_ _. . ,',-l~i!P 5 CH2C--CH CH2 1 O -~not isolated) (-not isolated) : ~
108 6 CH2CH=CH2 CH2 1 0 .. H.p. 175-177C ~ :
109 7 C2H5 CH~CH3) 1 0 .- ~.p. 192-194C
110 8 CH2C-CH CH(CH3) 1 0 .. H.p. 171-173C
111 9 CH3 _ Zero S H.p. 150-151C M.p. 250-251C : :-. -112 10 C2H5 _ Zero S H.p. 118-120C H.p. 195-197C - -1~35 11 CH2CH=CH2 _ 2ero S H.p. 113-115C H.p. 194-196C
114 12 CH(CH3)2 _ Zero S H.p. 166-167~C H.p. 186-187C : : .
115 13 nC3H7 _ Zero S ~.p. 116-117C H.p. 203-205C `: .116 14 CH(CH3)2 _ Zero 0 H.p. 167-169C H.p. 186-188C
117 lS CH3 _ Zero 0 H.p. 137-139C ~.p. 200-202C
~0 16 3 7 _ Zero 0 H.p. 105-107C ~.p. 159-160C
119 17 CH20CH3 Zero 0 H.p. 126-128C H.p. 181-183C :.
120 18 CH2COOC2H5 _ Zero 0 H.p. 143-145C H.p. 184-185C .
121 19 CH2CH=CH2 _ Zero 0 H.p. 106-107C ~.p. 149-151C
122 20 CH2C=CH Zero 0 p. 114-116C H. p. 199-200C
~:
" '' '~' ' :' . ,~ .
.: :' ,~
:
Table 5a ~continued) ___ _ _ _ _Physical data EYam~le E~ample No. R2 ~CR3R4) n X _ . _ of the end Compound ~"' Compound III' product I
~_ _ _ - . , _ . __ ~ _ ,'., ' .
123 21 H CH2 1 O H.p. ~230C . lH-N~RtCDC13, . 200 ~Hz): 11.50 pp~
. ~s,lH), 10.66 ppm C (s,lH~, 9.62 ppm . . ~s,lH), 7.56 ppm (d,lH), 6.96 ppm (d lH) 5 30 ppm .
~s,2H), 4.30 ppm ~q,2H), 2.26 ppm ~s,3H), 1.22 ppm ~t,3H) : :
420 22 2 CH2 1 S -(not isolated) H.p. 185-188C
6; 2 5 i:
.::
.:
; ~ :
3~ . .
. : ~ . ,, - , . ~, ,: ,-R O
2 R 7 ~ ~ COOC 2 H 5 R 2 ~N~ ~R ~ ~C HN~x~ F~4)D
X " " I I I "
Table 5b -' . ~ _ ~ _ _ _ ~
~ Physical data .i : Example Example No. R2 .(CR R ) n ~ R7 . H
of the end Co~pound X"" Compound III"
~pduct I
_ . _ _ _ . _ _ ~
,., 123 23 CH(CH3)2 _ 2ero S C2H5H.p. 167-168C ~.p. 150-152C
124 24 CH2CH=CH2 CH2 1 C2~l5 -(not isolated) M.p. 109-1154C .
125 25 CH2CH=CH2 CH2 1 0 nC3H7 -(not isolated) ~.p. ~6-884C :: .. ~
126 2~ CH C-CH CH2 1 C2H5 ~'P' 113-1150C ~.p. 132-133C
: 127 27 CH2C-CH CH2 1 0 nC3H7 ~,p, 88-93C H.p. 143-147C ..
128 28 CH~CH2)2 CH2 1 C2H5 -(not isolated) -(not isolated) ~ .
129 29 CH~CH3)C-CH CH2 1 C2H5 H.p. 110-114C -(not isolatedj ~-130 30 ~ H3~C2H5 CH2 1 0 C2H5 C131 31 CH(CH3)0CH3 CH2 1 0 C2H5 . .
132 ~25 CH~OCH3)C2H5 CH2 1 0 C2H5 . ~ .
133 33 CH~CH3)CH=CH2 CH2 1 0 C2H5 134 34 CH2CH=CH2 _ Ze~o S C2H5 . _ . _ .. ..... ~ ,, ~___ ,`'~
:
'. ;''~'',, !" . '.; , '~ , , . ' '' ' ~3~
Example 135 A solution of 11.0 g of 2,2-dimethyl-5-propionyl-1,3--dioxane-4,6-dione in 50 ml of toluene is added dropwi~e 5 at 30C during 15 minutes while ~tirring to a solution of 12.2 g of 6-amino-3,4-dihydro-7~fluoro-3-oxo-4-(2--propynyl)-2H-1,4-benzoxazine in 100 ml of ~oluene. The reaction mixture (still a solution) i5 stirred a~ 124C
for 4 hours and thereafter left to stand at room temperature for about 16 hours. Then, the precipitated crystal~ are separa~ed and dried.
.` :.
In this manner there is ob~ained 3,4-dihydro-7-fluoro--3-oxo-4-(2-propynyl)-6-propioacetylamino-2H-1,4-15-benzoxazine, m.p. 113-115C.
A suspension of the above intermediate, 6.14 g of ~ -ethyl carbamate and 0.2 g of p-toluenesulphonic acid monohydrate in 260 ml of benzene is heated at the boiling temperature under a water separator for 2.5 hours.
Subsequently, the mixture is again treated with 0.2 g of ~-p-toluenesulphonic acid monohydrate and heated for a further 2.5 hours. The reaction mixture is evaporated to dryness under reduced pressure, whereby 25.5 g of crude C 25 product are obtained. This is suspended with 200 ml of ethyl acetate, washed with 300 ml of water and crystal- -lized from ethyl acetate. In this manner there are obtained 7.2 g of 6-t3-(ethoxycarbonylamino)-2-pentenoyl-amino]-3,4-dihydro-7-fluoro-3~oxo-4-(2-propynyl)-2H-1,4-30 -benzoxazine, m.p. 133C (with decomposition). This product serves as the starting material in the manufacture of 6-ethyl-3-t3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)--2H-1,4-benzoxazin-6-yl]-2,4(lH,3H)-pyrimidinedione tsee Example 35).
,'.: ' .
, ", . , . .. , , . , . ., , ,. ,.. ~ .,. , .. . .. . .,.. ,. ., ;., . :
: , . ,., ,.. ,,, ., , ,. ... ~., ... . . . : ..
- 58 - ~33~
Example 136 Analogously to the procedure described in Example 47, 4-allyl-6-amino-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazine is reacted wi~h 2,2-dimethyl-5-~ropionyl-1,3--dioxane-4,6-dione in ocder to produce 4-allyl-3,4--dihydro-7-fluoro-3-oxo-6-propioacetylamino-2H-1,4--benzoxazine, mass spe~tcum (m/e): 3ZO(s5), M , and this can be reacted with ethyl carbama~e in order to produce the 6-[3-tethoxycarbonylamino)-2-pentenoylamino]-4-allyl--3,4-dihydro-7-fluoro-3-oxo-2H-1,4-benzoxazine, m.p. 115C
C (with decomposition), which is used as the starting ma~erial in Example ~6. ~
..
Example 137 ; ;
Analogously to the procedure described in Example 135, 5-amino-6-fluoro-3-(n-propyl)-2-benzothiazolinone is reacted with Z,2-dimethyl-5-propionyl-1,3-dioxane-4,6--dione in order to produce 6-fluoro-5-propioacetylamino-3--(n-propyl)-2-benzothiazolinone, ~.p. 87-88C, and this can then be reacted with ethyl carbamate in order to produce the 5-[3-(ethoxycarbonylamino)-2-pentenoylamino]--6-fluoro-3-(n-propyl)-2-benzothiazolinone, m.p.
25 174-175C, which is used as the starting material in Example 37.
. ~ ..
IV. Pcoduction of the com~ounds of formula IV: ~
. , .
Example 138 16.61 g of pyridine are added at 25C while stirring to a suspension of 25.55 g of 3-[3,4-dihydro-3-oxo-4-(2--propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-35 -2,4(1H,3H)-pyrimidinedione (see Example 3) and 32.13 g of phosphorus oxychloride in 250 ml of toluene. The reaction ~ f~ r mixture is heated to 100C for 6 hours, cooled to 25~C and poured on to 500 g of ice. Subsequently, the aqueous mixture is extracted three times with 150 ml of ethyl ace~ate each time and the organic phase is washed neutral with water, dried over anhydrous sodium sulphate and evaporated to dcyness under reduced pre~sure. The resinous product is purified by chromatography on a silica gel column with ethyl acetate/n-hexane (1:3) as th~ eluent.
Finally, the product i8 recrystallized from diethyl ethert n-hexane. In this manner there is ob~ained 6-~2-chloro-6--oxo-4-trifluoromethyl-1(6H~-pyrimidinyl~-4-(2-propynyl)-f -2~-1,4-benzoxazin-3(4H)-one, m.p. 143-145C (see , . .
Example 78).
V. Formulation Exam~le:
ExamPle 139 For the manufacture of a 50% spray powder, the ingredients listed hereinafter are mixed with one another:
: .
Compound in accordance with the invention (active ingredient) 50 g Silicic acid, hydrated (carrier material, milling aid) 5 g Sodium lauLyl sulphate (wett;ng agent~ 1 g Sodium lignosulphonate (dispersing agent) 2 g Kaolin (carrier material) 42 q 100 g Subsequently, the mixture is finely milled using a pinned disc mill or comearable milling aggregate.
Upon stirring in water the resulting spray powder give~ a fine ~uspen6ion which i~ suitable as a ready-for--use spray liquor.
Claims (21)
1. Compounds of the general formula I
wherein R1 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C2-5-alkenyl or C3-5-alkynyl, R2 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C2-5-alkoxy-C1-4-alkyl, C1-4-alkoxy--C1-4-alkoxy-C1-4-alkyl, C2-5-cyanoalkyl, C2-5-carboxyalkyl, C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-haloalkoxycarbonyl-C1-4--alkyl, C1-4-alkoxy-C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-alkoxycarbonyl-C2-5--alkoxycarbonyl-C1-4-alkyl, C4-7-cyclo-alkyloxycarbonyl-C1-4-alkyl, carbamoyl-C1-4--alkyl, mono(C1-4-alkyl)carbamoyl-C1-4-alkyl, di(C1-4-alkyl)carbamoyl-C1-4-alkyl, C3 or 4-alkenyl, C3 or 4-haloalkenyl, cinnamyl, C3 or 4-alkynyl or C3 or 4-halo-alkynyl, R3 and R4 each independently siqnify hydrogen, halogen, C1-4-alkyl or phenyl, R5 signifies hydrogen, fluorine or chlorine, R6 signifies hydrogen, halogen or C1-4-alkyl, R7 signifies C1-4-alkyl or, where R1 is not C1-4-haloalkyl, also C1-4-haloalkyl, n signifies zero or 1 and X signifies oxygen or sulphur, and the enol ethers of those compounds of formula I in which R1 signifies C1-4-alkyl, C2-5-alkenyl or C3-5-alkynyl as well as salts of those compounds of formula I in which R1 signifies hydrogen, R2 signifies hydrogen and/or R2 signifies C2-5-carboxyalkyl.
wherein R1 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C2-5-alkenyl or C3-5-alkynyl, R2 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C2-5-alkoxy-C1-4-alkyl, C1-4-alkoxy--C1-4-alkoxy-C1-4-alkyl, C2-5-cyanoalkyl, C2-5-carboxyalkyl, C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-haloalkoxycarbonyl-C1-4--alkyl, C1-4-alkoxy-C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-alkoxycarbonyl-C2-5--alkoxycarbonyl-C1-4-alkyl, C4-7-cyclo-alkyloxycarbonyl-C1-4-alkyl, carbamoyl-C1-4--alkyl, mono(C1-4-alkyl)carbamoyl-C1-4-alkyl, di(C1-4-alkyl)carbamoyl-C1-4-alkyl, C3 or 4-alkenyl, C3 or 4-haloalkenyl, cinnamyl, C3 or 4-alkynyl or C3 or 4-halo-alkynyl, R3 and R4 each independently siqnify hydrogen, halogen, C1-4-alkyl or phenyl, R5 signifies hydrogen, fluorine or chlorine, R6 signifies hydrogen, halogen or C1-4-alkyl, R7 signifies C1-4-alkyl or, where R1 is not C1-4-haloalkyl, also C1-4-haloalkyl, n signifies zero or 1 and X signifies oxygen or sulphur, and the enol ethers of those compounds of formula I in which R1 signifies C1-4-alkyl, C2-5-alkenyl or C3-5-alkynyl as well as salts of those compounds of formula I in which R1 signifies hydrogen, R2 signifies hydrogen and/or R2 signifies C2-5-carboxyalkyl.
2. Compounds according to claim 1, wherein R1 signifies methyl or difluoromethyl.
3. Compounds according to claim 1 or 2, wherein R2 signifies C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, C3 or 4-alkenyl or C3 or 4-alkynyl.
4. Compounds according to any one of claims 1 to 3, wherein R3 and R4 each signify hydrogen.
5. Compounds according to any one of claims 1 to 4, wherein R5 signifies hydrogen or fluorine.
6. Compounds according to any one of claims 1 to 5, wherein R6 signifies hydrogen, fluorine, chlorine, bromine or methyl.
7. Compounds according to any one of claims 1 to 6, wherein R7 signifies methyl, ethyl, trifluoromethyl or pentafluoroethyl.
8. Compounds according to any one of claims 1 to 7, wherein n signifies zero and X signifies sulphur.
9. Compounds according to any one of claims 1 to 7, wherein n signifies 1 and X signifies oxygen.
10. A compound according to claim 1, selected from 6-ethyl-3-[4-allyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidinedione and 6-ethyl-3-[3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)--2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidine-dione.
11. A compound according to claim 1, selected from 6-ethyl-3-[4-allyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazin-6-yl]-5-bromo-1-methyl-2,4(1H,3H)-pyrimidine-dione, 3-[3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4--benzoxazin-6-yl]-1-methyl-6-(n-propyl)-2,4(1H,3H)--pyrimidinedione.
6-ethyl-3-[3,4-dihydro-7-fluoro-4-isopropyl-3-oxo-2H--1,4-benzoxazin-6-yl]-1-methyl-2,4(1H.3H)-pyrimidinedione, 6-ethyl-3-[4-sec.butyl-3,4-dihydro-7-fluoro-3-oxo-2H--1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methoxyethyl)-3--oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methoxypropyl)-3--oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methyl-2--propenyl)-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4-(1H,3H)-pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methyl-2--propynyl)-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4-(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-isopropyl-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-sec.butyl-6-fluoro-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methoxyethyl)-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methoxypropyl)-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-allyl-6-fluoro-2-oxo-5-benzothiazolinyl]--1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methyl-2-propenyl)-2-oxo-5--benzothiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione and 6-ethyl-3-[6-fluoro-3-(1-methyl-2-propynyl)-2-oxo-5--benzothiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione.
6-ethyl-3-[3,4-dihydro-7-fluoro-4-isopropyl-3-oxo-2H--1,4-benzoxazin-6-yl]-1-methyl-2,4(1H.3H)-pyrimidinedione, 6-ethyl-3-[4-sec.butyl-3,4-dihydro-7-fluoro-3-oxo-2H--1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methoxyethyl)-3--oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methoxypropyl)-3--oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methyl-2--propenyl)-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4-(1H,3H)-pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methyl-2--propynyl)-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4-(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-isopropyl-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-sec.butyl-6-fluoro-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methoxyethyl)-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methoxypropyl)-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-allyl-6-fluoro-2-oxo-5-benzothiazolinyl]--1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methyl-2-propenyl)-2-oxo-5--benzothiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione and 6-ethyl-3-[6-fluoro-3-(1-methyl-2-propynyl)-2-oxo-5--benzothiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione.
12. A weed control composition, which contains an effective amount of at least one compound of the general formula I
wherein R1 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C2-5-alkenyl or C3-5-alkynyl, R2 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C1-4-alkoxy-C1-4-alkyl, C1-4-alkoxy--C1-4-alkoxy-C1-4-alkyl, C2-5-cyanoalkyl, C2-5-carboxyalkyl, C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-haloalkoxycarbonyl-C1-4--alkyl, C1-4-alkoxy-C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-alkoxycarbonyl-C2-5--alkoxycarbonyl-C1-4-alkyl, C4-7-cyclo-alkyloxycarbonyl-C1-4-alkyl, carbamoyl-C1-4--alkyl, mono(C1-4-alkyl)carbamoyl-C1-4-alkyl, di(C1-4-alkyl)carbamoyl-C1-4-alkyl, C3 or 4-alkenyl, C3 or 4-haloalkenyl, cinnamyl, C3 or 4-alkynyl or C3 or 4-halo-alkynyl, R3 and R4 each independently signify hydrogen, halogen, C1-4 alkyl or phenyl, R5 signifies hydrogen, fluorine or chlorine, R6 signifies hydrogen, halogen or C1-4-alkyl, R7 signifies C1-4-alkyl or, where R1 is not C1-4-haloalkyl, also C1-4-haloalkyl, n signifies zero or 1 and X signifies oxygen or sulphur, or of an enol ether of such a compound I in which R1 signifieS C1-4-alkyl, C2-5-alkenyl or C3-5-alkynyl or of a salt of such a compound I in which R1 signifies hydrogen, R2 signifies hydrogen and/or R2 signifies C2-5-carboxyalkyl, as well as formulation adjuvants.
wherein R1 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C2-5-alkenyl or C3-5-alkynyl, R2 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C1-4-alkoxy-C1-4-alkyl, C1-4-alkoxy--C1-4-alkoxy-C1-4-alkyl, C2-5-cyanoalkyl, C2-5-carboxyalkyl, C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-haloalkoxycarbonyl-C1-4--alkyl, C1-4-alkoxy-C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-alkoxycarbonyl-C2-5--alkoxycarbonyl-C1-4-alkyl, C4-7-cyclo-alkyloxycarbonyl-C1-4-alkyl, carbamoyl-C1-4--alkyl, mono(C1-4-alkyl)carbamoyl-C1-4-alkyl, di(C1-4-alkyl)carbamoyl-C1-4-alkyl, C3 or 4-alkenyl, C3 or 4-haloalkenyl, cinnamyl, C3 or 4-alkynyl or C3 or 4-halo-alkynyl, R3 and R4 each independently signify hydrogen, halogen, C1-4 alkyl or phenyl, R5 signifies hydrogen, fluorine or chlorine, R6 signifies hydrogen, halogen or C1-4-alkyl, R7 signifies C1-4-alkyl or, where R1 is not C1-4-haloalkyl, also C1-4-haloalkyl, n signifies zero or 1 and X signifies oxygen or sulphur, or of an enol ether of such a compound I in which R1 signifieS C1-4-alkyl, C2-5-alkenyl or C3-5-alkynyl or of a salt of such a compound I in which R1 signifies hydrogen, R2 signifies hydrogen and/or R2 signifies C2-5-carboxyalkyl, as well as formulation adjuvants.
13. A weed control composition according to claim 12, which contains an effective amount of 6-ethyl-3-[4-allyl--3,4-dihydro-7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl]-1--methyl-2,4(1H,3H)-pyrimidinedione and/or 6-ethyl-3-[3,4--dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin--6-yl]-1-methyl-2,4(1H,3H)-pyrimidinedione as well as formulation adjuvants.
14. A weed control composition according to claim 12, characterized in that it contains an effective amount of at least one compound selected from the group 6-ethyl-3-[4-allyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4--benzoxazin-6-yl]-5-bromo-1-methyl-2,4(1H,3H)-pyrimidine-dione, 3-[3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4--benzoxazin-6-yl]-1-methyl-6-(n-propyl)-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-isopropyl-3 oxo-2H--1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[4-sec.butyl-3,4-dihydro-7-fluoro-3-oxo-2H--1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methoxyethyl)-3--oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methoxypropyl)-3--oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4(1H,3H)--pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methyl-2--propenyl)-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4-(1H,3H)-pyrimidinedione, 6-ethyl-3-[3,4-dihydro-7-fluoro-4-(1-methyl-2--propynyl)-3-oxo-2H-1,4-benzoxazin-6-yl]-1-methyl-2,4-(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-isopropyl-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-sec.butyl-6-fluoro-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methoxyethyl)-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methoxypropyl)-2-oxo-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[3-allyl-6-fluoro-2-oxo-5-benzothiazolinyl]--1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-3-(1-methyl-2-propenyl)-2-oxo-5--benzothiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione, 6-ethyl-3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzo-thiazolinyl]-1-methyl-2,4(1H,3H)-pyrimidinedione and 6-ethyl-3-[6-fluoro-3-(1-methyl-2-propynyl)-2-oxo-5--benzothiazolinyl]-l-methyl-2,4(1H,3H)-pyrimidinedione as well as formulation adjuvants.
15. A process for the manufacture of compounds of the general formula I
wherein R1 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C2-5-alkenyl or C3-5-alkynyl, R2 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C1-4-alkoxy-C1-4-alkyl, C1-4-alkoxy -C1-4-alkoxy-C1-4-alkyl, C2-5-cyanoalkyl, C2-5-carboxyalkyl, C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-haloalkoxycarbonyl-C1-4--alkyl, C1-4-alkoxy-C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-alkoxycarbonyl-C2-5--alkoxycarbonyl-C1-4-alkyl, C4-7-cyclo-alkyloxycarbonyl-C1-4-alkyl, carbamoyl-C1-4--alkyl, mono(C1-4-alkyl)carbamoyl-C1-4-alkyl, di(C1-4-alkyl)carbamoyl-C1-4-alkyl, C3 or 4-alkenyl, C3 or 4-haloalkenyl, cinnamyl, C3 or 4-alkynyl or C3 or 4-halo-alkynyl, R3 and R4 each independently signify hydrogen, halogen, C1-4-alkyl or phenyl, R5 signifies hydrogen, fluorine or chlorine, R6 signifies hydrogen, halogen or C1-4-alkyl, R7 signifies C1-4-alkyl or, where R1 is not C1-4-haloalkyl, also C1-4-haloalkyl, n signifies zero or 1 and X signifies oxygen or sulphur, and of the corresponding enol ethers of those compounds of formula I in which R1 signifies C1-4-alkyl, C2-5--alkenyl or C3-5-alkynyl as well as of salts of those compounds of formula I in which R1 signifies hydrogen.
R2 signifies hydrogen and/or R2 signifies C2-5--carboxyalkyl, which process comprises a) for the manufacture of those compounds of formula which R1 signifies hydrogen and R6 signifies hydrogen, fluorine or C1-4-alkyl as well as, if desired, of metal salts of these compounds, subjecting a compound of the general formula II
wherein R2, R3, R4, R5, R7, n and X have the significances given above, R6' signifies hydrogen, fluorine or C1-4-alkyl and R8 signifies lower-alkyl, to a cyclization under basic conditions and, if desired, converting a metal salt of the uracil derivative of formula I which may be obtained into the acidic form (R1 = hydrogen) by treatment with an acid.
b) for the manufacture of those compounds of formula I in which R1 signifies hydrogen, R6 signifies hydrogen, fluorine or C1-4-alkyl and R7 signifies C1-4-alkyl as well as of salts of the compounds of formula I, subjecting a compound of the general formula III
wherein R2, R3, R4, R5, R6', n and X have the significances given above, R signifies C1-4-alkyl and R9 signifies lower alkyl, to a cyclization under basic conditions and, if desired, converting a metal salt of the uracil derivative of formula I which may be obtained into the acidic form (R1 = hydrogen) by treatment with an acid, c) for the manufacture of those compounds of formula I in which R1 signifies C1-4-alkyl, C1-4-haloalkyl, C2-5-alkenyl or C3-5-alkynyl, subjecting a uracil derivative of the general formula I' wherein R2, R3, R4, R5, R6, R7. n and X
have the significances given above, to an alkylation with an appropriate alkylating agent containing a C1-4-alkyl, C2-5-alkenyl or C3-5--alkynyl group.
d) for the manufacture of those compounds of formula I in which R2 signifies hydrogen, cleaving off the protecting group R10 in a uracil derivative of the general formula I"
wherein R1, R3, R4, R5, R6, R7. n and X
have the significances given above and R10 signifies a protecting group, e) for the manufacture of those compounds of formula I in which R2 is different from hydrogen, appropriately alkylating a uracil derivative of the general formula I " ' wherein R1, R3, R4, R5, R6, R7, n and X
have the significances given above, f) for the manufacture of those compounds of formula I in which R6 signifies chlorine, bromine or iodine, chlorinating, brominating or iodinating a uracil derivative of the general formula I " "
wherein R1, R2, R3, R4, R5, R7, n and X
have the significances given above, g) for the manufacture of the enol ethers of formula Ia treating a pyrimidinone derivative of the general formula IV
wherein R2, R3, R4, R5, R6, R7, n and X have the significances given above and Hal signifies chlorine or bromine, with an alkanol, alkenol or alkynol R1' OH in the presence of an organic base or with the corresponding alcoholate, alkenolate or alkynolate of the general formula R1'O?M? V
wherein R1' has the significance given above and M? signifies one equivalent of a metal ion, and, if desired, converting a thus-obtained compound of formula I in which R1 signifies hydrogen, R2 signifies hydrogen and/or R2 signifies C2-5-carboxyalkyl into a salt.
wherein R1 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C2-5-alkenyl or C3-5-alkynyl, R2 signifies hydrogen, C1-4-alkyl, C1-4-halo-alkyl, C1-4-alkoxy-C1-4-alkyl, C1-4-alkoxy -C1-4-alkoxy-C1-4-alkyl, C2-5-cyanoalkyl, C2-5-carboxyalkyl, C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-haloalkoxycarbonyl-C1-4--alkyl, C1-4-alkoxy-C2-5-alkoxycarbonyl--C1-4-alkyl, C2-5-alkoxycarbonyl-C2-5--alkoxycarbonyl-C1-4-alkyl, C4-7-cyclo-alkyloxycarbonyl-C1-4-alkyl, carbamoyl-C1-4--alkyl, mono(C1-4-alkyl)carbamoyl-C1-4-alkyl, di(C1-4-alkyl)carbamoyl-C1-4-alkyl, C3 or 4-alkenyl, C3 or 4-haloalkenyl, cinnamyl, C3 or 4-alkynyl or C3 or 4-halo-alkynyl, R3 and R4 each independently signify hydrogen, halogen, C1-4-alkyl or phenyl, R5 signifies hydrogen, fluorine or chlorine, R6 signifies hydrogen, halogen or C1-4-alkyl, R7 signifies C1-4-alkyl or, where R1 is not C1-4-haloalkyl, also C1-4-haloalkyl, n signifies zero or 1 and X signifies oxygen or sulphur, and of the corresponding enol ethers of those compounds of formula I in which R1 signifies C1-4-alkyl, C2-5--alkenyl or C3-5-alkynyl as well as of salts of those compounds of formula I in which R1 signifies hydrogen.
R2 signifies hydrogen and/or R2 signifies C2-5--carboxyalkyl, which process comprises a) for the manufacture of those compounds of formula which R1 signifies hydrogen and R6 signifies hydrogen, fluorine or C1-4-alkyl as well as, if desired, of metal salts of these compounds, subjecting a compound of the general formula II
wherein R2, R3, R4, R5, R7, n and X have the significances given above, R6' signifies hydrogen, fluorine or C1-4-alkyl and R8 signifies lower-alkyl, to a cyclization under basic conditions and, if desired, converting a metal salt of the uracil derivative of formula I which may be obtained into the acidic form (R1 = hydrogen) by treatment with an acid.
b) for the manufacture of those compounds of formula I in which R1 signifies hydrogen, R6 signifies hydrogen, fluorine or C1-4-alkyl and R7 signifies C1-4-alkyl as well as of salts of the compounds of formula I, subjecting a compound of the general formula III
wherein R2, R3, R4, R5, R6', n and X have the significances given above, R signifies C1-4-alkyl and R9 signifies lower alkyl, to a cyclization under basic conditions and, if desired, converting a metal salt of the uracil derivative of formula I which may be obtained into the acidic form (R1 = hydrogen) by treatment with an acid, c) for the manufacture of those compounds of formula I in which R1 signifies C1-4-alkyl, C1-4-haloalkyl, C2-5-alkenyl or C3-5-alkynyl, subjecting a uracil derivative of the general formula I' wherein R2, R3, R4, R5, R6, R7. n and X
have the significances given above, to an alkylation with an appropriate alkylating agent containing a C1-4-alkyl, C2-5-alkenyl or C3-5--alkynyl group.
d) for the manufacture of those compounds of formula I in which R2 signifies hydrogen, cleaving off the protecting group R10 in a uracil derivative of the general formula I"
wherein R1, R3, R4, R5, R6, R7. n and X
have the significances given above and R10 signifies a protecting group, e) for the manufacture of those compounds of formula I in which R2 is different from hydrogen, appropriately alkylating a uracil derivative of the general formula I " ' wherein R1, R3, R4, R5, R6, R7, n and X
have the significances given above, f) for the manufacture of those compounds of formula I in which R6 signifies chlorine, bromine or iodine, chlorinating, brominating or iodinating a uracil derivative of the general formula I " "
wherein R1, R2, R3, R4, R5, R7, n and X
have the significances given above, g) for the manufacture of the enol ethers of formula Ia treating a pyrimidinone derivative of the general formula IV
wherein R2, R3, R4, R5, R6, R7, n and X have the significances given above and Hal signifies chlorine or bromine, with an alkanol, alkenol or alkynol R1' OH in the presence of an organic base or with the corresponding alcoholate, alkenolate or alkynolate of the general formula R1'O?M? V
wherein R1' has the significance given above and M? signifies one equivalent of a metal ion, and, if desired, converting a thus-obtained compound of formula I in which R1 signifies hydrogen, R2 signifies hydrogen and/or R2 signifies C2-5-carboxyalkyl into a salt.
16. A process according to claim 15, wherein the compounds of formula I and their enol ethers and salts are manufactured by process variant a), b), c), f) or g) and, if desired, by conversion into a salt.
17. A process according to claim 15, wherein a compound according to any one of claims 1 to 11 is manufactured.
18. A method for the control of weeds, which method comprises treating the locus to be protected against weeds and/or the weeds with an effective amount of a compound in accordance with any one of claims 1, 2 and 10 or of a composition in accordance with claim 12 or 13.
19. A method for the control of weeds, which method comprises treating the locus to be protected against weeds and/or the weeds with an effective amount of a compound in accordance with any one of claims 3 to 9 and 11 or of a composition in accordance with claim 14.
20. The use of a compound in accordance with any one of claims 1, 2 and 10 or of a composition in accordance with claim 12 or 13 for the control of weeds.
21. The use of a compound in accordance with any one of claims 3 to 9 and 11 or of a composition in accordance with claim 14 for the control of weeds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2166/89 | 1989-06-09 | ||
| CH216689 | 1989-06-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2033346A1 true CA2033346A1 (en) | 1990-12-10 |
Family
ID=4227431
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002033346A Abandoned CA2033346A1 (en) | 1989-06-09 | 1990-05-31 | Heterocyclic compounds |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0434778A1 (en) |
| JP (1) | JPH04501567A (en) |
| KR (1) | KR920700211A (en) |
| AU (1) | AU631896B2 (en) |
| BR (1) | BR9006799A (en) |
| CA (1) | CA2033346A1 (en) |
| HU (1) | HU206708B (en) |
| WO (1) | WO1990015057A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8481723B2 (en) | 2009-11-13 | 2013-07-09 | Basf Se | 3-(3,4-dihydro-2H-benzo [1,4]oxazin-6-yl)-1H-Pyrimidin-2,4-dione compounds as herbicides |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU627906B2 (en) * | 1989-07-14 | 1992-09-03 | Nissan Chemical Industries Ltd. | Uracil derivatives and herbicides containing the same as active ingredient |
| US5314864A (en) * | 1989-09-26 | 1994-05-24 | Sumitomo Chemical Company, Limited | N-aminouracil derivatives, and their production and use |
| JP3064371B2 (en) | 1989-09-26 | 2000-07-12 | 住友化学工業株式会社 | Benzoxazyluracil derivative, process for producing the same and herbicide containing the same as active ingredient |
| BR9004801A (en) * | 1989-09-26 | 1991-09-10 | Sumitomo Chemical Co | COMPOUND AND PROCESS FOR ITS PREPARATION, HERBICIDE COMPOSITION, PROCESS FOR EXTERMINATING HARMFUL WEEDS AND USE OF THAT COMPOUND |
| JP3064374B2 (en) * | 1989-10-02 | 2000-07-12 | 住友化学工業株式会社 | Uracil derivative, method for producing the same, and herbicide containing the same as an active ingredient |
| EP0476697B1 (en) * | 1990-09-21 | 1996-03-20 | Sumitomo Chemical Company, Limited | Benzofuranyl- and benzothiophenyl substituted uracil derivatives, and their production and use as herbicides |
| US5238906A (en) * | 1990-11-27 | 1993-08-24 | Sumitomo Chemical Company, Limited | Pyridone derivatives and use |
| WO1993017005A1 (en) * | 1992-02-26 | 1993-09-02 | Central Glass Co., Ltd. | N-acyl-n-phenyltetrahydrophthalamic acid derivative, production thereof, and herbicide containing the same as active ingredient |
| JPH07502758A (en) * | 1992-10-23 | 1995-03-23 | チバ−ガイギー アクチエンゲゼルシャフト | 3-Aryluracil derivatives and their use for controlling weeds |
| US5441925A (en) * | 1994-06-28 | 1995-08-15 | Fmc Corporation | 1-amino-3-(bicyclic heterocyclyl)-6-fluoroalkyluracils |
| RU2001124602A (en) * | 1999-02-16 | 2004-03-20 | БАСФ Акциенгезельшафт (DE) | METHOD FOR PRODUCING 6- (PERFluoroalkyl) URACYL COMPOUNDS FROM UREA DERIVATIVES |
| WO2000049002A1 (en) * | 1999-02-16 | 2000-08-24 | American Cyanamid Company | Processes and intermediates for the preparation of 1,3-oxazin-6-ones and uracils |
| JP2005022974A (en) * | 2001-06-13 | 2005-01-27 | Idemitsu Kosan Co Ltd | Uracil derivative and herbicide composition |
| US20040186021A1 (en) * | 2001-07-12 | 2004-09-23 | Otto Schallner | Substituted benzo-nitro-heterocycles |
| JP5207382B2 (en) * | 2006-08-30 | 2013-06-12 | 塩野義製薬株式会社 | Urea derivatives |
| CN105272973B (en) * | 2014-06-10 | 2019-02-01 | 华中师范大学 | A kind of hybar X class compound containing benzoxazine ring and its application |
| CN117263930B (en) * | 2023-09-28 | 2025-09-19 | 西北农林科技大学 | N-pyridyl benzothiazole compound, and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2328188A (en) * | 1987-09-23 | 1989-04-18 | Ciba-Geigy Ag | Heterocyclic compounds |
| DE3734745A1 (en) * | 1987-10-09 | 1989-04-20 | Schering Ag | TETRAHYDROPYRROLO (2,1-C) (1,2,4) -THIADIAZOL-3-YLIDENIMINOBENZOXAZINONE AND OTHER HETEROCYCLICALLY SUBSTITUTED AZOLES AND AZINES, METHODS FOR THE PRODUCTION THEREOF AND THEIR USE AS AGENTS WITH HERBICIDES |
| DE69104071T2 (en) * | 1990-01-18 | 1995-05-11 | Nissan Chemical Ind Ltd | Uracil derivatives and pesticides containing them as effective substances. |
-
1990
- 1990-05-31 BR BR909006799A patent/BR9006799A/en not_active Application Discontinuation
- 1990-05-31 HU HU904272A patent/HU206708B/en not_active IP Right Cessation
- 1990-05-31 CA CA002033346A patent/CA2033346A1/en not_active Abandoned
- 1990-05-31 JP JP2507301A patent/JPH04501567A/en active Pending
- 1990-05-31 WO PCT/CH1990/000140 patent/WO1990015057A1/en not_active Application Discontinuation
- 1990-05-31 KR KR1019910700156A patent/KR920700211A/en not_active Withdrawn
- 1990-05-31 EP EP90906847A patent/EP0434778A1/en not_active Withdrawn
- 1990-05-31 AU AU56415/90A patent/AU631896B2/en not_active Ceased
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8481723B2 (en) | 2009-11-13 | 2013-07-09 | Basf Se | 3-(3,4-dihydro-2H-benzo [1,4]oxazin-6-yl)-1H-Pyrimidin-2,4-dione compounds as herbicides |
| US8748348B2 (en) | 2009-11-13 | 2014-06-10 | Basf Se | 3-(3,4-dihydro-2H-benzo [1,4]oxazin-6-yl)-1H-pyrimidin-2,4-dione compounds as herbicides |
Also Published As
| Publication number | Publication date |
|---|---|
| AU631896B2 (en) | 1992-12-10 |
| KR920700211A (en) | 1992-02-19 |
| JPH04501567A (en) | 1992-03-19 |
| HU904272D0 (en) | 1991-07-29 |
| EP0434778A1 (en) | 1991-07-03 |
| HU206708B (en) | 1992-12-28 |
| BR9006799A (en) | 1991-08-06 |
| HUT56840A (en) | 1991-10-28 |
| WO1990015057A1 (en) | 1990-12-13 |
| AU5641590A (en) | 1991-01-07 |
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| FZDE | Dead |