CA2065829A1 - Preparation of 1-carbamoylpyrazoles - Google Patents
Preparation of 1-carbamoylpyrazolesInfo
- Publication number
- CA2065829A1 CA2065829A1 CA002065829A CA2065829A CA2065829A1 CA 2065829 A1 CA2065829 A1 CA 2065829A1 CA 002065829 A CA002065829 A CA 002065829A CA 2065829 A CA2065829 A CA 2065829A CA 2065829 A1 CA2065829 A1 CA 2065829A1
- Authority
- CA
- Canada
- Prior art keywords
- reaction
- pyrazole
- urea
- preparation
- carbamoyl
- 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
- DVLHGMFTRAFHPR-UHFFFAOYSA-N pyrazole-1-carboxamide Chemical class NC(=O)N1C=CC=N1 DVLHGMFTRAFHPR-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims description 16
- 239000004202 carbamide Substances 0.000 claims abstract description 29
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 28
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 claims description 4
- AJDAWQUQDDHYHH-UHFFFAOYSA-N n-(3-methylpyrazol-1-yl)formamide Chemical compound CC=1C=CN(NC=O)N=1 AJDAWQUQDDHYHH-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- -1 alkali metal cyanate Chemical class 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- OHJMTUPIZMNBFR-UHFFFAOYSA-N biuret Chemical compound NC(=O)NC(N)=O OHJMTUPIZMNBFR-UHFFFAOYSA-N 0.000 description 5
- 239000000155 melt Substances 0.000 description 4
- 150000003217 pyrazoles Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- KJTRXVXWSSPHRV-UHFFFAOYSA-N 4-benzoyl-5-methyl-2-phenyl-1h-pyrazol-3-one Chemical compound O=C1C(C(=O)C=2C=CC=CC=2)=C(C)NN1C1=CC=CC=C1 KJTRXVXWSSPHRV-UHFFFAOYSA-N 0.000 description 1
- BADSZRMNXWLUKO-UHFFFAOYSA-N 4-chloro-1h-pyrazole Chemical compound ClC=1C=NNC=1 BADSZRMNXWLUKO-UHFFFAOYSA-N 0.000 description 1
- HXICDQUQAARULC-UHFFFAOYSA-N 4-chloropyrazole-1-carboxamide Chemical compound NC(=O)N1C=C(Cl)C=N1 HXICDQUQAARULC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000357437 Mola Species 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002844 continuous effect Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
O.Z. 0050/42353 Abstract of the Disclosure: 1-Carbamoylpyrazole and derivatives thereof are prepared by reacting pyrazole or a derivative thereof by a process in which pyrazole or the derivative thereof is reacted with urea at above 30°C.
Description
2~6~829 ~.Z. 0050/42353 Preparation of l-carbamoylpyrazole~
The present invention relates to a novel proce3s for the preparation of l-carbamoylpyrazole I
I
l'N
O=C--NH 2 and derivatives thereof by reacting pyrazole II
~ u II
or a d~rivative thereof.
The literature discloses various proce~se~ for the preparation o~ l-carbamoylpyrazoles. For example, the reaction of pyrazole derivatives with alkali metal cyanate~ in a weakly alkaline solution (DE-A 38 15 788, DD-A 259 860, DD-A 249 409 and DD-A 210,541~ and the two-stage reaction of pyrazole~ first with phosgene and then ~ with ammonia (Auwers et al., J. prakt. Chem. lI0 (1925), ;~ 15 253) are de~cri~ed.
~he3e known processes present problems with regard to large-3cale indu~trial u~e, owing to the highly `
toxic ~tarting material~ (alkali metal cyanates, phosgene ; ~ and a~ onia), and the disposal of the salts formed in such reactions.
It is also known that the reaction of~aliphatic aminQs ~ with urea leads to corrssponding carbamoyl derivatives (US-A~ 3,625,94~8, US-A ~4,766,115 and US-A 4,833,245)~ However, the attempt to pply the conditions de~cribed for this reaction to the preparation o~ l-carbamoylpyrazole does not lead to the~ desired 3uccess, owing to the compara~i~ely ;low nucleophilicity o~ the pyrazoles on~thH one~hand and the low reactivity o the urea on the o~her hand.
~ It i~ an ob~ect of the present in~enticn to make ;~ 30 l-carbamoylpyrazol~ and derivatives thereo~ available in a technically ~i~ple and economical manner.
We have found that thl~ ob~ect i9 achieved by a 2~ ~ 5 8 2 9 o.z . 0050/42353 novel proce~ for the preparation of l-carbamoylpyrazole I
I'N
O=C--NH 2 and derivative~ thereof by reacting pyrazole II
~N II
or a derivative thereof, wherein II or the derivative thereof is reacted with urea at above 30C.
The reac~ion generally begin3 at above 30C. It take~ place at a sufficient rate at 50C. In genQral, however, 250C should not be exceeded ~ince the reaction of urea to form a biuret, which competas with the de~ired reaction, becomes more predominan~ at higher temperatures.
Fox these rea30ns, the reaction tamperature ~hould in general be from 40 to 200C, preferably from 50 to 180C, in particular from 70 to 150C.
Since the ammonia liberated during the reaction of pyrazoles with uraa ha~ a highex ba~icity than pyraz-ole and i3 therefore capable of clea~ing the l-carbamoyl-pyrazole already formed and hence reducing the yield, it i8 advi~able to r~move it from the reactio~ mix~ure.
This i~ generally effected continuou~ly by a conventional m~thod, by passing a~ inert ga~ through the reaction mi~ture or carxying ollt the reaction under reduced pressure.
The ratio in which tha intermediate~ pyrazole and uraa ars reacted with one another may va~y withih wide rang~s (from 0.01 to 1 mola equivalQnt of urea, ba~ed on the pyrazole).
In general, ure~ i used in les~ than the stoichiometric amount, based on the pyrazole, since, at the reaction temperatures, excess urea would react to 3 2 0 6 ~ 8 2 9 o. Z . 0050/42353 form a biuret.
The urea is usually u~ed in amount~ of from 0.01 to 0.95, preferably from 0.03 to 0.8, in particular from 0.05 to 0.5, mole equivalent, based on the pyrazole used.
Another possible method of suppressing the formation of biuret during the reaction is to meter in the urea during the reaction at slevated temperatures, since this avoid~ an exces~ of urea in the reaction mixture. The metered addition may be effected con-tinuously or batchwise, with or without a solvent.
The reaction of pyrazoleq with urea i~ usually carried out in the melt, without the addition of a solvent or diluent.
According to inve~tigations to da~e, the use of a Lewis acid, in par~icular iron(IlI) salt~, can lead to an increase in the yield.
After the reaction mixture has cooled, the 1-carbamoylpyrazole i-~ obtained in a conventional manner:
If the reaction has been carried out in the melt, it is obtained for example by taking up the mixture in water, rec~ystallizing the insoluble residue which contains the product and carrying out distillation, extraction or chromatography.
It may be advisable here to remove the uncon-verted pyrazole by distillation before working up the reactio~ mixture.
If the reaction i3 carried out in a solvent, i~
iR advisable fir~t to remove the solvent and the uncon-vertad pyrazole by distilIation before adding water to the reaction mixture.
The novel proce~s is ~uitable for the preparation of l-carbamoylpyrazoIe and qubstituted l-carbamoyl-pyrazoles from the corre~ponding pyrazoles, in particular tho~e of the general formula Ia R 2~R 1 3 5 R 3J~N--N Ia o~NH 2 20~82~
_ 4 - ~.z. 0050/42353 where Rl, R2 and R3 are each hydrogen, nitro, halogen, or a C-organic radical which may be bonded via a hetero atom, Cuch a~ oxygen, sulfur or nitrogen, or are each carboxyl, knowledge gained to date indicating that the nature of the substituents has little effect.
Suitable radicals Rl, ~2 and R3 in addition to hydrogen and nitro are preferably from one to three of the following groups:
halogen, in particular fluorine, chlorine or iodine;
alkyl, in particular methyl, ethyl, propyl, l-methyl-ethyl, butyl, l-methylpropyl, 2-methylpropyl or 1,1-dLmethylethyl;
cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
alkenyl, in particular ethenyl, l-propenyl, 2-propenyl, l-methylethenyl, l-butenyl, 2-butenyl, 3-butenyl, 1-methyl-l-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl or l-ethylethenyl;
alkynyl, in particular ethynyl, l-propynyl, 2-propynyl, l-butynyl, 2-butynyl, 3-butynyl or 1-methyl-2-propynyl, and aryl or hetaryl, in particular phenyl.
~ The stated C-organic radical~ may in turn be bonded to the pyrazole ring via hetero atoms, such as oxygen, sulfur or nitrogen, or interrupted by hetero atoms, such as oxygen, sulfur or nitrogen, or may in turn carry further inert substituents, ~uch as halogen, nitro, aryl, ulfon~l, alkylsulfonyl, arylsulfonyl or carboxyl~
provided that they are inert under the reaction conditions.
The pyrazole3 IIa used as starting compound~ are Xnown or are obtainable by known method~ (DE-A 39 18 979).
The novel process also makes possible the preparation of l-carbamoylpyrazoles of the general formula Ib . _ 5 ~0 6 5 8 2 9 o. z . 0050/42353 R2 ~ Rl Ib o~NR4R5 where Rl, R2 and R3 have the abovementioned meanings and R4 and R5 are each one the abovementioned C-organic radical~.
S In thi~ ca~e, a compound of the general formula IIa i~ reacted with a ~ymmetrically substituted urea of the general formula IIIa under the condition~ described above.
o R2~Rl ll R2 R 3~N--N R 3~N--N
H o~NR4RS
IlaIlla Ib The l-carbamoylpyrazole , which are more readily obtainable by the novel process, are known bioregulator~
(eg. DE-A 27 45 833). In particular, l-carbamoyl-3-methylpyrazole (C~P) i~ a valuable product which i9 u~ed for inhibiting the nitrification of ammonium nitrogen in cultivated oil~ in agriculture.
Proce~s Examples ; EXAMPLE 1 A mixture of 40 g (0.488 mol) of 3 methylpyrazole and 3.0 g (0.048 mol) of urea wa~ haated ~o 110C. At this temp~ra~ure, a nitrogen ~trea~ of 10 l/h was passed through the reaction mixture for 30 hour~. ~It wa~ then cooled at -10C for 5 hours. 4.1 g (0.033 moI) of 1-carbamoyl-3-msthylpyrazola o~ melting point 127C were precipitated (yieldt 68% of theory, ba~ed on urea).
A mixture~of 20 g (0.244 mol~ of 3-methylpyrazole and l.S g (0.024 mol3 of urea was heatsd to 110C. After 24 hours, a fur~her 1.5 g o~ urea were added and the mixtura Wa8 kept at 100C for a further 24 hours. During 2 0 6 ~ 8 2 9 - 6 - O.Z. 0050/42353 the total reaction time, a nitrogen 3tream of 1 1/h was pa~ed throuyh the reaction mixture. After the m~xture had been cooled, 81.2~ by weight of 3-methyl~yrazole, 6.0% by weight of urea, 13.8% by weight of 1-carbamoyl-S3-methylpyrazole and 0.62~ of biuret were found (HPLC
analysis). The urea conversion was 56%, the yield of 1-carbamoyl-3-methylpyrazole was 48%, based on urea, the selectivity with respect to l-carbamoyl-3-mothylpyrazole was 86~, ba~ed on urea, and the selectivity with respect 10to biuret wa~ 5%, based on urea.
EXAMPL~ 3 A mixture of 20 g (0.24 mol) of 3-methylpyrazole and 14.7 g tO.24 mol) of urea was heated to 100C, and a nitrogen stream of 5 l/h was passed through for 32 hour~
15at this temperature. When the mixture was di~solved in 100 ml of water, 1.7 g of a solid remained. Recrystal-lization from chloroform gaYe 1.3 g of 1-carbamoyl-3-methylpyrazole of melting point 125C.
~0A mixture of 20 g (0.29 mol) of pyrazole and 1.8 g (0.03 mol) of urea was melted, and a nitrogen ~tream of 10 l/h wa~ passed through for 10 hours at 100C.
According to 1H-NNR, the cooled melt contained 7.80% by weight of pyrazole-l-carboxamid0 (8.3 ppm, lH; 7.9 ppm, 252H; 7.8 ppm, lH and 6.5 ppm~ lH~. This corxespond~ to a yield of 47% of theory7 ba~ed on urea.
EXAMPLE S
~ 51.3 g (0.5 mol) of 4-chloropyrazole were melted, -~ and the melt wa~ kept at 120C. 6.06 g (0.1 mol) of urea 30were dissolved therein. A nitrogen stream of ~0 l/h was passed through the reaction mixture at the tated temp-erature for 22 hours. The melt was cooled and was dissolved in 175 ml of methyl tert_butyl etherO The in~oluble residue was filtered off and wa hed with 70 ml 35of water. 6.2 g of 1-carbamoyl-4-chloropyrazole of melting point 191C remained (yield: 43~ of theory, based on urea~.
The present invention relates to a novel proce3s for the preparation of l-carbamoylpyrazole I
I
l'N
O=C--NH 2 and derivatives thereof by reacting pyrazole II
~ u II
or a d~rivative thereof.
The literature discloses various proce~se~ for the preparation o~ l-carbamoylpyrazoles. For example, the reaction of pyrazole derivatives with alkali metal cyanate~ in a weakly alkaline solution (DE-A 38 15 788, DD-A 259 860, DD-A 249 409 and DD-A 210,541~ and the two-stage reaction of pyrazole~ first with phosgene and then ~ with ammonia (Auwers et al., J. prakt. Chem. lI0 (1925), ;~ 15 253) are de~cri~ed.
~he3e known processes present problems with regard to large-3cale indu~trial u~e, owing to the highly `
toxic ~tarting material~ (alkali metal cyanates, phosgene ; ~ and a~ onia), and the disposal of the salts formed in such reactions.
It is also known that the reaction of~aliphatic aminQs ~ with urea leads to corrssponding carbamoyl derivatives (US-A~ 3,625,94~8, US-A ~4,766,115 and US-A 4,833,245)~ However, the attempt to pply the conditions de~cribed for this reaction to the preparation o~ l-carbamoylpyrazole does not lead to the~ desired 3uccess, owing to the compara~i~ely ;low nucleophilicity o~ the pyrazoles on~thH one~hand and the low reactivity o the urea on the o~her hand.
~ It i~ an ob~ect of the present in~enticn to make ;~ 30 l-carbamoylpyrazol~ and derivatives thereo~ available in a technically ~i~ple and economical manner.
We have found that thl~ ob~ect i9 achieved by a 2~ ~ 5 8 2 9 o.z . 0050/42353 novel proce~ for the preparation of l-carbamoylpyrazole I
I'N
O=C--NH 2 and derivative~ thereof by reacting pyrazole II
~N II
or a derivative thereof, wherein II or the derivative thereof is reacted with urea at above 30C.
The reac~ion generally begin3 at above 30C. It take~ place at a sufficient rate at 50C. In genQral, however, 250C should not be exceeded ~ince the reaction of urea to form a biuret, which competas with the de~ired reaction, becomes more predominan~ at higher temperatures.
Fox these rea30ns, the reaction tamperature ~hould in general be from 40 to 200C, preferably from 50 to 180C, in particular from 70 to 150C.
Since the ammonia liberated during the reaction of pyrazoles with uraa ha~ a highex ba~icity than pyraz-ole and i3 therefore capable of clea~ing the l-carbamoyl-pyrazole already formed and hence reducing the yield, it i8 advi~able to r~move it from the reactio~ mix~ure.
This i~ generally effected continuou~ly by a conventional m~thod, by passing a~ inert ga~ through the reaction mi~ture or carxying ollt the reaction under reduced pressure.
The ratio in which tha intermediate~ pyrazole and uraa ars reacted with one another may va~y withih wide rang~s (from 0.01 to 1 mola equivalQnt of urea, ba~ed on the pyrazole).
In general, ure~ i used in les~ than the stoichiometric amount, based on the pyrazole, since, at the reaction temperatures, excess urea would react to 3 2 0 6 ~ 8 2 9 o. Z . 0050/42353 form a biuret.
The urea is usually u~ed in amount~ of from 0.01 to 0.95, preferably from 0.03 to 0.8, in particular from 0.05 to 0.5, mole equivalent, based on the pyrazole used.
Another possible method of suppressing the formation of biuret during the reaction is to meter in the urea during the reaction at slevated temperatures, since this avoid~ an exces~ of urea in the reaction mixture. The metered addition may be effected con-tinuously or batchwise, with or without a solvent.
The reaction of pyrazoleq with urea i~ usually carried out in the melt, without the addition of a solvent or diluent.
According to inve~tigations to da~e, the use of a Lewis acid, in par~icular iron(IlI) salt~, can lead to an increase in the yield.
After the reaction mixture has cooled, the 1-carbamoylpyrazole i-~ obtained in a conventional manner:
If the reaction has been carried out in the melt, it is obtained for example by taking up the mixture in water, rec~ystallizing the insoluble residue which contains the product and carrying out distillation, extraction or chromatography.
It may be advisable here to remove the uncon-verted pyrazole by distillation before working up the reactio~ mixture.
If the reaction i3 carried out in a solvent, i~
iR advisable fir~t to remove the solvent and the uncon-vertad pyrazole by distilIation before adding water to the reaction mixture.
The novel proce~s is ~uitable for the preparation of l-carbamoylpyrazoIe and qubstituted l-carbamoyl-pyrazoles from the corre~ponding pyrazoles, in particular tho~e of the general formula Ia R 2~R 1 3 5 R 3J~N--N Ia o~NH 2 20~82~
_ 4 - ~.z. 0050/42353 where Rl, R2 and R3 are each hydrogen, nitro, halogen, or a C-organic radical which may be bonded via a hetero atom, Cuch a~ oxygen, sulfur or nitrogen, or are each carboxyl, knowledge gained to date indicating that the nature of the substituents has little effect.
Suitable radicals Rl, ~2 and R3 in addition to hydrogen and nitro are preferably from one to three of the following groups:
halogen, in particular fluorine, chlorine or iodine;
alkyl, in particular methyl, ethyl, propyl, l-methyl-ethyl, butyl, l-methylpropyl, 2-methylpropyl or 1,1-dLmethylethyl;
cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
alkenyl, in particular ethenyl, l-propenyl, 2-propenyl, l-methylethenyl, l-butenyl, 2-butenyl, 3-butenyl, 1-methyl-l-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl or l-ethylethenyl;
alkynyl, in particular ethynyl, l-propynyl, 2-propynyl, l-butynyl, 2-butynyl, 3-butynyl or 1-methyl-2-propynyl, and aryl or hetaryl, in particular phenyl.
~ The stated C-organic radical~ may in turn be bonded to the pyrazole ring via hetero atoms, such as oxygen, sulfur or nitrogen, or interrupted by hetero atoms, such as oxygen, sulfur or nitrogen, or may in turn carry further inert substituents, ~uch as halogen, nitro, aryl, ulfon~l, alkylsulfonyl, arylsulfonyl or carboxyl~
provided that they are inert under the reaction conditions.
The pyrazole3 IIa used as starting compound~ are Xnown or are obtainable by known method~ (DE-A 39 18 979).
The novel process also makes possible the preparation of l-carbamoylpyrazoles of the general formula Ib . _ 5 ~0 6 5 8 2 9 o. z . 0050/42353 R2 ~ Rl Ib o~NR4R5 where Rl, R2 and R3 have the abovementioned meanings and R4 and R5 are each one the abovementioned C-organic radical~.
S In thi~ ca~e, a compound of the general formula IIa i~ reacted with a ~ymmetrically substituted urea of the general formula IIIa under the condition~ described above.
o R2~Rl ll R2 R 3~N--N R 3~N--N
H o~NR4RS
IlaIlla Ib The l-carbamoylpyrazole , which are more readily obtainable by the novel process, are known bioregulator~
(eg. DE-A 27 45 833). In particular, l-carbamoyl-3-methylpyrazole (C~P) i~ a valuable product which i9 u~ed for inhibiting the nitrification of ammonium nitrogen in cultivated oil~ in agriculture.
Proce~s Examples ; EXAMPLE 1 A mixture of 40 g (0.488 mol) of 3 methylpyrazole and 3.0 g (0.048 mol) of urea wa~ haated ~o 110C. At this temp~ra~ure, a nitrogen ~trea~ of 10 l/h was passed through the reaction mixture for 30 hour~. ~It wa~ then cooled at -10C for 5 hours. 4.1 g (0.033 moI) of 1-carbamoyl-3-msthylpyrazola o~ melting point 127C were precipitated (yieldt 68% of theory, ba~ed on urea).
A mixture~of 20 g (0.244 mol~ of 3-methylpyrazole and l.S g (0.024 mol3 of urea was heatsd to 110C. After 24 hours, a fur~her 1.5 g o~ urea were added and the mixtura Wa8 kept at 100C for a further 24 hours. During 2 0 6 ~ 8 2 9 - 6 - O.Z. 0050/42353 the total reaction time, a nitrogen 3tream of 1 1/h was pa~ed throuyh the reaction mixture. After the m~xture had been cooled, 81.2~ by weight of 3-methyl~yrazole, 6.0% by weight of urea, 13.8% by weight of 1-carbamoyl-S3-methylpyrazole and 0.62~ of biuret were found (HPLC
analysis). The urea conversion was 56%, the yield of 1-carbamoyl-3-methylpyrazole was 48%, based on urea, the selectivity with respect to l-carbamoyl-3-mothylpyrazole was 86~, ba~ed on urea, and the selectivity with respect 10to biuret wa~ 5%, based on urea.
EXAMPL~ 3 A mixture of 20 g (0.24 mol) of 3-methylpyrazole and 14.7 g tO.24 mol) of urea was heated to 100C, and a nitrogen stream of 5 l/h was passed through for 32 hour~
15at this temperature. When the mixture was di~solved in 100 ml of water, 1.7 g of a solid remained. Recrystal-lization from chloroform gaYe 1.3 g of 1-carbamoyl-3-methylpyrazole of melting point 125C.
~0A mixture of 20 g (0.29 mol) of pyrazole and 1.8 g (0.03 mol) of urea was melted, and a nitrogen ~tream of 10 l/h wa~ passed through for 10 hours at 100C.
According to 1H-NNR, the cooled melt contained 7.80% by weight of pyrazole-l-carboxamid0 (8.3 ppm, lH; 7.9 ppm, 252H; 7.8 ppm, lH and 6.5 ppm~ lH~. This corxespond~ to a yield of 47% of theory7 ba~ed on urea.
EXAMPLE S
~ 51.3 g (0.5 mol) of 4-chloropyrazole were melted, -~ and the melt wa~ kept at 120C. 6.06 g (0.1 mol) of urea 30were dissolved therein. A nitrogen stream of ~0 l/h was passed through the reaction mixture at the tated temp-erature for 22 hours. The melt was cooled and was dissolved in 175 ml of methyl tert_butyl etherO The in~oluble residue was filtered off and wa hed with 70 ml 35of water. 6.2 g of 1-carbamoyl-4-chloropyrazole of melting point 191C remained (yield: 43~ of theory, based on urea~.
Claims (5)
1. A proces for the preparation of 1-carbamoyl-pyrazole I
I
or a derivative thereof by reacting pyrazole II
II
or a derivative thereof, wherein II or the derivative thereof is reacted with urea at above 30°C.
I
or a derivative thereof by reacting pyrazole II
II
or a derivative thereof, wherein II or the derivative thereof is reacted with urea at above 30°C.
2. A process for the preparation of 1-carbamoyl-pyrazole I or a derivative thereof as claimed in claim 1, wherein the reaction is carried out at from 30 to 250°C.
3. A process for the preparation of 1-carbamoyl-pyrazole I or a derivative thereof as claimed in claim 1, wherein the ammonia formed in the reaction is removed continuously from the reaction mixture.
4. A process for the preparation of 1-carbamoyl-pyrazole I or a derivative thereof as claimed in claim 1, wherein the ammonia formed in the reaction is removed from the reaction mixkure during the reaction.
5. A process for the preparation of 1-carbamoyl-pyrazole I or a derivative thereof as claimed in claim 1, wherein the reaction is carried out under reduced pressure.
5. A process for the preparation of 1-carbamoyl-pyrazole I or a derivative thereof as claimed in claim 1, wherein from 0.01 to 1 mole equivalent of urea, based on the pyrazole, is used.
7. A process for the preparation of 1-carbamoyl-3-methylpyrazole I as claimed in claim 1, wherein 3-methyl-pyrazole is reacted with urea.
8. A process for the preparation of 1-carbamoyl-3-methylpyrazole as claimed in claim 7, wherein the ammonia - 8 - O.Z. 0050/42353 formed in the reaction is removed continuously from the reaction mixture.
5. A process for the preparation of 1-carbamoyl-pyrazole I or a derivative thereof as claimed in claim 1, wherein from 0.01 to 1 mole equivalent of urea, based on the pyrazole, is used.
7. A process for the preparation of 1-carbamoyl-3-methylpyrazole I as claimed in claim 1, wherein 3-methyl-pyrazole is reacted with urea.
8. A process for the preparation of 1-carbamoyl-3-methylpyrazole as claimed in claim 7, wherein the ammonia - 8 - O.Z. 0050/42353 formed in the reaction is removed continuously from the reaction mixture.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4111922A DE4111922A1 (en) | 1991-04-12 | 1991-04-12 | METHOD FOR PRODUCING 1-CARBAMOYL PYRAZOLE |
| DEP4111922.3 | 1991-04-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2065829A1 true CA2065829A1 (en) | 1992-10-13 |
Family
ID=6429421
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002065829A Abandoned CA2065829A1 (en) | 1991-04-12 | 1992-04-10 | Preparation of 1-carbamoylpyrazoles |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0508191B1 (en) |
| JP (1) | JPH0570437A (en) |
| KR (1) | KR100201665B1 (en) |
| AT (1) | ATE138654T1 (en) |
| CA (1) | CA2065829A1 (en) |
| DE (2) | DE4111922A1 (en) |
| DK (1) | DK0508191T3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10676408B2 (en) * | 2014-12-18 | 2020-06-09 | Basf Se | Alkynylpyrazoles as nitrification inhibitors |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5183903A (en) * | 1991-11-26 | 1993-02-02 | A. H. Robins Company, Incorporated | Urea fusion process for the synthesis of 3-phenoxy-1-azetidinecarboxamides |
| KR19990000516A (en) * | 1997-06-05 | 1999-01-15 | 성재갑 | 1-diethylcarbamoylpyrazole derivatives and preparation method thereof |
| IN190806B (en) * | 1998-11-16 | 2003-08-23 | Max India Ltd | |
| DE10164103C1 (en) * | 2001-12-24 | 2003-01-30 | Compo Gmbh & Co Kg | Production of nitrification inhibitor containing mineral fertilizer comprises applying dilute solution or suspension of pyrazole derivative to heated fertilizer in powder, prill, compacted or granulate form |
| DE10343277A1 (en) | 2003-09-18 | 2005-04-21 | Piesteritz Stickstoff | N- (1H-Azolyl-methyl) amides, process for their preparation and their use as nitrification inhibitors |
| DE102006015705B4 (en) | 2006-04-04 | 2018-07-19 | Skw Stickstoffwerke Piesteritz Gmbh | 1,2-bis (azol-1-yl) ethane-1,2-diol derivatives, processes for their preparation and their use as nitrification inhibitors |
| DE102008020785B4 (en) | 2008-04-25 | 2021-11-04 | Skw Stickstoffwerke Piesteritz Gmbh | Use of simple derivatives of 5-amino-1,2,4-thiadiazole to inhibit or control nitrification |
| DE102011120098B4 (en) | 2011-12-02 | 2021-02-11 | Skw Stickstoffwerke Piesteritz Gmbh | N- (1H-pyrazolyl-methyl) formamides, process for their preparation and their use as nitrification inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3625948A (en) * | 1968-06-21 | 1971-12-07 | Geigy Chem Corp | Process for the preparation of hexahydromethanobenzazocines |
| DE2745833C2 (en) * | 1977-10-12 | 1986-10-16 | VEB Fahlberg-List Chemische und pharmazeutische Fabriken, DDR 3013 Magdeburg | Agent for inhibiting or regulating the nitrification of ammonium nitrogen in cultivated soils |
| DD249409A1 (en) * | 1981-06-01 | 1987-09-09 | Heiner Hoffmann | PROCESS FOR PREPARING 1-CARBAMOYL-3-METHYLPYRAZOLE (CMP) |
| DD259860A1 (en) * | 1981-07-23 | 1988-09-07 | Haase Hans Joachim | METHOD FOR THE CONTINUOUS PREPARATION OF 1-CARBAMOYL-3 (5) -METHYLPYRAZOLE |
| DD210541A3 (en) * | 1981-11-20 | 1984-06-13 | Fahlberg List Veb | METHOD FOR THE PRODUCTION OF SUBSTITUTED UREASES BZW. carbamoyl |
| DD265144A1 (en) * | 1987-09-08 | 1989-02-22 | Piesteritz Agrochemie | PROCESS FOR PREPARING 1-CARBAMOYL-3-METHYLPYRAZOLE |
-
1991
- 1991-04-12 DE DE4111922A patent/DE4111922A1/en not_active Withdrawn
-
1992
- 1992-03-21 EP EP92104938A patent/EP0508191B1/en not_active Expired - Lifetime
- 1992-03-21 DE DE59206398T patent/DE59206398D1/en not_active Expired - Lifetime
- 1992-03-21 DK DK92104938.3T patent/DK0508191T3/en active
- 1992-03-21 AT AT92104938T patent/ATE138654T1/en not_active IP Right Cessation
- 1992-03-30 JP JP4071925A patent/JPH0570437A/en not_active Withdrawn
- 1992-04-06 KR KR1019920005682A patent/KR100201665B1/en not_active Expired - Fee Related
- 1992-04-10 CA CA002065829A patent/CA2065829A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10676408B2 (en) * | 2014-12-18 | 2020-06-09 | Basf Se | Alkynylpyrazoles as nitrification inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| DK0508191T3 (en) | 1996-07-01 |
| EP0508191A1 (en) | 1992-10-14 |
| DE4111922A1 (en) | 1992-10-15 |
| JPH0570437A (en) | 1993-03-23 |
| EP0508191B1 (en) | 1996-05-29 |
| DE59206398D1 (en) | 1996-07-04 |
| KR920019757A (en) | 1992-11-19 |
| KR100201665B1 (en) | 1999-06-15 |
| ATE138654T1 (en) | 1996-06-15 |
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