CA2113956A1 - Application and method for the production of n-cyclic and n,n'-dicyclic ureas - Google Patents
Application and method for the production of n-cyclic and n,n'-dicyclic ureasInfo
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- CA2113956A1 CA2113956A1 CA002113956A CA2113956A CA2113956A1 CA 2113956 A1 CA2113956 A1 CA 2113956A1 CA 002113956 A CA002113956 A CA 002113956A CA 2113956 A CA2113956 A CA 2113956A CA 2113956 A1 CA2113956 A1 CA 2113956A1
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- urea
- atom
- general formula
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
Abstract
Abstract An application of ureas in which at least one of the urea's two nitrogen atoms is part of a non-aromatic ring which can be broken by an oxygen or sulphur atom as a chemical solvent, and a method of producing tri-or tetraalkylated ureas or bis ureas wherein at least one of the urea's nitrogen atoms is part of a non-aromatic ring which can be broken by an oxygen or sulphur atom by means of dialkylating the -NH2 group of a urea with an alkene or alkene arylene alkene dihalogenide, disulphonate or dihydrogen sulphonate in the presence of a solid base and a phase-transfer catalyst.
Description
3 ~ ~ ~
. .
An Application and Method for the Production of N-cyclic and N,N'-dicyclic Ureas In general, chemical reactions are carried out in a solvent and diluting agent, as the direct combination of reaction partners does no~ normally allow for control ov~r the reactions and many reactions take their course only when the reaction partners are dissolved. The requirements of a solven$ to he used for che~ical reactions are high thermal stability, good di~tillability, colorlessnes~, nonpoisonousness, inert-ness with regard to the reacta~ts, mi~abili~y with other solve~ts, and above all, the ability to easily di~solve both polar or hydrophile and non-polar or hydrophobic compounds. Hardly any golven~s exi~t, however, which fulfill all these requiremen~s.
It is known from E. ~uller, Houben-Weyl, 4th Edition, Volume E4~ page 335 that tetraalkylated ureas such as tetramethyl urea a~d tetraethyl urea or N,N' bridged ureas ~uch as 1,3-dimethyl-2-ogo-imidazolidine, 1,3-dimethyl-2-imidazolidinQne or 1,3-dime~h~1-2-ogo-hexahydxopyrimidine are u~ed as apro~ic solvent~ for t~ch~ic.al purpo~es ~ecau~e of their favorable quali~ies.
It wa~ ~o~nd u~e2pectedly tha~ ureas with different che~ical ~t~ucture~, n~mely te~raalkylated N-~yclic or N,~'-dicyclic urea~, a~d e~pecially N-sub~titu~ed 1-p~rrolidi~e, 1-piperid ~ e or 9-mor~oline carboxyli~
acid amide deri~ativ0s are ge~erally i~ a li~uid ~tate, have high thermal stabili~y a~d good di~tillabilit~
are ~o~poiso~ous a~d ~ompl~tely i~ert ~ith regard ~o.
funstional ~rOUp8, and repre~ent all-purpo~e a~d e~cellent ~olvent~ for various reac$ions a~d applicatioAs, bo~h with polar or hydrophile and ~o~-polar or hydrophobic compounds. It was shown unexpectedly that, de~pite th2ir high hydrophobic proportion, ~uch urea~ can also be mi~ed with water in .
~ 2 ~ ~ 13~3~
addition to other organic solvents. Furthermore, these ureas ~ossess an excellent ability to dissolve strongly polar or ionic compounds, e.g. salts. Since organic solvents are usually not able to dissolve strongl~ -polar or ionic compounds, this surprising effect can be used, for example, for reactions with salts in a non-aque~u-s medium.
Therefore, the object of the in~ention is the application of a urea of the General Formula Rl~, j~ ~ (CH2 3n ~
N - C N Y
P~2 ~ \ (CH2 )n in which Rt and R2 ~ndepende~tly of one another denote a straight-chain, branch~d or ~yclic alkyl ~
h~mg 1 to 2~ C atons, ~hich is un~ubstituted or sub~titut0d by flu~d~ ~tows nitr~ alke~yl- or alkyl~bn ~n~ h~ng 2 to 6 C ~tom~ yl ~ Which a~e unsubst~but~d cr ~ibut~d ~y flu~fin~ a~oms, nitnD ~ , alkyl gn~ h~ng 1 to 5 ~tom~, ~ g~ ng I to 5 C ~tsm~ ~r ~ xy ~n~5 b~nzy~ ~r phenyJ~l yn~ whi~h ~e u~b~itute~ or ~t~u~d ~y fl~ne , nitD~ lkyl ~x~ h~g 1 ~o 5 C atom~ y -$~x~3 b~ o 5 C ~ or ~h~x~y gn~, alkD~y g~s h~n~
1 to 5 C ~ t p~ gn~ ~h~d~ ~re un~u~st~tu~ea or ~titut~d n~ ~w~ ræ 5~ lkyl gn~ h~g 1 to 5 ~ ~tom3, : :
~ 9~ o 5 C ~t~ms or ph~xw~ sn~; Qr, tcg~ r with the ~i~roge~ ato~, a five or ~ embQr ~o~-aro~atic ri~ which can be broken by ~ o~ygen or ~ulphur ato~; ~ represent~ a methyle~e group, an o~en or sulphur acor~ a~d ~ repreE;en~c ind~pe~de~tly of o~e ~ i anokher th~ ~ber~ 1 ~o 3, whereby n plu~ m represe~t th~ nu~ber~ 3 or ~, a~ a chemical ~olve~t.
Alkyl group are to be under~tood as those alkyl groups with 1 to 22, preferably with 1 to l t) C atoms, more pre~erably with 1 to 8-, a~d mo~t prefexably with 1 to 6 _~ 3 ~ 1 A 3 ~ ~ ~
C aton~, e.g. ethyl, p~opyl, isopropylO tert ~ butyl, isoFentyl, meth~ cI~p~ntyl, ~yclohexy~, 2-e~hylhe~y~, oetyl, decyl, d~decyl, hexadecyl, or octad~cyl grou~s. The alkyl grcups can be unsubstituted or s~bstituted by fluorine atoms, nitro groups, alkenyl- or alkyliden gsoups havin~ 2 to 6 C atoms phenyl ~ s which are unsubstituted or ~ubstitu~ed by fluorine atoms, nitr~.gr~ups, alXyl group6 having 1 to 5 C atoms, alkoxy groups havLng 1 to 5 C atcms or pheno~y ~, prefe~ ~ ubstituted phenyl groups; or alko~y gn~
with 1 to 5 C atoos, e.g. methoxy, ethoxy, isopr~p~y, buSoxy or pheno~y ~p6. Alkyl gn~ are p~eferable when ~nsubstitutd.
Benzyl or phenylethyl ~ can be unsubstituted or substituted by alkyl groups with 1 to S C atoms, e.g.
ethyl, isopropyl, isopentyl, alkoxy groups with 1 to 5 C atoms, e.g. methoxy, e~hoxy. isopropoxy, or butoxy ~o~, fluDrine atoms or ~itr~ g~. Prefen~d are un~ti~ut~d benzyl or p~yle~hyl ~x~p~.
R1 and Rz can also form togethar with the nitrogen atom a five or six-mem~er non-aromatic ring which can be broken by an oxygen or sulphur atom, i.e. an o~a~olidine, pyrrolidine, piperidine, morpholine, thiomorpholine or thiazolidi~e ring, for ~ample.
Preferably, R1 and R2 represent independently of one another an unsubs~ituted straight-chain or branched -alky:L group with 1 ~c: 10 C atoms, or Ra and Rz reprc~ent together wi~h the ni'crogen atom a no~
aro~atic ring which ~ian be broken by a~ o~ygen or ~ulphur atom, preferably a pyrrolidine, piperidine or morpholine ring.
Y repre~snt~ a methyle~e group, an o~y~en or ~ulphur atom, preferably a methylene group or an oxygen atom, and m a~d .n repre~ent . ndependently o one a~other the nuu~ber~ 1 to 3~ preferably 1 to 2, whereby the sum of m plus n represents the n ~ bsrs 3 or 4.
.
~ethods for the productio~ of ureas ar~ disclosedO for example, in U. Petersen in E. Mullner, Houben-Weyl, 4th ~ ~ 3 ~ ~ ~
.~ ..
Edition, Volume E4, pages 336 ~f. us 4 ~35 312 contains a de~cription of the fact that amide compounds, among which ureas are also understood, can be alkylated in an aprotic, polar diluting agent at the nitrogen atom or at both nitrogen atoms by means of simultaneous contact and conversion of a strongly basic su~stance. with ~he amide compound and a halogen-substituted compound when the reaction is started as long as the basic substance is in a suspended state.
However, this method is suitable only for the production of symmetrical, if necessary sub~tituted, methyl ureas based on urea, and not for the production of N-cycli~ or N,N'-dicyclic ureas.
In ~P-BJ~8425 (Chemic~lAbstr~cts Voiume 112,1~8399),examplas 7 and 8 is indic~ted, that t,1~rbonyi bispyrrolidine r~spectively 1,1-carbonyl bispipendins mi~ht ~ pr6duced by reaction of u~ea with 1,4 dibrombutane r~speotiv03y wi~h 1,5-dibrampent~n~ in ~he presenoe of KOH in N,N~irnothylform~mide respectiv~ly in 1,3-dime~hy3imidazolidinor~ as solY0nt. Howeve- it was proved, th~t in ~ct absolutely no N,N'~ioyclic ure~ ori~in~ from the reaction acoordina to ~he method of examples 7 or 8 olF JP-B~8425.
Une~pectedly, it wa~ found that the free amino group present in a urea in which one of th0 two amino groups is alkylated can be dialkylated with a difunctional alke~e ~roup, whereby an N-cyclic urea is formed without N,N' bridge~ ~ppeari~g when a phase-tra~sfer catalyst is employed. The new metho~ is ~ot o~ly suitable for the produ~ion of tetraalkylated N-cyclic or N,N~-dic~clic urea~ of Formula I, but also for the production of trialkylated ~-cyclïc urea dexivatives or ~-cyclic bi~ U~#~.
~e obiec~ o~ the inven~ion i~ tXerefore al~o a method for the production of ure~ of the Ge~eral ~ormula R~ CH~
~ N - C - N ~ ~ II
R2 ' (~H2 )n in which Y, m and n have the meanings described in Claim l, and R~' a~d R2' have the meanings of Rl and R2 7 ~
described in Claim 1, and R1' additionally represents hydrogen, or Rl' represents hydrogen and R2 I represents a group o~ the FormuIa R3~
~ N - C - NH - Rs III
in ~hich R3 and ~ have the meani~gs of R1 and R2 described in Claim 1, whereby R3 and R4 additionally represent hydrogen, and Rs represents an alkene ~p w~th 2 to 20 C ~tcms ~r ~n alkene pbenylene ~lkene ~, ~he a~ne ~roups haYin~ ;ndependently of ~ne ~nother î to 3 C ~ms comprisin~
react;n~ ~ ure~ or a bis urea of ~he GenQral Fotmula R1' ~
~N - C - NH2 IV
R2~
in which Rl' and R2' have the meanin~s described above, ~ ~-in the presence of a solid base and pha~e-tra~sfer catalyst in a diluting agent which i5 ~
inert under rea~îon condition~ at ~e~pera~ure~ ffl 0 to ~ :
lS~ C with a compound of the General Formula `~
~: `
~ - R6 - X V
in w~ich R6 repxesents a ~traig~t chain ~lken~ group -~
with 4 or S C atoms in which the atom in the 2 or 3 po~i~io~ ca~ be replaced by a~ o~ygen or sulphur atom ~ -a~d ~ repre~ents a haloge~, sulpho~ic a~id, or h~drogen :
~ulphate group, whereby the -NH2 ~roup of the urea of :~
the Gen~ral Formula IV is dialkylated through elimi~atio~ o~ bo~h hydrogen atoms by the ~ompou~d of the Gen3ral Formula V through t~e elimination of the -~
leaving.~ by r~n~ c~ e.
I~ the co~pound o~ the General Formula II, Rq~ a~d R2 have the mea~ings de~cribed above for R1 and R2, whexeby R1' additionally represents hydrogen or, in the ~:
event that the compou~d of Formula II is a bis u~
Rl ' represen~ a hydro~gen atom and R2' represents a group of the Qeneral Formula III.
f~ 6 ~335~
In the compound of the General Formula III, R3 and R4 have the meaning of Rl and R2 described in Claim 1, whereby R3 and ~4 additionally represent hydrogen and Rs represents an alkene group with 2 to 20 C atoms, preferably with 2 to 8, for example ethylene, hexylene, dodecyl groups or an alkene Fhenylen~ alkene group in which the expression alkene preferably represents low alkene groups with 1 to 3 C atoms, for ex~np~e xylylene groups.
Ureas or bis ureas of the General Formula IV, in which R1' and ~2 ' have the meanings described above, can ~e produced according to the normal, known method, e.g. ~y converting urea or isocyuranic acid with a suitable amine.
Soli.-7 bases such as alkali hydroxides, e.g. potassium hydroxide, sodium hydroxide or alkali amides, e.g.
sodi~lm amide or potassium amide, are suitable.
Preferably, alkali hydroxides are employed, whereby the alkali hydroxide can contain a low concen~ration of a carbonate such as potassium carbonate or sodium carbonat~ amounting to 2 to 20 mole ~ in relation to the alkali hydroxide. The ~ase is used in solid, powdered form or in the foxm of pellets in excess in relation to tiile urea of Formula IV which is employed.
Preferably, 1.5 to 10 mole are employed p~r mole of the urea of Formula IV; more preferably, 3 to 5 mole of the solid base are employed.
:, Common phase-transfer catalysts are suitable as a catalyst. An abstract of suitable phase-transfer catalysts and their possible employment is disclosed in W. E. Keller: Phasetr~nsfer reactions (Fluka Compendium, Vol. 1, 2 and 3; Georg Thieme Verlag, Stuttgart - New York, 1986, 1987 and ~992). Prefer~bly, quaternary ammonium salts such as tetrabutyl ammonium hydrogen sulphate, tetrabutyl ammonium chloride or b~nzyl triethyl ammonium chloride are employed as phase-transfQr catalysts.
In the ~ompound of the ~neral Formula V, R6 represents a straight-chain alkene group with 4 or 5 C atoms in which one of the C atoms in the 2 or 3 position can be replaced by an oxygen or sulphur atom, preferably an oxygen atom.
X represents a halogen atom (especially chlorine, bromide or iodine should be understood by halogen), a sulphoni~ acid gr~up or a hydrogen sulphate group, preferably a halogen atom.
T~e compounds of Formu~a V are generally employed equimolar to the urea of Formula IV in so far as the urea of Formula IV is not a bis urea or in so far as the ur~a of Formula IV is a bi~ ~ in which only one of the two -NH2 groups are to be dialkylated.
If both -NH2 groups in a bis uI~a of Formula IV in which R3 and R4 represent hydrogen ar~ to be di-alkylated, generally two equivalents of a compound of Formula V are employed per equivalent of bis ~. In certain cases, however, an excess of one or the other reaction partners can be useful. It was determined that, in certain cases, the yield can be increased when 0.5 to 3 equivalents of the com-pound o Formula V are employed per -NH2 group in the urea of Formula IV.
Diluting agents which are inert under the rsaction conditions and which are solvents for the urea of Formula IV andfor the compound of Formula V are used as diluting ~gents. These are aromatic hydrocarbons, e.~
benzole, toluene, xylenes, higher aliphatic hydrocarbons, e.g. paraffins, aromatic halogenated hydrocarbons, e.g. chlorobanzene, trichlorobenzene, ethsr, e.g. tetrahydro~uran or dimethyl ~ulfo~ide, or mixture~ of such dilu~i~g agents. Preferably, aromatic hydrocarbons are employed; toluene is employed more preferably.
For the e~ecution of the method according to the inv~ntion, the urea of Formula IV i~ dis~olved in a diluting agent which can be predried before being employed. The soiid base is added in the form of pellets or in powdered form and well suspended by stirring vigorously, after which the catalyst is ~ ~ 8 2~39`~
.
introduced. The compound of Formula V can be added to this mixture, which is stirrsd vigorously and heated if necessary, before heating, or it can be added to the already heated mixture.
The reaction mixture is heated if necessary to a temperature of up to approximately 150 ~C, preferably to 70 to 150 C, more preferably to the reflux temperature of the diluting agent employed. When this is done, the -NH2 group of the urea of Formula IV is dialkylated by the compound of Formula V through elimination of both X lea~ing groups and both hydrogen ato~s of the -NH2 group, and the urea of the General Formula II is produced. Unexpectedly, hardly any N,N' bridges or bonds of 2 moles of the urea of t~e &eneral Formula IV result.
' ~
After the conversion has been completed, the reactio~
mixture is either allowed ~o chill and filtered and the liquid residue is distilled or chromatographed, or water is added to the reaction mixture and the urea of Formula II is ex~racted from the reaction ~i~ture with the aid of an e~tracting age~t. Water nmiscible oxganic e~tracting agents such as hydrocarbons, e.g.
he~ane, heptane, halogenated hydrocarbon~, e.g.
methylene chloride, chloroform or ether, e.g. diethyl ethex, diisoprop~l ether, carboxylic acid ether, e.g.
ethyl acetat3, butyl acetate are emplo~ed. The orga~ic pha~e is wa~hed with water and dried and the diluting agent i~ evaporated, whereby the mixture can be aftexdried ~n ~ac~
In general, the purity of the urea of Formula II
produced in this way is sufficient. If neces~ary, i~
may be purified afterwards, e.g. by mean~ o~
chromatography or distillation.
~' 9 21 ~ 3~5~
In a prefexred embodiment, a urea of the Formula IV in which R1' and R2' represent ind~pendently of one another an alkyl group with 1 to 10 C atoms and R1' additionally represents hydrogen~ or Rl' and R2' represent a pyrrolidine, piperidine or morpholine ring together with the nitrogen atom, is dissolved in toluene, and 3 to 5 equivalents of potassium or sodium hydroxide pellets containing 4 to 10 mole % of potassium or sodium carbonate, and 0.04 to 0.06 equivalents of a quaternary ammonium salt as a phase-tran~fer catalyst, are added while stirring vigorously, distilled to reflux, to which 1,~-buta~e dihalide or 1,5-pentane dihalide i~ ~hich one ~f the C atoms can be replaced by an oxygen atom in the 2 ox 3 position is added. Aftsr the reaction is co~plete, water is added to the reaction mi~ture which is the~ e~tracted several times with methylene chloride and/or ~hloroform. The combined organic pha~es are wa~hed with water and dried, the diluting agent is evaporated, and afterdryi~g is performed in vacuo.
A good yield of high purity N-cyclic or ~,N'-dicyclic ureas i~ produced f~om ~on-poi~onous raw makerials according to the de~cribed method.
~a~Ple l 3.~6 g of N piperidi~e carbo~yll~ acid a~id (0.02 ~ole) wa~ dis~ol~d in 40 ~1 of- ~oluene~ m~ed with 4.~8 g of K~H ~0.08 mole3, 0.28 g of tetrabutyl a~mo~ium .chloride ~ ole) and 2.16 ~ of 1,~-dibromobutane (0.01 1~lole) at room tem~erature and di~illed to re~lu~ while being ~tirred ~igorou81y. The ~Ourse of the reaction w~s observed with the aid of ~H-NMR. Af~2r 2 hours, the reactio~ wa~ complete, and the reacSion mixture ~a~ poured into water. The a~yeous mi~ture was then e~tracted several times with methylene chloride, and the organic phase was dried and , `~.` 10 2~ 3~
evaporated. When this was done, 1.73 g, i.e. 95 ~ of the theory, of. 1-piperidino-1-pyrrolidine carbonyl, relative to the 1,4-dibromobutane employed, was obtained.
1H-NMR (300MHz, CDC13, delta): 3.35 ppm (t, py-1,4;
J=5.6 Hz); 3.18 ppm (t, pip~l,S; J=6.7 Hz); 1.~1 ppm (m; py-2,3); 1.57 ppm (m; pip~2,3,4~
l3C~NMR (70 MHz, CDCl3, delta): 163.53 ppm (C=V3; 48.38 ppm ~py~1,4); 47.45 ppm (pip~l,S); 25.90 ppm (pip~2,4);
25.57 ppm (py~2,3); 24057 ppm (pip-3~
, ~am~l~s 2 The following examples 2 ~ 11 were performed in the manner de3~nbed in E~ample 1 and using the same amount of KOH and catalyst per mole of urea of the Formula IY; however, different ureas of Formula IV and different compounds of Formula V in different molar ratios w~re used. The result~ are ab~tracted in Table 1. The reaction time amounted to appn~n~ly 2 hours each.
able_1 ~o. IV-R~ ' IY-R2 ' Y~
2 C2~ - C~5 - - (CH2 )4- Br 2:1 65 3 C2Ns C2Hs-- --(CH2 )~--Br 1 1 53 4 - ( CH2 ) ~ - - S CH2 ~ r 2 ~L 71 -(CH2 ~4- --(CH2 )s- Br 2:1 50 6 -(C~2 )5- -~CH2 )4- Cl 2:1 73 7 -(CH2 ~s- --(CE~2 )5- Br 2:1 61 8 - ( C~ O- ( C~2 ) 2 - - ( CE3:2 ~ 4 - Br 1: q 76 9 -~CH2 )2-O-(CH2 ~2- -(CH2 3~- 13r 2:1 30 10 -(C~2 12-O--~CH2 )2- -~CEI~ )5- Br 2:1 65 11 H C4Hg- -(CH2 )~- Br 2:1 67 CharaC~eriS~iC dat~:
Examp 1eS 2 and 3 1H_NMR (300MHZ, CDC13, de1ta): 3.257 PPm (t, PY-~
JCN2CH2=6.6 HZ); 3.126 PPm (q; ethyl - 1; JC~2CH3=5.3 ~ :~
HZ); 1.742 PPm (m; PY-2,3~; 1.048 ppm (t, ethyl-2; :
JCN2CH3=6.6 HZ) 13C_NMR (70 MHZ~ CDC13, delta): 163.01 PPm (C=0); 48.68 ppm (py-1,4); 42.00 ppm (ethyl-1); 25.87 ppm (ethyl-2);
13.78 ppm (py-2,3) . ~
E:acam~le 4 `
lH-NMR (300MHz, CDCl3, delta): 3.36 ppm ~t; N-CHz;
J=5. 5 Hz ); 1.83 ppm (m, CH2_~H2) l3C-NMR (70 MHz, CDCl3, delta): 161.0 ppm ~C-0); 47.7 PPm ~N-CH2); 25.1 PPm (CH2-CH2) l :~cam~leæ 5 al~d 6 Characteristic data same as described in Example 1.
~aca~Ple 7 l~I_2~R (300M~z, CDCl3, delta~: 3.16 ppm (t; pip-1,5;
3=5.7); 1.57 ppm (m; pip-2,3,4) ~:~
13C-NMR (70 MHz, C!DCl3, delta): 164.75 ppm (C=O); 48.13 P2m (pip-1,5~; 25.71 ppm (pip-2,4); 24~99 ppm (pip-3) Ple~ 8_a~d 9 1H-N~R (300MHz, CDCl3, delta): 3.67 ppm (t; mor-0-C~2;
ar=~.7 Hz); 3.37 ppm (~; pyr~ CE~2; J-6.7 ~z~; 3.26 ppm ~t; mor-N-CH2; J=4.7 Hz) 1.84 ppm (m; pyr-N-CH2-CH2 ) 13C-I~MR (70 MHz, CDCl3, delta~: 162.58 ppm (C=0); 66.71 ppm (mor~O-CH2 ); 48.25 ppm ~pyr-N-CH2 ); 46.7B ppm (mor-N-CH2 ); 25.51 ppm; (pyr-2,3) E~ample 10 lH-NMR (300MHz, CDCl3, delta): 3.66 ppm (t; m~r-0-CH2;
J=4~8 Hz); 3.22 ppm (m; pip-1,5 and mor-N-CH2) 1.57 ppm (m; pip-2,3,4) 13C-NMR (70 MHz, CDCl3, delta): 164.56 ppm (C=0); 67.00 ppm (mor-0-CH2); 48.33 ppm (pip-N-CH2); 47.86 ppm (mor-N-CH2); 26.10 ppm; (pip-2,4); 24. 57 ppm (pip-3) E~am~le 11 lH-NMR ~200MHz, CDCl3, delta): 4.390 ppm ~t; NH; ~=5.8 Hz ); 3 . 340 ppm ~ t; N-CH2; J12 =6 . 7 Hz ~; 3 . 222 ppm ( dt;
HN-CH2; JCH2NH=508 HZ; JCH2C~2=7.0 Hz) 1.893 ppm (tt;
pyr-2,3; J~2-6.7 HZ; J23=3.5 HZ); 1.536-1.288 ppm (m;
but-2 ,3 ) ; 0 . 921 ppm (t; but-CH3; JCH2CH3 =7 . 1 Hz ) 3C-NMR (50 MHz, CDCl3, delta): 156.016 ppm (C=0~;
45.41 ppm (pyr-1,4); 40.28 ppm (but-1~; 32.61 ppm (but-2); 25.52 ppm IPyr-2,3); 20.03 ppm (but-3); 13.78 ppm;
(~ut-4) ~ha~ple 12 22.8 g o~ pyrrolidine carboxylic acid amide (0.2 mole3 was di~solved in 400 ml of toluene, mi~ed with 56 g of KOH l0.8 mole), 2.78 g of tQtrabutyl ammonium ~hloride (1 mmole) a~d 21.6 g of 1,4-dibromobutane ~O.1 mole) at room temperature a~d distilled to r~flu~ while being stirred vigorou~ly. The reaction wa~ observed with the aid o~ lH~NMR. After the reaction was complete, the diluting agent was eYaporated and the re~idue wa~
di~tille~ .in a vacuum. When thi~ was done, 8.27 g of 1,1-carbonyl bi~pyrrolidine, i.e. S4 ~ of the theory and relative to th~ 1,4-dibromobutane employed, was obtained.
Characteristic data same as described in E2ample 4.
~,.,. ;. . - ~ - - .
~ 3 9 ~xamPl~s 13 - 16 Examples 13 - 16 were conducted in the manner described in Example 12 with the same amounts of KOH and catalys~; however, eight times the molar amount of KOH
relative ~o the applied compound of ~ormula V was employed in Example 13, and in Example 14, the compound of Formula V was added by drops in the reflu~ng mixture of urea of Formula I, toluene, base and catalyst. The reaction times amounted to ap~
proximately 2 hours each with the ex~eption of Example lS. The reaction tiMe of E~ample lS amounted to 0.15 hours. The results are abstracted in Table 2.
l~o. IV-Rl '-R2 'V-R6 V-~ IV-V A~
13 -(CH2)~ H2~4- Br 1:1 65 14 -(CH2)4--(CH2)4- Br 1:1 59 -(CH2 )4--tCH2 )4- Br 1:1 67 16 -(CH2)4--(CH2 )4- Br 1:3 72 Characteristic data same as described in E~ample 4.
I~ tables 1 and 2, the followin~ symbols represent:
No.: Number of the example and the c~mpound IV-R1': R1' in For~ul~ IV
IV-R2': R~' in Formula IV
V-Rs: R6 i~ Formuia V
V-X: X i~ Formula V
IY:V: ~olar ratio of the compou~d~ i~ formulas IY and V
A~: Yield in mole per cent relative to the applied compo~nd o~ ~,ormula Y. The yield i~ relati~e to ~he applied compound of Formula IV in ~ample 16 only.
3 ~
Com~arative Examples ExamDle 7 of JP-B-4-8425 13 g of urea in 15û rnl of N,N-dimethylformamide were stirred ~ogether with 96 g of 1,4-dibrombutane and 50 9 of potassium hydroxide at a temperature of 20C over a~erieod o~ 4 hou~; After that the non-soluble pa~ts ware removed by filtration and the filtrate was distilled. Four fraction~ batween 23 and 80C (0.4 mrn Hg) were raceived which were anaiyzed ~sing 1H-NMR spectroscopy. Thersby only 1,4~ibrombutane and N,N-dimethylformamide but absolutely no 1,1-carbonyl bispyrrolidin were found.
ExamDlQ 8 o~ JP-8-4-8425 13 9 of urea in 150 ml of 1,3-dimethyl-2-imidazolidinone were stirred together with 150 ~ of 1 ,5-dibrompentane ~nd ~0 ~ ~f potassium hydroxide ~t a ~e~nperature o~ 20C over a perieod of 4 hours. Aft0r that tlie non-soluble parts were removed by filtration and the filtr~te was distllled. Four fraetions be~ween 23 and 76C (0.35 mm Hg~ were teceived, which were analyzed using 1 H-NMR spectroscopy. Thereby only 1 ,5~ibrompentane and 1,3~imethyl-Z-imidazolidinona but ~bsolutely no 1,1~arbonyl bispiperidin were found.
:,f"'', . . ~
. .
An Application and Method for the Production of N-cyclic and N,N'-dicyclic Ureas In general, chemical reactions are carried out in a solvent and diluting agent, as the direct combination of reaction partners does no~ normally allow for control ov~r the reactions and many reactions take their course only when the reaction partners are dissolved. The requirements of a solven$ to he used for che~ical reactions are high thermal stability, good di~tillability, colorlessnes~, nonpoisonousness, inert-ness with regard to the reacta~ts, mi~abili~y with other solve~ts, and above all, the ability to easily di~solve both polar or hydrophile and non-polar or hydrophobic compounds. Hardly any golven~s exi~t, however, which fulfill all these requiremen~s.
It is known from E. ~uller, Houben-Weyl, 4th Edition, Volume E4~ page 335 that tetraalkylated ureas such as tetramethyl urea a~d tetraethyl urea or N,N' bridged ureas ~uch as 1,3-dimethyl-2-ogo-imidazolidine, 1,3-dimethyl-2-imidazolidinQne or 1,3-dime~h~1-2-ogo-hexahydxopyrimidine are u~ed as apro~ic solvent~ for t~ch~ic.al purpo~es ~ecau~e of their favorable quali~ies.
It wa~ ~o~nd u~e2pectedly tha~ ureas with different che~ical ~t~ucture~, n~mely te~raalkylated N-~yclic or N,~'-dicyclic urea~, a~d e~pecially N-sub~titu~ed 1-p~rrolidi~e, 1-piperid ~ e or 9-mor~oline carboxyli~
acid amide deri~ativ0s are ge~erally i~ a li~uid ~tate, have high thermal stabili~y a~d good di~tillabilit~
are ~o~poiso~ous a~d ~ompl~tely i~ert ~ith regard ~o.
funstional ~rOUp8, and repre~ent all-purpo~e a~d e~cellent ~olvent~ for various reac$ions a~d applicatioAs, bo~h with polar or hydrophile and ~o~-polar or hydrophobic compounds. It was shown unexpectedly that, de~pite th2ir high hydrophobic proportion, ~uch urea~ can also be mi~ed with water in .
~ 2 ~ ~ 13~3~
addition to other organic solvents. Furthermore, these ureas ~ossess an excellent ability to dissolve strongly polar or ionic compounds, e.g. salts. Since organic solvents are usually not able to dissolve strongl~ -polar or ionic compounds, this surprising effect can be used, for example, for reactions with salts in a non-aque~u-s medium.
Therefore, the object of the in~ention is the application of a urea of the General Formula Rl~, j~ ~ (CH2 3n ~
N - C N Y
P~2 ~ \ (CH2 )n in which Rt and R2 ~ndepende~tly of one another denote a straight-chain, branch~d or ~yclic alkyl ~
h~mg 1 to 2~ C atons, ~hich is un~ubstituted or sub~titut0d by flu~d~ ~tows nitr~ alke~yl- or alkyl~bn ~n~ h~ng 2 to 6 C ~tom~ yl ~ Which a~e unsubst~but~d cr ~ibut~d ~y flu~fin~ a~oms, nitnD ~ , alkyl gn~ h~ng 1 to 5 ~tom~, ~ g~ ng I to 5 C ~tsm~ ~r ~ xy ~n~5 b~nzy~ ~r phenyJ~l yn~ whi~h ~e u~b~itute~ or ~t~u~d ~y fl~ne , nitD~ lkyl ~x~ h~g 1 ~o 5 C atom~ y -$~x~3 b~ o 5 C ~ or ~h~x~y gn~, alkD~y g~s h~n~
1 to 5 C ~ t p~ gn~ ~h~d~ ~re un~u~st~tu~ea or ~titut~d n~ ~w~ ræ 5~ lkyl gn~ h~g 1 to 5 ~ ~tom3, : :
~ 9~ o 5 C ~t~ms or ph~xw~ sn~; Qr, tcg~ r with the ~i~roge~ ato~, a five or ~ embQr ~o~-aro~atic ri~ which can be broken by ~ o~ygen or ~ulphur ato~; ~ represent~ a methyle~e group, an o~en or sulphur acor~ a~d ~ repreE;en~c ind~pe~de~tly of o~e ~ i anokher th~ ~ber~ 1 ~o 3, whereby n plu~ m represe~t th~ nu~ber~ 3 or ~, a~ a chemical ~olve~t.
Alkyl group are to be under~tood as those alkyl groups with 1 to 22, preferably with 1 to l t) C atoms, more pre~erably with 1 to 8-, a~d mo~t prefexably with 1 to 6 _~ 3 ~ 1 A 3 ~ ~ ~
C aton~, e.g. ethyl, p~opyl, isopropylO tert ~ butyl, isoFentyl, meth~ cI~p~ntyl, ~yclohexy~, 2-e~hylhe~y~, oetyl, decyl, d~decyl, hexadecyl, or octad~cyl grou~s. The alkyl grcups can be unsubstituted or s~bstituted by fluorine atoms, nitro groups, alkenyl- or alkyliden gsoups havin~ 2 to 6 C atoms phenyl ~ s which are unsubstituted or ~ubstitu~ed by fluorine atoms, nitr~.gr~ups, alXyl group6 having 1 to 5 C atoms, alkoxy groups havLng 1 to 5 C atcms or pheno~y ~, prefe~ ~ ubstituted phenyl groups; or alko~y gn~
with 1 to 5 C atoos, e.g. methoxy, ethoxy, isopr~p~y, buSoxy or pheno~y ~p6. Alkyl gn~ are p~eferable when ~nsubstitutd.
Benzyl or phenylethyl ~ can be unsubstituted or substituted by alkyl groups with 1 to S C atoms, e.g.
ethyl, isopropyl, isopentyl, alkoxy groups with 1 to 5 C atoms, e.g. methoxy, e~hoxy. isopropoxy, or butoxy ~o~, fluDrine atoms or ~itr~ g~. Prefen~d are un~ti~ut~d benzyl or p~yle~hyl ~x~p~.
R1 and Rz can also form togethar with the nitrogen atom a five or six-mem~er non-aromatic ring which can be broken by an oxygen or sulphur atom, i.e. an o~a~olidine, pyrrolidine, piperidine, morpholine, thiomorpholine or thiazolidi~e ring, for ~ample.
Preferably, R1 and R2 represent independently of one another an unsubs~ituted straight-chain or branched -alky:L group with 1 ~c: 10 C atoms, or Ra and Rz reprc~ent together wi~h the ni'crogen atom a no~
aro~atic ring which ~ian be broken by a~ o~ygen or ~ulphur atom, preferably a pyrrolidine, piperidine or morpholine ring.
Y repre~snt~ a methyle~e group, an o~y~en or ~ulphur atom, preferably a methylene group or an oxygen atom, and m a~d .n repre~ent . ndependently o one a~other the nuu~ber~ 1 to 3~ preferably 1 to 2, whereby the sum of m plus n represents the n ~ bsrs 3 or 4.
.
~ethods for the productio~ of ureas ar~ disclosedO for example, in U. Petersen in E. Mullner, Houben-Weyl, 4th ~ ~ 3 ~ ~ ~
.~ ..
Edition, Volume E4, pages 336 ~f. us 4 ~35 312 contains a de~cription of the fact that amide compounds, among which ureas are also understood, can be alkylated in an aprotic, polar diluting agent at the nitrogen atom or at both nitrogen atoms by means of simultaneous contact and conversion of a strongly basic su~stance. with ~he amide compound and a halogen-substituted compound when the reaction is started as long as the basic substance is in a suspended state.
However, this method is suitable only for the production of symmetrical, if necessary sub~tituted, methyl ureas based on urea, and not for the production of N-cycli~ or N,N'-dicyclic ureas.
In ~P-BJ~8425 (Chemic~lAbstr~cts Voiume 112,1~8399),examplas 7 and 8 is indic~ted, that t,1~rbonyi bispyrrolidine r~spectively 1,1-carbonyl bispipendins mi~ht ~ pr6duced by reaction of u~ea with 1,4 dibrombutane r~speotiv03y wi~h 1,5-dibrampent~n~ in ~he presenoe of KOH in N,N~irnothylform~mide respectiv~ly in 1,3-dime~hy3imidazolidinor~ as solY0nt. Howeve- it was proved, th~t in ~ct absolutely no N,N'~ioyclic ure~ ori~in~ from the reaction acoordina to ~he method of examples 7 or 8 olF JP-B~8425.
Une~pectedly, it wa~ found that the free amino group present in a urea in which one of th0 two amino groups is alkylated can be dialkylated with a difunctional alke~e ~roup, whereby an N-cyclic urea is formed without N,N' bridge~ ~ppeari~g when a phase-tra~sfer catalyst is employed. The new metho~ is ~ot o~ly suitable for the produ~ion of tetraalkylated N-cyclic or N,N~-dic~clic urea~ of Formula I, but also for the production of trialkylated ~-cyclïc urea dexivatives or ~-cyclic bi~ U~#~.
~e obiec~ o~ the inven~ion i~ tXerefore al~o a method for the production of ure~ of the Ge~eral ~ormula R~ CH~
~ N - C - N ~ ~ II
R2 ' (~H2 )n in which Y, m and n have the meanings described in Claim l, and R~' a~d R2' have the meanings of Rl and R2 7 ~
described in Claim 1, and R1' additionally represents hydrogen, or Rl' represents hydrogen and R2 I represents a group o~ the FormuIa R3~
~ N - C - NH - Rs III
in ~hich R3 and ~ have the meani~gs of R1 and R2 described in Claim 1, whereby R3 and R4 additionally represent hydrogen, and Rs represents an alkene ~p w~th 2 to 20 C ~tcms ~r ~n alkene pbenylene ~lkene ~, ~he a~ne ~roups haYin~ ;ndependently of ~ne ~nother î to 3 C ~ms comprisin~
react;n~ ~ ure~ or a bis urea of ~he GenQral Fotmula R1' ~
~N - C - NH2 IV
R2~
in which Rl' and R2' have the meanin~s described above, ~ ~-in the presence of a solid base and pha~e-tra~sfer catalyst in a diluting agent which i5 ~
inert under rea~îon condition~ at ~e~pera~ure~ ffl 0 to ~ :
lS~ C with a compound of the General Formula `~
~: `
~ - R6 - X V
in w~ich R6 repxesents a ~traig~t chain ~lken~ group -~
with 4 or S C atoms in which the atom in the 2 or 3 po~i~io~ ca~ be replaced by a~ o~ygen or sulphur atom ~ -a~d ~ repre~ents a haloge~, sulpho~ic a~id, or h~drogen :
~ulphate group, whereby the -NH2 ~roup of the urea of :~
the Gen~ral Formula IV is dialkylated through elimi~atio~ o~ bo~h hydrogen atoms by the ~ompou~d of the Gen3ral Formula V through t~e elimination of the -~
leaving.~ by r~n~ c~ e.
I~ the co~pound o~ the General Formula II, Rq~ a~d R2 have the mea~ings de~cribed above for R1 and R2, whexeby R1' additionally represents hydrogen or, in the ~:
event that the compou~d of Formula II is a bis u~
Rl ' represen~ a hydro~gen atom and R2' represents a group of the Qeneral Formula III.
f~ 6 ~335~
In the compound of the General Formula III, R3 and R4 have the meaning of Rl and R2 described in Claim 1, whereby R3 and ~4 additionally represent hydrogen and Rs represents an alkene group with 2 to 20 C atoms, preferably with 2 to 8, for example ethylene, hexylene, dodecyl groups or an alkene Fhenylen~ alkene group in which the expression alkene preferably represents low alkene groups with 1 to 3 C atoms, for ex~np~e xylylene groups.
Ureas or bis ureas of the General Formula IV, in which R1' and ~2 ' have the meanings described above, can ~e produced according to the normal, known method, e.g. ~y converting urea or isocyuranic acid with a suitable amine.
Soli.-7 bases such as alkali hydroxides, e.g. potassium hydroxide, sodium hydroxide or alkali amides, e.g.
sodi~lm amide or potassium amide, are suitable.
Preferably, alkali hydroxides are employed, whereby the alkali hydroxide can contain a low concen~ration of a carbonate such as potassium carbonate or sodium carbonat~ amounting to 2 to 20 mole ~ in relation to the alkali hydroxide. The ~ase is used in solid, powdered form or in the foxm of pellets in excess in relation to tiile urea of Formula IV which is employed.
Preferably, 1.5 to 10 mole are employed p~r mole of the urea of Formula IV; more preferably, 3 to 5 mole of the solid base are employed.
:, Common phase-transfer catalysts are suitable as a catalyst. An abstract of suitable phase-transfer catalysts and their possible employment is disclosed in W. E. Keller: Phasetr~nsfer reactions (Fluka Compendium, Vol. 1, 2 and 3; Georg Thieme Verlag, Stuttgart - New York, 1986, 1987 and ~992). Prefer~bly, quaternary ammonium salts such as tetrabutyl ammonium hydrogen sulphate, tetrabutyl ammonium chloride or b~nzyl triethyl ammonium chloride are employed as phase-transfQr catalysts.
In the ~ompound of the ~neral Formula V, R6 represents a straight-chain alkene group with 4 or 5 C atoms in which one of the C atoms in the 2 or 3 position can be replaced by an oxygen or sulphur atom, preferably an oxygen atom.
X represents a halogen atom (especially chlorine, bromide or iodine should be understood by halogen), a sulphoni~ acid gr~up or a hydrogen sulphate group, preferably a halogen atom.
T~e compounds of Formu~a V are generally employed equimolar to the urea of Formula IV in so far as the urea of Formula IV is not a bis urea or in so far as the ur~a of Formula IV is a bi~ ~ in which only one of the two -NH2 groups are to be dialkylated.
If both -NH2 groups in a bis uI~a of Formula IV in which R3 and R4 represent hydrogen ar~ to be di-alkylated, generally two equivalents of a compound of Formula V are employed per equivalent of bis ~. In certain cases, however, an excess of one or the other reaction partners can be useful. It was determined that, in certain cases, the yield can be increased when 0.5 to 3 equivalents of the com-pound o Formula V are employed per -NH2 group in the urea of Formula IV.
Diluting agents which are inert under the rsaction conditions and which are solvents for the urea of Formula IV andfor the compound of Formula V are used as diluting ~gents. These are aromatic hydrocarbons, e.~
benzole, toluene, xylenes, higher aliphatic hydrocarbons, e.g. paraffins, aromatic halogenated hydrocarbons, e.g. chlorobanzene, trichlorobenzene, ethsr, e.g. tetrahydro~uran or dimethyl ~ulfo~ide, or mixture~ of such dilu~i~g agents. Preferably, aromatic hydrocarbons are employed; toluene is employed more preferably.
For the e~ecution of the method according to the inv~ntion, the urea of Formula IV i~ dis~olved in a diluting agent which can be predried before being employed. The soiid base is added in the form of pellets or in powdered form and well suspended by stirring vigorously, after which the catalyst is ~ ~ 8 2~39`~
.
introduced. The compound of Formula V can be added to this mixture, which is stirrsd vigorously and heated if necessary, before heating, or it can be added to the already heated mixture.
The reaction mixture is heated if necessary to a temperature of up to approximately 150 ~C, preferably to 70 to 150 C, more preferably to the reflux temperature of the diluting agent employed. When this is done, the -NH2 group of the urea of Formula IV is dialkylated by the compound of Formula V through elimination of both X lea~ing groups and both hydrogen ato~s of the -NH2 group, and the urea of the General Formula II is produced. Unexpectedly, hardly any N,N' bridges or bonds of 2 moles of the urea of t~e &eneral Formula IV result.
' ~
After the conversion has been completed, the reactio~
mixture is either allowed ~o chill and filtered and the liquid residue is distilled or chromatographed, or water is added to the reaction mixture and the urea of Formula II is ex~racted from the reaction ~i~ture with the aid of an e~tracting age~t. Water nmiscible oxganic e~tracting agents such as hydrocarbons, e.g.
he~ane, heptane, halogenated hydrocarbon~, e.g.
methylene chloride, chloroform or ether, e.g. diethyl ethex, diisoprop~l ether, carboxylic acid ether, e.g.
ethyl acetat3, butyl acetate are emplo~ed. The orga~ic pha~e is wa~hed with water and dried and the diluting agent i~ evaporated, whereby the mixture can be aftexdried ~n ~ac~
In general, the purity of the urea of Formula II
produced in this way is sufficient. If neces~ary, i~
may be purified afterwards, e.g. by mean~ o~
chromatography or distillation.
~' 9 21 ~ 3~5~
In a prefexred embodiment, a urea of the Formula IV in which R1' and R2' represent ind~pendently of one another an alkyl group with 1 to 10 C atoms and R1' additionally represents hydrogen~ or Rl' and R2' represent a pyrrolidine, piperidine or morpholine ring together with the nitrogen atom, is dissolved in toluene, and 3 to 5 equivalents of potassium or sodium hydroxide pellets containing 4 to 10 mole % of potassium or sodium carbonate, and 0.04 to 0.06 equivalents of a quaternary ammonium salt as a phase-tran~fer catalyst, are added while stirring vigorously, distilled to reflux, to which 1,~-buta~e dihalide or 1,5-pentane dihalide i~ ~hich one ~f the C atoms can be replaced by an oxygen atom in the 2 ox 3 position is added. Aftsr the reaction is co~plete, water is added to the reaction mi~ture which is the~ e~tracted several times with methylene chloride and/or ~hloroform. The combined organic pha~es are wa~hed with water and dried, the diluting agent is evaporated, and afterdryi~g is performed in vacuo.
A good yield of high purity N-cyclic or ~,N'-dicyclic ureas i~ produced f~om ~on-poi~onous raw makerials according to the de~cribed method.
~a~Ple l 3.~6 g of N piperidi~e carbo~yll~ acid a~id (0.02 ~ole) wa~ dis~ol~d in 40 ~1 of- ~oluene~ m~ed with 4.~8 g of K~H ~0.08 mole3, 0.28 g of tetrabutyl a~mo~ium .chloride ~ ole) and 2.16 ~ of 1,~-dibromobutane (0.01 1~lole) at room tem~erature and di~illed to re~lu~ while being ~tirred ~igorou81y. The ~Ourse of the reaction w~s observed with the aid of ~H-NMR. Af~2r 2 hours, the reactio~ wa~ complete, and the reacSion mixture ~a~ poured into water. The a~yeous mi~ture was then e~tracted several times with methylene chloride, and the organic phase was dried and , `~.` 10 2~ 3~
evaporated. When this was done, 1.73 g, i.e. 95 ~ of the theory, of. 1-piperidino-1-pyrrolidine carbonyl, relative to the 1,4-dibromobutane employed, was obtained.
1H-NMR (300MHz, CDC13, delta): 3.35 ppm (t, py-1,4;
J=5.6 Hz); 3.18 ppm (t, pip~l,S; J=6.7 Hz); 1.~1 ppm (m; py-2,3); 1.57 ppm (m; pip~2,3,4~
l3C~NMR (70 MHz, CDCl3, delta): 163.53 ppm (C=V3; 48.38 ppm ~py~1,4); 47.45 ppm (pip~l,S); 25.90 ppm (pip~2,4);
25.57 ppm (py~2,3); 24057 ppm (pip-3~
, ~am~l~s 2 The following examples 2 ~ 11 were performed in the manner de3~nbed in E~ample 1 and using the same amount of KOH and catalyst per mole of urea of the Formula IY; however, different ureas of Formula IV and different compounds of Formula V in different molar ratios w~re used. The result~ are ab~tracted in Table 1. The reaction time amounted to appn~n~ly 2 hours each.
able_1 ~o. IV-R~ ' IY-R2 ' Y~
2 C2~ - C~5 - - (CH2 )4- Br 2:1 65 3 C2Ns C2Hs-- --(CH2 )~--Br 1 1 53 4 - ( CH2 ) ~ - - S CH2 ~ r 2 ~L 71 -(CH2 ~4- --(CH2 )s- Br 2:1 50 6 -(C~2 )5- -~CH2 )4- Cl 2:1 73 7 -(CH2 ~s- --(CE~2 )5- Br 2:1 61 8 - ( C~ O- ( C~2 ) 2 - - ( CE3:2 ~ 4 - Br 1: q 76 9 -~CH2 )2-O-(CH2 ~2- -(CH2 3~- 13r 2:1 30 10 -(C~2 12-O--~CH2 )2- -~CEI~ )5- Br 2:1 65 11 H C4Hg- -(CH2 )~- Br 2:1 67 CharaC~eriS~iC dat~:
Examp 1eS 2 and 3 1H_NMR (300MHZ, CDC13, de1ta): 3.257 PPm (t, PY-~
JCN2CH2=6.6 HZ); 3.126 PPm (q; ethyl - 1; JC~2CH3=5.3 ~ :~
HZ); 1.742 PPm (m; PY-2,3~; 1.048 ppm (t, ethyl-2; :
JCN2CH3=6.6 HZ) 13C_NMR (70 MHZ~ CDC13, delta): 163.01 PPm (C=0); 48.68 ppm (py-1,4); 42.00 ppm (ethyl-1); 25.87 ppm (ethyl-2);
13.78 ppm (py-2,3) . ~
E:acam~le 4 `
lH-NMR (300MHz, CDCl3, delta): 3.36 ppm ~t; N-CHz;
J=5. 5 Hz ); 1.83 ppm (m, CH2_~H2) l3C-NMR (70 MHz, CDCl3, delta): 161.0 ppm ~C-0); 47.7 PPm ~N-CH2); 25.1 PPm (CH2-CH2) l :~cam~leæ 5 al~d 6 Characteristic data same as described in Example 1.
~aca~Ple 7 l~I_2~R (300M~z, CDCl3, delta~: 3.16 ppm (t; pip-1,5;
3=5.7); 1.57 ppm (m; pip-2,3,4) ~:~
13C-NMR (70 MHz, C!DCl3, delta): 164.75 ppm (C=O); 48.13 P2m (pip-1,5~; 25.71 ppm (pip-2,4); 24~99 ppm (pip-3) Ple~ 8_a~d 9 1H-N~R (300MHz, CDCl3, delta): 3.67 ppm (t; mor-0-C~2;
ar=~.7 Hz); 3.37 ppm (~; pyr~ CE~2; J-6.7 ~z~; 3.26 ppm ~t; mor-N-CH2; J=4.7 Hz) 1.84 ppm (m; pyr-N-CH2-CH2 ) 13C-I~MR (70 MHz, CDCl3, delta~: 162.58 ppm (C=0); 66.71 ppm (mor~O-CH2 ); 48.25 ppm ~pyr-N-CH2 ); 46.7B ppm (mor-N-CH2 ); 25.51 ppm; (pyr-2,3) E~ample 10 lH-NMR (300MHz, CDCl3, delta): 3.66 ppm (t; m~r-0-CH2;
J=4~8 Hz); 3.22 ppm (m; pip-1,5 and mor-N-CH2) 1.57 ppm (m; pip-2,3,4) 13C-NMR (70 MHz, CDCl3, delta): 164.56 ppm (C=0); 67.00 ppm (mor-0-CH2); 48.33 ppm (pip-N-CH2); 47.86 ppm (mor-N-CH2); 26.10 ppm; (pip-2,4); 24. 57 ppm (pip-3) E~am~le 11 lH-NMR ~200MHz, CDCl3, delta): 4.390 ppm ~t; NH; ~=5.8 Hz ); 3 . 340 ppm ~ t; N-CH2; J12 =6 . 7 Hz ~; 3 . 222 ppm ( dt;
HN-CH2; JCH2NH=508 HZ; JCH2C~2=7.0 Hz) 1.893 ppm (tt;
pyr-2,3; J~2-6.7 HZ; J23=3.5 HZ); 1.536-1.288 ppm (m;
but-2 ,3 ) ; 0 . 921 ppm (t; but-CH3; JCH2CH3 =7 . 1 Hz ) 3C-NMR (50 MHz, CDCl3, delta): 156.016 ppm (C=0~;
45.41 ppm (pyr-1,4); 40.28 ppm (but-1~; 32.61 ppm (but-2); 25.52 ppm IPyr-2,3); 20.03 ppm (but-3); 13.78 ppm;
(~ut-4) ~ha~ple 12 22.8 g o~ pyrrolidine carboxylic acid amide (0.2 mole3 was di~solved in 400 ml of toluene, mi~ed with 56 g of KOH l0.8 mole), 2.78 g of tQtrabutyl ammonium ~hloride (1 mmole) a~d 21.6 g of 1,4-dibromobutane ~O.1 mole) at room temperature a~d distilled to r~flu~ while being stirred vigorou~ly. The reaction wa~ observed with the aid o~ lH~NMR. After the reaction was complete, the diluting agent was eYaporated and the re~idue wa~
di~tille~ .in a vacuum. When thi~ was done, 8.27 g of 1,1-carbonyl bi~pyrrolidine, i.e. S4 ~ of the theory and relative to th~ 1,4-dibromobutane employed, was obtained.
Characteristic data same as described in E2ample 4.
~,.,. ;. . - ~ - - .
~ 3 9 ~xamPl~s 13 - 16 Examples 13 - 16 were conducted in the manner described in Example 12 with the same amounts of KOH and catalys~; however, eight times the molar amount of KOH
relative ~o the applied compound of ~ormula V was employed in Example 13, and in Example 14, the compound of Formula V was added by drops in the reflu~ng mixture of urea of Formula I, toluene, base and catalyst. The reaction times amounted to ap~
proximately 2 hours each with the ex~eption of Example lS. The reaction tiMe of E~ample lS amounted to 0.15 hours. The results are abstracted in Table 2.
l~o. IV-Rl '-R2 'V-R6 V-~ IV-V A~
13 -(CH2)~ H2~4- Br 1:1 65 14 -(CH2)4--(CH2)4- Br 1:1 59 -(CH2 )4--tCH2 )4- Br 1:1 67 16 -(CH2)4--(CH2 )4- Br 1:3 72 Characteristic data same as described in E~ample 4.
I~ tables 1 and 2, the followin~ symbols represent:
No.: Number of the example and the c~mpound IV-R1': R1' in For~ul~ IV
IV-R2': R~' in Formula IV
V-Rs: R6 i~ Formuia V
V-X: X i~ Formula V
IY:V: ~olar ratio of the compou~d~ i~ formulas IY and V
A~: Yield in mole per cent relative to the applied compo~nd o~ ~,ormula Y. The yield i~ relati~e to ~he applied compound of Formula IV in ~ample 16 only.
3 ~
Com~arative Examples ExamDle 7 of JP-B-4-8425 13 g of urea in 15û rnl of N,N-dimethylformamide were stirred ~ogether with 96 g of 1,4-dibrombutane and 50 9 of potassium hydroxide at a temperature of 20C over a~erieod o~ 4 hou~; After that the non-soluble pa~ts ware removed by filtration and the filtrate was distilled. Four fraction~ batween 23 and 80C (0.4 mrn Hg) were raceived which were anaiyzed ~sing 1H-NMR spectroscopy. Thersby only 1,4~ibrombutane and N,N-dimethylformamide but absolutely no 1,1-carbonyl bispyrrolidin were found.
ExamDlQ 8 o~ JP-8-4-8425 13 9 of urea in 150 ml of 1,3-dimethyl-2-imidazolidinone were stirred together with 150 ~ of 1 ,5-dibrompentane ~nd ~0 ~ ~f potassium hydroxide ~t a ~e~nperature o~ 20C over a perieod of 4 hours. Aft0r that tlie non-soluble parts were removed by filtration and the filtr~te was distllled. Four fraetions be~ween 23 and 76C (0.35 mm Hg~ were teceived, which were analyzed using 1 H-NMR spectroscopy. Thereby only 1 ,5~ibrompentane and 1,3~imethyl-Z-imidazolidinona but ~bsolutely no 1,1~arbonyl bispiperidin were found.
:,f"'', . . ~
Claims (9)
1. An application of a urea of the General Formula I
in which R1 and R2 independently of one another denote a straight-chain, branched or cyclic alkyl group having 1 to 22 C atoms, which is unsubstituted or substituted by fluorine atoms, nitro groups; alkenyl- or alkyliden groups having
in which R1 and R2 independently of one another denote a straight-chain, branched or cyclic alkyl group having 1 to 22 C atoms, which is unsubstituted or substituted by fluorine atoms, nitro groups; alkenyl- or alkyliden groups having
2 to 6 C atom; phenyl groups which are unsubstituted or substituted by fluorine atoms, nitro groups, alkyl groups having 1 to 5 atoms, alkoxy groups having 1 to 5 C atoms or phenoxy groups; benzyl or phenylethyl groups which are unsubstituted or substituted by fluorine atoms, nitro groups, alkyl groups having 1 to 5 C atoms, alkoxy groups having 1 to 5 C atoms or phenoxy groups; alkoxy groups having 1 to 5 C atoms or phenoxy groups which are unsubstituted or substituted by fluorine atoms, nitro groups, alkyl groups having 1 to 5 C atoms, alkoxy groups having 1 to 5 C atoms or phenoxy groups; or, together with the nitrogen atom, a five or six-member non-aromatic ring which can be broken by an oxygen or sulphur atom; Y represents a methylene group, an oxygen or or sulphur atom; n and m represent independently of one another the numbers 1 to 3, whereby n plus m represent the numbers 3 or 4, as a chemical solvent.
2. The application as claimed in Claim 1, comprising R1 and R2 representing independently of one another straight-chain unsubstituted alkyl groups or representing together with the nitrogen atom an unsubstituted 5 or 6-member non-aromatic ring which can be broken by an oxygen atom.
2. The application as claimed in Claim 1, comprising R1 and R2 representing independently of one another straight-chain unsubstituted alkyl groups or representing together with the nitrogen atom an unsubstituted 5 or 6-member non-aromatic ring which can be broken by an oxygen atom.
3. The application as claimed in Claim 1, comprising Y representing a methylene group or an oxygen atom; n and m representing independently of one another the numbers 1 or 2, and n plus m representing the numbers 3 or 4.
4. The application as claimed in Claim 1, comprising R1 and R2 representing alkyl groups with 1 to 6 C atoms or, together with the nitrogen atom, a 5 or 6-member non-aromatic ring which can be broken by an oxygen atom.
5. A method for the production of ureas of the General Formula II
in which Y, m and n have the meanings described in Claim 1; R1' or R2' have the meanings of R1 and R2 as described in Claim 1; R1' additionally represents hydrogen, or R1' represents hydrogen and R2' represents a group of the General Formula III
in which R3 and R4 have the meanings of R1 and R2 as described in Claim 1, whereby R3 and R4 additionally represent hydrogen, and R5 represents an alkene group with 2 to 20 C atoms or an alkene phenylene alkene group, in which the alkene groups independently of one another have 1 to 3 C atoms comprising reacting a urea or a bis urea of the General Formula IV
in which R1' and R2' have the meanings as described above in the presence of a solid base and a phase-transfer catalyst in a diluting agent which is inert under reaction conditions at temperatures of 0 to 150 °C with a compound of the General Formula in which R6 represents a straight-chain alkene group with 4 or 5 C atoms in which the C atom can be replaced in the 2 or 3 position by an oxygen or sulphur atom, and X represents a halogen, sulphonic acid, or hydrogen sulphate leaving group, whereby the -NH2 group of the urea of the General Formula IV is dialkylated by elimination of both hydrogen atoms through the compound of the General Formula V by elimination of the X leaving groups through ring closure.
in which Y, m and n have the meanings described in Claim 1; R1' or R2' have the meanings of R1 and R2 as described in Claim 1; R1' additionally represents hydrogen, or R1' represents hydrogen and R2' represents a group of the General Formula III
in which R3 and R4 have the meanings of R1 and R2 as described in Claim 1, whereby R3 and R4 additionally represent hydrogen, and R5 represents an alkene group with 2 to 20 C atoms or an alkene phenylene alkene group, in which the alkene groups independently of one another have 1 to 3 C atoms comprising reacting a urea or a bis urea of the General Formula IV
in which R1' and R2' have the meanings as described above in the presence of a solid base and a phase-transfer catalyst in a diluting agent which is inert under reaction conditions at temperatures of 0 to 150 °C with a compound of the General Formula in which R6 represents a straight-chain alkene group with 4 or 5 C atoms in which the C atom can be replaced in the 2 or 3 position by an oxygen or sulphur atom, and X represents a halogen, sulphonic acid, or hydrogen sulphate leaving group, whereby the -NH2 group of the urea of the General Formula IV is dialkylated by elimination of both hydrogen atoms through the compound of the General Formula V by elimination of the X leaving groups through ring closure.
6. The method as claimed in Claim 5, comprising employing a urea of the General Formula IV in which R1' and R2' represent independently of one another a straight-chain alkyl group with 1 to 8 C atoms, and R1' additionally represents hydrogen, or R1' and R2' represent together with the nitrogen atom a 5 or 6-member non-aromatic ring which can be broken by an oxygen atom.
7. The method as claimed in Claim 5, comprising employing a compound of the General Formula V in which X represents a halogen atom.
8. The method as claimed in Claim 5, comprising employing an aromatic hydrocarbon as the diluting agent.
9. The method as claimed in Claim 5, comprising employing potassium or sodium hydroxide as the base and a quaternary ammonium salt as the phase-transfer catalyst.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0009493A AT400566B (en) | 1993-01-22 | 1993-01-22 | Use and process for the preparation of N-cyclic and N,N'- dicyclic ureas |
| ATA94/93 | 1993-01-22 | ||
| DE4302860A DE4302860A1 (en) | 1993-01-22 | 1993-02-02 | N-Cyclic and N, N'dicyclic ureas |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2113956A1 true CA2113956A1 (en) | 1994-07-23 |
Family
ID=25591437
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002113956A Abandoned CA2113956A1 (en) | 1993-01-22 | 1994-01-21 | Application and method for the production of n-cyclic and n,n'-dicyclic ureas |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5414083A (en) |
| EP (1) | EP0613892A1 (en) |
| JP (1) | JPH06293747A (en) |
| CA (1) | CA2113956A1 (en) |
| CZ (1) | CZ14194A3 (en) |
| DE (1) | DE4302860A1 (en) |
| HU (1) | HU214688B (en) |
| NO (1) | NO940193L (en) |
| PL (1) | PL301973A1 (en) |
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| US5798355A (en) * | 1995-06-07 | 1998-08-25 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity |
| US5846981A (en) * | 1993-05-28 | 1998-12-08 | Gpi Nil Holdings Inc. | Inhibitors of rotamase enzyme activity |
| US5859031A (en) * | 1995-06-07 | 1999-01-12 | Gpi Nil Holdings, Inc. | Small molecule inhibitors of rotamase enzyme activity |
| US5696135A (en) * | 1995-06-07 | 1997-12-09 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity effective at stimulating neuronal growth |
| US5801197A (en) * | 1995-10-31 | 1998-09-01 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
| US5801187A (en) | 1996-09-25 | 1998-09-01 | Gpi-Nil Holdings, Inc. | Heterocyclic esters and amides |
| US6218424B1 (en) * | 1996-09-25 | 2001-04-17 | Gpi Nil Holdings, Inc. | Heterocyclic ketone and thioester compounds and uses |
| US5786378A (en) * | 1996-09-25 | 1998-07-28 | Gpi Nil Holdings, Inc. | Heterocyclic thioesters |
| US5846979A (en) | 1997-02-28 | 1998-12-08 | Gpi Nil Holdings, Inc. | N-oxides of heterocyclic esters, amides, thioesters, and ketones |
| US6187784B1 (en) | 1998-06-03 | 2001-02-13 | Gpi Nil Holdings, Inc. | Pipecolic acid derivative hair growth compositions and uses |
| US6187796B1 (en) | 1998-06-03 | 2001-02-13 | Gpi Nil Holdings, Inc. | Sulfone hair growth compositions and uses |
| US5945441A (en) | 1997-06-04 | 1999-08-31 | Gpi Nil Holdings, Inc. | Pyrrolidine carboxylate hair revitalizing agents |
| US20010049381A1 (en) * | 1997-06-04 | 2001-12-06 | Gpl Nil Holdings, Inc., | Pyrrolidine derivative hair growth compositions and uses |
| US6271244B1 (en) | 1998-06-03 | 2001-08-07 | Gpi Nil Holdings, Inc. | N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses |
| US6274602B1 (en) | 1998-06-03 | 2001-08-14 | Gpi Nil Holdings, Inc. | Heterocyclic thioester and ketone hair growth compositions and uses |
| US6172087B1 (en) | 1998-06-03 | 2001-01-09 | Gpi Nil Holding, Inc. | N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses |
| US6429215B1 (en) | 1998-06-03 | 2002-08-06 | Gpi Nil Holdings, Inc. | N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses |
| AU770459B2 (en) * | 1998-06-03 | 2004-02-19 | Gpi Nil Holdings, Inc. | Heterocyclic ester and amide hair growth compositions and uses |
| US6337340B1 (en) | 1998-08-14 | 2002-01-08 | Gpi Nil Holdings, Inc. | Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders |
| US6335348B1 (en) | 1998-08-14 | 2002-01-01 | Gpi Nil Holdings, Inc. | Nitrogen-containing linear and azepinyl/ compositions and uses for vision and memory disorders |
| US6339101B1 (en) | 1998-08-14 | 2002-01-15 | Gpi Nil Holdings, Inc. | N-linked sulfonamides of N-heterocyclic carboxylic acids or isosteres for vision and memory disorders |
| US6506788B1 (en) | 1998-08-14 | 2003-01-14 | Gpi Nil Holdings, Inc. | N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders |
| US6376517B1 (en) | 1998-08-14 | 2002-04-23 | Gpi Nil Holdings, Inc. | Pipecolic acid derivatives for vision and memory disorders |
| US6218423B1 (en) | 1998-08-14 | 2001-04-17 | Gpi Nil Holdings, Inc. | Pyrrolidine derivatives for vision and memory disorders |
| US6333340B1 (en) | 1998-08-14 | 2001-12-25 | Gpi Nil Holdings, Inc. | Small molecule sulfonamides for vision and memory disorders |
| US6399648B1 (en) | 1998-08-14 | 2002-06-04 | Gpi Nil Holdings, Inc. | N-oxides of heterocyclic ester, amide, thioester, or ketone for vision and memory disorders |
| US7338976B1 (en) | 1998-08-14 | 2008-03-04 | Gpi Nil Holdings, Inc. | Heterocyclic esters or amides for vision and memory disorders |
| US6395758B1 (en) | 1998-08-14 | 2002-05-28 | Gpi Nil Holdings, Inc. | Small molecule carbamates or ureas for vision and memory disorders |
| US6384056B1 (en) | 1998-08-14 | 2002-05-07 | Gpi Nil Holdings, Inc. | Heterocyclic thioesters or ketones for vision and memory disorders |
| IN2014DN10324A (en) * | 2012-07-23 | 2015-08-07 | Saudi Basic Ind Corp | |
| NZ723446A (en) | 2014-01-31 | 2022-02-25 | Saudi Basic Ind Corp | Fertilizer capsule comprising one or more cores and method of making same |
| CN110981585B (en) | 2014-05-05 | 2023-04-07 | 赛贝克环球科技公司 | Coated granular fertilizer, method for producing same and method for fertilizing same |
| AU2016295632B2 (en) | 2015-07-20 | 2020-06-18 | SABIC Agri-Nutrients Company | Fertilizer composition and methods of making and using same |
| CN108026118B (en) | 2015-07-20 | 2021-11-05 | 沙特基础工业全球技术公司 | Fertilizer composition, preparation method and use method thereof |
| BR112018009872B1 (en) | 2015-11-16 | 2022-11-16 | Sabic Global Technologies B.V. | MANUFACTURING PROCESS OF A COATED FERTILIZER |
| WO2017087264A1 (en) | 2015-11-16 | 2017-05-26 | Sabic Global Technologies B.V. | Coated granular fertilizers, methods of manufacture thereof, and uses thereof |
| US11806689B2 (en) | 2016-02-08 | 2023-11-07 | Sabic Global Technologies B.V. | Method of making a fertilizer seed core |
| CN110770194A (en) | 2017-04-19 | 2020-02-07 | 沙特基础工业全球技术公司 | Synergistic fertilizer with urease inhibitor and nitrification inhibitor in separate granules |
| EP3612506A1 (en) | 2017-04-19 | 2020-02-26 | SABIC Global Technologies B.V. | Enhanced efficiency fertilizer with urease inhibitor and nitrification inhibitor separated within the same particle |
| EP3612507A1 (en) | 2017-04-20 | 2020-02-26 | SABIC Global Technologies B.V. | Enhanced efficiency fertilizer with embedded powder composition |
| EP3615512A1 (en) | 2017-04-24 | 2020-03-04 | SABIC Global Technologies B.V. | Urea condensation compositions and methods of making the same |
| CN111183126A (en) | 2017-08-09 | 2020-05-19 | 沙特基础工业全球技术公司 | Extruded fertilizer granules containing urease inhibitors and/or nitrification inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE923967C (en) * | 1951-06-14 | 1955-02-24 | Bayer Ag | Process for the production of tetra-substituted ureas |
| US2868328A (en) * | 1957-05-23 | 1959-01-13 | Monsanto Chemicals | Acetylene solvent |
| CH367171A (en) * | 1958-08-12 | 1963-02-15 | Cilag Chemie Aktiengesellschaf | Process for the production of new N, N-pentamethylene ureas |
| DE1105866B (en) * | 1959-08-24 | 1961-05-04 | Shell Int Research | Process for the preparation of N, N'-substituted urea compounds |
| GB1369250A (en) * | 1970-08-07 | 1974-10-02 | Pfizer | Amines the preparation thereof and their use in pharmacejtical compositions |
| GB2092136B (en) * | 1981-01-17 | 1985-06-05 | Mitsui Toatsu Chemicals | Production of n-substituted amide compounds |
| JPH0616505B2 (en) * | 1987-08-18 | 1994-03-02 | 株式会社半導体エネルギ−研究所 | Insulation film formation method |
| JPH01287078A (en) * | 1988-12-12 | 1989-11-17 | Mitsui Toatsu Chem Inc | Production of n-acyl cyclic imine compound |
| DE4018070A1 (en) * | 1990-06-06 | 1991-12-12 | Bayer Ag | New morpholino-urea deriv. are insect repellents |
| US5169954A (en) * | 1990-08-14 | 1992-12-08 | Chemie Linz Gesellschaft M.B.H. | Process for the N-alkylation of ureas |
-
1993
- 1993-02-02 DE DE4302860A patent/DE4302860A1/en not_active Withdrawn
-
1994
- 1994-01-13 EP EP94100394A patent/EP0613892A1/en not_active Withdrawn
- 1994-01-19 NO NO940193A patent/NO940193L/en unknown
- 1994-01-20 JP JP6004860A patent/JPH06293747A/en not_active Withdrawn
- 1994-01-20 PL PL94301973A patent/PL301973A1/en unknown
- 1994-01-21 CA CA002113956A patent/CA2113956A1/en not_active Abandoned
- 1994-01-21 HU HU9400186A patent/HU214688B/en not_active IP Right Cessation
- 1994-01-21 CZ CZ94141A patent/CZ14194A3/en unknown
- 1994-01-24 US US08/185,246 patent/US5414083A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0613892A1 (en) | 1994-09-07 |
| HUT72170A (en) | 1996-03-28 |
| CZ14194A3 (en) | 1994-10-19 |
| NO940193D0 (en) | 1994-01-19 |
| HU214688B (en) | 1998-04-28 |
| DE4302860A1 (en) | 1994-08-04 |
| PL301973A1 (en) | 1994-07-25 |
| US5414083A (en) | 1995-05-09 |
| NO940193L (en) | 1994-07-25 |
| HU9400186D0 (en) | 1994-05-30 |
| JPH06293747A (en) | 1994-10-21 |
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