Title of Invention

"PROCESS FOR THE PREPARATION OF TRIAZOLOPYRIMIDINES"

Abstract Process for the preparation of unsubstituted or substituted 2-amino-| 1,2,4]triazolopyrimidines which comprises com bining A) 2-amino-pyrimidine or its derivatives with alkyloxycarbonyl isothiocyanate or aryloxycarbonyl isothiocyanate with B) hydroxyl ammonium salt and a base wherein the reaction is carried out in a polar aprolic organic solvent in the temperature range of from 40 to 150°C.
Full Text Process for the preparation of triazolopyrimidines Description
Triazolopyrimidine derivates are valuable building blocks in pharmaceutical or agrochemical synthesis, e.g. fungicide, insecticide or herbicide synthesis.
WO 02/38595 A2 (Dow Agrosciences LLC) describes a synthesis route to 2-amino-5,7-dimethoxy[1,2,4]-triazolo[1,5-a]pyrimidine via reaction of 2-amino-4,6-dlmethoxy pyrimidine plus ethoxycarbonylisothlocyanate.
The latter reaction is carried out at room temperature In tetrahydrofuran (THF) and the intermediate was isolated. This intermediate was than reacted with hydroxylamlnehydrochlorlde and diisopropyiamine in ethanol at room temperature yielding the 2-amlno-5l7-dlmethoxy[1,2,4]-triazolo[1,5-a]pyrimidine.
Yields of this two step process are not satisfying and the synthesis is not simple enough e.g. to be scaled up for commercial purposes.
The object of the present invention is to provide a simple process which leads to 2-amino-triazolopyrimidines in high yields, which in turn can be used as building blocks e.g. in agrochemical synthesis, such as fungicide, insecticide or herbicide synthesis.
Therefore the process as defined In the claims as well as the use of such process in the preparation of 2-amlno[1,2,4]-triazole[1,5-a]pyrlmidine structure containing agrochemicals or pharmacenticais has been found.
Stage A of the process of the instant invention is the combination of a substituted or unsubstituted 2-amlno-pyrimldln and alkoxycarbonyl isothiocyanate or aryloxycarbonyl-isothiocyanate.
Prefered unsubstituted or substituted 2-amino-pyrimidines are such of formula I
(Formula Removed)
In which the variables have the following meaning.
E = independently the same or different are O, S, N, P;
R = independently the same or different are C1.10-alkyl, C6.20-aryl, C1-20-arylalkyl, C7-.20-
alkylaryl which each of those may be substituted with one or more of the following
groups: F, Cl, Br, I, C1-20-alkoxy, C6-2o-aryloxy, non substituted or preferably substituted
amino; F, Cl, Br, I;
n * 0 or 1
m = 1 for E= O, S
m = 2 for E = N, P
p = 0,1,2 or 3
Preferred groups R are linear or branched C1-6-alky! such as methyl, ethyl, n-propyl, I-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, neo-pentyl, n-pentyl, n-hexyl or C7-20.arylalkyl such as benzyl or dlphenylmethyl.
Preferred groups E are oxygen (O) or nitrogen (N).
Preferably E is 0, p is 1 or 2 and the ER-groups are positioned meta to each other.
Most preferably R is C1-6-alkyl, E is 0, p is 2 and the ER-groups are postloned meta to each other.
Suitable compounds of formula I are 2-amino-pyrimldine; 2-amino-4,6-,dimethoxy-pyrimldine; 2-amino-4,6-diethoxy-pyrimldine; 2-amino-4,8-dl-n-propoxy pyrimidine; 2-amino-4,6-dl-n-butoxy pyrimidine.
The alkoxycarbonyl or aryloxycarbonyl isothlocyanate of the present invention have preferably the following formula II:
In which R has the same meaning - including the preferable meanings - as for compounds of formula I.
Suitable compounds of formula II are methoxycarbonylisothiocyanate, ethoxycarbonyl-isothiocyanate.
Compounds of formula II are know in the literature and can be prepared by known methods e.g. by reaction of the respective organochloroformiates with alkalimetal (K, Na, Rb, Cs) or alkaline earth metal (e.g. Ca, Ba, Sr) thiocyanates in an organic solvent (see for example J. Heterocycl. Chem. 5,837 (1968); J. Org. Chem. 55 (18), 5230-5231 (1990); US 4160037; US 4778921; US 5194673). The organic solvent is preferably the one in which the reactions of the instant invention are conducted.
The foregoing combination yields a N-pyrimidin-2-yl-N'-carboalkoxy (or aryloxy)thiourea of the formula III
(Formula Removed) In which the variables have the same meaning - including the preferable meaning - as in formula I above.
Suitable compounds III are the ones with E = O, R= C1-6-alkyl, m = 1, p = 1, 2 or 3, preferably are compounds 111 in which E = O, R = C1-6-alkyl, m = 1, p = 2 In which the ER groups are positioned meta to each other. Very suitable compounds III are the following: N-(4,6-dlmethoxypyrimldin-2yl)-N'-carboethoxythlourea1 N-(4,6-diethoxypyrimidln-2yl)-N'-carboethoxythiourea.
Stage B of the instant invention is the combination of the compound III with a hydroxylammonium salt such as hydroxyl ammonium sulfate, hydroxyrammonium chloride, hydroxyl ammonium nitrate, hydroxyl ammonium phosphate, preferably hydroxyl ammonium sulfate, in the presence of a base.
Preferable bases are alkali metal hydroxides (e.g. KOH, NaOH, RbOH, CsOH), earth alkali metal hydroxides (e.g. Mg(OH)2l Ca(OH)2, Ba(OH)2, Sr(OH)2) and organic bases like amines -preferably tertiary amines - pyridines and other herterocyclic organic bases, preferably cyclic amine bases. Most preferable bases are alkali hydroxides, in particular caustic soda (NaOH).
Preferably the base, e.g. caustic soda, Is Initially slowly added to establish a pH value of the reaction mixture of from 1 to 7,5 which is then maintained at pH 5 to 7,5, in particular pH 6,5 to 7,0 until the reaction is completed.
The above reaction sequence yields finally the respective 2-amino-[1,2,4]triazolopyrimidinelV

(Formula Removed) In which the variables, including their preferable meaning, have the same meaning as under formula I.
Suitable compounds IV are the ones in which E = 0, R = C1-6-alkyl, m = 1,p = 1,2or3 Preferable are compounds IV in which E = O, R = C1-6-alkyl, m = 1, p = 2 in which the ER-groups are positioned meta to each other or in other words which occupy the 5-and 7-position (according to Chemical Abstract Nomenclature) of the triazolo pyrimidine ring system In formula (IV).
Very suitable compounds IV are: 2-amino-5,7-dimethoxy[1,2,4]triazolopyrimidine, 2-amino-5,7-diethoxy[1,2,4]triazolopyrimidine, 2-amino-5,7-di n or di iso propoxy[1,2,4]triazolopyrimidine , 2-amino-5,7-di n- or di tert. or dl iso butoxy[1,2,4]triazolopyrimidine, in particular 2-amino-5,7-dimethoxy[1,2,4]triazolopyrimidlne.
Usually stages A and B are conducted in polar aprotic solvents such as nitrites (e.g.aceto nitrite), ethers (e.g. thf, dimethoxyethane, dimethoxymethane, diethoxymethane, diisopropylether, 1,4-dioxan, methyltertbutylether (MTBE)), ketons (e.g. acetone, diethylketone, methylisobutylketone) or preferably in carboxylic acid esters, such as C1.20-carboxyllc-acld - C1.10-alkylesters or the respective C7.2o-alkylarylesters or C7.2o-arylalkylesters.
Preferably C1.20 carboxylic acid C1-10-alkylesters are used as solvents.
Mixtures of the above-mentioned solvents are also suitable.Most preferably the solvent in stage A is the same as the solvent in stage B.
Very most preferably the solvent in stage A and/or in stage B is a carboxylic acid ester, such as C1.20-carboxyllc-acld C1-10-alkylester, preferably C1-6-carboxylic-acid C1-6-alkylester in which the carboxylic acid is a straight chain aliphatic carboxylic acid or a benzole acid and the alcohol alkyl moiety is a straight chain alkyl; suitable examples for the carboxylic acid esters are methylacetate, ethylacetate, n-propylacetate, i-propylacetate, n-butylacetate, in particular ethylacetate.
Preferably reactions in stage A and/or stage B are conducted at temperatures of from 40 to 150 °C, preferably 60 to 100 °C, most preferably 70 to 90 °C.
Very most preferably reactions of stage A as well as stage B are conducted under reflux of the respective solvent e.g. from 60 to 100°C, preferably 70 to 90°C.
Sometimes it might be necessary to conduct the reaction under pressure in order to achieve the abovementloned reaction temperatures.
Preferably no intermediates are isolated in the process of the instant invention ("one pot procedure"), although this isolation is easily possible by generally known methods.
The overall reaction time of stages A and B is usually of from 2 to 14 hours, preferably 5 to 8 hours.
The reaction products IV are in general worked up and isolated with the usual organic techniques.
The process of the instant invention can be used in the synthesis of agrochemicals or pharmacenticals e.g. agrochemicals as described in WO 02/36595 A2 (DOW Agrosciences LLC) or US 5,571,775 (DOW Elanco) which are expressly incorporated by reference herein.
For example compounds IV, obtained by the process of the instant invention can be reacted with aryl - or heteroarylsulfonyl halogenides Ar-S02-Hal or (Hetaryl)-SO2-Hal yielding respectlce N([1,2,4]triazolo[1,5-a]pyrimidin-2-yl) aryl or heteroaryl sulfonamide compounds V, as described in WO 02/36595 A2 (DOW Agrosciences LLC)
(Formula Removed) in which the variables have the same meaning as in formula I and R' independently the same or different is H or R and E1 is CR' or N, preferably N.
Suitable compounds V are for example:
3-Pyridlnesulfonamide, N-(5,7-dlmethoxy[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-2-methoxy-4-(trifluoromethyl), as disclosed in Research Disclosure July 2002,1230-1231;
3-Pyridinesulfonamide, N-(5,7-diethoxy[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-2-methoxy (trifluoromethyl).
The process of the instant invention leads in a simple, usually one pot procedure, to the valuable compounds IV in high yield, usually overall yield above 85 %, In particular over 90%.
Examples
One pot procedure for the synthesis of 2-amino-5,7-dimethoxy [1,2,4]triazolopyrimidine (ADTP) from 2-amino-4,6-dimethoxypyrimld!ne (ADP)
11.9 g (0.075 mol) ADP was dissolved in 68 g ethyl acetate. 11 g (0.0825 mol) ethoxycarbonyl isothlocyanate was added within 20 min. at 78°C (no exotherm). The mixture was stirred over 5 h at reflux (78-79°C). 49.2 g (0.075 mol) hydroxylammonium sulfate (25 % solutbn In water) were added and the mixture heated to 71 °C (reflux aceotrope). 50 g (0.1 mol) diluted caustic soda (2 mol/l) was added within 1 h to establish the pH from 1.3 to 6.5 and hold at 6.5-7.0 (offgas CO2 and H2S, slightly exotherm). The mixture was stirred over 6 h under reflux (71 °C) for reaction completion. The mixture was cooled down over night to 20°C. The product (ADTP) was filtrated and washed 3 times with each 25 g water to remove the salt (Na content after first wash 0.42 %, after second 0.20 %, aner third 0.025 %). Finally the solid ADTP was dried. Yield: 91.1 % In respect to ADP, purity 95.3 % (quantitative HPLC assay).
Claims
1. Process for the preparation of unsubstituted or substituted 2-amino-
[1,2,4]trlazolopyrimidines which comprises combining A) 2-Amino-pyrimidine or its derivatives with alkyloxycarbonyl isothiocyanate or aryloxycarbonyi isothiocyanate with B) hydroxyl ammonium salt and a base wherein the reaction Is carried out In a polar aprotic organic solvent in the temperature range of from 40to150°C.
The process according to claim 1 wherein the pH value in step B) is increased
over time and finally maintained In the range of from 5.5 to 7,5.
The process as in claims 1 to 2, wherein the hydroxylammonium salt is hydroxyl-
ammonlum sulfate.
The process as in claims 1 to 3, wherein the polar aprotic solvent is selected from
the group consiting of carboxylic add esters.
The process as claimed in claims 1 to 4 wherein the 2-amino-pyrimidine or its
derivatives is described by formula I.
(Formula Removed)
and the 2-amlno-[1,2,4]triazolopyrimidine is described by formula IV
(Formula Removed)
wherein the variables have the following meaning:
*
E = independently the same or different are 0, S, N, P; R = independently the same or different are C1-10-alkyl; C6-20-aryl; C7-2o-arylalkyl; C7-20-alkylaryl which each of those may be substituted with one or more of the following groups: F, Cl, Br, I, C1.20-alkoxy, C6-20-aryloxy, non substituted or preferably substituted amlno; F, Cl, Br, I;
n = 0 or 1 m = 1 for E = O, S rn = 2 for E = N, P p = 0,1,2or3.
Process as claimed in claims 1 to 5, wherein the process is conducted without
isolation of intermediates.
Process for the preparation of N-([1,2,4]triazolo[1,5-a]pyrimidin-yl)aryl sulfona-
mides or N-([1,2,4]triazolot[1,5-a]pyrimidin-yOheteroaryl sulfonamldes which com­
prises preparing unsubstituted or substituted 2-amino-[1,2,4]triazolopyrimidines
according to claim 1 to 6 and subsequently reacting the yielded unsubstituted or
substituted 2-am!no-[1,2,4]triazolopyrimidines with an arylsulfonylhalogenide Ar-
SO2-Hal or an heteroarylsulfonylhalogenide Hetar-SO2-Hal.
Use of a process as claimed in claims 1 to 6 in the synthesis of
N-([1,2,4]triazolo[1,5-a]pyrimidin-yl) structure containing agrochemicals or phar-
maceuticals.




WE CLAIM:
1. A process for the preparation of unsubstituted or substituted 2-amino-
[1 ,2,4)triazolopyrimidines which comprises combining A) 2-Amino-pyrimidine or its derivatives with alkyloxycarbonyl isothiocyanate or aryloxycarbonyl isothiocyanate with B) hydroxyl ammonium salt and a base wherein the reaction is carried out in a polar aprotic organic solvent in the temperature range of from 40 to 150°C.
2. The process as claimed in claim 1 wherein the pH value in step B is increased over time and finally maintained in the range of from 5.5 to 7.5.
3. The process as claimed in claims 1 to 2, wherein the hydroxylammonium salt is hydroxyl ammonium sulfate.
4. The process as claimed in claims 1 to 3, wherein the polar aprotic solvent is selected from the group consisting of carboxylic acid esters.
5. The process as claimed in claims 1 to 4 wherein the 2-amino-pyrimidine or its
derivatives is described by formula I
(Formula Removed)
and the 2-amino-[l,2,4]triazolopyrimidine is described by formula IV
(Formula Removed)
wherein the variables have the following meaning:
E = independently the same or different are O, S, N, P;
R = independently the same or different are C1-10-alkyl; C6-20-aryl; C7-20-arylalkyl;
C7-20-alkylaryl which each of those may be substituted with one or more of the
following groups: F, CI, Br, I, C1-20-alkoxy, C6-20-aryloxy, non substituted or

preferably substituted amino; F, C1, Br, I;
n = 0 or 1 m = 1 for E = O, S m = 2 for E = N, P p = 0,1, 2 or 3.
6. Process as claimed in claims 1 to 5, wherein the process is conducted without
isolation of intermediates.
7. The process as claimed in any of claims 1 to 6 as and when used in the synthesis of N-([l,2,4]triazolo[l,5-a]pyrimidin-yl) structure containing agrochemicals or pharmaceuticals.

Documents:

3607-delnp-2006-abstract.pdf

3607-delnp-2006-assignment.pdf

3607-delnp-2006-Claims-(03-08-2011).pdf

3607-delnp-2006-claims.pdf

3607-delnp-2006-Correspondence Others-(03-08-2011).pdf

3607-delnp-2006-correspondence-others-1.pdf

3607-delnp-2006-correspondence-others.pdf

3607-delnp-2006-description (complete).pdf

3607-delnp-2006-form-1.pdf

3607-delnp-2006-form-18.pdf

3607-delnp-2006-form-2.pdf

3607-delnp-2006-Form-3-(03-08-2011).pdf

3607-delnp-2006-form-3.pdf

3607-delnp-2006-form-5.pdf

3607-delnp-2006-GPA-(03-08-2011).pdf

3607-delnp-2006-gpa.pdf

3607-delnp-2006-pct-101.pdf

3607-delnp-2006-pct-210.pdf

3607-delnp-2006-pct-304.pdf

3607-delnp-2006-pct-306.pdf

3607-delnp-2006-Petition-137-(03-08-2011).pdf


Patent Number 251883
Indian Patent Application Number 3607/DELNP/2006
PG Journal Number 16/2012
Publication Date 20-Apr-2012
Grant Date 13-Apr-2012
Date of Filing 22-Jun-2006
Name of Patentee DOW AGROSCIENCES LLC
Applicant Address 9330 ZIONSVILLE ROAD, INDIANAPOLIS, IN 46268-1054, USA
Inventors:
# Inventor's Name Inventor's Address
1 JOACHIM GEBHARDT PEGAUER STRASSE 51, 67157 WACHENHEIM, GERMANY
PCT International Classification Number C07D 487/04
PCT International Application Number PCT/EP2004/014596
PCT International Filing date 2004-12-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03029728.7 2003-12-23 EUROPEAN UNION
2 60/531,613 2003-12-23 EUROPEAN UNION