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Title:
PROCESS FOR THE PREPARATION OF 1,5-DISUBSTITUTED-3-AMINO-1,2,4-TRIAZOLES AND SUBSTITUTED AMINOGUANIDINES AS INTERMEDIATE COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2002/034729
Kind Code:
A1
Abstract:
New process for the preparation of 1,5-disubstituted-3-amino-1,2,4-triazoles of the general formula (I), wherein the meaning of R is C¿1-5?alkyl group; C¿3-13?cycloalkyl-C¿0-4?alkyl group, optionally substituted by one or more C¿1-3?alkyl group; phenyl-C¿0-2?alkyl-, (CH¿2?)¿n?-morpholino-, piperidino-, pyrrolidino- or piperazino-group, optionally substituted by one or more halogen atom, C¿1-3?alkyl group, C¿1-3?alkoxy group, n is 1-5, R?1¿, R?2¿, R?3¿, and R?4¿ stand independently for hydrogen, halogen, C¿1-6?alkyl group, C¿1-3?alkoxy group or trifuluoromethyl group, with the proviso that of the substituents R?1¿, R?2¿, R?3¿, and R?4¿ at least one stands for hydrogen.

Inventors:
BOKOTEY SANDOR (HU)
CSIKOS EVA (HU)
GOENCZI CSABA (HU)
HAJDU FELIX (HU)
HERMECZ ISTVAN (HU)
HEJA GERGELY (HU)
PODANYI BENJAMIN (HU)
SANTANE CSUTOR ANDREA (HU)
SZOMOR TIBORNE (HU)
SZVOBODA GYOERGYNE (HU)
Application Number:
PCT/HU2001/000103
Publication Date:
May 02, 2002
Filing Date:
October 25, 2001
Export Citation:
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Assignee:
SANOFI SYNTHELABO (FR)
BOKOTEY SANDOR (HU)
CSIKOS EVA (HU)
GOENCZI CSABA (HU)
HAJDU FELIX (HU)
HERMECZ ISTVAN (HU)
HEJA GERGELY (HU)
PODANYI BENJAMIN (HU)
SANTANE CSUTOR ANDREA (HU)
SZOMOR TIBORNE (HU)
SZVOBODA GYOERGYNE (HU)
International Classes:
C07C281/16; C07D249/14; C07D295/13; (IPC1-7): C07D249/14; C07C281/16; C07D295/12
Domestic Patent References:
WO1999055321A11999-11-04
Foreign References:
DE1808677A11970-01-02
CH530965A1972-11-30
CH530964A1972-11-30
CH533603A1973-02-15
US3714363A1973-01-30
DE4321109A11995-01-05
US3541218A1970-11-17
US3541217A1970-11-17
FR1537892A1968-08-30
Other References:
ER-RHAIMINI, ABDERRAHMAN ET AL: "Synthesis and photochemical degradation of N-arylmethyl derivatives of the herbicide 3-amino-1,2,4-triazole", J.HETEROCYCL.CHEM. (1992), 29(6), 1561-6, XP002192018
DATABASE CROSSFIRE BEILSTEIN [online] BEILSTEIN INSTITUT ZUR FOERDERUNG DER CHEMISCHEN WISSENSCHAFT, FRANKFURT AM MAIN, DE; XP002192019, Database accession no. 571876
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; AROYAN, A. A. ET AL: "Syntheses based on 4-alkoxybenzylhydrazines", XP002192020, retrieved from STN Database accession no. 75:118088
J. F. KING; A. HAWSON; B. L. HUSTON; L. J. DANKS; J. KOMERY: "49", CAN. J. CHEM., 1971, pages 943
J. ORG. CHEM., vol. 53, 1988, pages 3621
J. ORG. CHEM., vol. 68, 2003, pages 4123
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING CO.
OJA; SARANSAARI, PROC. WEST. PHARMACOL. SOC., vol. 50, 2007, pages 8 - 15
SZYMANSKY; WINIARSKA, POSTEPY. HIG. MED DOSW., vol. 62, 2008, pages 75 - 86
WARSKULAT IS MTSAI, METHODS ENZYMOL., vol. 428, 2007, pages 439 - 58
Attorney, Agent or Firm:
Sanofi-synthelabo (Tó u. 1-5, Budapest, HU)
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Claims:
Claims 1) Process for the preparation of 1, 5-disubstituted-3-amino-1, 2,4-triazoles of the general formula (I), wherein the meaning of R is C
1. 5alkyl group; C3. 13cycloalkyl. C0. 4alkyl group, optionally substituted by one or more C1. 3alkyl group; phenyl. Co 2alkyl. , (CH2) n. morpholino. , piperidino. , pyrrolidino. or piperazino. group, optionally substituted by one or more halogen atom, C1. 3alkyl group, C1. 3alkoxy group, n is 1. 5, Rl, R2, R3, and R4 stand independently for hydrogen, halogen, C1. 6alkyl group, C1. 3ealkoxy group or trifluoromethyl group, with the proviso that of the substituents Rl, R2, R3, and R4 at least one stands for hydrogen, which comprises reacting an aldehyde of the general formula (II) RCHO (II) wherein the meaning of R is defined above. with an aminoguanidine of the general formula (III) or its salt, and treating the resulting aminoguanidine derivative of the general formula (IV) . wherein the meaning of R is defined above. with the acid derivative of the general formula (V) . wherein the meanings of Rl, R2, R3, and R4 are defined above and R 5 stands for hydrogen atom or for Cl alkyl group. in the presence of an alkali alcoholate.
2. The process defined in Claim 1, which comprises the use of sodium. or potassium alcoholate as alkali alcoholate.
3. The process defined in Claim 1, which comprises the use of 1. cyclohexylacetaldehyde for compound of the general formula (II).
4. The process defined in Claim 1, which comprises the use of methyl 2,5. dimethoxy. 4. methylbenzoate for compound of the general formula (V).
5. Compounds of the general formula (IV), wherein the meaning of R is C1. 5alkyl group; C313cycloalkyl. C04alkyl group, optionally substituted by one or more C1. 3alkyl group; phenyl. C02alkyl. , (CH2) n. morpholino. , piperidino. , pyrrolidino. or piperazino. group, optionally substituted by one or more halogen atom, C1. 3alkyl group, C1. 3alkoxygroup.
Description:
PROCESS FOR THE PREPARATION OF 1,5-DISUBSTITUATED-3-AMINO-1,2,4-TRIAZOLES AND SUBSTITUTED AMINOGUANIDINES AS INTERMEDIATE COMPOUNDS The invention relates to a process for the preparation of 1, 5-disubstituted-3-amino-1, 2,4- triazoles of the general formula (I), wherein the meaning of R is C1-5alkyl group; C3-i3cycloalkyl-Co-4alkyl group, optionally substituted by one or more Cl 3alkyl group; phenyl-CO 2alkyl-, (CH2) n-morpholino-, piperidino-, pyrrolidino-or piperazino-group, optionally substituted by one or more halogen atom, C1-3alkyl group, C1-3alkoxy group, n is 1-5, Rl, R2, R3, and R4 independently stand for hydrogen, halogen, C1-6alkyl group, C1-3alkoxy group or trifluoromethyl group, with the proviso that at least one of the substituents Rl, R2, R3, and R4 stands for hydrogen.

1, 5-disubstituted-3-amino-1, 2,4-triazoles of the general formula (I) are intermediates to the therapeutically useful compounds of the general formula (VI), described in patent application WO 98/51686.

For the synthesis of 3-amino-1, 2,4-triazoles the route starting from amino-guanidine is known for a long time (K. T. Potts. Chem. Rev. 61, (1961)): an aminoguanidine salt is treated with a suitable acid at high temperature, or the isolated acylaminoguanidine is treated with alkali and/or subjected to thermal ring closure. Except for ring closures in acetic acid, yields are low to medium.

The case is similar when the aminoguanidine is prepared by Schotten-Baumann acylation, where hydrolysis takes place as a competing reaction. The isolated acylaminoguanidine derivative is then cyclized thermally, at 180°C in DMSO or with NaOEt (J. Med. Chem.

41.2985-93 (1998)).

Reactions of aminoguanidines with esters leading to 3-amino-1, 2,4-triazoles are also known (J. Med. 41,2985 (1998); and Chem Rev. 61,87 (1961)).

Synthesis of 1-substituted-3-amino-triazoles cannot be solved economically by preparation and subsequent substitution of the amino-triazoles, since reactivities of the nitrogens in positions 1 and 2 towards electrophiles are almost the same, therefore derivatives substituted in position 1 and in position 2 are equally formed, approximately in the same ratio. Separation of the isomers which have very similar physico-chemical properties is not easy and usually can only be solved by chromatography, which in industrial scale is expensive and complicated.

There is only one example to find in the literature where a substituted aminoguanidine is cyclized to 1,2,4-triazole. The substituted aminoguanidine is synthesized step-by step starting from hydrazide and cyanamide, the ring closure is carried out by thermolysis in pyridine hydrochloride. The synthesis, however, does not utilize some reasonable possibilities given in the aminoguanidine structure [Ger. Offen. 1,808,677 (C. A. 72, 90561m 1970)].

We have found, to our surprise, that the 1, 5-disubstituted-3-amino-1, 2,4-triazoles of the general formula (I)

can be prepared in good yield via a regioselective synthesis, by the reaction of the aminoguanidine derivative of the general formula (IV) with the acid derivative of the general formula (V), in the presence of sodium-or potassium-alcoholate.

This means that of the four nitrogens of the aminoguanidine, the acylation took place exclusively on the one in desired position. By-products were not obtained even by working up the mother-liquor. A further surprise was that the aminoguanidine, which is sensitive to bases (Houben-Weil VIII, 193.), furnished the product in good yield, this means that decomposition of the aminoguanidine was avoided.

The subject of our invention, in agreement with the above, is a process for the preparation of 1, 5-disubstituted-3-amino-1, 2,4-triazoles of the general formula (I), wherein the meaning of R is C1-5alkyl group; C3 l3cycloalkyl-C04alkyl group, optionally substituted by one or more C1-3alkyl group; phenyl-C02alkyl-, (CH2) n-morpholino-, piperidino-, pyrrolidino-or

piperazino-group, optionally substituted by one or more halogen atom, C1-3alkyl group, C1-3alkoxy group, n is 1-5, Rl, R2, R3, and R4 stand independently for hydrogen, halogen, C1-6alkyl group, C1-3alkoxy group or trifluoromethyl group, with the proviso that of the substituents Rl, R2, R3, and R4 at least one stands for hydrogen, which comprises reacting an aldehyde of the general formula (II) RCHO (II) -wherein the meaning of R is the same as defined above-with an aminoguanidine of the general formula (III) or its salt, and treating the resulting aminoguanidine derivative of the general formula (IV) -wherein the meaning of R is the same as defined above-with the acid derivative of the general formula (V) -wherein the meanings of Rl, R2, R3, and R4 are the same as defined above and Rs stands for hydrogen atom or for C1-5alkyl group-in the presence of an alkali alcoholate.

The aldehydes of formula II are commercially available or they can be prepared by methods known from the literature.

In the process according to the invention for alkali alcoholate preferably sodium-or potassium alcoholate is used.

For compound of the general formula (II) preferably 1-cyclohexylacetaldehyde, and for the acid derivative of the general formula (V) preferably methyl 2,5-dimethoxy-4- methylbenzoate are applied.

Our process is demonstrated by the following examples:

Example 1 51.74g of cyclohexylethylaminoguanidine HCl salt and 49.4g of ethyl 2,5-dimethoxy- 4-methylbenzoate are dissolved in 150ml of methanol, to the solution 28g of sodium methylat in methanol are added and the reaction mixture is refluxed for 5 hours. After addition of diluted alkali the mixture is refluxed for an additional hour and cooled. The resulting crystals are filtered off, washed and dried, to obtain 55. 1g (67%) of 1- (2- cyclohexylethyl)-5- (2, 5-dimethoxy-4-methylphenyl)-3-amino-1,2,4-triazole.

Mp.: 136-137°C. Purity by HPLC 99.5%.

Preparation of the starting cyclohexylethylaminoguanidine HCl : 11.05 g (0.1 mol) of aminoguanidine hydrochloride are dissolved in 150 ml of 96% ethanol and 12.62 g (0.1 mol) of 1-cyclohexylacetaldehyde are added. The resulting Schiff-base is hydrogenated under atmospheric pressure, at room temperature, using palladium on charcoal catalyst. At the end the catalyst is filtered off, the filtrate is evaporated, the residue is crystallized from water, to obtain 17.2 g (78 %) of product.

Mp.: 132-134°C.

Examples 2-43 Applying the procedure as described in Example 1 and using the appropriate starting materials the following products can be prepared (R4=H), see Table 1.

Table 1 I 2 2 Example R R RJ RCH2-Mp. °C No HC1 2 2-OCH3 4-CH3 6-OCH3 135 -CH2t 2-OCH3 4-CH3 6-OCH3-CH2-C6Hs 215 4 2-OCH3 4-CH3 6-OCH3- (CH2) 4-CH3 143 5 2-OCH3 4-CH3 6-OCH3-CH2< 236 z 6 2-OCH3 4-CH3 6-OCH3-CH2CH2-C6Hs 200 2-OCH3 4-CH3 6-OCH3-(CH2) 2-CH (CH3) 2 172 8 2-OCH3 4-CH3 6-OCH3 187 -CH2-CH2 2-OCH3 4-CH3 6-OCH3 160 -CH2-CH2-N 0 10 2-OCH3 4-CH3 6-OCH3 190 -(CH2) 3<) 11 2-OCH3 4-CH3 6-OCH3-(CH2) 3-CH3 212 12 2-OCH3 4-CH3 6-OCH3 198 - (CH-N 13 2-OCH3 4-CH3 6-OCH3-CH2-CH (C2Hs) 2 132 142-OCH34-CH36-OCH3/7\" -CH 2 OCHg . o OCH3 15 2-OCH3 4-CH3 6-OCH3 217 - (CH 16 2-OCH3 4-CH3 6-OCH3-CH--- 208 2

17 2-OCH3 4-CH3 6-OCH3 136 -c2 Cul 182-OCH34-CH36-OCH3/r-\"204 -CH2 Cl 19 2-OCH3 4-CH3 6-OCH3 202 -CH2 Cl 20 2-OCH3 4-Cl 5-OCH3 196 -CH2CH2 21 2-OCH3 4-Cl 5-OCH3 148 -CH 22 2-OCH3 4-CH3 5-OCH3 192 -(CH23 23 2-OCH3 4-CH3 5-OCH3 188 -CH 2---o 24 2-OCH3 4-CH3 5-OCH3 166 -CH2CH2 25 2-OCH3 4-OCH3 6-OCH3 189 -CH2CH2 26 2-OCH3 4-OCH3 6-OCH3 180 -CH 27 2-OCH3 4-CH3 6-CH3 168 -CH3 V 28 2-OCH3 4-CH3 6-CH3-CH2CH2< 188 -CH2CHa 29 2-OCH3 4-CH3 5-CH3 200 -CHZ 30 2-OCH3 4-CH3 5-CH3 206 -CH2CH2

31 2-OCH3 4-CH3 5-OCH3 218 -CHZ-CH2-N 32 2-OCH3 4-Cl 5-OCH3 127 -CH2CH2 33 2-OCH3 3-Cl 6-OCH3 159 -CH2CH2 34 2-OCH3 3-CH3 G-OCH3 168 -CH2CH2