Claims
- 1. A method of making a pyrazole compound of the formula (I): wherein R1, R2, R3 and R4 are defined as follows:each R1 and R3 are independently chosen from: amino and C1-10 alkyl optionally partially or fully halogenated and optionally substituted with one to three C3-10 cycloalkanyl, C1-6alkoxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups chosen from halogen, C1-6 alkyl which is optionally partially or fully halogenated, C3-8 cycloalkanyl, C5-8 cycloalkenyl and C1-3 alkoxy which is optionally partially or fully halogenated; wherein both R1 and R3 cannot simultaneously be amino; R2 is chosen from: hydrogen, C1-6 branched or unbranched alkyl optionally partially or fully halogenated and aryl optionally partially or fully halogenated; R4 is chosen from: phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl) amino-C1-5 alkyl, amino-S(O)2, di-(C1-3alkyl)amino-S(O)2, R7—C1-5 alkyl, R8—C1-5 alkoxy, R9—C(O)—C1-5 alkyl, R10—C1-5 alkyl(R11)N or carboxy-mono-or di-(C1-5 alkyl)-amino; R11 is chosen from hydrogen and C1-4 branched or unbranched alkyl which may optionally be partially or fully halogenated; each R7, R8, R9, R10, is independently chosen from: morpholine, piperidine, piperazine, imidazole and tetrazole; wherein said method comprises:reacting a compound of the formula (II) with a compound of the formula (III) under acid pH conditions, in a polar protic solvent under reflux for 5-16 hours, according to the scheme below: wherein X is chosen from —CN and —C(O)—R3, wherein if X is CN then R3 in the product formula (I) is amino; to form the product compound of the formula (I): and subsequently isolating said product.
- 2. The process according to claim 1, whereinR2 is hydrogen.
- 3. The process according to claim 2, whereinthe acid is chosen from HCl, AcOH, TFA and p-TsOH; the solvent is a C1-C3 alcohol; R1 and R3 are chosen from amino, C1-10 alkyl, alkoxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each of the aforementioned being optionally substituted with one to three groups chosen from halogen, C1-6alkyl and C1-3 alkoxy; wherein when either R1 or R3 is amine the other is not amino; and R4 is chosen from: phenyl, naphthyl, pyridinyl, pyrimidinyl and pyrazinyl, each of the aforementioned is optionally substituted with C1-6 branched or unbranched alkyl or C1-3 alkoxy each of which is optionally partially or fully halogenated.
- 4. The process according to claim 3 wherein:the acid is chosen from HCl and p-TsOH; the solvent is ethanol, the reflux time is 5-8 hours; R3 is amino and X is CN.
RELATED APPLICATION DATA
This application claims benefit to U.S. provisional application Nos. 60/192,651 filed Mar. 28, 2000 and 60/162,476 filed Oct. 29, 1999.
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
5162360 |
Creswell et al. |
Nov 1992 |
A |
5616723 |
Muhr et al. |
Apr 1997 |
A |
5969153 |
Hamper et al. |
Oct 1999 |
A |
Foreign Referenced Citations (3)
Number |
Date |
Country |
WO-9852558 |
Nov 1998 |
WO |
WO 9923901 |
Apr 1999 |
WO |
PCT US0029891 |
Oct 2000 |
WO |
Non-Patent Literature Citations (5)
Entry |
Hartwig Angew. Chem. Int. Ed. 37 (1998) 2090-2093.* |
Wagaw et al J. Org. Chem. (1996) 7240-7241.* |
Wagaw et al J. Am. Chem. Soc. 121 (1999) 10251-10263.* |
X. Jung Lee, et a l; Synthesis of Pyrazolo-fused Hetercyles by a Tandem Appel's Dehydration/Electrocylization Methodolgy, J. Heterocyclic Chem. 34, (1997) 1795-1799. |
S. Wagaw, et al; A Palladium-Catalyzed Strategy for the Preparation of Indoles: A Novel Entry into the Fischer Indole Synthesis, J. Am. Chem. Soc. 1998, 120, 6621-6622. |
Provisional Applications (2)
|
Number |
Date |
Country |
|
60/192651 |
Mar 2000 |
US |
|
60/162476 |
Oct 1999 |
US |