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US 2002/0055641 A1Published application
Synthesis of 1,3,5-trisubstituted pyrazoles
AssigneeBristol-Myers Squibb Pharma Company
InventorsJiacheng Zhou, Lynette May Oh, Pasquale N. Confalone, Hui-Yin Li, Philip Ma
Life of this patent
Estimating the term…
Abstract
A novel process for making 1,3,5-trisubstituted pyrazoles of the type shown below from appropriate phenyl hydrazines is described. 1 These compounds are useful as factor Xa inhibitors.
Claims14
A process for preparing a compound of formula I:
- 84
- wherein ring D is selected from 2-(aminomethyl)phenyl, 3-(aminomethyl) phenyl, and (3-amino)benz[d]isoxazol-6-yl;
- and
- B is 2-MeSO2-phenyl or 2-NH2SO2-phenyl, the process comprising:
- (a) acylating a hydrazine of formula II to form a compound of formula III:
- 85
- wherein ring D is selected from 2-cyanophenyl, 3-cyanophenyl, 3-cyano-4-fluorophenyl, 2-(PgNHCH2)phenyl, and 3-(PgNHCH2)phenyl, and Pg is an amine protecting group;
- (b) converting a compound of formula III to a compound of formula IV, wherein X is selected from Cl, OMs, Br, OSO2Ph, and OTs;
- (c) contacting a compound of formula IV with a base to form a dipolar compound of formula V:
- 86
- (d) contacting a compound of formula V in situ with a dipolarophile of formula VI to form a compound of formula VII, wherein Y is selected from Br, 2-MeSO2-phenyl, 2-MeS-phenyl, 2-NH2SO2-phenyl, and 2-PgNHSO2-phenyl;
- (e) converting a compound of formula VII to a compound of formula I by subjecting it to the following reactions, which may be performed, when applicable, in any order:
- (e1) oxidizing the pyrazoline to a pyrazole;
- (e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2—SO2Me-phenyl, or 2—SO2NH2-phenyl;
- (e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2—;
- (e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
- (e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
- and,
- (e4) when Pg is present, removing the protecting group.
16 more elements
A process for preparing a compound of formula I:
- 87
- wherein ring D is 2-(aminomethyl)phenyl, 3-(aminomethyl) phenyl, or (3-amino)benz[d]isoxazol-6-yl and B is 2-MeSO2-phenyl or 2-NH2SO2-phenyl, the process comprising:
- (e) acylating a hydrazine of formula II to form a compound of formula III:
- 88
- wherein ring D is selected from 2-cyanophenyl, 3-cyanophenyl, 3-cyano-4-fluorophenyl, 2-(PgNHCH2)phenyl, and 3-(PgNHCH2)phenyl, and Pg is an amine protecting group;
- (f) converting a compound of formula III to a compound of formula IV, wherein X is selected from Cl, OMs, Br, OSO2Ph, and OTs;
- (g) contacting a compound of formula IV with a base to form a dipolar compound of formula V:
- 89
- (h) contacting a compound of formula V in situ with a dipolarophile of formula VIa to form a compound of formula VIIa, wherein R is selected from H, Me, Et, and n-Pr;
- (i) converting a compound of formula VIIa to a compound of formula I by subjecting it to the following reactions, which may be performed, when applicable, in any order:
- (e1) oxidizing the pyrazoline to a pyrazole;
- (j1) when R is other than H, hydrolyzing the compound of formula VIIa to its corresponding acid;
- (j2) when R is H, contacting the acid of formula VIIa with an aniline of formula Vib to form an amide;
- 90
- wherein Y is selected from Br, 2-MeSO2-phenyl, 2-MeS-phenyl, 2-NH2SO2-phenyl, and 2-PgNHSO2-phenyl;
- (e2a′) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO2Me-phenyl, or 2-SO2NH2-phenyl;
- (e2b′) when Y=2-MeS-phenyl, converting the MeS-group to MeSO2-;
- (e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH2)phenyl;
- (e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
- and,
- (e4) when Pg is present, removing the protecting group.
18 more elements
A compound of formula IX:
- 91
- wherein ring D is 2-cyanophenyl, 2-(PgNHCH2)phenyl, 2-(aminomethyl) phenyl, 3-cyanophenyl, 3-(PgNHCH2)phenyl, 3-(aminomethyl)phenyl, 3-cyano-4-fluorophenyl, and (3-amino) benz[d]isoxazol-6-yl;
- Y′ is selected from Br, H, PgHNSO2Ph, H2NSO2Ph, 2-MeSPh, and 2-MeSO2Ph;
- bond a is absent or is a single bond;
- and,
- Pg is an amine protecting group selected from Boc and TFA.
3 more elements
A compound of formula X:
- 92
- wherein R is selected from H, Me, Et, and n-Pr;
- ring D is 2-cyanophenyl, 2-(PgNHCH2)phenyl, 2-(aminomethyl) phenyl, 3-cyanophenyl, 3-(PgNHCH2)phenyl, 3-(aminomethyl)phenyl, 3-cyano-4-fluorophenyl, and (3-amino) benz[d]isoxazol-6-yl;
- bond a is absent or is a single bond;
- and,
- Pg is an amine protecting group selected from Boc and TFA.
3 more elements
Dependencies are inferred from the claim text.