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US 7,396,932 B2Granted
Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones
AssigneeBristol-Myers Squibb Company
InventorsRafael Shapiro, Lucius T Rossano, Boguslaw M Mudryk, Nicolas Cuniere, Matthew Oberholzer, Huiping Zhang, Bang-Chi Chen
Life of this patent
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Abstract
A novel process and intermediates thereof for making 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones of the type shown below from appropriate phenyl hydrazines is described. These compounds can be useful as factor Xa inhibitors.
Claims39
A process for preparing a compound of formula III, comprising:
- (a) contacting a compound of formula I with a compound of formula II in the presence of a first base;
- wherein:
- Z is selected from Cl, Br, I, OSO2Me, OSO2Ph, and OSO2Ph-p-Me;
- ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, and 4-methoxyphenyl;
- R1a is selected from CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2CH2CH2CH3, OCH(CH3)CH2CH3, OCH2CH(CH3)2, OC(CH3)3, O-phenyl, OCH2-phenyl, OCH2CH2-phenyl, and OCH2CH2H2-phenyl;
- R is selected from Cl, Br, and I;
- ring A is substituted with 0-1 R4;
- B is NO2;
- and
- R4 is selected from H, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, —CN, and CF3.
7 more elements
A process for preparing a compound of formula IV:
- the process comprising:
- (b) reducing the B group of formula III to an amino group in the presence of hydrogen and Pd/Al2O3, and a second aprotic solvent;
- and
- (c) contacting the resulting amino compound with an alkyl-acid halide to form a compound of formula IV,
- wherein:
- the alkyl-acid halide is X-C3-5-alkylene-C(O)-X1;
- X is selected from Cl, Br, and I;
- X1 is selected from the group Cl, Br, OS(O)2CH3, OS(O)2CF3, OS(O)2-phenyl, and OS(O)2-tolulyl;
- n is selected from the group 3, 4, and 5;
- ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, and 4-methoxyphenyl;
- R1a is selected from CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2CH2CH2CH3, OCH(CH3)CH2CH3, OCH2CH(CH3)2, OC(CH3)3, O-phenyl, OCH2-phenyl, OCH2CH2-phenyl, and OCH2CH2CH2-phenyl;
- ring A is substituted with 0-1 R4;
- B is NO2;
- and
- R4 is selected from H, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, —CN , and CF3.
12 more elements
A process for preparing a compound of formula V:
- the process comprising:
- (d) cyclizing the compound of formula IV to form a compound of formula V, wherein:
- p is selected from 0, 1, and 2;
- ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, and 4-methoxyphenyl;
- R1a is selected from CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2CH2CH2CH3, OCH(CH3)CH2CH3, OCH2CH(CH3)2, OC(CH3)3, O-phenyl, OCH2-phenyl, OCH2CH2-phenyl, and OCH2CH2CH2-phenyl;
- ring A is substituted with 0-1 R4;
- and
- R4 is selected from H, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, —CN , and CF3.
5 more elements
A process for preparing a compound of formula VI:
- the process comprising:
- (e) amidating ester R1a of the compound of formula V to form a compound of formula VI,
- wherein:
- p is selected from 0, 1, and 2;
- ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, and
- 4-methoxyphenyl;
- R1a is selected from OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2CH2CH2CH3, OCH(CH3)CH2CH3, OCH2CH(CH3)2, OC(CH3)3, O-phenyl, OCH2-phenyl, OCH2CH2-phenyl, and OCH2CH2CH2-phenyl;
- ring A is substituted with 0-1 R4;
- R4 is selected from H, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, —CN , and CF3;
- and
- R5 is selected from H, CH3, and CH2CH3;
- wherein in reaction (e), the compound of formula V and a fourth aprotic solvent are contacted with second chemical dehydrating agents prior to contacting with a second base.
9 more elements
A process for preparing a compound of formula V:
- the process comprising:
- contacting a compound of formula I with a compound of formula II in the presence of a first base;
- reducing the B group of formula III to an amino group;
- contacting the resulting amino compound with an alkyl-acid halide to form a compound of formula IV;
- and
- cyclizing the compound of formula IV to form a compound of formula V,
- wherein:
- Z is selected from Cl, Br, I, OSO2Me, OSO2Ph, and OSO2Ph-p-Me;
- alkyl-acid halide is X-C3-5-alkylene-C(O)-X1;
- X is selected from Cl, Br, and I;
- X1 is selected from Cl, Br, OS(O)2CH3, OS(O)2CF3, OS(O)2-phenyl, and OS(O)2-tolulyl;
- n is selected from 3, 4, and 5;
- p is selected from 0, 1, and 2;
- ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, and 4-methoxyphenyl;
- R1a is selected from CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2CH2CH2CH3, OCH(CH3)CH2CH3, OCH2CH(CH3)2, OC(CH3)3, O-phenyl, OCH2-phenyl, OCH2CH2-phenyl, and OCH2CH2CH2-phenyl;
- R is selected from Cl, Br, and I;
- ring A is substituted with 0-1 R4;
- B is NO2;
- and
- R4 is selected from H, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, —CN , and CF3.
17 more elements
A process for preparing a compound of formula VI:
- the process comprising:
- contacting a compound of formula I with a compound of formula II in the presence of a first base;
- reducing the B group of formula III to an amino group;
- contacting the resulting amino compound with an alkyl-acid halide to form a compound of formula IV;
- cyclizing the compound of formula IV to form a compound of formula V;
- and
- amidating ester R1a of the compound of formula V to form a compound of formula VI,
- wherein:
- Z is selected from Cl, Br, I, OSO2Me, OSO2Ph, and OSO2Ph-p-Me;
- alkyl-acid halide is X-C3-5-alkylene-C(O)-X1;
- X is selected from Cl, Br, and I;
- X1 is selected from Cl, Br, OS(O)2CH3, OS(O)2CF3, OS(O)2-phenyl, and OS(O)2-tolulyl;
- n is selected from 3, 4, and 5;
- p is selected from 0, 1, and 2;
- ring D is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, and 4-methoxyphenyl;
- R1a is selected from CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2CH2CH2CH3, OCH(CH3)CH2CH3, OCH2CH(CH3)2, OC (CH3)3, O-phenyl, OCH2-phenyl, OCH2CH2-phenyl, and OCH2CH2CH2-phenyl;
- R is selected from Cl, Br, and I;
- ring A is substituted with 0-1 R4;
- B is NO2;
- R4 is selected from H, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, —CN , and CF3;
- and
- R5 is selected from H, CH3, and CH2CH3.
19 more elements
Dependencies are inferred from the claim text.