| US 7,498,439 B2 | ||
| Synthesis of heteroaryl acetamides from reaction mixtures having reduced water content | ||
| Esa Jarvi, Ballwin, Mo. (US); Douglas C. Miller, University City, Mo. (US); Frank W. Moser, Arnold, Mo. (US); and Robert E. Halvachs, Belleville, Ill. (US) | ||
| Assigned to Mallinckrodt Inc., Hazelwood, Mo. (US) | ||
| Appl. No. 10/594,486 PCT Filed Jun. 03, 2005, PCT No. PCT/US2005/019810 § 371(c)(1), (2), (4) Date Sep. 27, 2006, PCT Pub. No. WO2006/007289, PCT Pub. Date Jan. 19, 2006. |
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| Prior Publication US 2007/0213537 A1, Sep. 13, 2007 | ||
| Int. Cl. C07D 235/06 (2006.01); C07D 403/02 (2006.01); C07D 471/04 (2006.01); C07D 491/04 (2006.01) | ||
| U.S. Cl. 546—118 [548/303.1; 548/309] | 23 Claims |
1. A process for the preparation of a heteroaryl acetamide from a heteroaryl α-hydroxyacetamide, the process comprising directly
hydrogenating a heteroaryl α-hydroxyacetamide in the presence of hydrogen gas in a reaction mixture comprising a solvent system,
the heteroaryl α-hydroxyacetamide, at least one strong acid, a halide and a precious metal catalyst, wherein the reaction
mixture has a molar ratio of the starting heteroaryl α-hydroxyacetamide to water at the initiation of hydrogenolysis of at
least about 2:1, the heteroaryl α-hydroxyacetamide corresponding to Formula 1 and the heteroaryl acetamide product corresponding
to Formula 1A:
 wherein
Z is O, NR20 or CR21;
X1 and X2 are independently selected from the group consisting of hydrogen, halogen, C1-4 alkoxy, C1-6 alkyl, —CF3 and CH3SO2—;
R1 and R2 are independently hydrogen or hydrocarbyl;
R10 is hydrogen, halogen, C1-4 alkyl, or a member of a fused ring wherein the fused ring is (i) a substituted or unsubstituted, saturated or unsaturated,
five or six-membered, heterocyclic or carbocyclic ring fused to the A ring comprising R10, the carbon atom to which R10 is attached, R20, and the nitrogen atom to which R20 is attached, or (ii) a six-membered, aromatic, carbocyclic ring fused to the A ring comprising R10, R11, and the carbon atoms to which R10 and R11 are attached, optionally substituted with Y at a substitutable position thereof;
R11 is hydrogen, halogen, C1-4 alkyl, or a member of a fused ring wherein the fused ring is (i) a six-membered, aromatic, carbocyclic ring fused to the A
ring comprising R10, R11, and the carbon atoms to which R10 and R11 are attached, optionally substituted with Y at a substitutable position thereof, or (ii) a six-membered, aromatic, carbocyclic
ring fused to the A ring comprising R11, R12, and the carbon atoms to which R11 and R12 are attached, optionally substituted with Y at a substitutable position thereof;
R12, if present, is hydrogen, halogen, C1-4 alkyl, or a member of a fused ring wherein the fused ring is (i) a six-membered, aromatic, carbocyclic ring fused to the A
ring comprising R11, R12, and the carbon atoms to which R11 and R12 are attached, optionally substituted with Y at a substitutable position thereof;
R20 is C1-5 alkyl or a member of a fused ring wherein the fused ring is a substituted or unsubstituted, saturated or unsaturated, five
or six-membered, heterocyclic or carbocyclic ring fused to the A ring comprising R10, the carbon atom to which R10 is attached, R20, and the nitrogen atom to which R20 is attached;
R21 is hydrogen, halogen or C1-4 alkyl;
n is 0 or 1;
each Y is independently hydrogen, halogen or C1-4 alkyl; and
when Z is CR21, the A ring is aromatic.
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