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US 6,586,615 B1Granted
α-aminoboronic acids prepared by novel synthetic methods
AssigneeBristol-Myers Squibb Company
InventorsCharles A. Kettner, Sharada Jagannathan, Timothy Patrick Forsyth
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Abstract
The present invention relates to a novel class of α-aminoboronic acids of Formula (V), which are useful as intermediates in synthetic processes for inhibitors of the serine proteases, leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin. More specifically, the α-aminoboronic acids are useful as intermediates for the synthesis of Hepatitis C Virus (HCV) protease inhibitors. This invention also generally relates to novel methods for the preparation of α-aminoboronic acids.
Claims21
A process for the synthesis of a compound of Formula (V):
- wherein:
- R2 is —CH2(CH2)mW, —CH2(C═O)R5, —CH2CH2(C═O)R5, —CHR4(CR4aR3)mW, —CHR4a(C═O)R5, —CHR4CHR4a(C═O)R5, —CHP4a(P═O)(OR6)2, —CHR4CHR4a(P═O)(OR6)2, —CHR4aSO2NH2, —CHR4CHR4aSO2NH2, —CHR4aSO3R6, —CHR4CHR4aSO3R6;
- R3 is H, F, Cl or Br;
- m is 0-4;
- W is —CH2F, —CHF2, —CF3, —CH2Cl, —CHCl2, or —CCl3;
- R4 and R4a are independently H or C1-C6 alkyl, aryl, or aryl-C1-C6 alkyl-;
- R5 is C1-C6 alkyl, aryl, aryl-C1-C6 alkyl-, —OR6, —NH2, —N(R6)2, or —NHR6;
- R6 is C1-C6 alkyl, aryl, or aryl-C1-C6 alkyl-;
- and
- OY1 and OY2 are independently selected from:
- b) C1-C8 alkoxy, and
- when taken together with B, OY1 and OY2 form:
- c) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
- said process comprising:
- (1) contacting a compound of Formula (I):
- wherein Ar is aryl;
- with a hindered base followed by addition of a hydrocarbon containing an electrophilic center selected from:
- L—CH2(CH2)mW,
- L—CH2(C═O)R5,
- CH2═CH2(C═O)R5,
- L—CHR4(CR4aR3)mW,
- L—CHR4a(C═O)R5,
- CHR4═CHR4a(C═O)R5,
- L—CHR4a(P═O)(OR6)2,
- CHR4═CHR4a(P═O)(OR6 )2,
- L—CHR4aSO2NH2,
- CHR4═CHR4aSO2NH2,
- L—CHR4aSO3R6,
- CHR4═CHR4aSO3R6;
- to form a compound of Formula (II):
- wherein L is a leaving group;
- (2) contacting the compound of Formula (II) with an alkylating agent to form a compound of Formula (III):
- wherein R8 is C1-C6 alkyl;
- (3) contacting the compound of Formula (III) with a metal halide M—X to form a compound of Formula (IV):
- wherein X is halogen;
- M is an alkali metal or an alkaline-earth metal;
- and
- (4) aminating the compound of Formula (IV) by either
- (i) contacting the compound of Formula (IV) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V);
- or
- (ii) contacting the compound of Formula (IV) wherein R2 is —CH2(CH2)mW or —CHR4(CR4aR3)mW;
- with lithium hexamethyldisilazane followed addition of a strong acid;
- to form the compound of Formula (V);
- or alternatively, Step (2) may be followed by
- (5) aminating the compound of Formula (III) by either
- (i) contacting the compound of Formula (III) with NaN3 followed by addition of a hydrogenation agent to form a compound of Formula (V);
- or
- (ii) contacting the compound of Formula (III) wherein R2 is —CH2(CH2)mW or —CHR4(CR4aR3)mW;
- with lithium hexamethyldisilazane followed addition of a strong acid;
- to form a compound of Formula (V).
47 more elements
A compound of Formula (V-a):
- wherein:
- R1 is H or C1-C6 alkyl;
- R2 is —CH2(CH2)mW, —CH2(C═O)R5, —CH2CH2(C═O)R5, —CHR4(CR4aR3)mW, —CHR4a(C═O)R5, —CHR4CHR4a(C═O)R5, —CHR4a(P═O)(OR6)2, —CHR4CHR4a(P═O)(OR6)2, —CHR4aSO2NH2, —CHR4CHR4aSO2NH2, —CHR4aSO3R6, —CHR4CHR4aSO2NH2;
- R3 is H, F, Cl or Br;
- m is 0-4;
- W is —CH2F, —CHF2, —CF3, —CHCl2, or —CCl3;
- R4 and R4a are independently H or C1-C6 alkyl, aryl, or aryl-C1-C6 alkyl-;
- R5 is C1-C6 alkyl, aryl, aryl-C1-C6 alkyl-, —OR6, —NH2, —N(R6)2, or —NHR6;
- R6 is H, C1-C6 alkyl, aryl, or aryl-C1-C6 alkyl-;
- and
- OY1 and OY2 are independently selected from:
- b) C1-C8 alkoxy, and
- when taken together with B, OY1 and OY2 form:
- c) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O.
11 more elements
Dependencies are inferred from the claim text.