α-aminoboronic acids prepared by novel synthetic methods
First Claim
Patent Images
1. A process for the synthesis of a compound of Formula (V):
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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).
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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.
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Citations
21 Claims
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1. A process for the synthesis of a compound of Formula (V):
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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).- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
R2 is —
CH2(CH2)mW, —
CH2(C═
O)R5, or —
CH2CH2(C═
O)R5;
m is 0-2;
W is —
CH2F, —
CHF2, —
CF3, —
CH2Cl, —
CHCl2, or —
CCl3;
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 taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base followed by a hydrocarbon containing an electrophilic center selected from;
L—
CH2(CH2)mW,L—
CH2(C═
O)R5, andCH2═
CH2(C═
O)R5;
to form a compound of Formula (II);
wherein L is a leaving group selected from;
I, Br, Cl, methylsulfonyloxy, p-toluylsulfonyloxy and trifluoromethylsulfonyloxy;
(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 a 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;
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 the compound of Formula (V);
or(ii) contacting the compound of Formula (III) wherein R2 is —
CH2(CH2)mW;
with lithium hexamethyldisilazane followed addition of a strong acid;
to form the compound of Formula (V).
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3. A process according to claim 2 for the synthesis of a compound of Formula (V) wherein:
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R2 is —
CH2(CH2)mW, —
CH2(C═
O)OR6, or —
CH2CH2(C═
O)OR6;
m is 0-2;
W is —
CH2F, —
CHF2, —
CF3, —
CH2Cl, —
CHCl2, or —
CCl3;
R6 is C1-C6 alkyl, aryl, or aryl-C1-C6 alkyl-; and
OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazane and n-butyllithium;
followed by a hydrocarbon containing an electrophilic center selected from;
L—
CH2(CH2)mW,L—
CH2(C═
O) OR6, andCH2═
CH2(C═
O)OR6;
to form a compound of Formula (II);
wherein L is a leaving group selected from;
I, Br, Cl, methylsulfonyloxy, p-toluylsulfonyloxy and trifluoromethylsulfonyloxy;
(2) contacting the compound of Formula (II) with an alkylating agent selecting from;
C1-C6 alkyl halides, trimethyloxonium tetrafluoroborate, dimethylsulfate and methyltriflate;
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 selected from sodium iodide, lithium bromide and potassium iodide;
to form a compound of Formula (IV);
wherein X is I or Br; and
(4) aminating the compound of Formula (IV) by either (i) contacting the compound of Formula (IV) with NaN3 followed by contacting a hydrogenation agent selected from;
H2/Pd—
C; and
SnCl2 in methanol;
to form the compound of Formula (V);
or(ii) contacting the compound of Formula (IV) wherein R2 is —
CH2(CH2)mW lithium hexamethyldisilazane followed by contacting a strong acid selected from;
anhydrous HCl; and
trifluoroacetic acid;
to form the compound of Formula (V).
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4. A process according to claim 3 for the synthesis of a compound of Formula (V) wherein:
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R2 is —
CH2(CH2)mW, —
CH2(C═
O)OR6, or —
CH2CH2(C═
O)OR6;
m is 0-2;
W is —
CH2F, —
CHF2, —
CF3, —
CH2Cl, —
CHCl2, or —
CCl3;
R6 is C1-C6 alkyl, aryl, or aryl-C1-C6 alkyl-; and
OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol and pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine and lithium hexamethyldisilazane;
followed by a hydrocarbon containing an electrophilic center selected from;
L—
CH2(CH2)mW,L—
CH2(C═
O)OR6, andCH2═
CH2(C═
O)OR6;
to form a compound of Formula (II);
wherein L is I or Br;
(2) contacting the compound of Formula (II) with an alkylating agent selected from;
methyl iodide, ethyl iodide and trimethyloxonium tetrafluoroborate;
to form a compound of Formula (III);
wherein R8 is methyl or ethyl;
(3) contacting the compound of Formula (III) with sodium iodide to form a compound of Formula (IV);
wherein X is I; and
(4) aminating the compound of Formula (IV) by either (i) contacting the compound of Formula (IV) with NaN3 followed by addition of H2/Pd—
C to form the compound of Formula (V);
or(ii) contacting the compound of Formula (IV) wherein R2 is —
CH2(CH2)mW;
with lithium hexamethyldisilazane followed addition of a strong acid selected from;
anhydrous HCl; and
trifluoroacetic acid;
to form the compound of Formula (V).
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5. A process according to claim 2 for the synthesis of a compound of Formula (V-1):
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wherein OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base followed by L—
CH2CHF2;
to form a compound of Formula (II-1);
wherein L is a leaving group;
(2) contacting the compound of Formula (II-1) with an alkylating agent to form a compound of Formula (III-1);
wherein R8 is C1-C6 alkyl;
(3) contacting the compound of Formula (III-1) with a metal halide M—
X to form a compound of Formula (IV-1);
wherein X is halogen;
M is a alkali metal or an alkaline-earth metal; and
(4) aminating the compound of Formula (IV-1) by either (i) contacting the compound of Formula (IV-1) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V-1);
or(ii) contacting the compound of Formula (IV-1) with lithium hexamethyldisilazane followed addition of a strong acid;
to form the compound of Formula (V-1);
or alternatively, Step (2) may be followed by(5) aminating the compound of Formula (III-1) by either (i) contacting the compound of Formula (III-1) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V-1);
or(ii) contacting the compound of Formula (III-1) with lithium hexamethyldisilazane followed addition of a strong acid;
to form the compound of Formula (V-1).
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6. A process according to claim 5 for the synthesis of a compound of Formula (V-1) wherein:
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OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol and pinacol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazane and n-butyllithium;
followed by L—
CH2CHF2;
to form a compound of Formula (II-1);
wherein L is a leaving group selected from;
I, Br, Cl, methylsulfonyloxy, p-toluylsulfonyloxy and trifluoromethylsulfonyloxy;
(2) contacting the compound of Formula (II-1) with an alkylating agent selected from;
C1-C6 alkyl halides, trimethyloxonium tetrafluoroborate, dimethylsulfate and methyltriflate;
to form a compound of Formula (III-1);
wherein R8 is C1-C6 alkyl;
(3) contacting the compound of Formula (III-1) with a metal halide M—
X selected from sodium iodide, lithium bromide and potassium iodide;
to form a compound of Formula (IV-1);
wherein X is I or Br; and
(4) aminating the compound of Formula (IV-1) by either (i) contacting the compound of Formula (IV-1) with NaN3 followed by addition of a hydrogenation agent selected from;
H2/Pd—
C; and
SnCl2 in methanol;
to form the compound of Formula (V-1);
or(ii) contacting the compound of Formula (IV-1) with lithium hexamethyldisilazane followed addition of a strong acid a strong acid selected from;
anhydrous HCl; and
trifluoroacetic acid;
to form the compound of Formula (V-1).
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7. A process according to claim 6 for the synthesis of a compound of Formula (V-1) comprising:
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(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine and lithium hexamethyldisilazane;
followed by L—
CH2CHF2;
to form a compound of Formula (II-1);
wherein L is I or Br;
(2) contacting the compound of Formula (II-1) with an alkylating agent selected from;
methyl iodide, ethyl iodide and trimethyloxonium tetrafluoroborate;
to form a compound of Formula (III-1);
wherein R8 is methyl or ethyl;
(3) contacting the compound of Formula (III-1) with sodium iodide to form a compound of Formula (IV-1);
wherein X is I; and
(4) aminating the compound of Formula (IV-1) by either (i) contacting the compound of Formula (IV-1) with NaN3 followed by addition of H2/Pd—
C to form the compound of Formula (V-1);
or(ii) contacting the compound of Formula (IV-1) with lithium hexamethyldisilazane followed addition of a strong acid a strong acid selected from;
anhydrous HCl; and
trifluoroacetic acid;
to form the compound of Formula (V-1).
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8. A process according to claim 2 for the synthesis of a compound of Formula (V-2):
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wherein OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base followed by L—
CH2CH2CF3;
to form a compound of Formula (II-2);
wherein L is a leaving group;
(2) contacting the compound of Formula (II-2) with an alkylating agent to form a compound of Formula (III-2);
wherein R8 is C1-C6 alkyl;
(3) contacting the compound of Formula (III-2) with a metal halide M—
X to form a compound of Formula (IV-2);
wherein X is halogen;
M is a alkali metal or an alkaline-earth metal; and
(4) aminating the compound of Formula (IV-2) by either (i) contacting the compound of Formula (IV-2) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V-2);
or(ii) contacting the compound of Formula (IV-2) with lithium hexamethyldisilazane followed addition of a strong acid;
to form the compound of Formula (V-2);
or alternatively, Step (2) may be followed by(5) aminating the compound of Formula (III-2) by either (i) contacting the compound of Formula (III-2) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V-2);
or(ii) contacting the compound of Formula (III-2) with lithium hexamethyldisilazane followed addition of a strong acid;
to form the compound of Formula (V-2).
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9. A process according to claim 8 for the synthesis of a compound of Formula (V-2) wherein:
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OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol and pinacol;
said process comprising;
(1) contacting a compound of Formula (I);
(2)
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazane and n-butyllithium;
followed by L—
CH2CH2CF3;
to form a compound of Formula (II-2);
L is a leaving group selected from;
I, Br, Cl, methylsulfonyloxy, p-toluylsulfonyloxy and trifluoromethylsulfonyloxy;
(2) contacting the compound of Formula (II-2) with an alkylating agent selected from;
C1-C6 alkyl halides, trimethyloxonium tetrafluoroborate, dimethylsulfate and methyltriflate;
to form a compound of Formula (III-2);
wherein R8 is C1-C6 alkyl;
(3) contacting the compound of Formula (III-2) with a metal halide M—
X selected from sodium iodide, lithium bromide and potassium iodide;
to form a compound of Formula (IV-2);
wherein X is I or Br; and
(4) aminating the compound of Formula (IV-2) by either (i) contacting the compound of Formula (IV-2) with NaN3 followed by addition of a hydrogenation agent selected from;
H2/Pd—
C; and
SnCl2 in methanol;
to form the compound of Formula (V-2);
or(ii) contacting the compound of Formula (IV-2) with lithium hexamethyldisilazane followed addition of a strong acid a strong acid selected from;
anhydrous HCl; and
trifluoroacetic acid;
to form the compound of Formula (V-2).
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10. A process according to claim 9 for the synthesis of a compound of Formula (V-2) comprising:
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(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine and lithium hexamethyldisilazane;
followed by L—
CH2CH2CF3;
to form a compound of Formula (II-2);
wherein L is I or Br;
(2) contacting the compound of Formula (II-2) with an alkylating agent selected from;
methyl iodide, ethyl iodide and trimethyloxonium tetrafluoroborate;
to form a compound of Formula (III-2);
wherein R8 is methyl or ethyl;
(3) contacting the compound of Formula (III-2) with sodium iodide to form a compound of Formula (IV-2);
wherein X is I; and
(4) aminating the compound of Formula (IV-2) by either (i) contacting the compound of Formula (IV-2) with NaN3 followed by addition of H2/Pd—
C to form the compound of Formula (V-2);
or(ii) contacting the compound of Formula (IV-2) with lithium hexamethyldisilazane followed addition of a strong acid a strong acid selected from;
anhydrous HCl; and
trifluoroacetic acid;
to form the compound of Formula (V-2).
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11. A process according to claim 2 for the synthesis of a compound of Formula (V-3):
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wherein R6 is Me or t-Bu; and
OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base followed by L—
CH2C(═
O)OR6;
to form a compound of Formula (II-3);
wherein L is a leaving group;
(2) contacting the compound of Formula (II-3) with an alkylating agent to form a compound of Formula (III-3);
wherein R8 is C1-C6 alkyl;
(3) contacting the compound of Formula (III-3) with a metal halide M—
X to form a compound of Formula (IV-3);
wherein X is halogen;
M is a alkali metal or an alkaline-earth metal; and
(4) aminating the compound of Formula (IV-3) by contacting the compound of Formula (IV-3) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V-3);
or
or alternatively, Step (2) may be followed by(5) aminating the compound of Formula (III-3) by contacting the compound of Formula (III-3) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V-3).
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12. A process according to claim 11 for the synthesis of a compound of Formula (V-3) wherein:
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R6 is Me or t-Bu; and
OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol and pinacol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazane and n-butyllithium;
followed by L—
CH2C(═
O)OR6;
to form a compound of Formula (II-3);
wherein L is a leaving group selected from;
I, Br, Cl, methylsulfonyloxy, p-toluylsulfonyloxy and trifluoromethylsulfonyloxy;
(2) contacting the compound of Formula (II-3) with an alkylating agent selected from;
C1-C6 alkyl halides, trimethyloxonium tetrafluoroborate, dimethylsulfate and methyltriflate;
to form a compound of Formula (III-3);
wherein R8 is C1-C6 alkyl;
(3) contacting the compound of Formula (III-3) with a metal halide M—
X selected from sodium iodide, lithium bromide and potassium iodide;
to form a compound of Formula (IV-3);
wherein X is I or Br; and
(4) aminating the compound of Formula (IV-3) by contacting the compound of Formula (IV-3) with NaN3 followed by addition of a hydrogenation agent selected from;
H2/Pd—
C; and
SnCl2 in methanol;
to form the compound of Formula (V-3).
-
-
13. A process according to claim 12 for the synthesis of a compound of Formula (V-3) comprising:
-
(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine and lithium hexamethyldisilazane;
followed by L—
CH2C(═
O)OR6;
to form a compound of Formula (II-3);
wherein L is I or Br;
(2) contacting the compound of Formula (II-3) with an alkylating agent selected from;
methyl iodide, ethyl iodide and trimethyloxonium tetrafluoroborate;
to form a compound of Formula (III-3);
wherein R8 is methyl or ethyl;
(3) contacting the compound of Formula (III-3) with sodium iodide to form a compound of Formula (IV-3);
wherein X is I; and
(4) aminating the compound of Formula (IV-3) by contacting the compound of Formula (IV-3) with NaN3 followed by addition of H2/Pd—
C to form the compound of Formula (V-3).
-
-
14. A process according to claim 2 for the synthesis of a compound of Formula (V-4):
-
wherein OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base followed CH2═
CH(C═
O)OMe;
to form a compound of Formula (II-4);
(2) contacting the compound of Formula (II-4) with an alkylating agent to form a compound of Formula (III-4);
wherein R8 is C1-C6 alkyl;
(3) contacting the compound of Formula (III-4) with a metal halide M—
X to form a compound of Formula (IV-4);
wherein X is halogen;
M is a alkali metal or an alkaline-earth metal; and
(4) aminating the compound of Formula (IV-4) by contacting the compound of Formula (IV-4) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V-4);
or
or alternatively, Step (2) may be followed by(5) aminating the compound of Formula (III-4) by contacting the compound of Formula (III-4) with NaN3 followed by addition of a hydrogenation agent to form the compound of Formula (V-4).
-
-
15. A process according to claim 14 for the synthesis of a compound of Formula (V-4) wherein:
-
OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol and pinacol;
said process comprising;
(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazane and n-butyllithium;
followed by by CH2═
CH(C═
O)OMe;
to form a compound of Formula (II-4);
(2) contacting the compound of Formula (II-4) with an alkylating agent selected from;
Cl-C6 alkyl halides, trimethyloxonium tetrafluoroborate, dimethylsulfate and methyltriflate;
to form a compound of Formula (III-4);
wherein R8 is C1-C6 alkyl;
(3) contacting the compound of Formula (III-4) with a metal halide M—
X selected from sodium iodide, lithium bromide and potassium iodide;
to form a compound of Formula (IV-4);
wherein X is I or Br; and
(4) aminating the compound of Formula (IV-4) by contacting the compound of Formula (IV-4) with NaN3 followed by addition of a hydrogenation agent selected from;
H2/Pd—
C; and
SnCl2 in methanol;
to form the compound of Formula (V-4).
-
-
16. A process according to claim 15 for the synthesis of a compound of Formula (V-3) comprising:
-
(1) contacting a compound of Formula (I);
with a hindered base selected from;
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine and lithium hexamethyldisilazane;
followed by CH2═
CH(C═
O)OMe;
L is I or Br;
to form a compound of Formula (II-4);
(2) contacting the compound of Formula (II-4) with an alkylating agent selected from;
methyl iodide, ethyl iodide and trimethyloxonium tetrafluoroborate;
to form a compound of Formula (III-4);
wherein R8 is methyl or ethyl;
(3) contacting the compound of Formula (III-4) with sodium iodide to form a compound of Formula (IV-4);
wherein X is I; and
(4) aminating the compound of Formula (IV-4) by contacting the compound of Formula (IV-4) with NaN3 followed by addition of H2/Pd—
C to form the compound of Formula (V-4).
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-
17. 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. - View Dependent Claims (18, 19, 20, 21)
R1 is H or C1-C6 alkyl;
R2 is —
CH2CHF2, —
CH2CH2CF3, —
CH2(C═
O)R5, or —
CH2CH2—
(C═
O)R5;
R5 is C1-C6 alkyl, aryl, aryl-C1-C6 alkyl-, —
OR6, or —
N(R6)2;
R6 is H, C1-C6 alkyl, aryl, or aryl-C1-C6 alkyl-; and
OY1 and OY2 are independently selected from;
a) —
OH,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 14 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O.
-
-
19. A compound of claim 17 wherein:
-
R1 is H;
R2 is —
CH2CHF2, —
CH2CH2CF3, —
CH2(C═
O)OR6, or —
CH2CH2—
(C═
O)OR6;
R6 is H or C1-C6 alkyl; and
OY1 and OY2 are taken together with B to form a cyclic boronic ester where said cyclic boronic ester is formed from the group;
pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol.
-
-
20. A compound of claim 17 is:
-
1-amino-3,3-difluoropropyl boronate pinacol ester; and
1-amino-4,4,4-trifluorobutyl boronate pinanediol ester.
-
-
21. A compound of claim 17 is selected from:
-
1-amino-2-t-butoxycarbonylethane-1-boronate pinanediol ester;
1-amino-2-methoxycarbonylethane-1-boronate pinanediol ester;
1-amino-2-hydroxycarbonylethane-1-boronate pinanediol ester;
1-amino-3-methoxycarbonyl-propane-1-boronate pinanediol ester; and
1-amino-3-hydroxycarbonyl-propane-1-boronate pinanediol ester.
-
Specification