α-aminoboronic acids prepared by novel synthetic methods

• US 6,586,615 B1
• Filed: 01/09/2002
• Issued: 07/01/2003
• Est. Priority Date: 01/10/2001
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Forsyth, Timothy Patrick, Jagannathan, Sharada, Kettner, Charles A.
• Primary Examiner(s): Vollano, Jean F.
• Application Number:
  US10/043,865
• Time in Patent Office: 538 Days
• Field of Search: 558/286, 558/287, 558/288, 558/298
• US Class Current: 558/288
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

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.

Claims

1. 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(CR^4aR³)_mW, —

CHR^4a(C═

O)R⁵, —

CHR⁴CHR^4a(C═

O)R⁵, —

CHP^4a(P═

O)(OR⁶)₂, —

CHR⁴CHR^4a(P═

O)(OR⁶)₂, —

CHR^4aSO₂NH₂, —

CHR⁴CHR^4aSO₂NH₂, —

CHR^4aSO₃R⁶, —

CHR⁴CHR^4aSO₃R⁶;

R³ is H, F, Cl or Br;

m is 0-4;

W is —

CH₂F, —

CHF₂, —

CF₃, —

CH₂Cl, —

CHCl₂, or —

CCl₃;

R⁴ and R^4a 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(CR^4aR³)_mW,

L—

CHR^4a(C═

O)R⁵,

CHR⁴═

CHR^4a(C═

O)R⁵,

L—

CHR^4a(P═

O)(OR⁶)₂,

CHR⁴═

CHR^4a(P═

O)(OR⁶ )₂,

L—

CHR^4aSO₂NH₂,

CHR⁴═

CHR^4aSO₂NH₂,

L—

CHR^4aSO₃R⁶,

CHR⁴═

CHR^4aSO₃R⁶;

 

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(CR^4aR³)_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(CR^4aR³)_mW;

with lithium hexamethyldisilazane followed addition of a strong acid;

to form a compound of Formula (V).

2. A process according to claim 1 for the synthesis of a compound of Formula (V) wherein:

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, and

CH₂═

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).

3. A process according to claim 2 for the synthesis of a compound of Formula (V) wherein:

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, and

CH₂═

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).

4. A process according to claim 3 for the synthesis of a compound of Formula (V) wherein:

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, and

CH₂═

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).

5. A process according to claim 2 for the synthesis of a compound of Formula (V-1):

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).

6. A process according to claim 5 for the synthesis of a compound of Formula (V-1) 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 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).

7. A process according to claim 6 for the synthesis of a compound of Formula (V-1) 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—

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).

8. A process according to claim 2 for the synthesis of a compound of Formula (V-2):

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).

9. A process according to claim 8 for the synthesis of a compound of Formula (V-2) 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);

(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).

10. A process according to claim 9 for the synthesis of a compound of Formula (V-2) 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—

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).

11. A process according to claim 2 for the synthesis of a compound of Formula (V-3):

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).

12. A process according to claim 11 for the synthesis of a compound of Formula (V-3) 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 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;

C_l-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).

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(CR^4aR³)_mW, —

CHR^4a(C═

O)R⁵, —

CHR⁴CHR^4a(C═

O)R⁵, —

CHR^4a(P═

O)(OR⁶)₂, —

CHR⁴CHR^4a(P═

O)(OR⁶)₂, —

CHR^4aSO₂NH₂, —

CHR⁴CHR^4aSO₂NH₂, —

CHR^4aSO₃R⁶, —

CHR⁴CHR^4aSO₂NH₂;

R³ is H, F, Cl or Br;

m is 0-4;

W is —

CH₂F, —

CHF₂, —

CF₃, —

CHCl₂, or —

CCl₃;

R⁴ and R^4a 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.

18. A compound of claim 17 wherein:

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.