&agr;-aminoboronic acids prepared by novel synthetic methods

Details &agr;-aminoboronic acids prepared by novel synthetic methods &agr;-aminoboronic acids prepared by novel synthetic methods

2002-01-09

2003-07-01

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Borate esters

C558S298000

Reexamination Certificate

active

06586615

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel class of &agr;-aminoboronic acids, which are useful as intermediates in synthetic processes for boronic acid inhibitors of the serine proteases, leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin. More specifically, the &agr;-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 &agr;-aminoboronic acids.
BACKGROUND OF THE INVENTION
Inhibitors of HCV protease have been prepared by replacing the scissile bond cleaved in peptide substrates with electrophillic groups. Of the various electrophilic groups examined, boronic acids have a distinct advantage. The concept of using boronic acids as serine protease inhibitors was introduced in the early 70's Antonov et al.
FEBS Lett
7, 23 (1970); Koelhler and Lienhard
Biochemistry
10, 2477-2483 (1971). An &agr;-aminoboronic acids, Ac-boroPhe-OH, was first prepared by Matteson
J. Am. Chem. Soc.
103, 5241-5242 (1981). This compound inhibits chymotrypsin with a K
i
of 2.1 &mgr;M. Kettner and Shenvi
J. Biol. Chem.
259, 15106-15114 (1984) were able to couple &agr;-aminoboronic acids to peptides and were able to show that they were very effective inhibitors of the serine proteases, leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin. Their specificity was highly dependent on the nature of the side chain of the &agr;-aminoboronic acid. These initial compounds are described in U.S. Pat. No. 4,499,082 (1985). U.S. Pat. No. 4,499,082 also discloses the use of side chain protected amino acids and equivalent amino acids known to those skilled in the art. More recent patents cover peptide boronic acids containing basic side chains. U.S. Pat. No. 5,187,157 discloses boronic acid inhibitors specially designed as inhibitors of trypsin-like serine proteases. U.S. Pat. No. 5,658,885 (1997) discloses boronic acid inhibitors containing the following side chains: C
1
-C
12
-alkyl substituted with —NHC(NH)H, —ONHR
6
, or —ONHC(NH)NHR
6
as well as phenylalanine analog substituted with a cyano group. Other boronic acid inhibitors containing basic sidechain are disclosed in Fevig et al U.S. Pat. No. 5,462,964 (1995), Dominguez et al. U.S. Pat. No. 5,639,739 (1997) and Amparo et al. U.S. Pat. No. 5,698,538 (1997). Additionally, boronic acid inhibitors of Hepatitis C Virus (HCV) protease are disclosed in Kettner et al PCT Publication WO 01/02424 (Jan. 11, 2001).
Schemes 1A, 1B and 1C outline the different approaches that have been used in the synthesis of &agr;-aminoboronic acids containing a variety of sidechains. These include compounds where R is alkyl, aryl, and alkylaryl containing various degrees of unsaturation.
In Scheme 1A, a Grignard reagent or other suitable nucleophile is added to a trialkyl boronate to give a substituted dialkyl boronate. Transesterification with a suitable diol protecting group gives the boronate ester 2. 2 is shown protected as the pinanediol ester, however, pinacol or C
2
symmetrical diol, such as (R,R)2,3-butandiol, and (R,R)dicyclohexaneethanediol can also be used effectively. The &agr;-chloroalkyl intermediate 3 is obtained by the nucleophilic addition of the anion of methylene chloride to the boronic acid ester. Nucleophilic additions to boronates are generally performed under harsh conditions and sub-zero temperatures. 3 is treated with the lithium salt of hexamethyldisilazane to give the bis-silane protected amine 4. Compound 4 is treated with either anhydrous HCl or trifluoroacetic acid to give the amine 5 as a hydrochloride salt or trifluoroacetate salt. For example of Scheme 1A see U.S. Pat. No. 4,499,082 (1985).
Scheme 1B shows the introduction of an alkyl sidechain as an olefin (see Matteson et al.
Organometallics
3, 1284-1288, 1984 and U.S. Pat. No. 5,187,157, 1993). Hydroboration with catacholborane give the alkyl boronate. After transesterification with pinanediol, compound 2 is obtained. For example hydroboration of 3-bromopropene provide a 3-bromopropyl sidechain intermediate. These reactions are amenable for nucleophilic additions but not for electrophilic additions.
Scheme 1C shows the preparation of &agr;,&agr;-dichloromethyl boronate ester 7, which then allows the nucleophilic addition of a sidechain to give 3 (see Kinder et al
J. Med. Chem.
28, 1917-1925, 1985). The presence of acidic protons in reagents diminishes their ability to undergo nucleophilic addition reactions.
Although, the procedures in Schemes 1A, 1B and 1C allow the synthesis of a number of &agr;-aminoboronic acids, there are limitations on this chemistry for the preparation of &agr;-aminoboronic acids of the present invention. First, a stable nucleophile or olefin must be available for generation of 2. Second, the sidechain of 2 must be stable to the harsh reaction conditions (highly basic and sub-zero temperatures) required to convert 2 to 3. These reaction conditions are not amenable to hydrocarbons containing electrophilic centers.
None of the above-cited references provide methods for introducing boroaminoacid sidechains as electrophiles. The present invention provides a novel procedure as shown herein that allows the synthesis of &agr;-aminoboronic acids with primary or secondary amino groups required for the preparation of aminoboronic acids peptides with versatile sidechains. The present invention provides synthesis of novel &agr;-aminoboronic acid by introducing sidechains as electrophiles such as 2,2-difluoro-1-bromoethane, 3,3,3-trifluoro-1-bromopropane, and 2-bromoacetate esters. Similarly, sidechains can be introduced as olefins, wherein the harsh conditions such as treatment with the anion of methylene chloride are avoided. The sequence of reactions of the present invention has made it possible to prepare structurally diverse &agr;-aminoboronic acids. In addition to the specific compounds demonstrated in the present invention, higher order acrylates or alkyl halides can be used to give more complex sidechains. This is particularly valuable for the preparation of compounds with sidechains containing sensitive groups such as ketones, phosphonates and sulfonamides.
SUMMARY OF THE INVENTION
The present invention concerns novel processes for the preparation of &agr;-aminoboronic acids which are useful as HCV protease inhibitors.
There is provided by this invention a process for preparation of a compound of Formula (V):
wherein:
R
2
is —CH
2
(CH
2
)
m
W, —CH
2
(C═O)R
5
, —CH
2
CH
2
(C═O)R
5
, —CHR
4
(CR
4a
R
3
)
m
W, —CHR
4a
(C═O)R
5
, —CHR
4
CHR
4a
(C═O)R
5
, —CHR
4a
(P═O)(R
6
)
2
, —CHR
4
CHR
4a
(P═O) (OR
6
)
2
, —CHR
4a
SO
2
NH
2
—CHR
4
CHR
4a
SO
2
NH
2
, —CHR
4a
SO
3
R
6
, —CHR
4
CHR
4a
SO
3
R
6
;
R
3
is H, F, Cl or Br;
m is 0-4;
W is —CH
2
F, —CHF
2
, —CF
3
, —CH
2
Cl, —CHCl
2
, or —CCl
3
;
R
4
and R
4a
are independently H or C
1
-C
6
alkyl, aryl, or aryl-C
1
-C
6
alkyl-;
R
5
is C
1
-C
6
alkyl, aryl, aryl-C
1
-C
6
alkyl-, —OR
6
, —NH
2
, —N(R
6
)
2
, or —NHR
6
;
R
6
is C
1
-C
6
alkyl, aryl, or aryl-C
1
-C
6
alkyl-; and
OY
1
and OY
2
are independently selected from:
b) C
1
-C
8
alkoxy, and
when taken together with B, OY
1
and OY
2
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) (addition) 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—CH
2
(CH
2
)
m
W,
L—CH
2
(C═O)R
5
,
CH
2
═CH
2
(C═O)R
5
,
L—CHR
4
(CR
4a
R
3
)
m
W,
L—CHR
4a
(C═O)R
5
,
CHR
4
═CHR
4a
(C═O)R
5
,
L—CHR
4a
(P═O)(OR
6
)
2
,
CHR
4
═CHR
4a
(P═O)(OR
6
)
2
,
L—CHR
4a
SO
2
NH
2
,
CHR
4
═CHR
4a
SO
2
NH
2
,
L—CHR
4a
SO
3
R
6
,
CHR
4
═CHR
4a
SO
3
R
6
;
 to form a compound of Formula (II):
 wherein L is a leaving group;
(2) (alkylatio

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