Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-07
2001-10-09
Higel, Floyd G. (Department: 1609)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S319100
Reexamination Certificate
active
06300503
ABSTRACT:
BACKGROUND OF THE INVENTION
Omapatrilat (I) is a potent inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo:
Omapatrilat was developed at the Bristol-Myers Squibb Pharmaceutical Research Institute as the first of a new class of compounds capable of simultaneously inhibiting ACE and NEP and is currently undergoing large scale clinical trials as an anti-hypertensive. See Omapatrilat.
Drugs R D
1999 Apr;1(4):350-1.
Currently, omapatrilat is synthesized using (S)-hydroxy amino acid (II) as one of the key starting materials:
The hydroxyl group of compound (II) must be converted to an aldehyde as a prerequisite step in the syntheis of compound (I), omapatrilat. This oxidation to an aldehyde currently requires several steps and/or noxious reagents. See Robl, J. A., et al.
J. Med. Chem.
1997, 40, 1570-1577; Robl, J. A. et al.
J. Med. Chem.
1996, 39 494-502.
It is therefore desirable to find alternatives to compound (II) that reduce the number of requisite synthetic steps and eliminate the use of noxious reagents.
SUMMARY OF THE INVENTION
The invention is directed to novel compounds of the formula:
wherein R
1
is —H, a C
1
-C
5
alkyl group or a benzyl group and R
2
is represented by one of the two following formulae:
wherein R
3
, R
4
, R
5
, and R
6
are independently selected from the group consisting of —H or a C
1
-C
5
alkyl group and R
7
and R
8
are independently selected from the group consisting of a C
1
-C
5
alkyl group.
The invention further relates to a method of producing and using the hydantoins of formula (III). Such compounds may be produced directly from a monoacetal (XI)
or via a dinitrile intermediate of formula (IV):
Hydantoin (III) is an intermediate in the manufacture of racemic mixture (V):
The S-stereoisomer, isolated from the racemic mixture, may be used, in place of compound (II), to produce omapatrilat. The overall reaction sequence for production of racemic mixture (V) is:
As used herein, “Method A” refers to the production of the novel hydantoin (III) of the invention directly from the monoacetal (XI). “Method B” refers to the production of the hydantoin via the dicyano intermediate and “Method C” refers to the production of the dicyano intermediate from the monoacetal (XI).
In another aspect of the invention, the novel hydantoin is employed to produce racemic mixture (V). The S-isomer, isolated from the racemic mixture, is used to produce omapatrilat. Production of the racemic from the novel hydantoin of the invention is referenced as “Method D.”
The use of compound (V) with its protected aldehyde avoids the need to oxidize the alcohol on compound (II) and thus reduces the number of steps necessary for the synthesis of omapatrilat and further avoid the use of noxious chemicals. See Robl, J. A., et al.
J. Med. Chem.
1997, 40, 1570-1577; Robl, J. A. et al.
J. Med. Chem.
1996, 39, 494-502.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention relates to novel hydantoin compounds of the formula (III):
and to processes of preparing the same. The invention further relates to a process of preparing a racemic mixture of formula (IV) from the hydantoin. The S-stereoisomer of the racemic mixture can be isolated and employed, as a substitute for formula (II), in the production of omapatrilat.
The hydantoin of the invention may be produced directly from the monoacetal of formula (XI) as well as via the dinitrile intermediate of formula (IV). The overall reaction sequence to generate the racemic mixture of formula (V) may be summarized as follows:
In the reaction sequence, R
1
is —H, a C
1
-C
5
alkyl group or a benzyl group. In a preferred embodiment, R
1
is —H or a C
1
-C
3
alkyl group. In the sequence above, R
2
is represented by either of the two following formulae,
wherein R
3
, R
4
, R
5
, and R
6
are independently selected from the group consisting of —H or a C
1
-C
5
alkyl group. (In a preferred embodiment R
3
, R
4
, R
5
, and R
6
are independently selected from a group consisting of —H or a C
1
-C
3
alkyl group. In a more preferred embodiment R
3
, R
4
, R
5
, and R
6
are independently selected from the group consisting of a C
1
-C
3
alkyl group; or R
3
, R
4
, R
5
, and R
6
are all —H);
R
7
and R
8
are independently selected from a group consisting of a C
1
-C
5
alkyl group. In a preferred embodiment R
7
and R
8
are independently selected from a group consisting of a C
1
-C
3
alkyl group.
Where the dinitrile (IV) is employed, each of the R
2
groups may independently be selected from (VII) and (VIII). Compound (IV) can be used as a starting material for synthesis of hydantoin (III). Hydantoin (III) is used as an intermediate in the synthesis of compound (V):
The S stereoisomer of compound (V) may be obtained by subjecting the racemic mixture of formula (V) to amidation in water. A molar excess (generally 10 to 20 percent excess) of acetic anhydride is typically used to ensure complete acylation of all of the nitrogen groups on the compound of formula (V). The reaction is conducted at approximately 35° C. The amide linkage on the desired S-isomer may then be cleaved by enzymatic activity, thereby leaving the undesired R isomer in solution. The free amino acid is then collected and purified. The S stereoisomer of compound (V) may be purified in the same manner as the (S)-hydroxy amino acid compound (II) with a theoretical yield of 50%. (See Robl, J. A., et al.
J. Med. Chem.
1997, 40, 1570-1577). The purified isomer may then be used to substitute for compound (II) as a synthetic starting material for generating omapatrilat.
An advantage in using compound (V) with its protected aldehyde is that it avoids the need to oxidize the alcohol on compound (II) and thus reduces the number of steps necessary for the synthesis of omapatrilat. It further avoids the use of noxious chemicals often employed in the oxidation of compound (II). See Robl, J. A., et al.
J. Med. Chem.
1997, 40, 1570-1577; Robl, J. A., et al.
J. Med. Chem.
1996, 39, 494-502.
An additional advantage in using compound (III) in the synthesis is the high efficiency evidenced when converting compound (III) to the S stereoisomer of compound (V). Hydantoins, such as compound (III), can be enzymatically racemized so that resolved R stereoisomer can be converted to and purified as the S stereoisomer, thereby increasing the possible yields of the desired S stereoisomer.
Compound (III) may be synthesized by either Method A or Method B. Method A is summarized below:
Any alkali cyanide, such as LiCN, as well as any organic cyanohydrin, such as a C
1
-C
6
aliphatic cyanohydrin, may be used in place of NaCN in Method A. The reaction scheme for Method A presented above illustrates the use of a H
2
O/EtOH blend as reaction medium, though a pure aqueous reaction medium may be used. The alcohol, which may be either methanol, ethanol, isopropyl alcohol, propyl alcohol, butyl alcohol or i-butyl alcohol, increases the solubility of the monoacetal of formula (I) in water. Typically, the weight ratio of water:C
1
-C
4
alcohol in the reaction medium is 1:1 or more. The weight ratio of monoacetal:cyanide compound is typically between 2:1. The weight ratio of cyanide:ammonium carbonate is generally 1:13; and the weight ratio of reaction medium:monoacetal is typically 28:1.
In a preferred embodiment, the reaction mixture is heated above room temperature, (20° C.). In a more preferred embodiment, the reaction mixture is heated to about 50° C. to about 57° C. The reaction mixture is allowed to react for a time sufficient to effectuate the reaction, preferably more than 2 hrs and more preferably greater than 6 hrs and even more preferably greater than 12 hours. In a preferred embodiment, the reaction product is recovered by adjusting the system pH from about 6 to about 10, preferably about 7, at which time the reaction product forms a solid white powder. The reaction is conducted at ambient pressure. Method (A) may further generate a minor amount of compound (IV) as an intermediate chemical species.
The dicyano compoun
Brown Robert E.
Raff Dwight E.
Rongione Joseph C.
Dixie Chemical Company
Higel Floyd G.
Locke Liddell & Sapp LLP
Shameen Golam M. M.
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