Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-01
2004-03-16
Huang, Evelyn Mei (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06706883
ABSTRACT:
BACKGROUND OF THE INVENTION
Tricyclic compounds useful as inhibitors of farnesyl protein transferase (FPT) are known in the art.
WO97/23478 published Jul. 3, 1997 discloses the preparation of an intermediate useful in the preparation of FPT inhibitors. The intermediate
is prepared by reacting
with diisobutylaluminum hydride followed by separation of the racemic mixture using a chiralpak AD column.
Processes which provide improved yields of the above intermediate would be a welcome contribution to the art. This invention provides such a process.
SUMMARY OF THE INVENTION
This invention provides a process for producing a compound of the formula:
comprising:
(1) separating the atropisomers of
to obtain the atropisomers
(2) heating the atropisomer of formula 2.0B at a suitable temperature in a suitable solvent to obtain a mixture of atropisomers of formulas 2.0A and 2.0B;
(3) separating the atropisomers of formulas 2.0A and 2.0B of step (2); and
(4) reducing the atropisomer of formula 2.0A to obtain a compound of formula 1.0;
wherein:
R
1
, R
2
, and R
3
are independently selected from halogen (i.e., Cl, Br, or I), C
1
to C
6
alkyl or —OR
4
wherein R
4
is a C
1
to C
6
alkyl.
Preferably, R
1
is Br, R
2
is Cl and R
3
is Br—i.e., preferably this invention provides a process for producing a compound of the formula:
comprising:
(1) separating the atropisomers of
to obtain the atropisomers
(2) heating the atropisomer of formula 2.1B at a suitable temperature in a suitable solvent to obtain a mixture of atropisomers of formulas 2.1A and 2.B;
(3) separating the atropisomers of formulas 2.1A and 2.1B of step (2); and
(4) reducing the atropisomer of formula 2.1A to obtain a compound of formula 1.1.
DETAILED DESCRIPTION OF THE INVENTION
The process of this invention provides the compound of formula 1.0 (preferably 1.1) as the specific (R)-isomer—i.e., no racemic mixture (based on C-11) is produced in the reduction step. Those skilled in the art will appreciate that C-11 position in the tricyclic ring is
The intermediate compound of formula 1.1 is useful in the preparation of FPT inhibitors disclosed, for example, in WO97/23478. Thus, the compound of formula 1.1 is useful in the preparation of:
In the process of this invention atropisomer 2.0A obtained in step 1 above can be reduced while additional atropisomer 2.0A is being obtained in steps 2 and 3 above. Thus, atropisomer 2.0A from step 1 above can be reduced as soon as it is obtained. Alternatively, atropisomer 2.0A obtained from step 1 above can be combined with atropisomer 2.0A obtained from steps 2 and 3 above, and the total amount of atropisomer 2.0A can be reduced at one time. Steps 2 and 3 above can be repeated to obtain additional atropisomer 2.0A from atropisomer 2.0B.
Preferably, formula 2.0 is separated, in step 1, into its atropisomers using HPLC and a suitable column (i.e., a column that will provide the desired degree of separation in a reasonable amount of time). Preferably, for separating compound 2.1, the column is packed with amylose tris(3,5-dimethylphenyl carbamate) coated on a 10 micron silica gel. This column is commercially available under the tradename Chiralpak AD.
A suitable elution solvent is used to obtain separation of the atropisomers. A suitable solvent is one which provides the desired degree of polarity to sufficiently separate the isomers in a reasonable amount of time. For example, the solvent can comprise: (1) a low boiling alcohol (e.g., isopropanol, methanol, ethanol, mixtures thereof, or the like); (2) a low boiling organic co-solvent (e.g., hexane, pentane, heptane, mixtures thereof, or the like); and (3) an organic base (e.g., diethylamine, diisopropylamine, triethylamine, mixtures thereof, or the like). The solvent, for example, can comprise from about 15 to about 35% alcohol, and about 40 to about 85% organic co-solvent, and about 0.1 to about 1% base, such that the total amount equals 100%v/v. For example, the elution solvent can comprise about 15 to about 35% isopropyl alcohol, and about 40 to about 85% hexane, and about 0.1 to about 1% diethylamine such that the total amount equals 100%v/v. Preferably, for compound 2.1, the elution solvent comprises 35% isopropyl alcohol and 0.2% diethylamine in hexane.
To convert atropisomer 2.0B to a mixture of atropisomers 2.0A and 2.0B, atropisomer 2.0B is heated at a suitable temperature in a suitable organic solvent. For example, atropisomer 2.0B can be heated to 100 to 200° C. in an appropriate high boiling solvent. Generally, atropisomer 2.0B is heated to reflux in the solvent. Examples of solvents include dimethyl formamide, toluene, and and 1,2-dichlorobenzene. Preferably, atropisomer 2.1B is heated in 1,2-dichlorobenzene at a temperature of about 150° C.
The atropisomer of formula 2.0A is reduced using a suitable reducing agent. Preferably, diisobutylaluminum hydride is used. The reduction is carried out using conditions well known to those skilled in the art. For example, atropisomer 2.0A can be dissolved in a suitable organic solvent (e.g., toluene) to which a suitable amount of diisobutylaluminum hydride is added to effectively reduce 2.0A. The solution is then refluxed under nitrogen. The desired product can then be isolated by known separation procedures.
REFERENCES:
patent: 4659671 (1987-04-01), Klibanov
patent: 5200555 (1993-04-01), Kessels
patent: 97/23478 (1997-07-01), None
patent: WO 98/58073 (1998-12-01), None
Girijavallabhan Viyyoor M.
Njoroge F. George
Vibulbhan Bancha
Huang Evelyn Mei
Jeanette Henry C.
Schering Corporation
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