Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-09-14
2002-10-08
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S177000, C564S200000, C564S202000, C564S213000
Reexamination Certificate
active
06462234
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is a process, including intermediates, to produce (2S)-2-dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide which is a useful pharmaceutical agent.
2. Description of the Related Art
U.S. Pat. No. 6,084,130 discloses racemic (2S)-2-(dipropylarnino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide, see Example 38, and a process to prepare it.
U.S. provisional application Serial No. 60/184,020 discloses optically pure (2S)-2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide as well as a method of its preparation.
SUMMARY OF INVENTION
Disclosed is N-[(2S)-6-Ethoxy-2,3-dihydro-1-oxo-1H-inden-2-yl]-2,2,2-trifluoroacetamide.
Also disclosed is N-[(1S,2S)-6-Ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]1-2,2,2-trifluoroacetamide.
Further disclosed is N-[(2S)-5-Ethoxy-2,3-dihydro-1H-inden-2-yl]-2,2,2-trifluoroacetamide.
Additionally disclosed are compounds selected from the group consisting of:
2-[(1S,2S)-6-ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]-1H-isoindole-1,3(2H)-dione,
2-[(1R,2S)-6-ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]-1H-isoindole-1,3(2H)-dione,
N-[(1S,2S)-6-ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]-2-(hydroxymethyl)benzamide and
N-[(1R,2S)-6-ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]-2-(hydroxymethyl)benzamide.
Disclosed is a process for the preparation of N-[(2S)-6-Ethoxy-2,3-dihydro-1-oxo-1H-inden-2-1-2,2,2-trifluoroacetamide (V) which comprises:
(1) contacting O-ethyl-L-tyrosine (IV) with an activating reagent,
(2) contacting the reaction mixture ot step (1) with a Lewis acid for a period of less than 24 hr,
(3) quenching the reaction mixture of step (2) with a protic solvent.
Also disclosed is a process for the preparation of 2-[(2S)-6-ethoxy-2,3-dihydro-1-oxo-1H-inden-2-yl]-1H-isoindole-1,3(2H)-dione (XV) which comprises:
(1) contacting (&agr;S)-&agr;-[(4-ethoxyphenyl)methyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (XIV) with an activating reagent,
(2) contacting the reaction mixture of step (1) with a Lewis acid for a period of less than 24 hr,
(3) quenching the reaction mixture of step (2) with a protic solvent.
DETAILED DESCRIPTION OF THE INVENTION
U.S. Pat. No. 6,084,130, EXAMPLE 38, discloses (2S)-2-dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide in racemic form and a process for its preparation. U.S. provisional application Serial No. 60/184,020 discloses optically pure (2S)-2-(dipropylarnino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide as well as a method of its preparation. The present patent application discloses a process to produce optically pure (2S)-2-dipropyla mino)-6-ethoxy-2,3-dihydro-1H-indenc-5-carboxamide.
Optically pure (2S)-2-dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide is made by the process of the present invention as set forth in the CHARTS and EXAMPLES 1-18.
The processes of Steps (D) and (O), the transformation of the amine (IV) to the trifluoroacetamide (V) are inventive. What is described for the process of Step (D) is the same as for the process of Step (O), only the reactant is different resulting in a correspondingly different product.
In the process of Step (D), the O-ethyl-L-tyrosine (IV) is reacted with an activating reagent. It is preferred that the activating reagent be selected from the group consisting of trifluoroacetic anhydride, thionyl chloride and oxalyl chloride. It is more preferred that the activating reagent is trifluoroacetic anhydride. The O-ethyl-L-tyrosine (IV) is contacted with the activating agent in an inert solvent, preferably a chlorinated hydrocarbon solvent, more preferably methylene chloride. The reaction is operable front about −20° to about 80°, preferably from about 0° to about 40°. The reaction mixture of step (1) is then contacted with a Lewis acid. It is preferred that the Lewis acid be ferric chloride or galliun chloride, more preferably ferric chloride. The reaction of step (2) is preferably performed in an inert solvent, more preferably a chlorinated hydrocarbon solvent. even more preferably methylene chloride and is operable from about −20° to about 80°, preferably from about 0° to about 40°. The reaction mixture of step (2) is then quenched with a suitable quenching agent as is known to those skilled in the art. It is preferred that the quenching of step (3) be performed in an inert solvent, preferably a chlorinated hydrocarbon solvent, more preferably methylene chloride and is operable from about −20° to about 80°, preferably from about 0° to about 40°. The process of Step (O) is virtually the same except it starts with (&agr;S)-&agr;-[(4-ethoxyphenyl)methyl]1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (XIV).
In the conversion of amino compound (VI) to the dipropylamino compound (VII) it is apparent to those skilled in the art that other similar alkylating reagents can be utilized in place of n-bromopropane, such as n-propyliodide, etc. Also, other bases can be utilized in place of the phosphate base, such as sodium carbonate, organic tertiary amine bases such as diisopropylethylamine, etc. The preferred procedure is to use n-bromopropane and tribasic sodium phosphate. Additionally, it is apparent to those skilled in the art that reductive amination procedures can also be used to perform this chemical transformation, including using propanal in the presence of a hydride transfer reducing reagent such as sodium triacetoxyborohydride, sodium cyanoborohydride, etc. Alternatively, the amine can be repetitively acylated to form the propionamide of the amine and then reduced to the amine with lithium aluminum hydride, diisobutylhydride, a borane reagent, etc. two times to introduce the required propyl groups. The preferred method to obtain (VIII) is to heat (VII) with n-bromopropane in the presence of tribasic sodium phosphate. An analytical sample can be crystallized from ethyl acetate/hexane.
In the conversion of the dipropyl compound (IX) to the bromo compound (X), it will be apparent to one skilled in the art that other methods of brominating (IX) exist, such as direct treatment with bromine, N-bromosuccinimide, dibromohydantoin, etc. Other acid catalysts can also be utilized, such as acetic acid and other low molecular weight carboxylic acids, mineral acids, organic sullonic acids, etc. Tritluoroacetic acid is the preferred acid catalyst.
In the transformation of the bromo compound (X) to the amide (XI), it is readily apparent to one skilled in the art that a variety of palladium catalysts (PdCl
2
, Pd
n
(dba)
m
, etc.) and associated ligands (triphenylphosphine, tri-ortho-tolulyphosphine, etc) can be utilized in varying catalytic quantities.
The ALTERNATE PROCESS chart, discloses an alternate process for the transformation of O-ethyl-L-tyrosine (IV) to the dipropylamino compound (VII). See also EXAMPLEs 14-16.
(2S)-2-dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide (XI) is known to be a useful pharmaceutical agent, see U.S. Pat. No. 6,084,130.
DEFINITIONS AND CONVENTIONS
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
Definitions
All temperatures are in degrees Celsius.
TLC refers to thin-layer chromatography.
HPLC refers to high pressure liquid chromatography.
DMF refers to dimethylformamide.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
LC-MS refers mass spectroscopy analysis after liquid-liquid chromatography separation.
rt refers to retention time.
CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (&dgr;) downfield from TMS.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) downfield from TMS.
FMR refers to F-19 magnetic resonance spectroscopy, chemical s
Bystrom Styrbjorn
Chen Jiong Jack
Romero Arthur Glenn
Kumar Shailendra
Pharmacia & Upjohn Company
Stein Bruce
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