Enantioselective synthesis

Details Enantioselective synthesis Enantioselective synthesis

1999-08-11

2001-07-17

Chang, Ceila (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S320000

Reexamination Certificate

active

06262270

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a short efficient enantioselective synthesis of the orally active a antiestrogen of the formula I or XIV
or a pharmaceutically acceptable salt thereof.
The synthesis and the antiestrogenic activity of the compound of formula 1, i.e., (S)-7-hydroxy-3-(4′-hydroxyphenyl)-4-methyl-2-(4″-[2′″-(1-piperidino)-ethoxy]phenyl)-2H-benzopyran 4′,7-bistrimethylacetate, is disclosed in
J. Med Chem.,
1997, 40, 2117-2122. See also U.S. Pat. Nos. 5,395,842, and 5,407,947 and
J. Med. Chem.,
1990, 33, 3216-3222. Each of the synthetic schemes disclosed is a laboratory scale procedure involving costly steps not suitable for a practical commercial scale process.
There is a need for a short, efficient, enantioselective synthesis suitable for the large scale manufacture of the compounds of formulas I and XIV.
SUMMARY OF THE INVENTION
The present invention provides a process which comprises reacting the compound of formula IV with the compound represented by formula VII
in the presence of piperidine, a hindered organic amine base and a (C
3
-C
6
) alkanol at temperature and for a time sufficient to produce the compound of formula IX essentially free of the cis-isomer of the compound of formula IX, and of the E and Z-chalcones of formula VIII wherein HPG is an acid-labile phenolic hydroxyl protecting group:
The present invention also provides a process which comprises the steps of:
(a). reacting the compound of formula IV with the compound represented by formula VII:
in the presence of piperidine, a hindered organic amine base and a (C
3
-C
6
) alkanol at temperature and for a time sufficient to produce the compound of formula IX essentially free of the cis-isomer of the compound of formula IX, and substantially free of the E and Z-chalcones of formula VIII wherein HPG is an acid labile phenolic hydroxyl protecting group;
(b). reacting the compound of formula IX with a stoichiometric excess of methyl lithium in an aprotic solvent for a time and temperature sufficient to produce the compound of formula X;
(c). contacting the compound of formula X with a stoichiometric excess of (S)-(+)-camphorsulfonic acid in a solvent comprising a C
1
-C
6
alkanol for a time and at a temperature sufficient to produce the racemic R,S/S,S-acid addition salt of the formula XI;
(d). contacting the racemic acid addition salt of the formula XI with a catalytic amount of (S)-(+)-camphorsulfonic and in a solvent comprising ethanol for a time and at a temperature sufficient to produce the single S,S-diastereometric acid addition salt of the formula XII;
substantially free of the opposite R,S-diastereomeric salt of the formula XIII,
(e)(i). contacting the the S,S-diastereometric acid addition salt of compound XII with a stoichiometric excess of pivaloyl chloride in the presence of tertiary organic base at a temperature and time sufficient to produce the compound of formula I:
(e)(ii) contacting the the S,S-diastereometric acid addition salt of compound XII with sufficient amount of a tertiary organic base at a temperature and time sufficient to produce a compound of formula XIV:
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention provides a short, practical commercial process for the efficient enantioselective synthesis of the potent orally active nonsteroidal, antiestrogen compounds of formulas I and XIV, substantially chemically and enantiomerically pure. By the term “enantioselective synthesis” as used herein in reference to the compounds of formulas I and XIV is meant that the process of this invention produces the S-enantiometer of formulas I and XIV in preference to the enantiomer of the opposite R-configuration. The process, summarized in Schemes I and IA, comprises a selection of reagents and reaction conditions which avoid the use of separation techniques such as fractional crystallization and chromatography while providing chemically and enantiometrically pure compounds. Steps B and C of the process in Scheme I involves reactions and reactions conditions to shift the chalcone (compound VIII)/chromanone-(compound IX) equilibrium to produce essentially only the pivotal 2,3-trans-diaryl-2,3-dihydro-4H-1-benzopyran-4-one of formula IX a precursor of the compound of formula 1. The conversion of this racemic precursor to a single S,S-diastereomer of formula XII is effected by a kinetic (dynamic) resolution in Step F. Specifically, the present invention provides conditions and reagents in Steps B and C which allow production of a single trans compound of formula IX substantially chemically pure and essentially free of the cis-isomer of the compound of formula IX and free of the E and Z chalcones of formula VIII. By the term “chemically pure” as used herein means greater than 95% preferably greater than 99% free of other chemicals, e.g. the E and Z chalcones of formula VIII. By the phrase “essentially free of the cis-isomer of compound of the formula IX” as used herein means that the compound of formula IX contains less than about 2% preferably less than about 1% of the cis-isomer of the compound of the formula IX.
By the term “(C
3
-C
6
) alkanol” is meant a straight or branched chain (C
3
-C
6
) alkanol including isopropanol isobutanol, isopentanol and isohexanol, and the secondary alcohols, 2-butanol, 2-pentanol, 3-pentanol, and 2-hexanol. Use of 2-butanol, isobutanol or isopropanol are preferred. Use of 2-butanol is more preferred.
By the term “acid labile phenolic hydroxyl protecting group” (HPG) as used herein is meant means protecting groups which are removed under acidic conditions, e.g., conditions of step E of the present invention. Typically suitable acid labile phenolic hydroxyl protecting groups include phenolic protecting groups commonly employed in organic chemistry including, but not limited to, tetrahydropuranyl, methoxymethyl, methoxyethoxymethyl and cyclopropylmethyl. The introduction of phenolic hydroxyl protecting groups is disclosed in “Protecting Groups in Organic Synthesis, T. W. Greene, pp. 87-113. J. Wiley & Sons, NY, 1984. Use of tetrahydropyranyl as a phenolic hydroxyl protecting group is preferred. (See Example 1.)
By the term “a hindered organic amine base” as used herein means non-nucleophilic organic amines. Typically suitable hindered organic amine bases include 1,5-diazabicyclo[4.3.0]non-5-ene (“DBN”), 1,4-diazabicyclo[2.2.2.]octane (“Dabco™”), 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”) and 1,1,3′,3′-tetramethylguanidine (“TMG”). DBN, Dabco, DBU and TMG are available from Aldrich, Milwaukee Wis. 53233. Use of DBU and DBN are preferred. Use of DBU is more preferred.
By the term “tertiary amine base” as used herein means tri (C
1
-C
6
) alkyl amines such as triethylamine, N-methyl-piperidine and N-methyl morpholine. The preferred tertiary amine base is triethylamine.
Details of the steps in the Schemes I and IA are provided herein below.
Step A: The compound of formula IV may be prepared by reaction of the compound of formula III with dihydropyran (“DHP”) in the presence of p-toluenesulfonic acid (“p-tsa”) in ethyl acetate. The compound of formula III may be prepared as described in
J. Med. Chem.,
1997, 40, 2117-2122 at page 2117.
Steps B and C: Step B, formation of the carbon-carbon double bond in compound of the formula VIII, involves a Knoevenagel condensation reaction of the ketone compound of formula IV with the aldehyde of formula VII in the presence of a solvent and a catalytic amount of piperidine. The preferred solvent is 2-butanol but other (C
3
-C
6
) alkanols such as isopropanol or isobutanol may also be used. The condensation reaction is normally carried out by heating the reacton mixture of compounds IV and VII and piperidine in a (C
3
-C
6
)alkanol to reflux temperature under an inert atmosphere such as nitrogen or argon. The Knoevenagel condensation is an equilibrium reaction and must be driven to completion by removal of water from the reaction mixture. Removal of water is achieved by d

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