Phenyl inden-1-one compounds

Details Phenyl inden-1-one compounds Phenyl inden-1-one compounds

2003-03-28

2004-09-14

Davis, Brian (Department: 1621)

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

Organic compounds

Oxygen containing

Reexamination Certificate

active

06790998

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process of preparing tolterodine and analogues thereof, as well as to novel intermediates prepared in the process.
BACKGROUND OF THE INVENTION
Tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, is useful for treating urinary incontinence. The major, active metabolite of tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine, contributes significantly to the therapeutic effect of tolterodine. Tolterodine and analogues thereof, including the corresponding (S)-enantiomer, as well as processes for the preparation thereof are disclosed in U.S. Pat. No. 5,382,600. The active metabolite and analogues are disclosed in U.S. Pat. No. 5,559,269. The (S)-enantiomer and its use in the treatment of urinary and gastrointestinal disorders is further described in WO 98/03067.
One of the processes described in U.S. Pat. No. 5,382,600 comprises the steps of preparing the lactone 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, reductively ring-opening the lactone to prepare the corresponding alcohol, reacting the alcohol with isopropylamine, and resolving the racemate formed to isolate tolterodine.
U.S. Pat. No. 5,922,914 discloses a modified process for preparing tolterodine by reducing the above-mentioned lactone to the corresponding alcohol, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol, reductively aminating the alcohol, and resolving the racemate formed to isolate tolterodine.
While the above prior art methods thus produce a racemate which has to be resolved to obtain the desired tolterodine enantiomer, Andersson, Pher G. et al., J. Org. Chem. 1998, 63, 8067-8070 discloses an enantioselective synthesis of tolterodine which obviates the need of the enantiomer separation step. This method comprises a copper bromide catalyzed asymmetric addition of 2-methoxy-5-methylphenylmagnesium bromide to a 3-phenyl-prop-2-enoyl-oxazolidinone to produce the (5S)-phenyl-(3R)-(2-benzyloxy-5-methylphenyl)-3-phenylpropanoyl-2-oxazolidinone, hydrolyzation of the oxazolidinone to the corresponding propanoic acid, reaction with diisopropylamine to form the amide, and reduction of the amide to tolterodine.
SUMMARY OF THE INVENTION
The present invention provides an alternate enantioselective synthesis of tolterodine which is more convenient to perform than the prior art method outlined above and which gives a final product of high enantiomeric purity. A key step of the present method is the preparation of the above-mentioned lactone, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (also referred to as 6-methyl-4-phenyl-chroman-2-one), in an enantiomerically enriched form by enantioselective reactions.
Thus, in a first aspect the present invention provides a process for the enantioselective preparation of a compound of the general formula (Ia) or (Ib):
wherein R
1
, R
2
and R
3
independently of each other are hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, and R
4
and R
5
independently of each other are C
1-6
-alkyl, or a salt thereof, which process comprises the steps of:
a) enantioselectively reducing the carbonyl function in a compound of formula (II):
wherein R
1
, R
2
and R
3
are as defined above, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb):
wherein R
1
, R
2
and R
3
are as defined above, or a salt thereof,
b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb):
wherein R
1
, R
2
and R
3
are as defined above, or a salt thereof;
c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form a corresponding enantiomerically enriched compound of the general formula (Va) or (Vb):
wherein R
1
, R
2
and R
3
are as defined above or a salt thereof;
d) converting the compound of formula (Va) or (Vb) to form the corresponding enantiometrically enriched compound of formula (Ia) or (Ib), or a salt thereof; and
e) optionally converting a compound of formula (Ia) or (Ib) in base form to a salt thereof, or converting a salt form to the free base.
In one embodiment of the first aspect of the invention, step d) comprises:
d1) reacting the compound of formula (Va) or (Vb) with an amine of the general formula (VI):
wherein R
4
and R
5
are as defined above, to form a corresponding enantiomerically enriched compound of the general formula (VIIa) or (VIIb):
wherein R
1
, R
2
, R
3
, R
4
and R
5
are as defined above; and
d2) reducing the carbonyl function in the compound of formula (VIIa) or (VIIb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).
Optionally, steps d1) and d2) are performed simultaneously in a single step.
In an alternative embodiment, step d) comprises:
d1′) reducing the compound of formula (Va) or (Vb) to form a corresponding enantiomerically enriched hydroxy compound of the general formula (VIIIa) or (VIIIb):
wherein R
1
, R
2
and R
3
are as defined in claim
1
; and
d2′) reductively aminating the hydroxy compound of formula (VIIIa) or (VIIIb) with the amine of formula (VI) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).
In second aspect, the present invention provides a process for the enantioselective preparation of a compound of the general formula (Va) or (Vb):
wherein R
1
, R
2
and R
3
are as defined above, or a salt thereof, which process comprises the steps of:
a) enantioselectively reducing the carbonyl function in a compound of formula (II):
wherein R
1
, R
2
and R
3
are as defined above, or a salt thereof, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb):
wherein R
1
, R
2
and R
3
are as defined above, or a salt thereof;
b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb):
wherein R
1
, R
2
and R
3
are as defined above, or a salt thereof; and
c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form the corresponding enantiomerically enriched compound of the general formula (Va) or (Vb), or salt thereof.
The compound of formula (II) may be prepared by subjecting a compound of the general formula (IX):
wherein R
1
, R
2
, and R
3
are as defined in claim 1, and Hal is halogen (preferably bromine), or a salt thereof, to a reductive ring closure reaction.
The compound of formula (IX) may be prepared by reacting a compound of the general formula (X):
wherein R
1
and Hal are as defined above, with a compound of the general formula (XI):
wherein R
2
and R
3
are as defined above.
Preferably, compounds of formula Ia or Ib are prepared in which R
1
is methyl or hydroxymethyl in 5-position, R
2
and R
3
are hydrogen, and R
4
and R
5
are both iso-propyl.
In a third aspect, the present invention provides novel compounds of the above of the formulae (II), (IIa), (IIIb), (IVa), (IVb), (Va), (Vb), and (IX) as defined above and wherein R
1
is methyl or hydroxymethyl in 5-position, or for (Va) and (Vb), in 6-position, and R
2
and R
3
are hydrogen and compounds of the formulae (IX) wherein R
1
is methyl or hydroxymethyl in 5-position or 4-position, R
2
and R
3
are hydrogen and halogen is Br, I or F.


REFERENCES:
patent: 6566537 (2003-05-01), Anderson et al.
patent: WO8906644 (1989-07-01), None
patent: WO97107330 (1997-05-01), None
patent: WO9829402 (1998-07-01), None
Clark, et al., A Highly Enantioselective Conjugate Reduction of 3-Arylinden-1-ones Using Bakers' Yeast for the Preparation of (S)-3-Arylindan-1-ones†,Organic Letters, vol. 1, No. 11, pp. 1839-1842 (1999).
Meyers et al., An Asymmetric Synthesis of 5-Methoxy-3-Substituted Acids and Their Related Lactones in High Enantiomeric Purity,Tetrahedron Letters, No. 23, pp. 1947-1950 (1976).
Andersson, et al., Asymmetric Total Synthesis of (+)-Tolterodine, a New Muscarinic Receptor Antagonist, v

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