Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-11
2003-11-04
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S080000
Reexamination Certificate
active
06642384
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a commercial process for the production of (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compounds (1) and their derivatives from Levodopa (L-Dopa). The ultimately prepared compounds are used as intermediates for, but not limited to, the preparation of substituted derivatives of 1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid such as those described in U.S. Pat. No. 4,344,949.
BACKGROUND OF THE INVENTION
The ACE inhibitor moexipril hydrochloride contains the 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid moiety in its structure, and it is known that the enantiomer possessing the (S) or (L)-configuration is required for optimum ACE inhibitory activity. This is disclosed in U.S. Pat. No. 4,344,949, and in Klutchko, S. et al.
J. Med. Chem.
1986, 29, pp. 1953-1961 “Synthesis of Novel Angiotensin Converting Enzyme Inhibitor Quinapril and Related Compounds. A Divergence of Structure-Activity Relationships for non-Sulfhydryl and Sulfhydry Types”. The prior art synthetic techniques for enantiomerically-enriched 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid requires an enantiomerically-enriched L-3,4-dimethoxyphenylalanine precursor, which was made by asymmetric hydrogenation of &agr;-amino-3,4-dimethoxycinnamic acid derivatives (O'Reilly, N. J. et al. U.S. Pat. No. 4,912,221) or enzymatic transamination of 3,4-RO(R1O)C
6
H
3
CH
2
CO—CO
2
H (DE 2148953) or enzymatic/chemical resolution (U.S. Pat. No. 3,669,837, GB 1241405). These approaches have limited commercial use due to cost and the necessity for specialized equipment. Also, the prior art synthetic technique have failed to produce compounds having optical purity levels of over 97% ee. The designation %ee (enantiomeric excess) represents: [(amount of desired isomer−amount of undesired isomer)/total amount of both isomers]×100%. Therefore, an efficient method for preparing enantiomerically-enriched (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compounds (1) and their derivatives was needed to overcome the above deficiencies.
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided a method for the preparation of (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compounds and their derivatives represented by the general formula 1:
which process comprises reacting Levodopa of formula 2 with formaldehyde or formaldehyde precursors to obtain (S)-1,2,3,4-tetrahydro-6,7-dihydroxy-3-isoquinolinecarboxylic acid of formula 3; protecting the amino group of the compound of formula 3; alkylating the phenol groups of formula 4 to form compound of formula 5; and esterifying the carboxylic acid of formula 5 and optionally removing the N-protecting group.
where R
1
is hydrogen, lower alkyl, C2-C12 acyl, or R
1
O together are methylenedioxy. When R
1
is a lower alkyl group, the preferred substituents are those of 1 to 9 carbon atoms. R
2
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, aralkyl or substituted aralkyl group. When R
2
represents an alkyl group, the preferred alkyls are those of 1 to 8 carbon atoms. R
3
is hydrogen, C2-C12 acyl group, benzyl, alkoxycarbonyl group, or aralkoxycarbonyl group. The process of instant invention provides an enantiomerically-enriched compound useful for, but not limited to, preparing moexipril and salts thereof. The preferred enantiomerically-enriched compounds obtained by the instant invention are (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid benzyl ester, and (S)-1,2,3,4-tetrahydro-6,7-diethoxy-3-isoquinolinecarboxylic acid. According to a further aspect of the invention, there are provided processes for making moexipril and salts thereof by reacting known compound of formula 9
with compound of formula 1 wherein compound of formula 1 is (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid or (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid benzyl ester. The coupling of compound (1) prepared according to instant invention with compound of formula 9 may be carried out by traditional method known to those skilled in the art.
The present invention also relates to new intermediate compounds of formulas A and B, useful for, but not limited to, the production of substituted acyl derivatives of tetrahydroisoquinoline carboxylic acids.
In accordance with the present invention, the (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compound (1) and their derivatives are prepared from commercially available and inexpensive material Levodopa (2) (L-Dopa) in high yield.
Surprisingly, the absolute (S)-configuration of Levodopa was transferred to compound (1) after multistep transformation. The starting material Levodopa (2) is a drug used for the treatment of Parkinson's disease, and can be obtained in one step enzymatically from L-tyrosine, which is an inexpensive, readily available amino acid. Scheme 1 outlines the method utilized for the preparation of the compound (1).
wherein R
1
, R
2
, R
3
are defined as above. P could be hydrogen or various amino protective groups. For a comprehensive review of amino protective groups, see Greene, T. W. and Wuts, P. G. M., ‘Chapter 7. Protection for the Amino Group’, in “Protective Groups in Organic Synthesis”, Second Edition, John Wiley & Sons, Inc., 1999, pp. 494-653. In this context, the preferred groups are selected from C2-C12 carbonyl group, benzyl, aralkoxy and alkoxycarbonyl groups.
The preparation of (S)-1,2,3,4-tetrahydro-6,7-dihydroxy-3isoquinolinecarboxylic acid (3) comprises reacting its precursor Levodopa (2) with formaldehyde or formaldehyde precursor, for example paraformaldehyde, in the presence of an acid or mixture of acids. [Some Isoquinoline Derivatives” (
J. Org. Chem.
1961, 26, pp. 3533-3534) and Brossi, A. et al. “‘Alkaloids’ in Mammalian Tissues. I. Condensation of L-Dopa and its two Mono-O-methyl Ethers with Formaldehyde and Acetaldehyde” (
Helv. Chim. Acta,
1972, 55, pp.15-21)].
The amino group in compound (3) is protected by amino protective groups, such as carbamates, amides, alkyl, aryl, silyl and sulfenyl derivatives, to form compound (4). The compounds (3) or (4) are then reacted with O-alkylating reagents to produce the compound (1).
The novel process of this invention provides the following advantages:
The overall chemical yield and the procedure is suitable for large scale production and does not require specialized equipment. Starting material Levodopa (2) is commercial available and inexpensive. Levodopa can also be obtained in one step enzymatically from L-tyrosine. The absolute (S)-configuration of Levodopa (2) could be transferred to compound (1) after multistep transformation. If Levodopa is made from L-tyrosine, the chirality of compound (1) ultimately comes from L-tyrosine.
DETAILS OF THE INVENTION
In the present invention, (S)-1,2,3,4-tetrahydro-6,7-dialkoxy-3-isoquinolinecarboxylic acid compounds and their derivatives are prepared from Levodopa with high chemical and optical purity and in good to excellent yield.
Scheme 2 depicts such a process, where R
1
is hydrogen, lower alkyl, C2-C12 acyl, or R
1
O together are methylenedioxy. When R
1
is a lower alkyl group, the preferred substituents are those of 1 to 9 carbon atoms. R
2
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, aralkyl or substituted aralkyl group. When R
2
represents an alkyl group, the preferred alkyls are those of 1 to 8 carbon atoms. R
3
is hydrogen, C2-C12 acyl group, benzyl, alkoxycarbonyl group, aralkoxycarbonyl group. P is hydrogen, C2-C12 acyl groups, benzyl, alkoxycarbonyl or aralkoxycarbonyl groups.
Levodopa (2) is reacted with formaldehyde or formaldehyde precursors, for example paraformaldehyde, in a solution in the presence of an acid or a mixture of the acids, such as hydrochloric acid, su
Horne Stephen E.
Wang Zhi-Xian
Brantford Chemicals Inc.
Davis Zinna Northington
Hughes Ivor M.
Sarkis Marcelo K.
Sinden Kitt
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