Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-01-29
2004-08-17
Desai, Rita (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S205000, C560S219000, C562S400000, C562S507000, C562S510000
Reexamination Certificate
active
06777574
ABSTRACT:
The invention relates to 2-alkyl-5-halogen-pent-4-enecarboxylic acid and its esters and salts in the form of its racemates and enantiomers and a process for the preparation of these carboxylic acids.
In the EP-A-0 678 503, &dgr;-amino-&ggr;-hydroxy-&ohgr;-aryl-alkanecarboxamides are described, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing procedures described are unsatisfactory in terms of the number of process steps and yields and are not suitable for an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.
In a new process, one starts from 2,7-dialkyl-8-aryl-4-octenoyl amides, whose double bond is simultaneously halogenated in the 5-position and hydroxylated in the 4-position under lactonization, then the halogen is substituted by azide, the lactone amidated and the azide then transferred to the amine group. The desired alkanecarboxamides are obtained with the new process both in high total yields and in a high degree of purity, and selectively pure diastereomers can be prepared. The halolactonization of process step a), the azidation of process step b), and the azide reduction of process stop d) are described by P. Herold in the Journal of Organic Chemistry, Vol. 54 (1989), pages 1178-1185.
The 2,7-dialkyl-8-aryl-4-octenoyl amides may correspond for example to formula A,
and especially to formula A1
wherein R
1
and R
2
independently of one another are H, C
1
-C
6
alkyl, C
1
-C
6
halogenalkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxy-C
1
-C
6
alkyl, or C
1
-C
6
alkoxy-C
1
-C
6
alkyloxy, R
3
is C
1
-C
6
alkyl, R
4
is C
1
-C
6
alkyl, R
6
is C
1
-C
6
alkyl, R
5
is C
1
-C
6
alkyl or C
1
-C
6
alkoxy, or R
5
and R
6
together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH
2
CH
2
O—C(O)— substituted if necessary with C
1
-C
4
alkyl, phenyl or benzyl.
The compounds of formulae A and A1 are obtainable by reacting a compound of formula B
as racemate or enantiomer, with a compound of formula C, as racemate or enantiomer,
wherein R
1
to R
4
, R
5
and R
6
are as defined above, Y is Cl, Br or I and Z is Cl, Br or I, in the presence of an alkali metal or alkaline earth metal. Y and Z are preferably Br and especially Cl.
It is expedient to prepare the compounds of formula C from the carboxylic acids corresponding to the amides, and their esters or acid halides, and these thus represent valuable intermediates for the preparation of the antihypertensive compositions mentioned previously. The formation of carboxamides from carboxylic acid esters and amines in the presence of trialkyl aluminium or dialkyl aluminium halide, for example using trimethyl aluminium or dimethyl aluminium chloride, is described by S. M. Weinreb in Org. Synthesis, VI, page 49 (1988).
A further object of the invention is represented by compounds of formula I in the form of racemates and enantiomers,
wherein
R
4
is C
1
-C
6
alkyl, Z is chlorine, bromine or iodine, and X is —OH, chloride, bromide or iodide, or X forms an ester group with the carbonyl substituent as well as salts of carboxylic acids.
Especially preferred enantiomers are those of formula Ia
R
4
is preferably C
1
-C
4
alkyl. Examples of alkyl are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. It is very particularly preferred when R
4
is i-propyl.
It is especially preferred when Z is Cl.
In the ester group, X is preferably a substituent of formula R
2
O—, where R
7
is an organic group with 1 to 18, preferably 1 to 12, and especially preferably 1 to 8 C-atoms and it necessary comprises heteroatoms selected from group O and N.
R
7
may be a branched and preferably linear alkyl, preferably comprising 1 to 4 C-atoms. Examples are methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl and octyl. Especially preferred are methyl and ethyl. The alkyl may be substituted, for example with C
1
-C
4
alkoxy, such as methoxy or ethoxy. Examples of substituted alkyl are methoxethyl and ethoxyethyl.
R
7
may be cycloalkyl with 3 to 8, and preferably 5 or 6 ring-carbon atoms. Examples are cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl may be substituted with C
1
-C
4
alkyl or C
1
-C
4
alkoxy.
R
7
may be cycloalkyl-C
1
-C
4
alkyl with 3 to 8, and preferably 5 or 6 ring-carbon atoms, which is unsubstituted or substituted with C
1
-C
4
alkyl or C
1
-C
4
alkoxy. Examples are cyclopentylmethyl, cyclohexylmethyl, methylcyclohexylmethyl and cyclohexylethyl.
R
7
may be C6-C
10
aryl which is unsubstituted or substituted with C
1
-C
4
alkyl or C
1
-C
4
alkoxy. Examples are phenyl, naphthyl, methylphenyl, ethylphenyl and i-propylphenyl.
R
7
may be C
6
-C
10
aryl-C
1
-C
4
alkyl which is unsubstituted or substituted with C
1
-C
4
alkyl or C
1
-C
4
alkoxy. Examples are benzyl, methylbenzyl and phenylethyl.
Of the acid halides of formula I, the chlorides and bromides are preferred.
The salts of carboxylic acids may for example be alkali metal or alkaline earth metal salts, as well as ammonium salt. Of the alkali metals and alkaline earth metals, lithium, sodium, potassium, magnesium and calcium are preferred. Suitable forms of ammonium are the ammonium cation, the cations of primary, secondary, and tertiary amines, and quaternary ammonium; these cations may comprise 1 to 20, preferably 1 to 16 C-atoms.
Especially preferred compounds of formulae I and Ia are those wherein Z is chlorine, R
4
is C
1
-C
4
alkyl and especially preferably i-propyl, and X is OH, Cl, Br or C
1
-C
4
alkoxy.
A particularly preferred embodiment includes compounds of formulae I and Ia wherein Z is chlorine, R
4
is i-propyl, and X is OH, Cl, Br, methoxy or ethoxy.
Especially preferred are compounds of formulae I and Ia wherein Z is chlorine, R
4
is i-propyl, and X is Cl or ethoxy.
The compounds of formula I are obtainable for example by reacting isovaleric acid esters with 1,3-dihalogenpropene in the presence of strong amine bases, such as alkali metal amides (Li-N(i-propyl)
2
or lithium hexamethyldisilazane) to form the esters of formula I, and preparing therefrom by derivatization in a manner known per se the carboxylic acids, carboxylic acid halides and carboxylic acid salts. The desired enantiomers can be obtained from the racemates in a manner known per se by separating the racemates, for example by crystallization from addition salts of carboxylic acids using optically active bases. It is more advantageous to separate the racemates by treating esters of formula I with esterases.
A further object of the invention is a process for the preparation of compounds of formula I comprising the reaction of a compound of formula II,
wherein Z and Z″ are independently of one another chlorine, bromine or iodine, and preferably chlorine or bromine, in the presence of strong amine bases with a compound of formula III,
wherein X forms an ester group with the carbonyl substituent and R
4
is C
1
-C
6
alkyl, and if necessary derivatization of the resulting carboxylic acid esters of formula I to form carboxylic acids, carboxylic acid halides or carboxylic acid salts.
The strong amine bases are preferably alkali metal amides. It is expedient to carry out the reaction using ether as solvent and cooling to approximately ambient temperature. Cooling can mean down to about −20° C.
The compounds of formula Ia can also be obtained by asymmetric synthesis.
A further object of the invention is a process for the preparation of compounds of formula Ia comprising the reaction of a compound of formula IV,
with a carboxylic acid halide of formula R
4
CH
2
—CO—X, wherein R
4
is as defined above and X is chlorine, bromine or iodine, and reaction of the resulting compound of formula V,
first with lithium hexamethyldisilazide and then with a compound of formula II,
wherein Z and Z″ are independently of one another chlorine, bromine or iodine, followed by hydrolyzation of the resulting compound of formula VI
with a base which isolates t
Herold Peter
Stutz Stefan
Desai Rita
Reyes Hector M.
Speedel Pharma AG
Wenderoth , Lind & Ponack, L.L.P.
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