Process for preparing 1,4-dihydropyridine compounds

Details Process for preparing 1,4-dihydropyridine compounds Process for preparing 1,4-dihydropyridine compounds

2002-08-20

2003-11-18

Davis, Zinna Northington (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S286000, C546S287000, C546S318000, C546S321000

Reexamination Certificate

active

06649767

ABSTRACT:

TECHNICAL FIELD
This invention relates to a process for preparing 1,4-dihydropyridine compounds. Compounds having 1,4-dihydropyridine structure are widely used in pharmaceutical industry. The compounds have been used, for example, in treating or preventing diseases such as cardiovascular disease and inflammation diseases.
BACKGROUND ART
Nifedipine and amlodipine are well-known 1,4-dihydropyridine compounds as calcium channel blockers.
Recently, it has been discovered that certain 1,4-dihydropyridine compounds possess bradykinin antagonistic activity. For example, PCT international patent publications WO 96/06082 and WO97/30048, and U.S. Pat. No. 5,861,402 disclose 1,4-dihydropyridine compounds possessing bradykinin antagonistic activity which are thus useful in the treatment of diseases or symptoms including an inflammation disease, a cardiovascular disease, and a pain producing trauma. These bradykinin-antagonist compounds are characterized by having, at its 2-position with a substituent comprising such as carbonyl, ester, amide or imide moiety.
Various 1,4-dihydropyridine preparation processes have been disclosed. For example, Hantzsch synthesis has been widely used as a 1,4-dihydro-2,6-dimethyl-pyridine preparation process. The process can be carried out by condensation of two moles of a &bgr;-dicarbonate with one mole of an aldehyde in the presence of ammonia. J. B. Sainani reported synthesis of a 1,4-dihydro-2,6-dimethyl-pyridine compound which has asymmetrical substituents at its 3- and 5-positions (
Org. Chem. Incl. Med. Chem
. (1994), 33b (6),573-575).
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing 1,4-dihydropyridine compounds which comprises the steps of (a) contacting an enamine compound having structure of
and a compound having a structure of
in the presence of a base; and (b) treating the reaction mixture thus obtained in the presence of an acid or a combination of acids.
The present invention also provides a process for preparing a compound of formula (I):
wherein
R
1
is selected from hydrogen and (C
1
-C
4
)alkyl;
R
2
is selected from nitrile; —SO
3
H; —SO
2
—(C
1
-C
6
)alkyl; —SO—(C
1
-C
6
)alkyl; —PO[O(C
1
-C
6
)alkyl]; —C(═O)—R
7
, wherein R
7
is selected from hydroxy or its salt, (C
1
-C
6
)alkyl-O—, amino, (C
1
-C
6
)alkyl-NH— and di[(C
1
-C
6
)alkyl]-N—;
R
3
and R
5
are independently selected from nitrile and (C
1
-C
5
)alkoxy-C(═O)—;
R
4
is an unsubstituted or a mono-, di-, tri-, tetra- or penta-substituted phenyl wherein the substituents are independently selected from halo; (C
1
-C
4
)alkyl optionally substituted with one to three halo; (C
1
-C
4
)alkoxy optionally substituted with one to three halo; nitro; amino; mono(C
1
-C
4
)alkylamino and di[(C
1
-C
4
)alkyl]amino;
R
6
is selected from hydrogen; (C
1
-C
10
)alkyl; phenyl optionally substituted with one to two substituents independently selected from halo, (C
1
-C
4
)alkyl, tri-halo(C
1
-C
4
)alkyl and (C
1
-C
4
)alkoxy; and a 4- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms or heteroatom containing moieties independently selected from —O—, —S—, —NH— and —N[(C
1
-C
4
)alkyl]-, wherein said heterocyclic ring is saturated, partially-saturated or aromatic, and said heterocyclic ring is optionally substituted with one halo or (C
1
-C
4
)alkyl; and
Y is selected from a covalent bond, methylene, oxygen and sulfur; the process comprising the steps of
(a) addition reaction of an enamine compound of formula
 to a compound of formula
 wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and Y are as defined above in the presence of a base under reaction conditions sufficient for coupling the compounds; and
(b) cyclization of the resulting compound in step (a) in the presence of an acid catalyst selected from a protonic acid, and a combination of a protonic acid and a non-protonic Lewis acid.
In the above described processes, compounds of formula (I) or (II) wherein R
2
is a salt of carboxyl group (i.e., R
2
is —C(═O)—R
7
wherein R
7
is a salt of hydroxy) are inorganic or organic salts of the carboxylic acid. Those salts are formed with a cation such as alkali or akaline earth metal (e.g., sodium, potassium, calcium, and magnesium), hydroxide or alkoxide in water or an appropriate organic solvent such as ethanol, isopropyl alcohol or mixture thereof.
According to the present invention, in general, desired 1,4-dihydropyridine compounds can be prepared under mild conditions, in a one-pot synthesis and high-yield.
In the above process, preferred substrates of formula (II) and resulting compounds of formula (I) are those compounds of each formula wherein R
1
is hydrogen.
DETAILED DISCLOSURE OF THE INVENTION
The term “(C
1
-C
4
)alkyl”, as used herein, unless otherwise indicated, means a straight or branched saturated monovalent hydrocarbon radical selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
The term “(C
1
-C
4
)alkoxy”, as used herein, unless otherwise indicated, means a straight or branched (C
1
-C
4
)alkyl-O radical selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy.
The term “heterocyclic ring”, as used herein, unless other wise indicated, means a monocyclic or bicyclic hydrocarbon group which has one or more hetero atoms in the ring, preferably has 6 to 9 carbon atoms and 1 to 4 hetero atoms or independently selected from —O—, —S—, —NH—, —N[(C
1
-C
4
)alkyl]-, wherein said heterocyclic is saturated, partially-saturated or aromatic. Examples of those groups include, but not limited to piperidino, morpholino, thiamorphorino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl.
The term “halo”, as used herein, refers to F, Cl, Br or I, preferably F or Cl.
Preferred bases used in reaction step (a) of this invention include bases capable of promoting a Michael-type reaction.
Preferred combination of “base in step (a)” and “acid catalyst in step (b)” may be “a magnesium (II) base in step (a)” and “a protonic acid in step (b)”.
Preferably, an amount of the base is equal or more than 1 equivalent.
Other preferred combination of “base in step (a)” and “acid catalyst in step (b)” may be “bases other than magnesium (II) bases (e.g., alkyl-magnesium-halides, halo-magnesium-alkoxides and magnesium-dialkoxides) which are capable of promoting a Michael-type reaction in step (a)” and “a combination of a protonic acid and a non-protonic Lewis acid”. Any non-protonic Lewis acids known to those skilled in the art such as metal halides, metal triflates (i.e., metal trifluoromethanesulfonate) or the like may be used in step (b). Examples of the Lewis acid include magnesium bromide, magnesium chloride, zinc bromide, zinc chloride, zinc iodide, tin(IV) chloride, titanium(IV) chloride, aluminium trichloride, ethylaluminum dichloride, diethylaluminum chloride, boron trifluoride, copper(II) triflate, scandium(III) triflate, lanthanum triflate, ytterbium triflate, lanthanum chloride, cerium(III) chloride and iron(III) chloride. Preferred individual Lewis acids include magnesium bromide and its ether complex such as magnesium bromide diethyl etherate, magnesium chloride and its ether complex such as magnesium chloride diethyl etharate, zinc chloride, zinc bromide and scandium(III) triflate. Among the Lewis acids, preferred ones include magnesium (II) salts such as magnesium halides, magnesium bromides and their ether complexes such as magnesium bromide diethyl etherate. Another preferred ones include magnesium (II) salts such as a magnesium sulfate, magnesium acetate, halomagnesiumacetate and halomagnesium sulfate.
Non-protonic Lewis acid such as MgCl
2
can be added in the step (a) in advance.
When the starting compounds contain Lewis basic atom(s) such as N and O, an amount of the Lewis acid added may be increased for the success of step (b).
Preferably, a process of

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