Method for the production of...

Details Method for the production of... Method for the production of...

2003-08-21

2004-08-31

Huang, Evelyn Mei (Department: 1625)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S562000, C548S235000, C549S349000, C549S359000, C549S436000, C560S052000

Reexamination Certificate

active

06784292

ABSTRACT:

The invention relates to a new process for the production of imidazo[1,2-c][2,3]benzodiazepines of general formula (1) as well as new intermediate products in the process,
in which
R
1
=hydrogen, C
1
-C
6
-alkyl, nitro, halogen, cyano, C
1
-C
4
-alkoxy, —CF
3
, hydroxy or C
1
-C
6
-alkanoyloxy,
R
2
and R
3
are the same or different and mean hydrogen, halogen, C
1
-C
6
-alkoxy, hydroxy, cyano, C
1
-C
6
-alkanoyl, C
2
-C
6
-alkynyl, C
2
-C
6
-alkenyl; C
1
-C
6
-alkyl or C
3
-C
7
-cycloalkyl optionally substituted by halogen, hydroxy or C
1-6
-alkoxy; or an aryl or hetaryl radical that is optionally substituted by halogen, C
1-4
-alkoxy or C
1-4
-alkyl,
X=hydrogen or halogen,
Y=C
1
-C
6
-alkoxy, or
X and Y together mean —O—(CH
2
)
n
—O— with
n=1, 2 or 3.
The invention also contains, as new intermediate products for the production of pharmacologically active compounds, phenylacetic acid derivatives of general formula 5,
in which
R
1
=hydrogen, C
1
-C
6
-alkyl, nitro, halogen, cyano, C
1
-C
4
-alkoxy, —CF
3
, hydroxy or C
1
-C
6
-alkanoyloxy,
R
2
and R
3
are the same or different and mean hydrogen, halogen, C
1
-C
6
-alkoxy, hydroxy, cyano, C
1
-C
6
-alkanoyl, C
2
-C
6
-alkynyl, C
2
-C
6
-alkenyl; C
1
-C
6
-alkyl or C
3
-C
7
-cycloalkyl optionally substituted by halogen, hydroxy or C
1-6
-alkoxy, or an aryl or hetaryl radical that is optionally substituted with halogen, C
1-4
-alkoxy or C
1-4
-alkyl,
X=hydrogen or halogen,
Y=C
1
-C
6
-alkoxy or
X and Y together mean —O—(CH
2
)
n
—O— with
n=1, 2 or 3, and
oxazole derivatives of general formula 6,
in which
R
1
=hydrogen, C
1
-C
6
-alkyl, nitro, halogen, cyano, C
1
-C
4
-alkoxy, —CF
3
, hydroxy or C
1
-C
6
-alkanoyloxy,
R
2
and R
3
are the same or different and mean hydrogen, halogen, C
1
-C
6
-alkoxy, hydroxy, cyano, C
1
-C
6
-alkanoyl, C
2
-C
6
-alkynyl, C
2
-C
6
-alkenyl; C
1
-C
6
-alkyl or C
3
-C
7
-cycloalkyl optionally substituted by halogen, hydroxy or C
1-6
-alkoxy, or an aryl or hetaryl radical optionally substituted by halogen, C
1-4
-alkoxy or C
1-4
-alkyl,
X=hydrogen or halogen,
Y=C
1
-C
6
-alkoxy or
X and Y together mean —O—(CH
2
)
n
—O— with
n=1, 2 or 3.
The radicals within the general formulas have the following meanings:
C
1
-C
6
-Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl.
R
2
and R
3
in the meaning of C
2
-C
6
-alkenyl contain, in each case, at least one double bond, such as, for example, vinyl, propenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-dimethyl-buten-1-yl, 3-methylbuten-1-yl, or hexen-1-yl.
If R
2
and R
3
mean C
1
-C
6
-alkynyl, at least one triple bond is present, such as, for example, ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, or hexyn-1-yl. The above-described alkenyl or alkinyl radicals can optionally also be substituted with halogen atoms. If a halogenated alkyl radical is present, the latter can be halogenated in one or more places, but can also be perhalogenated, such as, for example, —CF
3
.
Within the above radicals, halogen is defined respectively as fluorine, chlorine, bromine and iodine.
R
2
and R
3
in the meaning of aryl and hetaryl radicals can optionally be substituted in one, two or three places with halogen, C
1-4
-alkoxy-, or C
1-4
-alkyl radicals; any permutations are possible.
The aryl and hetaryl radicals can be present as monocyclic or bicyclic compounds and contain 5-12 ring atoms, preferably 5-9 ring atoms, such as, for example, phenyl, biphenyl, naphthyl, or indenyl as an aryl radical, and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyridazinyl, oxazolyl, isooxazolyl, thiazolyl, isothioazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, benzo[1]thienyl, or benzofuranyl as a hetaryl radical, containing 1-3 heteroatoms, such as, for example, sulfur, oxygen, and/or nitrogen. As preferred radicals, 2-thienyl, 3-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl and phenyl can be mentioned.
With R
2
and R
3
in the meaning of C
3
-C
8
-cycloalkyl, for example, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals are meant.
As C
1
-C
6
-alkanoyl radicals, in each case straight-chain or branched aliphatic carboxylic acid radicals, such as, for example, formyl, acetyl, propinoyl, butanoyl, isopropylcarbonyl, caproyl, valeroyl or trimethylacetyl, are suitable.
R
1
preferably means hydrogen, chlorine, nitro, methoxy; R
2
and R
3
preferably mean hydrogen, or C
1-4
-alkyl or phenyl; X and Y together preferably mean —O—CH
2
—O—.
Processes for the production of the compounds of general formula 1 are described within WO 97/28163.
The object of this invention is a new process for the synthesis of the compounds of general formula 1. Subjects of this invention are also new, previously unknown intermediate products of general formulas 5 and 6, which are processed within the framework of the synthesis and can be used per se or derivatized as starting materials for the synthesis of other target molecules.
This object is achieved by the teaching of the claims.
By the process according to the invention, fewer intermediate stages are processed than in the known synthesis from the prior art, the number of purification steps is significantly lower and the total yield is increased. The process according to the invention makes possible the production of the compounds of formula I on an industrial scale.
The invention thus contains a process for the production of imidazo[1,2-c][2,3]benzodiazepines of general formula 1
in which R
1
, R
2
and R
3
as well as X and Y have the above meaning,
from phenylacetic acids of general formula 4,
 in which X, Y and R
1
have the above-mentioned meaning
a) by esterification with an alcohol of Formula 5 a
 to form phenylethyl acetate of general formula 5,
 in which
X, Y, R
1
, R
2
and R
3
have the above-mentioned meaning,
b) by condensation with ammonia or an ammonia donor to form the oxazole of general formula 6,
 in which
X, Y, R
1
, R
2
and R
3
have the above-mentioned meaning, and subsequent hydrazinolysis to form the compounds of general formula 1.
Imidazo[1,2-c][2,3]benzodiazepines of general formula 1 are synthesized according to Diagram 1.
The reaction of a compound of general formula 2 to form a compound of general formula 3 is carried out according to a process that is known in the art (e.g.,
J. Chem. Soc., Perkin Trans
. 1 1991, 169-173) of a Friedel-Crafts reaction. For example, compounds of general formula 2 are reacted in the presence of Lewis acids, such as, for example, tin tetrachloride, aluminum trichloride, titanium tetrachloride and an acylating agent, such as, for example, benzoyl chloride, benzoic acid anhydride or another activated carboxylic acid derivative. A significant increase in yield is achieved if additional N,N-dimethyl acetamide is added to the reaction mixture. As a solvent, halogenated hydrocarbons, such as, e.g., methylene chloride or ethylene chloride and mixtures thereof can be used. The reaction is performed in a temperature range of −30° to 50° C., but preferably in a temperature range of 0° to 25° C.
The reaction of a compound of general formula 3 to form a compound of general formula 4 is carried out according to a process of a saponification reaction that is known in the art. For example, a compound of general formula 3 is heated in the presence of a base, such as alkali hydroxide, but preferably sodium hydroxide, in a solvent, such as a lower, preferably primary alcohol or water or mixtures thereof. The reaction is performed in a temperature range of 25° to 150° C., but preferably in the temperature range of 70° to 110° C.
The reaction of a compound of general formula 4 to form a compound of formula 5 is carried out according to a process of an ester

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