Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-12
2002-05-07
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06384226
ABSTRACT:
The present invention relates to a process for the preparation of 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides.
More particularly, the invention relates to a process for the preparation of Zolpidem (N,N-dimethyl-6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate), a pharmaceutical compound with hypnotic-sedative activity at present widely used in clinic, disclosed in EP 50.563.
Zolpidem has the following structural formula:
TECHNOLOGICAL BACKGROUND
Zolpidem is the parent compound of a chemical class with hypnotic activity which has recently arisen interest: 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides, having the following general formula:
wherein X, Y, R
1
and R
2
are substituents widely documented in a number of patents and articles published in the last two decades, concerning the preparation of a great deal of derivatives as well as the hypnotic-sedative properties thereof.
The known processes for the preparation of Zolpidem are part of the general procedures used for the preparation of variously substituted imidazo[1,2-a]pyridine-3-acetamides. These syntheses differ in the procedure for the introduction of the acetamide chain at the 3- position of 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine, which molecule is common to all said processes.
6-Methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine, in the following referred to as imidazo-pyridine for sake of shortness, can be obtained according to a procedure comprising condensation of a variously substituted 2-amino-pyridine with a suitably substituted &agr;-halo-acetophenone, which is prepared by halogenation of the corresponding substituted acetophenone (GB 991,589) or by reacting a suitably substituted benzene with an &agr;-halo-acetyl halide under the Friedel-Crafts acylation conditions (WO 00/08021) as reported in Scheme 1.
The numerous works published concerning the functionalization of the midazo-pyridine at the 3-position 3 describe four synthetic routes, according to the following Scheme 2.
2.1 Synthesis of Zolpidem via Mannich amino-methylation
This synthetic route involves the imidazo-pyridino-3-acetonitrile intermediate whose preparation is disclosed in GB 991,589 and GB 1,076,089.
This approach has subsequently been applied to the synthesis of the Zolpidem in EP 50.563, as shown in Scheme 3.
The amino methylation of the imidazo-pyridine (step 1) yields the 3-dimethylamino derivative, which is alkylated with methyl iodide (step 2), to obtain the quaternary ammonium salt, which is then reacted with sodium cyanide (step 3) to give the corresponding nitrile. The acid hydrolysis of the nitrile yields the carboxylic acid (step 4) which is activated with carbonyldiimidazole (CDI), then treated with a dimethylamine excess (step 5) to obtain the corresponding dimethylamide (Zolpidem).
The use of methyl iodide (highly toxic, low-boiling alkylating agent) in the alkylation step and the nucleophilic substitution of the quaternary ammonium salt with sodium cyanide (which is per se a dangerous starting product) restricts the industrial application of this synthetic approach.
2.2 Synthesis of Zolpidem via Formylation
A second synthetic route (EP 92,459) shares with the above one the acetonitrile intermediate and the subsequent hydrolysis and amidation steps, but such intermediate is prepared by a different procedure (see the following Scheme 4).
The imidazo-pyridine is formylated according to the Vilsmeier-Haack's reaction (step 1) to obtain the aldehyde which is reduced with sodium borohydride (step 2) to yield the corresponding alcohol. This is reacted with p-toluenesulfonyl chloride in pyridine to obtain the quaternary ammonium salt (step 3) which is reacted with the cyanide ion (step 4), to yield the 3-acetonitrile derivative. The resulting intermediate is transformed into the acid with conventional methods, then is amidated to give Zolpidem.
Compared with the procedure described above (scheme 3), an alternative to the preparation of the quaternary ammonium salt has been found, which however still involves the critical use of cyanides.
2.3 Synthesis of Zolpidem by Pummerer Modified Reaction
This synthetic route, shown in Scheme 5, is described in Actual Chim Ther., 1991, 18, 215-39.
The precursor of the acetamide chain used in this procedure is N,N-dimethylmethylsulfoxy-acetamide, which reacts with imidazopyridine in acid medium according to a modified procedure of the Pummerer reaction, to give the &agr;-methylmercaptoacetamido derivative, which is desulfonated with nickel-Raney to obtain Zolpidem.
This procedure, although being direct and requiring only two steps, is critical due to formation of methylmercaptan (toxic gas) from the reduction reaction, to the use of nickel-Raney (cancerogenic) and to the poor yield.
2.4 Synthesis of Zolpidem via Glyoxylic Acid and Derivatives
The synthetic routes making use of the reactivity of imidazo-pyridine toward glyoxylic acid and derivatives thereof are the easiest to carry out from the industrial point of view.
From the chemical standpoint, all of the procedures based on this type of reaction yield the &agr;-hydroxy-acetic intermediate (or a derivative thereof) which has to be reduced to obtain the desired product.
The synthetic general scheme general is reported in the following Scheme 6.
R=H, alkyl (also mixed)
X=OH, O-alkyl, —N(CH
3
)
2
Two processes for the preparation of imidazo-pyridine derivatives, and particularly Zolpidem, follow said synthetic procedure.
The first process (FR 2,600,650) comprises the use of N,N-dimethyglyoxamide, prepared in situ from the corresponding acetal, which is in its turn prepared according to the following Scheme 7.
The acetal is treated with concentrated hydrochloric acid in acetic acid, to obtain the glyoxylic amide which is then used for the functionalization of the imidazo-pyridine, as shown in the following Scheme 8.
The &agr;-hydroxyacetamide resulting from the reaction (1) is treated with thionyl chloride to obtain the corresponding &agr;-chloro derivative, which is reduced with either a boron hydride, dithionite or a zinc/hydrochloric acid mixture to yield Zolpidem.
The second process (WO 00/08021) uses methyl glyoxalate or its methyl hemiacetal prepared according to the following Scheme 9.
Imidazopyridine is reacted with glyoxylic acid methyl ester (or its hemiacetal) (step 1) to obtain the &agr;-hydroxyacetate derivative which is treated with the chloroiminium salt, prepared in situ from DMF and thionyl chloride, to give the corresponding &agr;-chloro-derivative (step 2). The latter is reduced with sodium formaldehyde sulfoxylate (or sodium hydroxymethanesulfinate) (step 3) and the resulting ester is treated gaseous dimethylamine in a polyhydroxylated solvent under mild pressure (step 4) to obtain Zolpidem.
In conclusion, all known synthesis of Zolpidem use either reagents commercially available with difficulty, toxic reagents, or industrially unsuitable procedures due to low yields and/or products with poor purity which should undergo repeated purification procedures.
DISCLOSURE OF THE INVENTION
It has now been found an efficient, convenient process for the preparation of 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides, in particular Zolpidem.
According to the invention, 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides of formula 5
wherein
X is hydrogen, halogen, C
1
-C
4
alkyl, C
1
-C
6
alkoxy, CF
3
, CH
3
S, nitro, CH
3
SO
2
;
Y is hydrogen, a halogen atom or C
1
-C
4
alkyl;
are prepared with a process which comprises:
a) reacting a 2-phenyl-imidazo[1,2-a]pyridine of formula 1
wherein X and Y have the meanings defined above, with an oxalate of formula 2
wherein R
1
is a halogen or a carboxy-activating group, R
2
is C
1
-C
6
alkoxy, aralkoxy or phenoxy (both optionally substituted with C
1
-C
6
alkyl or alkoxy), or is C
1
-C
6
alkylamino or arylamino;
b) reducing the resulting compound of formula 3
wherein X and Y have the meanings defined above;
c) reacting the
Dentz Bernard
Dinamite Dipharma S.p.A.
Young & Thompson
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