Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-08-30
2001-02-27
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06194569
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to an efficient and practical synthesis of [S-(R,S)]-N-[1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2[4-[4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidine carboxamide. This compound is an inhibitor of human leukocyte elastase (HLE) and useful for the treatment of abnormalities such as cystic fibrosis, acute respiratory distress syndrome, chronic bronchritis and other immuno response disorders.
BACKGROUND
Human leukocyte elastase (HLE) is a serine protease present in the azurophilic granules of human polymorphonuclear leukocytes. In the intracellular environment, HLE is capable of degrading a variety of structural proteins, including elastin and collagen. The destructive power of HLE is controlled by its natural inhibitors, but in diseases such as emphysema, cystic fibrosis and rheumatoid arthiritis, it is believed that the balance between HLE and its inhibitor is disrupted and the unbound HLE causes destruction of connective tissue.
U.S. Pat. No. 5,229,381 indicates the value of the compound of formula (I) as an effective inhibitor of human leukocyte elastase.
International publication WO 97/16448 describes a general synthesis of (I) which involves the displacement of the propionate group of 3,3-diethyl-4-(propionyloxy)-2-azetidinone by benzyl 4-hydroxybenzoate (benzyl paraben) to give the desired 3,3-diethyl-4-[(4′-benzyloxycarbonyl) phenoxy]-2-azetidinone.
The racemic ester is converted to the racemic carboxylic acid by transfer hydrogenolysis, and the (S) enantiomer obtained by precipitating the undesired salt with (R)-a-methylbenzyl amine. The desired 3-(S) acid is then isolated from the filtrate by adding (S)-a-methyl benzyl amine (S-MBA) and filtering the solid S,S-MBA salt. The chiral purity is typically brought to an acceptable level by recrystallization, and the purified 3-(S)-acid liberated from the salt by the addition of acid.
The subsequent coupling with N-methyl piperazine is accomplished through the use of dicyclohexylcarbodiimide and hydroxybenzotriazole to give the key S-azetidinone intermediate (IV-b).
The S-azetidinone (IV-b) is ultimately condensed with the appropriate R-isocyanate in the presence of a catalytic amount of a weak base such as 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) to give the desired [S-(R,S)]-N-[1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2[4-[4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidine carboxamide (I).
The utility of the present invention lies in the discovery of an efficient process which permits a more favorable commercial manufacture of (I). Reaction of the &bgr;-lactam 3,3-diethyl-4-propionyloxy-2-azetidinone directly with 1-(4-hydroxybenzoyl)-4-methylpiperazine provides the racemic (R,S)-1-[4-[(3,3-diethyl-4-oxo-2-azetidinyl) oxy]benzoyl]-4-methylpiperazine. The resolution of the racemate is achieved through the formation of the 2,3:4,6-Di-O-isopropylidene-2-L-gulonic acid (DAG) salt of the undesired (R)-isomer, which precipitates under proper conditions. The desired (S)-isomer (IV-b) is recovered from the reaction liquors by the addition of an antisolvent. The resolution of this intermediate obviates the need for a carboxylic acid for salt formation, thus avoiding the use of harmful and expensive reagents such as dicyclohexyl-carbodiimide and hydroxybenzotriazole in favor or a shorter synthetic route.
The desired (S) &bgr;-lactam (IV-b) is isolated from the filtrate in high chemical yield and enantiomeric purity. The recovered (R) &bgr;-lactam/DAG salt may be racemized back to (S,R) &bgr;-lactam to optimize yield of the (S)-isomer, and the DAG recovered from an aqueous stream by controlled acidification. Overall, the process allows for maximum yield of an advanced intermediate in addition to cost saving recovery of the resolving agent.
The product of the resolution is condensed with (R)-5-(1-isocyanatobutyl)-1-3-benzodioxole to give (I) under conditions which offer advantages over previously reported procedures. Specifically, the present invention describes the use of a catalytic amount of strong base, which minimizes degradation by enhancing reaction rate.
The present invention further describes a unique phosgenation protocol for the preparation of an isocyanate from (R)-a-propyl-piperonylamine. The process minimizes epimerization resulting from trace amounts of iron found to be a common contaminant in commercial phosgene. This discovery also allows for isocyanate formation in iron equipment which would otherwise be a likely source of dissolved iron. Such flexibilty ultimately allows for significant cost reduction and versatility in the commercial manufacture of (I).
SUMMARY OF THE INVENTION
The present invention relates generally to processes for the efficient production of [S-(R,S)]-N-[1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2[4-[4-methyl-1-piperazinyl) carbonyl]phenoxy]-4-oxo-1-azetidine carboxamide (I):
which has been achieved by the inventors' discovery that a compound of formula (I) or a pharmaceutically acceptable salt form thereof, is formed by a high yielding process, comprising the reactions:
(1) contacting a compound of formula (II):
with a compound of formula (III):
in a polar solvent system, in the presence of an aqueous base and a phase transfer catalyst to form a compound of formula (IV):
(2) contacting the compound of formula (IV) with 2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid (DAG) in a suitable solvent to form a precipitate of formula (IV-a):
and a mother liquor containing a compound formula (IV-b):
and contacting the mother liquor with an antisolvent to precipitate the compound of formula (IV-b) as a crystalline solid;
(3) racemizing the free base of the compound of formula (IV-a), as necessary, to form a compound of formula (IV) and repeating reaction (2);
(4) contacting a compound of formula (V):
or a salt form thereof, with phosgene or an equivalent thereof, in a suitable solvent, at a suitable temperature in the presence of a catalytic amount of a complexing agent to form a compound of formula (VI):
(5) contacting the compound of formula (IV-b) with the compound of formula (VI), at a suitable temperature, in the presence of a catalytic amount of a strong base to form a compound of formula (I), or a pharmaceutically acceptable salt form thereof.
DETAILED DESCRIPTION OF THE INVENTION
Thus, in a first embodiment, the present invention provides a process for the preparation of compounds of formula (IV):
or a salt form thereof; the process comprising:
(a) contacting a compound of formula (II):
with a compound of formula (III):
in a polar solvent system in the presence of an aqueous base and a phase transfer catalyst, to form a compound of formula (IV), or a salt form thereof.
In a preferred embodiment, in reaction (a):
the first polar solvent system comprises a mixture of water and a cosolvent selected from:
isopropyl acetate, methyl acetate, ethyl acetate, tert-butyl acetate, toluene, and tert-butyl methyl ether;
the aqueous base is selected from:
lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; and
the phase transfer catalyst is selected from:
tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, and tetrabutylammonium chloride.
In a second embodiment, the present invention describes a process for the preparation of a compound of formula (IV-b):
the process comprising:
(b) contacting a compound of formula (IV):
with 2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid in a suitable solvent to precipitate a compound of formula (IV-a):
and a mother liquor containing the compound of formula (IV-b);
(c) isolating the mother liquor; and
(d) contacting the mother liquor with an antisolvent to precipitate a compound of formula (IV-b) as a crystalline solid.
In a preferred embodiment, the suitable solvent in (b) is selected from:
isopropyl acetate, methyl acetate, ethyl acetate, ter
Anzalone Luigi
Fortunak Joseph M.
Li Hui-Yin
Sheeran Patrick J.
Storace Louis
Berch Mark L.
DuPont Pharmaceuticals Company
McKenzie Thomas
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