Process for preparing a 10,11-methanodibenzosuberane derivative

Details Process for preparing a 10,11-methanodibenzosuberane derivative Process for preparing a 10,11-methanodibenzosuberane derivative

2003-03-03

2003-09-23

Bernhardt, Emily (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S363000

Reexamination Certificate

active

06624304

ABSTRACT:

This invention relates to the art of synthetic organic chemistry. Specifically, the invention is a process to prepare (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride salt of formula I:
Among the problems in cancer chemotherapy is the development of resistance to treatment regimens. Tumors that respond well to a particular drug or drugs initially often develop a tolerance to the drug(s).
This disease state, called multi-drug resistance, is discussed in greater detail in Kuzmich and Tew, “Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs,” particularly section VII “The Multidrug-Resistant Phenotype (MDR),”
Medical Research Reviews
, Vol. 11, No. 2, 185-217, particularly 208-213 (1991); and in Georges, Sharom and Ling, “Multidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy,”
Advances in Pharmacology
, Vol. 21, 185-220 (1990).
U.S. Pat. Nos. 5,643,909 and 5,654,304, incorporated herein by reference, disclose a series of 10,11-methanobenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride disclosed therein, is currently under development as a pharmaceutical agent. The present invention involves an improved process to prepare (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (compound of formula I), wherein the chemistry is more efficient and adaptable to large scale processing in anticipation of development needs.
The art disclosed in U.S. Pat. No. 5,776,939, and U.S. Pat. No. 5,643,909 both incorporated herein by reference, and PCT Patent Applications (Publication numbers WO 94/24107 and 98/22112) teach the use of 1-formylpiperazine to introduce the piperazine group of the compound of formula II
Compound II is a mixture of syn isomer (III)
and anti isomer (IV)
The process as disclosed in U.S. Pat. Nos. 5,643,909 and 5,654,304 (represented by scheme A, below) involves (a) chromatographic separation(s) of the formyl piperazine compound; and (b) deformylation of the formyl piperazine compound to provide compound IV.
The process of the present invention uses piperazine to react with the (1a&agr;,6&agr;,10b&agr;)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cycloheptene compound or derivative, instead of formylpiperazine.
The process of the present invention is advantageous because piperazine is readily available in commercial quantities whereas 1-formylpiperazine, which was utilized in the process disclosed in U.S. Pat. No. 5,643,909 is often not readily available in commercial quantities. Additionally piperazine enjoys a significant cost advantage over 1-formylpiperazine.
The use of piperazine instead of 1-formylpiperazine is a significant advancement over the prior art because it obviates the need to deformylate or hydrolyze off the formyl group (step 6, scheme A), thereby providing fewer operational steps. U.S. Pat. No. 5,643,909 teaches the separation of the 1-formylpiperazine compounds by chromatography or repeated crystallizations. The present invention obviates the need for chromatographic separations of the formylpiperazine diastereomeric addition compounds (see step 4, scheme A).
The present invention provides a process for preparing a compound of the formula (IVa):
wherein HX is an acid, comprising the steps of:
(a) dissolving a compound of formula (II)
in acetonitrile to form a solution;
(b) crystallizing a syn stereoisomer compound of formula (III)
from the solution of (II);
(c) removing the acetonitrile from the filtrate to provide a mixture enriched in an anti stereoisomer compound of formula (IV)
(d) adding an acid, and a solvent selected from the group consisting of methylene chloride, ethanol and ethyl acetate to said enriched mixture; and
(e) crystallizing the anti-stereoisomer compound of formula (IVa).
The present invention also provides a process for preparing a compound of formula (IVa),
comprising the steps of:
(a) converting 10,11-dibenzosuberenone (i),
to the alcohol (ii),
(b) reacting alcohol (ii) in one operational step with a halogenating agent to form (1a&agr;,6&agr;,10b&agr;)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]-cyclopropa[c]cycloheptene (iii);
where X is I, Br, or Cl;
(c) reacting (1a&agr;,6&agr;,10b&agr;)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cycloheptene (iii) with piperazine in a solvent to form the mixture of syn (III)
and anti (IV)
piperazine compounds, and
(d) separating the compound of formula III from the compound of formula IV by the method of the invention.
The present invention also provides a process for preparing a compound of formula (I) from the anti stereoisomer IVa, according to the invention, comprising the steps of:
(a) reacting the anti-stereoisomer (IVa) as the free base, with (R)-1-(5-quinolinyloxy)-2,3-epoxypropane to provide compound of formula (V);
and
(b) optionally reacting hydrogen chloride with compound (V) to form a compound of formula (I):
The present invention further provides a process for preparing the syn isomer compound (III) and pharmaceutically acceptable salts thereof, by the method of the invention.
The terms and abbreviations used herein have their normal meanings unless otherwise designated. For example “° C.” refers to degrees Celsius; “N” refers to normal or normality; “mmol” refers to millimole or millimoles; “g” refers to gram or grams; “d” refers to density, “min.” refers to minutes, “mL” means milliliter or milliliters; “M” refers to molar or molarity; “HPLC” refers to high performance liquid chromatography; “mm” refers to millimeters; “cm” refers to centimeters; “nm” refers to nanometers; and “rt” refers to retention time. The term “halo” refers to fluoro, bromo, chloro and iodo.
As used herein the term “halogenating agent” refers to halogenic acids or other acidic groups capable of converting alcohols to halides. Illustrative halogenating agents include hydrogen bromide, hydrogen chloride, hydrogen iodide, thionyl chloride, oxalyl chloride, phosphorus trichloride or pentachloride, and the like.
As used herein, the term “pharmaceutically acceptable salt” refers to all non-toxic organic or inorganic acid addition salts. Illustrative inorganic acids or “acidic groups” which form salts include hydrochloric, hydrobromic, sulfuric, phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative acids or “acidic groups” which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxy-benzoic, and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, and 2-hydroxyethane sulfonic acid. Preferred acids include those selected from the group comprising of hydrobromic acid, hydrochloric acid, camphorsulfonic acid, p-toluenesulfonic acid, and sulfuric acid. A particularly preferred acidic group is hydrochloric acid. Acid addition salts formed from these acids can exist in either hydrated or substantially anhydrous form, all of which are within the scope of this invention.
The terms “HX,” “acidic group,” and “acid” are synonymous as used herein.
The compounds of formula II may be prepared according to the following steps illustrated in Scheme B, starting from 5H-dibenzo[a,d]cyclohepten-5-one (dibenzosuberenone), which is commercially available, e.g., from Aldrich Chemical Company, Milwaukee, Wis. Other reactants are likewise commercially available or may be readily prepa

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