Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-06-30
2003-01-28
Coleman, Brenda (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
06512114
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for the preparation of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (Midazolam) from 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid (tricyclic acid).
BACKGROUND OF THE INVENTION
8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazopine (Midazolam), a pre-operative anesthetic, belongs to a class of imidazobenzodiazepine compounds which are useful as anticonvulsants, sedatives, and muscle relaxants.
The last step in the synthesis of Midazolam is thermal decarboxylation of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazopine-3-carboxylic acid (tricyclic acid). Also produced in this step is 8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazopine (Isomidazolam) and decomposition biproducts resulting from high temperature dehalogenation and dimerization of tricyclic acid. Removal of the decomposition biproducts and purification of Midazolam and Isomidazolam are accomplished by column chromatography (GB Patent 1,549,836 and U.S. Pat. Nos. 4,280,957, 4,440,685 and 4,377,523), a method which is impractical for large scale preparation of Midazolam because of the costly chromatography equipment required.
Attempts at improving the overall yield of Midazolam have focused on isomerizing purified Isomidazolam to Midazolam by treatment of the former with potassiun tert-butoxide in N,N-dimethylformamide (DMF) under kinetically controlled conditions (U.S. Pat. Nos. 4,377,523 and 4,440,685). This method is also impractical for large scale syntheses of Midazolam because of the amount of thermal energy required for removal of the DMF.
Thus, there is a continuing need in the pharmaceutical manufacturing industry for a large scale conversion of tricyclic acid to Midazolam which minimizes Isomidazolam formation and provides for non-chromatographic removal of biproducts.
SUMMARY OF THE INVENTION
The process of the present invention provides a large scale conversion of tricyclic acid to Midazolam which minimizes Isomidazolam formation and provides for non-chromatographic removal of biproducts.
In one embodiment of the present invention is provided a process for the synthesis of a compound of formula I (Midazolam)
or a pharmaceutically acceptable salt or prodrug thereof, comprising:
(a) forming a first reaction medium comprising from about 1 to about 20 parts by
weight of a first solvent system per 1 part by weight of tricyclic acid II,
wherein said tricyclic acid exhibits a first critical solution temperature behavior in said first solvent system;
(b) maintaining said first reaction medium at a second temperature of between about 190° C. and about 260° C. such that said compound of formula II decarboxylates to substantially form said compound of formula I; and
(c) isolating said compound of formula I from said first solvent system.
In another embodiment of the present invention is disclosed a method of decarboxylating tricyclic acid to form a Midazolam/Isomidazolam product ratio of about 6:1.
In yet another embodiment of the present invention is disclosed a method of converting the Midazolam/Isomidazolam product ratio from about 6:1 to about 50:1 using thermodynamic, basic workup conditions.
In still yet another embodiment of the present invention is disclosed a method of isolating and purifying Midazolam without using column chromatography.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
Percentages obtained by HPLC analysis are defined by peak area calculations.
As used in the specification and the claims, the following terms have the meanings specified:
The term “alkali metal alkoxide,” as used herein, refers to M—OR
1
, wherein M is a cation selected from the group consisting of lithium, sodium, and potassium, and R
1
is an is an alkyl group, as defined herein.
The term “alkyl,” as used herein, refers to a straight or branched chain hydrocarbon radical having from one to twelve carbon atoms. Alkyl groups of this invention include methyl, ethyl, n-propyl, iso-propyl, 2-methylpropyl, n-butyl, 2-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like.
The term “base,” as used herein, refers to a species capable of abstracting a proton in either a polar or nonpolar solvent. Examples of bases include alkali metal alkoxides as defined herein, alkali metal hydrides such as lithium, sodium, or potassium hydride, and nitrogen-containing bases such as lithium diisopropyl amide (LDA), lithium, sodium, or potassium bis(trimethylsilyl)amide, and the like. It will be obvious to those skilled in the art that individual base and solvent combinations may be preferred for specific reaction conditions depending upon such factors as the solubility of reagents, reactivity of reagents with Isomidazolam or the solvent, and preferred temperature ranges.
The term “first organic extraction solvent,” as used herein, refers to a polar solvent, as defined herein.
The term “first solvent system,” as used herein, refers to a solvent with a boiling range high enough to promote decarboxylation of tricyclic acid, typically between about 190° C. and about 260° C. First solvent systems of the present invention include. but are not limited to, N,N-dimethylacetamide, phenyl ether, ethylene glycol, propylene glycol, mineral oil, tetrahydronaphthalene, Decalin™ (decahydronaphthalene), and mixtures thereof.
The term “nonpolar solvent” as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton donor. Examples include, but are not limited to, hydrocarbons such as pentane, hexane, heptane, cyclopentane, cyclohexane, and isomers thereof, aromatic solvents such as benzene, toluene, and o-, m-, and p-xylenes 5 halogenated hydrocarbons, such as, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether and bis(methoxymethyl) ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example:
Organic Solvents Physical Properties and Methods of Purification,
4th ed., edited by John A. Riddick, et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
The term “pharmaceutically acceptable prodrugs,” as used herein, refers to those prodrugs of Midazolam which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
The term “polar solvent,” as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, or a solvent polarized due to the presence of an electron withdrawing group, such as acetonitrile or tetrahydrofuran, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temp
Bhatia Ashok V.
Davis Deborah A.
Dhaon Madhup K.
Esser Grant L.
Abbott Laboratories
Coleman Brenda
Donner B. Gregory
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