Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-03-23
2001-07-17
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
06262260
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)benzodiazepine (Midazolam), a pre-operative anesthetic, belongs to a class of imidazobenzodiazepine compounds which are useful as anticonvulsants, sedatives, and muscle relaxants. Because of the therapeutic usefulness of these compounds, there is sustained interest in improving their synthesis, particularly the thermal decarboxylation step of the substituted tricyclic acid precursor.
U.S. Pat. No. 4,280,957, U.S. Pat. No. 4,440,685, U.S. Pat. No. 4,377,523, and GB 1,549,836 teach a high temperature decarboxylation of tricyclic acid to provide Midazolam, 8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo (1,5-a)(1,4)benzodiazepine (Isomidazolam) and decomposition by-products resulting from concomitant high temperature dehalogenation and dimerization of the tricyclic acid precursor. This method is impractical for large-scale preparation of Midazolam because of the costly chromatography equipment, plant time, and solvents required.
Attempts at improving the yield of Midazolam have focused on isomerizing purified Isomidazolam to Midazolam. U.S. Pat. No. 4,377,523 and U.S. Pat. No. 4,440,685 teach the isomerism of Isomidazolam to Midazolam by treatment of the former with potassium tert-butoxide in N,N-dimethylformamide (DMF) under kinetically controlled conditions. This method is also impractical for the large-scale syntheses of Midazolam because of the amount of thermal energy required for removal of the DMF.
Commonly owned, pending U.S. application Ser. No. 09/344280, filed Jun. 30, 1999, teaches isomerizing Isomidazolam to Midazolam in a lower-boiling solvent such as methanol, a solvent which is more easily removed than DMF. While this approach is an improvement over the art, there still remains a need in the pharmaceutical manufacturing industry for a lower temperature decarboxylation of imidazobenzodiadepines in general and tricyclic acid, in particular.
SUMMARY OF THE INVENTION
The process of the present invention therefore provides a large-scale decarboxylation of compounds of formula (I) to provide compounds of formula (II) which minimizes isomer formation and provides for non-chromatographic removal of by-products.
In one embodiment of the present invention is provided a process for the synthesis of a compound of formula (II)
or a pharmaceutically acceptable salt thereof, wherein
R
1
is hydrogen or alkyl; and
R
2
, R
3
, R
4
, and R
5
are independently selected from the group consisting of hydrogen, halo, alkyl, and nitro;
the method comprising:
(a) decarboxylating a compound of formula (I)
in a solvent of formula (III)
wherein R
6
and R
7
are alkyl; and
(b) reacting the product from step (a) with base.
In another embodiment of the present invention is disclosed a method of purifying Midazolam without using column chromatography.
DETAILED DESCRIPTION OF THE INVENTION
Percentages obtained by HPLC analyses were obtained by peak area calculations.
When used throughout this specification, the following terms have the meanings indicated:
The term “activated charcoal,” as used herein, represents powdered carbon which is used for the removal of impurities during recrystallization. Activated charcoal of this invention includes Darco®, Norit®, and the like.
The term “alkali metal hydroxide,” as used herein, represents (M)
+n
(OH)
n
−
, wherein (M)
+
is a cation selected from the group consisting of lithium, sodium, potassium, cesium magnesium, calcium, and barium; and n is one or two.
The term “C
5
-C
10
alkane,” as used herein, represents a straight or branched chain saturated hydrocarbon of five to ten carbon atoms. Alkanes of this invention include pentane, hexane, heptane, and the like.
The term “alkyl,” as used herein, represents a straight or branched chain saturated hydrocarbon radical having from one to six carbon atoms. Alkyl groups of this invention include methyl, ethyl, propyl, tert-butyl, and the like.
The term “base,” as used herein, represents a species capable of abstracting a proton in either a polar or a non-polar solvent. Examples of bases include alkali metal hydroxides as defined herein; alkali metal hydrides such as lithium, sodium, or potassium hydride; and nitrogen-containing bases such as lithium diisopropyl amide (LDA), lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide; and the like. It will be apparent to a skilled practioner that individual base and solvent combinations can be preferred for specific reaction conditions depending on such factors as the solubility of reagents, reactivity of reagents with Isomidazolam or the solvent, and preferred temperature ranges.
The term “continuous process,” as used herein, represents the conduction of a reaction to provide an intermediate followed by use of the intermediate, without purification, in a subsequent reaction.
The term “halo,” as used herein, represents F, Cl, Br, and I.
The term “nitro,” as used herein, represents —NO
2
.
The term “non-polar solvent,” as used herein, represents a solvent which is relatively inert to proton activity, i.e., not acting as a proton donor. Examples of non-polar solvents include hydrocarbons such as pentane, hexane, and heptane; aromatic solvents such as benzene, toluene, and nitrobenzene; halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, and 1,2-dichloroethane; and the like.
The term “pharmaceutically acceptable salt,” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the instant invention or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, trifluoroacetate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
The term “polar solvent,” as used herein, represents a solvent which provides protons. Examples of polar solvents include methanol, ethanol, and butanol and solvents polarized by a electron withdrawing groups such as 1,3-dimethyl-2-imidazolidinone, acetonitrile, and the like.
The terms “treated” and “treating,” as used herein, refer to contacting, mixing, diluting, or reacting one or more chemical entities by the reasonable and usual manner in which chemicals are combined. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (−10° C. to 250° C., typically −78° C. to 150° C., more typically −78° C. to 100° C., still more typically 0° C. to 1
Abbott Laboratories
Berch Mark L.
Donner B. Gregory
McKenzie Thomas
Sickert Dugal S.
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