MXPA01002113A - Process for the preparation of imidazodiazepine intermediates - Google Patents

Abstract

The present invention relates to a process for the synthesis of a compound having formula (I), from a compound of formula (II), which allows the synthesis to be carried out in a single reaction vessel and without column chromatography purification.

Description

PROCESS FOR THE PREPARATION OF I NTERMED I I I I DAZOD1AZEP INA TECHNICAL FIELD The present invention relates to a process for the preparation of the acid 8-chloro-6- (2-fluorophenyl) -1-methyl-4 / - / - imidazo [1, 5-a:] [1, 4 ] benzodiazepine-3-carboxylic acid.

BACKGROUND OF THE INVENTION Ei Midazolam (8-chloro-6- (2-fluorophenyl) -1-methyl-4 / - / - imidazo [1, 5-a] [1,4] benzodiazepine), a pre-operative anesthetic, belongs to a class of imidazobenzodiazepine compounds that are useful as anticonvulsants, sedatives and muscle relaxants. The synthesis of Midazolam has been described in E.U. 4307237.

A key step in this synthesis is the construction of the imidazole ring by conversion of methyl 7-chloro-5- (2-fluorophenyl) -a- (hydroxomino) -3H-1, 4-benzodiazepine-2, to acid. -chloro-6- (2-fluorophenyl) -1-methyl-4 / -imidazo [1, 5-a] [1,4] benzo-diazepine-3-carboxylic acid. This conversion is carried out via a three-step process that requires the isolation of intermediates and column chromatography for the penultimate ester. The large-scale production of commercial drugs requires the invention of chemical syntheses that avoid complicating factors, such as the use of high-cost reagents, chemicals that require special handling, long multi-step synthetic sequences, chromatography or intermediate and low performance steps. An effective strategy to lower costs associated with multi-step processes is the reduction in the number of steps required to complete a synthesis, combining several steps in a "one pot" transformation. However, running multiple steps in a single-reaction vessel or without purification of intermediates poses a challenge due to the competition of lateral reactions, solvent incompatibility and purification difficulties. The present invention describes a novel synthesis of 8-chloro-6- (2-fluorophenyl) -1-methyl-4 / - / - imidazo [1, 5-a] [1,4] benzodiazepine-3-carboxylic acid, which allows multiple reaction steps in a single reaction vessel, without isolation or intermediates. In addition, this invention provides a process that avoids the costly chromatography of the intermediates or the product.

BRIEF DESCRIPTION OF THE INVENTION In one embodiment, the present invention describes a process for preparing a compound having the formula I, wherein X1 and X2 are independently selected from the group consisting of halogen, nitro and amino which comprises reacting a compound having the formula II, wherein R3 is hydrogen or alkyl and X1 and X2 are independently selected from the group consisting of halogen, nitro and amino in a mixture comprising hydrogen, hydrogenation catalyst, trialkyl orthoacetate or triaryl orthoacetate and an acid followed by the removal of the catalyst and the reaction with an alkali metal hydroxide, to produce a compound of formula I. In another embodiment, the present invention describes a process for preparing a compound having the formula III, which comprises reacting a compound having the formula IV, wherein R3 is an alkyl group in a mixture comprising hydrogen, hydrogenation catalyst, trialkyl orthoacetate or triaryl orthoacetate and an acid followed by removal of the catalyst and reaction with an alkali metal hydroxide, to produce a compound of formula I. In yet another embodiment, the present invention describes a process for preparing a compound having the formula m, which comprises reacting a compound having the formula iv, wherein R3 is an alkyl group in a mixture containing hydrogen, Raney nickel, trimethyl orthoacetate and para-toluenesulfonic acid, followed by removal of the Raney nickel catalyst and reaction with potassium hydroxide, to produce a compound of formula III.

DESCR I I DETAILED PC OF THE I NVEN TION All patents, applications for patents and literary references cited in the specification, are incorporated herein for reference in their entirety. In the case of inconsistencies, the present description will prevail, including definitions. As used in the specification and in the claims, the following terms have the specific meanings. The term "alcohol solvent", as used herein, refers to R8OH, wherein R8 is an alkyl group, as defined herein. Representative alcoholic solvents include methanol, ethanol, iso-propanol, n-propanol, n-butanol, sec-butanol and the like. The term "alkali metal ion", as used herein, refers to an ion derived from a metal selected from the group consisting of lithium, sodium, potassium, rubidium and cesium and the like. The term "alkali metal alkoxide", as used herein, refers to M-O R8, wherein M represents an alkali metal ion, as defined herein and R8 represents an alkyl group, as defined herein. Representative alkali metal alkoxides include potassium fer-butoxide, sodium ethoxide and sodium io-butoxide and the like. The term "alkoxide", as used herein, refers to a T O-RB species having the formula "", wherein R8 represents an alkyl group as defined above and T represents an individual negative charge. Representative alkoxides include tert-butoxide and ethoxide and the like.

The term "alkyl", as used herein, refers to a straight or branched chain hydrocarbon radical having one to twelve carbon atoms. Representative alkyl groups include methyl, ethyl, n-propynyl, / so-propyl, 2-methylpropy, n-butynyl, 2-butyl, rt-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2- methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. The term "amino", as used herein, refers to -NH2. The term "aryl", as used herein, refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. The term "dialkyl halofosphate", as used herein, refers to X-P (= O) (-OR9) 2, wherein X is a halogen, as defined herein and R9 is an alkyl group. Representative dialkyl halophosphates include dimethyl chlorophosphate and diethyl chlorophosphate and the like. The term "diary halofosphate", as used herein, refers to X-P (= O) (-OR10) 2, wherein X is a halogen, as defined herein and R10 is an aryl group, as defined herein. Representative diaryl halophosphates include diphenyl chlorophosphate and the like. The term "halogen", as used herein, refers to -Cl, -Br and -I. The term "hydrogenation catalyst", as used herein, refers to a substance that facilitates hydrogenation. Hydrogenation catalysts include nickel, palladium, platinum, rhodium, rhenium, copper and iridium and the compounds derived therefrom. Representative hydrogenation catalysts include Raney nickel and palladium on carbon and the like. The term "hydroxy" or "hydroxyl", as used herein, refers to -OH. The term "mineral acid", as used herein, refers to an acid that does not contain carbon. Representative mineral acids include hydrochloric, sulfuric, nitric and phosphoric acids and the like. The term "nitro", as used herein, refers to -NO2. The term "organic acid," as used herein, refers to an acid containing carbon. Representative organic acids include acetic and para-toluenesulfonic acid and the like. The term "pharmaceutically acceptable salt", as used herein, refers to those salts which are, from the standpoint of medical judgment, suitable for use in contact with human tissue and lower animals, without excessive toxicity, irritation. , allergic response and the like and that are provided with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the medium. For example, S. M Berge, et al., Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1997, 66: 1-19. The salts can be prepared in situ during the final isolation of the Midazolam or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, canfersulfonate, citrate, cyclopentapropionate, 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, solvate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valeriato salts and the like. The term "kg / cm2," as used herein, refers to kilograms per square centimeter. Representative torric alkaline or alkaline metal cations include sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium and tetraethylammonium and the like. The term "trialkyl orthoacetate", as used herein, refers to CH 3 C (-O R 1 1) 3, wherein R 1 1 is an alkyl group. The term "triaryl orthoacetate", as used herein, refers to CH3C (-OR12) 3, wherein R12 is an aryl group.

The present invention contemplates geometric isomers and mixtures thereof. The symbol "> AA" denotes a single isomer or a mixture of isomers. For example, denotes a simple isomeric oxime or a mixture of regioisomeric oximes, where the hydroxyl can be placed on the same side of R3 or on the opposite side of R3.

METHODS OF SYNTHYSIS The compounds and processes of the present invention will be better understood in relation to the following synthesis scheme, which illustrates the method by which the compounds of the invention can be prepared.

Halobenzodiazepine V (for example, X1 is chlorine and X2 is fluorine) was converted to vinyl compound VI by the following reaction sequence: 1) a dialkyl malonate or, alternatively, an alkyl cyanoacetate or another doubly activated methylene compound, was reacted with an alkali metal alkoxide such as potassium fer-butoxide in a solvent system containing a mixture of hydrocarbon and polar solvents such as heptane / acetonitrile to produce the malonate anion; 2) the malonate anion was reacted with a dialkyl halophosphate, such as, for example, diethyl chlorophosphate to form the phosphate anion; and 4) the phosphate anion was reacted with V to give VI (R1 and R2 are independently selected from the group comprising -CN and -C0R3, where R3 is alkyl). The vinyl compound vi was reacted with an alkali metal hydroxide such as, for example, potassium hydroxide in a suitable alcohol solvent at a temperature of about 45 ° C to about 100 ° C to give the ester , ß-unsaturated Vi l (for example, R3 is methyl). The Vi 1 ester was reacted with an alkali metal nitrite, such as sodium nitrite and an acid, such as acetic acid, to give the oxime VI H. The oxime was converted to IX in a simple reaction vessel by the reaction sequence following: 1) the oxime VI II was reacted with a hydrogen mixture of between 1.055-3.166 kg / cm2, a trialkyl orthoacetate, such as triethyl orthoacetate and a hydrogenation catalyst, such as Raney nickel, in a polar solvent, such as THF / methanol; 2) the catalyst was removed by filtration; and 3) the resulting mixture was reacted with an alkali metal hydroxide, such as potassium hydroxide, dissolved in a polar solvent, such as water, at a temperature of from about 20 ° C to about 40 ° C to give IX . The compounds and processes of the present invention will be better understood in connection with the following examples, which are understood as an illustration and not a limitation on the point of view of the invention.

EXAMPLE 1 Methyl 8-chloro-5- (2-fluorophenyl) - - (hydroxyimino) -3H-1 .4-benzodizepine-2 Acetate EXAMPLE 1 a Potassium tert-butoxide (51 g) in a mixture of acetonitrile (60 g) and heptane (240 g), was stirred for 15 minutes, then cooled to 5 ° C under a nitrogen atmosphere. A solution of diethyl malonate (71 g) in acetonitrile (90 g) was added after 30 minutes. To the resulting suspension, diethium chlorophosphate (26 g) in acetonitrile (30 g) was added. After stirring for one hour, 7-chloro-5- (2-phorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (desacylflur-azepam) (21 g) was added in portions. The resulting reaction mixture was stirred at room temperature for 16 hours, cooled to 10 ° C and then decomposed by the addition of water (160 ml). The pH of the solution was adjusted to 5.0-5.6 with dilute hydrochloric acid, mixed for 1 hour and filtered. The solid material obtained was washed with water (300 g) and heptane (100 g) and dried on the filter by applying a stream of nitrogen to give example 1 a.

EXAMPLE 1 b Example 1 a was again charged to the reaction bottle and methanol (250 g) and potassium hydroxide (5 g) were added. The suspension was heated to reflux under nitrogen for 5 hours, cooled to 5 ° C and stirred for 1 hour. The solid material obtained was filtered and the filtered mass was washed with methanol (45 g) and dried under nitrogen to produce Example 1b.

EXAMPLE 1 c Example 1 b was dissolved in acetic acid (165 g) at room temperature and sodium nitrite (15 g) was added in portions. The reaction mixture was mixed for 2 hours and filtered. The filtered mass was washed with water (100 g), toluene (50 g) and methanol (60 g). The solids were suspended in methanol (160 g), heated to reflux for 4 hours, cooled to room temperature and filtered. The filtered mass was washed with methanol (50 g) and dried under nitrogen to yield 16.8 g methyl 8-chloro-5- (2-fluorophenyl) -α- (hydroximino) -3H-1,4-benzodiazepine acetate. (example 1 c).

EX EMPLO 2 Acid 8-Chloro-6- (2-fluorophenyl-1-methyl-4H-imidazo M .5-lf 1.41 benzodiazepine-3-carboxylic acid (tricyclic acid) Raney (18.7 g) was washed with methanol and transferred to a hydrogenation vessel.To this, methanol (94 g), example 1 c (18.7 g), para-toluenesulfonic acid (2.9 g), triethyl orthoacetate (57.0 g) and THF (168 g) were added. The reaction mixture was hydrogenated at 2.1 1 1 kg / cm2 for 16 hours and filtered under hydrogen.The Raney nickel mass was washed with methanol and a cooled solution of potassium hydroxide was added in portions to the reaction solution. (22 g in 1000 g of water) The temperature was maintained below 30 ° C and the reaction solution was stirred for 2 hours.The solvent was distilled under vacuum and water (125 g) was added. aqueous was washed with isopropyl acetate (3 X 125 g) The aqueous phase was adjusted to a pH of 5.6 - 6.1 with glacial acetic acid and with vigorous stirring. it was separated, filtered, washed with water (50 g) and then heptane (100 g) and dried on the filter. The purification was carried out by heating a mixture of isopropyl / heptane alcohol and the product, to reflux, filtering and drying to give 10 g of tricyclic acid. mp 270-273 ° C (lit. 271 ° C - 274 ° C); MS (M + H) + m / e 370.

Claims (21)

1. CLAIMS 1. A process for preparing a compound having the formula I, wherein X1 and X2 are independently selected from the group consisting of halogen, nitro and amino; said process comprises reacting a compound having the formula II, wherein R3 is hydrogen or alkyl and X1 and X2 are independently selected from the group consisting of halogen, nitro and amino in a mixture comprising hydrogen, hydrogenation catalyst, trialkyl orthoacetate or triaryl orthoacetate and an acid followed by catalyst removal and the reaction with an alkali metal hydroxide to produce a compound of formula I. The process, according to claim 1, wherein the compound I has the following formula: and compound II has the following formula: wherein R3 is an alkyl group. 3. The process, according to claim 2, wherein the catalyst is a hydrogenation catalyst. 4. The process according to claim 3, wherein the catalyst is Raney nickel. The process, according to claim 2, wherein the trialkyl orthoacetate is selected from the group consisting of triethyl orthoacetate and trimethyl orthoacetate. 6. The process according to claim 5, wherein the trialkyl orthoacetate is triethyl orthoacetate. The process, according to claim 2, wherein the acid is selected from the group consisting of a mineral acid and an organic acid. 8. The process according to claim 7, wherein the acid is selected from the group consisting of para-toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. 9. The process, according to claim 8, wherein the acid is para-toluenesulfonic acid. The process, according to claim 2, wherein the alkali metal ion of the alkali metal hydroxide is selected from the group consisting of lithium, sodium and potassium. eleven . The process according to claim 10, wherein the alkali metal hydroxide is potassium or sodium hydroxide. 12. The process, according to claim 1, wherein the alkali metal hydroxide is potassium hydroxide. The process, according to claim 2, wherein the compound III is produced without isolation or purification of intermediates. 14. The process for the preparation of a compound of formula XI wherein X1, X2, R1 and R2 are defined above, said process comprising (a) reacting a doubly-activated methylene compound with base in a first solvent system; (b) reacting the product of step (a) with a reagent selected from the group comprising a dialkyl halophosphate and a diaryl halophosphate; and (c) reacting the product of step (b) with a compound of formula X X. 15. The process, according to claim 14, wherein the compound of formula X has the following formula: wherein X1 is Cl and X2 is F. 16. The process, according to claim 14, wherein the doubly activated methylene compound is selected from the group comprising a dialkyl maionate and an alkyl cyanoacetate. 17. The process, according to claim 16, wherein the doubly activated methylene compound is a dialkyl malonate. 18. The process according to claim 14, wherein the base is an alkali metal alkoxide selected from the group comprising potassium tert-butoxide, sodium ethoxide and sodium tert-butoxide. 19. The process, according to claim 18, wherein the base is potassium fer-butoxide. 20. The process according to claim 14, wherein the system of a first solvent comprises a mixture of hydrocarbon and polar solvents. twenty-one . The process, according to claim 20, wherein the system of a first solvent comprises a mixture of heptane and acetonitrile.