Process for the preparation of imidazobenzodiazepines

A process for synthesizing a compound of formula XIX,

• comprising the steps of:
• a. mixing a compound of formula XVII
• with a sufficient quantity of a polar, water miscible solvent;
• b. adding diethylacetamidomalonate, potassium tert-butoxide, and diphenylphosphorylchloride (DPPC) or dimorpholinophosphinyl chloride (DMPC);
• and
• c. allowing the reaction to proceed a sufficient period of time to produce the compound of formula XIX;
• wherein:
• R1-R7 are each independently selected from the group consisting of H, a halogen, an alkyl, an aryl, and a heteroaryl, wherein the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio.

A process for making a compound of formula XX;

• comprising the steps of:
• a. mixing the compound of formula XIX with a sufficient quantity of the following:
• dimethyl sulfoxide (DMSO), an alcohol, and an alkali hydroxide and allowing the reaction to proceed for a period of time sufficient to synthesize the compound of formula XX;
• b. quenching the alkali hydroxide with a sufficient amount of acid;
• and
• c. heating the reaction mixture for a sufficient amount of time and a temperature to distill the alcohol off;
• wherein:
• R1-R7 are each independently selected from the group consisting of H, a halogen, an alkyl, an aryl, and a heteroaryl, wherein the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio.

A process for making a compound of formula XXI comprising the steps of:

• a. mixing a compound of formula XX with an alcohol;
• b. adding to the mixture of a) a solution of aqueous alkali hydroxide;
• c. acidifying the solution of b) with the addition of a sufficient quantity of inorganic acid with stirring to precipitate the compound of formula XXI resulting in a slurry;
• and
• d. collecting the crystals formed in c) by filtration and washing with a solution of about 1:1 acetone:water;
• wherein:
• R1-R7 are each independently selected from the group consisting of H, a halogen, an alkyl, an aryl, and a heteroaryl, wherein the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio.

A process for the preparation of 4H-imidazo[1,5-a][1,4]benzodiazepine compounds of formula IX or a salt thereof;

• the process comprising the steps of:
• a. mixing a compound of formula X, a compound of formula XI, a compound of formula XII, or any combination thereof with about 3 to about 7 molar equivalents of a sulfonic acid to form a reaction mixture, wherein the compound of formula XI is a 6H-imidazo[1,5-a][1,4]benzodiazepine isomer of the compound of formula IX and the compounds of formula XII is a 6H-imidazo[1,5-a][1,4]benzodiazepine isomer of the compound of formula X;
• b. if the reaction mixture of a) comprises a compound of formula XI, a compound of formula XII, or any combination thereof, converting the 6H-imidazo[1,5-a][1,4]benzodiazepine isomer of formula XI to the 4H-imidazo[1,5-a][1,4]benzodiazepine isomer of formula IX to thereby synthesize the compound of formula IX and converting the 6H-imidazo[1,5-a][1,4]benzodiazepine isomer of formula XII to the 4H-imidazo[1,5-a][1,4]benzodiazepine isomer of formula X by heating the reaction mixture to a temperature ranging from about 130° C. to about 160° C. for a period of time ranging from about 60 minutes to about 120 minutes;
• c. decarboxylating the 4H-imidazo[1,5-a][1,4]benzodiazepines of formula X and formula XII by heating any mixture from a) or b) comprising the 4H-imidazo[1,5-a][1,4]benzodiazepines of formula X and formula XII to a temperature ranging from about 170° C. to about 230° C. for a period of time ranging from about 30 minutes to about 240 minutes to thereby synthesize produce the 4H-imidazo[1,5-a][1,4]benzodiazepine of formula IX or a salt thereof;
• wherein:
• R1-R8 are each independently selected from the group consisting of H, a halogen, an alkyl, an aryl, and a heteroaryl, wherein the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio.

A process for making a compound of formula II:

• the process having the steps of:
• a. making a solution of toluene, trifluoracetic acid (TFA), and about 0.5 mole of 2-amino-5-chloro-2′-fluorobenzophenone;
• b. stirring the mixture of a) and adding about 1.1 mole equivalents of glycine N-carboxyanhydride;
• c. pumping the solution of b) into a plug flow reactor heated to about 50° C. with a flow rate of about 8 to 15 ml/min for about 10-20 minutes residence time;
• d. converging the first outlet stream flow from c) with a second stream flow of triethylamine flowing at a rate of between about 0.7 to about 1.5 ml/min into a tank reactor heated to about 75° C. for about 90 minutes;
• e. pumping the reaction solution of d) out of the reactor at a rate of about 10 to about 15 ml/min as a second outlet stream flow;
• f. converging the second outlet stream flow of e) with a stream of saturated aqueous alkali bicarbonate solution at a flow rate of about 15 to about 25 ml/min;
• g. separating the organic and inorganic fractions by combining the streams of f) into a membrane separator and collecting the organic layer created or in a gravity separator;
• h. pumping the organic layer of g) into a crystallizer together with n-heptane (anti-solvent) at a flow rate of about 0.5 to 1.5 ml/min;
• and
• i. collecting and drying the crystallized product.

A process for making a compound of formula Ill (midazolam-AFP)

• comprising the steps of:
• a. adding to a reactor at a temperature of about 0° C., a sufficient quantity of a polar, water miscible solvent with stirring;
• b. adding to the solvent of a) about a mole of diethylacetamidomalonate, and about 0.6 mole of compound of formula II (midazolam-lactam or norflurazepam) to create a solution with stirring;
• c. adding to the solution of b) about two moles of potassium tert-butoxide over a sufficient time to keep the temperature of the solution at about 0° C.;
• d. adding to the solution of c) about 0.7 mole of diphenylphosphorylchloride (DPPC);
• and
• e. allowing the reaction to proceed for about 1 hour.

A process for making the compound of formula IV

• comprising the steps of:
• a. adding about 2 moles of the compound of formula III into a reactor at a temp of about 25° C.;
• b. adding to the reactor of a) a sufficient quantity of the following:
• dimethyl sulfoxide (DMSO), ethanol, and about 1.5 mol of alkali hydroxide, and stirring the resultant solution for about 30 to about 60 minutes;
• c. optionally, determining the completeness of the reaction of b) by taking a sample of the solution of b) and measuring the quantity of yield of the intermediate formed midazolam-olefin intermediate (ethyl-2-acetamido-2-(7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ylidene)acetate in the solution of b);
• d. adding to the intermediate containing solution of b) a sufficient quantity, about 6 to 7 moles, of acetic acid and heating to 125° C.;
• e. sparging the reactor with N2 once the reactor reaches a temperature of at least about 70° C.;
• f. stopping the N2 sparging once the reactor reaches 125° C. and then stirring the reactor for between 30 to 60 minutes;
• g. cooling the reactor to about 70° C.;
• h. adding a sufficient quantity of deionized water and cooling the reactor to about 35° C. with the addition of one or more seed crystals to create a crystallization slurry;
• i. cooling the slurry of h) to about -10° C. and stirring for at least about 30 min;
• j. collecting the crystals of the compound of formula IV formed in step i) by filtration and washing with a sufficient quantity of deionized water;
• and
• k. drying the crystals formed in j).

A process for making the compound of formula V comprising the steps of:

• a. adding to a reactor heated to about 50° C., a sufficient quantity of methanol with stirring;
• b. adding to the methanol solution of a) about 1 to about 2 moles of the compound of formula IV and stirring the solution until the compound is dissolved;
• c. adding to the solution of b) about 1 to 2 L of a about 2 to 3 molar aqueous alkali hydroxide solution and heating the reactor to about 70° C. for about 45 to 75 minutes;
• d. optionally, determining the completeness of the reaction of c) by taking a sample of the solution of c) and measuring the quantity of yield of the compound of formula V formed in the solution of c);
• e. acidifying the solution of c) with the addition of a sufficient quantity of 1M inorganic acid with stirring to precipitate the compound of formula V;
• f. cooling the resulting slurry of e) to about room temp for about an hour and adjusting the pH of the slurry to about 5.2-5.7;
• g. collecting the crystals formed in f) by filtration and washing with a solution of about 1:1 acetone:water;
• and
• h. drying the crystals of the compound of formula V.

A process for making the compound of formula VI

• comprising the steps of:
• a. adding about 0.1 to 0.3 moles of the compound of formula V
• to a container and adding about 5 to 6 mole equivalents of para-toluene sulfonic acid monohydrate and heating the container to about 150° C. for about 20 to 40 minutes to form a melted mixture;
• b. heating the mixture of a) to 220° C. for about 2 to 3 hours to form a product;
• comprising the compound of formula VI;
• c. cooling the reacted product of b) to about 100° C.;
• d. adding to the mixture of c) a sufficient quantity of water to solubilize the product of c);
• e. basifying the solution of d) with a sufficient quantity of concentrated aqueous alkali hydroxide solution;
• f. extracting the solution of e) with a water-immiscible organic solvent at least two times, and collecting the organic layers;
• g. treating the collected organic layers of f) with a sufficient quantity of activated charcoal for about 20 to 40 minutes;
• h. filtering the charcoal treated organic solution through celite to remove the charcoal;
• and
• i. concentrating the resultant solution under vacuum to obtain the compound of formula VI as a solid.

The process of 44, further comprising:

• j) dissolving the solids of step i) in a sufficient quantity of acetonitrile and heating the resulting solution to about 70° C. to produce an optically clear solution;
• k) cooling the solution of j) to about 60° C. and seeding with crystals of the compound of formula VI;
• l) cooling the solution of k) to about −2° C. and held at this temperature for about 30 mins;
• m) collecting the resulting crystals by filtration;
• and
• n) washing the crystals of m) in about a 1:4 isopropanol:n-heptane solution followed by n-heptane and drying under vacuum.