WO2012121701A1 - Procédé de résolution racémique (±)-10,11-dihydro -10-hydroxy -5 h-dibenz / b, f / azépine -5-carboxamide - Google Patents

Procédé de résolution racémique (±)-10,11-dihydro -10-hydroxy -5 h-dibenz / b, f / azépine -5-carboxamide Download PDF

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WO2012121701A1
WO2012121701A1 PCT/US2011/027406 US2011027406W WO2012121701A1 WO 2012121701 A1 WO2012121701 A1 WO 2012121701A1 US 2011027406 W US2011027406 W US 2011027406W WO 2012121701 A1 WO2012121701 A1 WO 2012121701A1
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Prior art keywords
dibenz
carboxamide
dihydro
azepine
formula
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Santosh Richard Fredric CRASTA
Ashutosh Vijay Joshi
Manjunath Narayan Bhanu
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Actavis Laboratories UT Inc
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Actavis Laboratories UT Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
    • B01J31/0247—Imides, amides or imidates (R-C=NR(OR))
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/49—Esterification or transesterification

Definitions

  • the present invention relates to a process for the resolution of racemic ( ⁇ )-10,l l- dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide to yield the R and S stereoisomers, and a process for the preparation of (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5- carboxamide, also known as eslicarbazepine acetate.
  • the pharmaceutical industry aggressively investigates compounds containing chiral centers to determine if one of the enantiomers possesses greater efficacy, fewer side effects or both. Because one isomer of a racemic mixture is often pharmacologically inactive or significantly less active, employing a racemic mixture of a chiral drug can be viewed as introducing an unnecessary impurity into a pharmaceutical product. One isomer of the racemic mixture may also produce unwanted side-effects. Isomeric molecules may also undergo different metabolic processes which further complicates pharmacokinetic issues. Accordingly, the U.S. Food and Drug Administration (FDA) often requires stringent investigation of active molecules that contain chiral centers to determine potential efficacy and safety issues.
  • FDA U.S. Food and Drug Administration
  • oxcarbazepine which is the 10- keto analogue of carbamazepine.
  • carbamazepine is structurally similar and both are used for the treatment of epilepsy
  • oxcarbazepine was designed to avoid the oxidative metabolic transformation of carbamazepine and is claimed to be better tolerated. See Grant, S. M. et al, Drugs, 43, 873-888 (1992). Unfortunately, oxcarbazepine undergoes rapid and complete metabolism in vivo to form a racemic 10-hydroxy derivative of oxcarbazepine. See Schutz, H.
  • Eslicarbazepine acetate is an anticonvulsant or antiepileptic drug which is used in the treatment of epilepsy, seizures, partial-onset seizures in adults with epilepsy, affective and attention disorders, anxiety, psychiatric disorders with underlying anxiety symptomatologies, mental disorders and/or other deficits in the sensory organs.
  • Eslicarbazepine acetate is re resented by the chemical structure:
  • WO 2002/092572 discloses methods for the preparation of eslicarbazepine acetate by reacting racemic ( ⁇ )-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide with diacetyl L-tartaric anhydride, followed by diastereomeric separation in water to yield an insoluble precipitate of tartaric ester of ( ⁇ )-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide having an SRR configuration, while the mother liquor is enriched with a soluble RRR diastereomer.
  • WO 2007/012793 describes processes for the preparation of eslicarbazepine acetate by enantioselective reduction of oxcarbazepine in the presence of a catalyst, such as [RuX 2 (L)]2 and a hydride source under controlled pH.
  • a catalyst such as [RuX 2 (L)]2 and a hydride source under controlled pH.
  • WO 2007/117166 discloses asymmetric hydrogenation of a double bond formed on the central azepine ring of a dibenzazepine in the presence of a hydrogen source and chiral catalysts, such as a ruthenium catalyst. Specifically, the double bond, which is asymmetrically reduced, is located at the ether linkage of the azepine ring. This asymmetric hydrogenation yields (S)-(-)- 10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide with a chiral purity of up to 94%.
  • the prior art resolving techniques generally involve either: (1) chiral reduction of oxcarbazepine with enantioselective catalysts to give the S or R isomer; or (2) racemic reduction of oxcarbazepine followed by esterification with expensive chiral acids to form diastereomers, which can then be separated using known enantiomeric separation techniques.
  • resolution agents such as (+) and (-) menthoxy acetic acid, and (+) and (-) menthol are extremely expensive and not readily available.
  • the present invention provides a process for the resolution of ( ⁇ )-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide using S-ibuprofen or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present invention employs a reaction of S-ibuprofen or a pharmaceutically acceptable salt thereof and racemic ( ⁇ )-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide to yield the SR and SS-ibuprofen diastereomer esters of ( ⁇ )- 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide.
  • the SR and SS-ibuprofen diastereomer esters of ( ⁇ )-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide may be separated to yield the SS-ibuprofen diastereomer ester. Removal of the S-ibuprofen moiety from the SS-ibuprofen ester yields the (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine- 5-carboxamide.
  • the physical and chemical differences of the diastereomer esters enables the SS and SR compounds to be prepared and/or separated using less costly and less complex techniques then many of the known prior art methods.
  • An embodiment of the present invention for resolving racemic ( ⁇ )-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide using S-ibuprofen or a pharmaceutically acceptable salt thereof can be represented as follows:
  • the resolved (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide may be employed in the production of compounds such as (S)-(-)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide (eslicarbazepine acetate). Additional compounds that can be formed from the (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide are recited in WO 2002/092572 and are incorporated herein by reference. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to a process for resolving the racemic ( ⁇ )-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of Formula (III):
  • Suitable reducing agents include but are not limited to sodium borohydride, lithium aluminum hydride, hydrogen, nickel borohydride, diisobutylaluminum hydride, formic acid, hydrazine, sodium hydrosulfite, trichlorosilane, sodium hydroxymethanesulfmate, and mixtures of the foregoing.
  • Suitable organic solvents include, but are not limited to, methylene dichloride, methanol, hexane, benzene, toluene, chloroform, diethyl ether, 1,4-dioxane or mixtures thereof.
  • One embodiment of the present invention involves reacting the racemic ( ⁇ )-10,l l- dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of Formula (III) with S-ibuprofen of Formula (IV) or a pharmaceutically acceptable salt thereof in a solution, and in the presence of a reaction catalyst.
  • S-ibuprofen of Formula (IV) or a pharmaceutically acceptable salt thereof in a solution, and in the presence of a reaction catalyst.
  • pharmaceutically acceptable salts of S-ibuprofen include, but are not limited to, chloride, bromide, iodide, succinate, fumarate, mesylate, citrate, tartrate and sulfate.
  • the solvent for the reaction is an organic solvent such as methylene chloride, methylene dichloride, ethanol, methanol, propanol, isopropanol, acetone, methyl acetate, ethyl acetate, hexane, and mixtures thereof.
  • the reaction catalyst may be any catalyst such as dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC), or a combination thereof.
  • Other catalysts that can be employed in the reaction include mineral acid catalysts, hafnium (IV) salts and zirconium (IV) salts.
  • the reaction mixture may be heated to assist in the formation of the SS and SR esters.
  • the reaction mixture is heated to about 20°C, preferably at least 25°C, and most preferably at least about 30°C.
  • the reaction mass is filtered and washed to produce a solid.
  • the reaction product is a mixture of SS and SR ibuprofen diastereomer esters of 10,11- dihydro- 10-hydroxy-5H-dibenz[b,fJazepine-5-carboxamide.
  • One method of diastereomeric crystallization involves obtaining a racemic mixture of the SS and SR ibuprofen diastereomer esters of 10,1 l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide, preferably in a crystal form, and placing the racemic mixture into a solvent so that the SS-ibuprofen ester is crystallized from the reaction mixture.
  • the SS-ibuprofen ester is preferably crystallized at a chiral purity level of at least 90%.
  • One embodiment of the diastereomeric crystallization of the present invention comprises placing a racemic mixture of the SS and SR powder into an organic solvent.
  • the organic solvent may be any solvent, but a mixture of an organic ester and a Ci-C 6 alcohol is preferred.
  • the organic ester may be selected from the group consisting of methylacetate, ethylacetate, propylacetate, butylacetate or mixtures thereof.
  • the Ci-C 6 alcohol may be straight or branched alcohols and may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, pentanol, tertbutyl alcohol, isobutyl alcohol, or mixtures of the foregoing.
  • the ratio of the mixed solvents should be about 1 :20 to 20: 1, preferably 1 : 15 to 15: 1, and most preferably 1 : 10 to 10: 1.
  • the amount of the organic ester should exceed the amount of Ci-C 6 alcohol.
  • the amount of organic ester is at least twice the amount of the Ci-C 6 alcohol.
  • the organic ester is at least four (4) times the amount of the Ci-C 6 alcohol, and most preferably, the organic ester is at least eight (8) times the amount of the Ci-C 6 alcohol.
  • the SS-ibuprofen ester product can be prepared using various solvent ratios, some of which are set forth below: Solvents/ ratio
  • the reaction mixture of an organic ester, a Ci-C 6 alcohol and racemic mixture of SS and SR ibuprofen diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide may be heated to assist in the dissolution of the SS and SR esters.
  • the reaction mixture is heated to about 35°C, preferably at least 40°C, and most preferably to at least about 50°C.
  • the SS-ibuprofen ester is isolated as a crystal from the reaction mass with a purity of at least 90% or greater, preferably at least 92% or greater, and most preferably at least 95% or greater.
  • Another embodiment of the present invention separates the SS and SR ibuprofen diastereomer esters using a solvent based separation technique to obtain the SS-ibuprofen ester with a chiral purity ranging from 90-100%.
  • One method of solvent based separation involves obtaining the racemic mixture of the SS and SR ibuprofen diastereomer esters of 10,1 l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide, and placing the racemic mixture into a solvent so that the SS-ibuprofen ester can be separated from the SR ibuprofen ester.
  • the SS-ibuprofen ester is preferably obtained at a chiral purity level of at least 90%.
  • One embodiment of the solvent based separation of the present invention comprises placing a racemic mixture of the SS and SR powder into an organic solvent.
  • the organic solvent may be any solvent, but a mixture of an organic ester and a halogenated Ci-C 6 compound is preferred.
  • the organic ester may be selected from the group consisting of methylacetate, ethylacetate, propylacetate, butylacetate or mixtures thereof.
  • the halogenated Ci-C 6 compound may be straight, branched or cyclical compounds and may be selected from the group consisting of chlorobutane, chlorobenzene, 1 ,2-dichlorobenzene, methylene chloride, methyl dichloride, trichloroethylene, 2,2,2-Trifluoroethanol, chloroform, 1 , 1 ,2-Trichlorotrifluoroethane, carbon tetrachloride, tetrachloroethylene, tetrafluromethane, ethylene dibromide, methylene chlorobromide, methyl bromine, n-butyl iodide, methyl iodide, n- propyl iodide, or mixtures of the foregoing.
  • the ratio should be about 1 : 10 to 10: 1 , preferably 1 :5 to 5 : 1 , and most preferably 1 :2 to 2: 1.
  • the amount of the organic ester can be lower, equal to, or greater than the amount of halogenated Ci-C 6 compound.
  • the amount of organic ester is greater than the amount of the halogenated Ci-C 6 compound, and in a more preferred embodiment the organic ester is two (2) times the amount of the halogenated Ci-C 6 compound.
  • the reaction mixture of an organic ester, a halogenated Ci-C 6 compound and racemic mixture of SS and SR ibuprofen diastereomer esters of 10, 1 l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide may be heated to assist in the dissolution of the SS and SR esters.
  • the reaction mixture is heated to about 25°C, preferably at least about 35°C, and most preferably at least about 40°C.
  • the SS-ibuprofen ester is isolated as a solid from the reaction mass with a purity of at least 90% or greater, preferably at least 92% or greater, and most preferably at least 95% or greater.
  • Subsequent separation reactions after the initial isolation of the SS-ibuprofen ester by either solvent based separation, diastereomeric crystallization, or both, can produce the SS- ibuprofen ester of 10, 1 l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide with a chiral purity (or enantiomeric excess) greater than 95%, preferably greater than 99% and most preferably greater than 99.5%.
  • the ibuprofen moiety may be removed from the SS-ibuprofen ester.
  • the removal or cleaving of the ibuprofen moiety can be accomplished by known techniques.
  • One embodiment of the present invention comprises dissolving the SS-ibuprofen ester in an organic solvent, such a Ci-C 6 alcohol as previously described. Once the SS-ibuprofen ester is in solution, a molar excess of a base is added to the solution to hydrolyze the SS-ibuprofen.
  • the base employed can be sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, barium hydroxide, calcium hydroxide, lithium hydroxide, sodium amide, sodium hydride or other suitable bases known in the art.
  • the base is preferably added to the SS-ibuprofen solution as a solution, and preferably as an aqueous solution.
  • the reaction mixture may be heated to assist in the hydrolysis. In certain embodiments the reaction mixture is heated to about 20°C, preferably at least about 25°C, and most preferably at least about 30°C.
  • 10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide is collected.
  • the S-(+)-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide is collected by known techniques such as titration, evaporation and/or filtration.
  • the collected S-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide and may be washed with a suitable solvent and dried.
  • the resulting S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide exhibits a chiral purity of at least 90%, preferably 92%, and most preferably 95%>.
  • S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide may be reacted with an acetylating agent, such as acetyl chloride, in an organic solvent to form the (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound.
  • Additional acetylating agents include, but are not limited to, acetic acid, formic acid, propionic acid, ethyl acetate, acetyl chloride, acetic anhydride, sodium acetate, potassium acetate, or mixtures thereof.
  • Suitable organic solvents can be selected from the group consisting of methylene chloride, methylene dichloride, ethanol, methanol, propanol, isopropanol, acetone, methyl acetate, ethyl acetate, hexane, and mixtures thereof.
  • the preferred organic solvent in the acetylation step is methylene dichloride.
  • the above acetylation reaction can be performed in the presence of a catalyst, a preferred catalyst is pyridine.
  • the (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, and other compounds prepared in accordance with the present invention may be mixed with at least one additional conventional pharmaceutical excipient to prepare a pharmaceutical dosage forms such as tablets, capsules or solutions.
  • Step 1 Reduction of oxcarbazepine
  • step 1 product The product, namely, ( ⁇ )-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide (step 1 product) was dried in an oven at 70°C.
  • the dry weight of the step 1 product was 90 gm (with a chemical purity of 99.4%).
  • step 1 product 25 gm of the step 1 product, 22.3 gm of S-ibuprofen, and 1.2 gm dimethylaminopyridine
  • DMAP dicyclohexylcarbodiimide
  • step 2 product The product, namely, the racemic mixture of SS and SR ibuprofen diastereomer esters of 10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (step 2 product) was dried in an oven at 60-65°C.
  • the dry weight of the step 2 product was 40.5 gm (with a chemical purity of 50:50 of the R:S esters).
  • step 3(a) product The product was dried in an oven at 65°C, to obtain the SS enriched ibuprofen ester of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,fJazepine-5-carboxamide (step 3(a) product) (with a chiral purity of 92% of the SS-ibuprofen ester).
  • step 2 product 5 gm was dissolved in 120 ml of an ethyl acetate :methylene dichloride (2: 1) mixture at 35-40°C and maintained at this temperature for 30 min.
  • the reaction mass was then cooled to 25-30°C within 1-2 hours, and further cooled to 0-5°C and maintained at this temperature for 15-30 minutes.
  • the reaction mass was then filtered and the solid obtained was washed twice with 20 ml of hexane.
  • step 3(b) product The product was dried in an oven at 65°C to obtain the SS-ibuprofen enriched ester of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (step 3(b) product) (with a chiral purity of 95% of the SS ester).
  • the S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of Step 4 was converted into (S)-(-)-10-acetoxy-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide by dissolving the S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide in a solution of acetylchloride, dichloromethane and pyridine as described in U.S. Patent No. 5,753,646. The reaction mass was heated until the reaction was complete, followed by cooling, filtering and washing. The reaction product is the (S)-(-)-10-acetoxy-10,l 1-dihydro- 10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide.
  • Step 1 Esterification of ( ⁇ )-10,ll-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide using S-ibuprofen chloride
  • the solution was then subjected to distillation where the methylene dichloride was distilled off, stripped with hexane and the resulting slurry was washed with 225 ml of hexane and filtered.
  • the product namely, the racemic mixture of SS and SR ibuprofen diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide was dried in an oven at 60-65°C.
  • the dry weight was 358.9 gm (with a chemical purity of 48.71 :50.17 ofthe R:S esters).
  • Step 1 350 gm of the product prepared by the process described within Example 2, Step 1 was dissolved in 4550 ml of an ethyl acetate: methanol (8:2) mixture at 60-70°C and maintained at this temperature for 60 min. The reaction mass was then cooled to 25-30°C within 1-2 hours, and maintained at this temperature for 12-16 hours. The reaction mass was then filtered and the solid obtained was washed twice with 175 ml of ethyl acetate.
  • the product was dried in an oven at 65°C, to obtain the SS enriched ibuprofen ester of 10,1 l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide (with a chemical purity of 96.88%, and chiral purity of 99.2% of the SS-ibuprofen ester).
  • the SS-ibuprofen ester product can be prepared using various solvent ratios and volumes, some of which are set forth below:
  • Step 2(a) 110 gm of the product that was prepared by the process described within Example 2, Step 2(a) was dissolved in 550 ml of methanol and NaOH aqueous solution (30 gm of sodium hydroxide dissolved in 55 ml of DM water). The heterogeneous reaction was stirred at 20-30°C until complete hydrolysis. The reaction mass was subjected to distillation under vacuum at 45°C to obtain an oil/solid and to it 220 ml of DM water was added and stirred at 20-30°C. The mass was neutralized with 440ml of dilute sulfuric acid. 330ml of hexane was further added to mass and stirred for 30-60 min.

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Abstract

L'invention concerne un procédé permettant de résoudre racémique (±)-10,11-dihydro -10-hydroxy -5 h-dibenz / b, f / azépine -5-carboxamide consistant notamment à faire réagir (±)-10,11-dihydro -10-hydroxy -5 h-dibenz / b, f / azépine -5-carboxamide avec S-ibuprofène ou un sel pharmaceutiquement acceptable de celui-ci pour former un mélange SS et SR diastéréomère esters de 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azépine-5- carboxamide, puis à séparer le SS-ibuprofène ester du SR ibuprofène ester, et à évacuer la fraction du S-ibuprofène pour former S-(+)-10,l l-dihydro-10-hydroxy-5h- dibenz[b,f]azépine-5-carboxamide d'une pureté chirale dépassant 90%.
PCT/US2011/027406 2011-03-07 2011-03-07 Procédé de résolution racémique (±)-10,11-dihydro -10-hydroxy -5 h-dibenz / b, f / azépine -5-carboxamide Ceased WO2012121701A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
EP3064490A1 (fr) 2015-03-06 2016-09-07 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé amélioré pour la préparation d'eslicarbazépine et d'acétate d'eslicarbazépine

Citations (5)

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