WO2012058031A2 - Nouveau procédé de préparation de bisnorcymérine et ses sels - Google Patents

Nouveau procédé de préparation de bisnorcymérine et ses sels Download PDF

Info

Publication number
WO2012058031A2
WO2012058031A2 PCT/US2011/056415 US2011056415W WO2012058031A2 WO 2012058031 A2 WO2012058031 A2 WO 2012058031A2 US 2011056415 W US2011056415 W US 2011056415W WO 2012058031 A2 WO2012058031 A2 WO 2012058031A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
salt
solid
acid
Prior art date
Application number
PCT/US2011/056415
Other languages
English (en)
Other versions
WO2012058031A3 (fr
Inventor
Maria Maccecchini
Original Assignee
Qr Pharma, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Qr Pharma, Inc. filed Critical Qr Pharma, Inc.
Publication of WO2012058031A2 publication Critical patent/WO2012058031A2/fr
Publication of WO2012058031A3 publication Critical patent/WO2012058031A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • AD Alzheimer's disease
  • the major neuropathological hallmarks of the disease are ⁇ -amyloid plaques, neurofibrillary tangles, and synaptic loss (Khachaturian, 1985, Arch. Neurol. 42: 1095-1 105).
  • the cholinergic system is the earliest and most profoundly affected neurotransmitter system in AD, with substantial losses in the forebrain, cortex, and hippocampus, which are critical in the acquisition, processing, and storage of memories (Terry et al., 1991 , Ann. Neurol.
  • AChE acetylcholinesterase
  • BChE butyry!cholinesterase
  • BChE The role of BChE in normal, aging, and diseased brain remains largely unknown, and there has been minimal interest in the design, synthesis, and development of selective inhibitors of BChE, except in the agricultural industry where toxic irreversible BChE inhibitors have long been used as insecticides (Giacobini, In “Alzheimer's Disease: Molecular Biology to Therapy”; Becker & Giacobini, Eds.; Birkhauser: Boston, 1997; p 188-204).
  • the invention includes a composition comprising a compound of formula 10:
  • the invention also includes a method of preparing a salt comprising acid and a compound of formula 1 :
  • the method comprises the step of dissolving one equivalent of the compound of formula 1 in a first volume of a first solvent, to generate a first solution.
  • the method further comprises the step of dissolving a number of equivalents of the acid in a second volume of a second solvent, to generate a second solution.
  • the method further comprises the step of contacting the second solution with the first solution under stirring, to generate a first system comprising a first solid.
  • the method further comprises the step of stirring the first system at a first temperature for a first period of time.
  • the method further comprises the step of isolating the first solid from the first system by filtration.
  • the method further comprises the step of washing the first solid with a third volume of a third solvent, to generate a second solid.
  • the method further comprises the step of washing the second solid with a fourth volume of a fourth solvent, to generate a third solid.
  • the method further comprises the step of washing the third solid with a fifth volume of a fifth solvent, to generate a fourth solid.
  • the method further comprises the step of isolating and removing volatiles from the fourth solid, to generate the salt.
  • the number of equivalents of the acid ranges from about 1 to about 3, In another embodiment, in the salt the ratio of the acid to the compound of formula 1 ranges from about 1 : 1 to about 3: 1. In yet another embodiment, the acid is L-tartaric acid. In yet another embodiment, in the salt the ratio of L-tartaric acid to the compound of formula 1 is about 1 : 1 . In yet another embodiment, the first solvent and the second solvent each comprise isopropanol. In yet another embodiment, the first volume and the second volume are about 5 volumes each. In yet another embodiment, the first temperature ranges from about 45 to about 75 °C and the first period of time is about one hour, In yet another embodiment, the third solvent comprises isopropanol and the third volume is about 3 volumes.
  • the fourth solvent comprises 10 volumes of DMSO and 22 volumes of water.
  • the fifth solvent comprises acetonitrile and the fifth volume is about 1 1 volumes.
  • the volatiles are removed by spray-drying or freeze-drying the fourth solid,
  • the invention further includes a method of preparing a compound of formula 1 :
  • the compound of formula 10 is hydrolyzed with a solution of trifiuoroacetic acid in dichloromethane.
  • the compound of formula 10 or a salt thereof is prepared from a compound of formula 9 or a salt thereof:
  • the compound of formula 9 or a salt thereof is prepared from a compound of formula 8 or a salt thereof:
  • a reagent selected from the group consisting of phosgene, diphosphene, triphosgene, carbonyldiimidazole and para-nitrophenyl chloroformate, to form an intermediate, and further reacting the intermediate with para-isopropylaniline.
  • the compound of formula 8 or a salt thereof is prepared from a compound of formula 1_ or a salt thereof:
  • the compound of formula 7 or a salt thereof is prepared from a compound of formula 6 or a salt thereof:
  • a reagent selected from the group consisting of boron tribroniide, trimethylsilyl iodide, trimethylsilyl chloride, trifluoro boron etherate, tetrachlorosilane, aluminum tribiomide, aluminum trichloride, ferric trichloride, and bromodimethyiborane.
  • the compound of formula 6 or a salt thereof is prepared from a compound of formula 5 or a salt thereof:
  • the compound of formula 5 or a salt thereof is prepared from a compound of formula 4 or a salt thereof:
  • the compound of formula 4 or a salt thereof is prepared from a compound of formula 3 or a salt thereof: 3
  • the compound of formula 3 or a salt thereof is prepared from a compound of formula 2 or a salt thereof:
  • Figure 1 is a drawing illustrating a TLC separation performed for Preparative Example 1.
  • Figure 2 is an illustrative representation of a ⁇ NMR spectrum obtained for Compound 3.
  • Figure 3 is an illustrative representation of a 1H NMR spectrum obtained for Compound 4.
  • FIG. 4 is a drawing illustrating a TLC separation performed for Preparative Example 3.
  • Figure 5 is an illustrative representation of a ⁇ NMR spectrum obtained for Compound 5.
  • Figure 6 is an illustrative representation of a HPLC trace obtained for
  • FIG. 7 is a drawing illustrating a TLC separation performed for Preparative Example 4.
  • Figure 8 is an illustrative representation of a ⁇ NMR spectrum obtained for Compound 6.
  • Figure 9 is an illustrative representation of a LC-MS trace obtained for
  • FIG. 10 is a drawing illustrating a TLC separation performed for
  • Figure 1 1 is an illustrative representation of a ⁇ NMR spectrum obtained for Compound 7.
  • Figure 12 is an illustrative representation of a LC-MS trace obtained for Compound 7.
  • Figure 13 is a drawing illustrating a TLC separation performed for Preparative Example 6.
  • Figure 14 is an illustrative representation of a ! ⁇ NMR spectrum obtained for Compound 8,
  • FIG. 15 is a drawing illustrating a TLC separation performed for
  • Figure 16 is an illustrative representation of a ⁇ NMR spectrum obtained for Compound 9.
  • Figure 17 is an illustrative representation of a LC-MS trace obtained for Compound 9.
  • Figure 18 is a drawing illustrating a TLC separation performed for Preparative Example 8.
  • Figure 19 is an illustrative representation of a ⁇ NMR spectrum obtained for Compound 10.
  • Figure 20 is an illustrative representation of a LC-MS trace obtained for Compound 10.
  • Figure 21 is an illustrative representation of a HPLC trace obtained for the reaction in Example 1 .
  • Figure 22 is a drawing illustrating a TLC separation performed for
  • Figure 23 is an illustrative representation of a ⁇ NMR spectrum obtained for a crude material isolated in Example 1.
  • Figure 24 is an illustrative representation of a ⁇ NMR spectrum obtained for a purified material isolated in Example 1.
  • Figure 25 is an illustrative representation of a ⁇ NMR spectrum obtained for Compound 11.
  • the present invention relates to the discovery of a novel synthetic route that allows the high-yield synthesis of (--)-N i ,N 8 -bisnorcymserine or a salt thereof.
  • This route is easily scalable and reliable, and minimizes the risk of contamination of the final product with undesirable impurities as compared to previously disclosed synthetic routes.
  • the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, more preferably ⁇ 5%, even more preferably ⁇ 1 %, and stili more preferably ⁇ 0.1 % from the specified value, as such variations are appropriate to perform the disclosed methods.
  • the invention includes a composition comprising a compound of formula 10:
  • the compound of formula 10 is useful within the methods of the invention in the preparation of the compound of formula 1, as described below.
  • the invention further includes a composition comprising a salt, wherein the salt comprises a compound of formula 1 and an acid, wherein in the salt the ratio of the acid to the compound of formula 1 ranges from about 1 : 1 to about 3: 1. In another embodiment, in the salt the ratio of the acid to the compound of formula 1 ranges from about 1 : 1 to about 2.5: 1. In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 ranges from about 1 : 1 to about 2: 1 . In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 ranges from about 1 : 1 to about 1.5: 1 . In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 is about 1 : 1.
  • the ratio of the acid to the compound of formula 1 is about 1 .5: 1. In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 is about 1 .6: 1. in yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 is about 1.8: 1. In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 is about 2: 1.
  • the invention includes a method of preparing a salt comprising a acid and a compound of formula 1:
  • the acid is L-tartaric acid.
  • the number of equivalents of the acid ranges from about 1 to about 3. In another embodiment, the equivalent of the acid ranges from about 1 to about 2. In yet another embodiment, the equivalent of the acid ranges from about 1 to about 1.5.
  • the ratio of the acid to the compound of formula 1 ranges from about 1 : 1 to about 3: 1 . In another embodiment, in the salt the ratio of the acid to the compound of formula 1 ranges from about 1 : 1 to about 2,5: 1 . In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 , ranges from about 1 : 1 to about 2: 1. In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 ranges from about 1 : 1 to about 1 ,5: 1. In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 is about 1 : 1. In yet another embodiment, in the salt the ratio of the acid to the compound of formula 1 is about 1.5: 1.
  • the ratio of the acid to the compound of formula 1 is about 1.6: 1. In yet another embodiment, in the salt the ratio of the acid to the compound of formula i is about 1.8: 1. In yet another embodiment, in the alt the ratio of the acid to the compound of formula 1 is about 2 : 1.
  • the acid is tartaric acid
  • the ratio of the tartaric acid to the compound of formula 1 is about 1 : 1 :
  • the first solvent and the second solvent each comprise isopropanol. In another embodiment, the first volume and the second volume are about 5 volumes each. In yet another embodiment, the first temperature ranges from about 45 to about 75 °C and the first period of time is about one hour, in yet another embodiment, the third solvent comprises isopropanol and the third volume is about 3 volumes. In yet another embodiment, the fourth solvent comprises 10 volumes of DMSO and 22 volumes of water. In yet another embodiment, the fifth solvent comprises acetonitrile and the fifth volume is about 1 1 volumes. In yet another embodiment, the volatiles are removed by freeze-d tying the fourth solid. In yet another embodiment, the volatiles are removed by spray-drying the fourth solid.
  • the invention further includes a method of preparing a compound of formula 1:
  • the compound of formula 10 is hydrolyzed with a solution of trifluoroacetic acid in dichloromethane.
  • the compound of formula 10 or a salt thereof is prepared from a compound of formula 9:
  • the compound of formula 9 or a salt thereof is prepared from a compound of formula 8:
  • a reagent selected from the group consisting of phosgene, diphosphene,
  • triphosgene 1,3-bis(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-(trimethyl)-2-nitrophenyl chioroformate, to form an intermediate, and further reacting the intermediate with para- isopropylaniline.
  • the compound of formula 8 or a salt thereof is prepared from a compound of formula 7:
  • the compound of formula 7 or a salt thereof is prepared from a compound of formula 6:
  • a reagent selected from the group consisting of boron tribroniide, trimethyisilyl iodide, trimethylsily! chloride, trifluoroboron etherate, tetrachlorosilane, aluminum tribroniide, aluminum trichloride, ferric trichloride, and bromodimethylborane.
  • the compound of formula 6 or a salt thereof is prepared from a compound of formula 5:
  • the compound of formula 5 or a salt thereof is prepared from a compound of formula 4:
  • the compound of formula 4 or a salt thereof is prepared from a compound of formula 3:
  • the compound of formula 3 or a salt thereof is prepared from a compound of formula 2:
  • compound 1 and a salt thereof, such as the tartrate salt
  • compound 2 also known as (3aS)-5-ethoxy-l ,3a,8- trimethyl-l ? 2,3,3a,8,8a-hexahydiOpyrrolo[2,3-b]indole or (— )-eserethole, is useful within the methods of the invention.
  • Compound 2 may be prepared according to methods described in the literature (see, for example, U.S. Patent Nos. 5,5 19, 144 and 5,610,316).
  • the methylation of Compound 2 may be performed with a methylation agent such as, but not limited to, methyl iodide, methyl bromide, methyl triflate or methyl mesylate.
  • a methylation agent such as, but not limited to, methyl iodide, methyl bromide, methyl triflate or methyl mesylate.
  • the reaction may be performed in an organic solvent that is partially soluble or insoluble in water, such as an ether (as non-limiting examples, diethyl ether or tetrahydrofuran), Progress of the reaction may be followed by a method such as TLC, HPLC or NMR. Once deemed sufficiently complete, the reaction mixture may be concentrated under vacuum and treated with an aqueous solution comprising an inorganic base, such as but not limited to sodium carbonate, sodium bicarbonate, sodium hydroxide or sodium phosphate.
  • an inorganic base such as but not limited to sodium carbonate, sodium bicarbonate, sodium hydroxide or sodium
  • the product of the reaction may be isolated by concentration or Filtration of the reaction mixture.
  • Compound 3 may be isolated in sufficient purity to be used as is in the next step.
  • Compound 3 may be purified by any purification method known to one skilled in the art, such as but not limited to preparative HPLC, silica gel column chromatography or crystallization from a solvent system.
  • the methylation of 3 may be performed in an organic solvent, such as an ether.
  • organic solvent such as an ether.
  • ethers considered with the methods of the invention are diethyl ether or tetrahydrofuran.
  • Progress of the reaction may be followed by a method such as TLC, HPLC or NMR. Once deemed sufficiently complete, the reaction mixture may be concentrated under vacuum to isolate the product.
  • Compound 4 may be isolated in sufficient purity to be used as is in the next step.
  • Compound 4 may be purified by any purification method known to one skilled in the art, such as but not limited to preparative HPLC, silica gel column chromatography or crystallization from a solvent system.
  • Compound 4 may be treated with benzylamine in a polar organic solvent, such as but not limited to dimethylsulfoxide, dimethylformamide or N- methyl-pyrrolidinone. Progress of the reaction may be followed by a method such as TLC, HPLC or NMR.
  • the product of the reaction may be isolated by addition of water to the reaction mixture and: (a) isolation of the resulting precipitate; or (b) extraction of the product with an organic solvent that is not water soluble, such as diethyl ether or tetrahydrofuran, and isolation of the product by concentration under vacuum.
  • Compound 5 may be isolated in sufficient purity to be used as is in the next step.
  • Compound 5 may be purified by any purification method known to one skilled in the art, such as but not limited to preparative HPLC, silica gel column chromatography or crystallization from a solvent system. Compound 5 may be converted to Compound 6
  • Compound 5 may be treated with an oxidant that is reactive enough to oxidize the N-methyl group to a N-formyl group, yet mild enougli not to further oxidize the N-formyl or any other functional group in Compound 5.
  • an oxidant that is reactive enough to oxidize the N-methyl group to a N-formyl group, yet mild enougli not to further oxidize the N-formyl or any other functional group in Compound 5.
  • suitable oxidants for this transformation are pyridinium dichromate, silver nitrate/sodium persulfate, potassium permanganate, t-butyi hydrochiorite, N- bromosuccinimide, N-ch!orosuccinimide and hydrogen peroxide.
  • the reaction may be run in a solvent system comprising an aqueous solution and an organic solvent that is not soluble in the organic solution, such as diethyl ether or dichloromethane.
  • the solvent system may further comprise an inorganic base, such as but not limited to sodium carbonate, sodium bicarbonate, sodium hydroxide or sodium phosphate.
  • the reaction may be run at a temperature ranging from -20 °C to room temperature, and progress of the reaction may be followed by a method such as TLC, HPLC or NMR. Crude product may be isolated by filtering the reaction mixture and washing the solid residue with an organic solvent.
  • Compound 6 may be isolated in sufficient purity to be used as is in the next step.
  • Compound 6 may be purified by any purification method known to one skilled in the art, such as but not limited to preparative HPLC, silica gel column chromatography or crystallization from a solvent system.
  • Compound 6 may be dissolved in an organic solvent, such as dichloromethane or diethyl ether, and treated with a dealkylating reagent, such as but not limited to boron tribromide, ti'imethylsilyi iodide, trimethylsilyl chloride, trifluoroboron etlierate, tetrachlorosiiane, aluminum tribromide, aluminum trichloride, ferric trichloride, or bromodimethylborane.
  • a dealkylating reagent such as but not limited to boron tribromide, ti'imethylsilyi iodide, trimethylsilyl chloride, trifluoroboron etlierate, tetrachlorosiiane, aluminum tribromide, aluminum trichloride, ferric trichloride, or bromodimethylborane.
  • the reaction may be run at a temperature ranging from -78 °C to room temperature, and progress of the reaction may be followed by a method such as TLC, HPLC or NMR,
  • the reaction mixture may be quenched with an aqueous solution optionally comprising a dilute inorganic acid or an acidic inorganic salt.
  • the product may separate as a solid upon the addition of the aqueous solution, in which case the product may be isolated by filtering the reaction mixture and washing the solid with water and appropriate organic solvents.
  • Compound 7 may be isolated in sufficient purity to be used as is in the next step.
  • Compound 7 may be purified by any purification method known to one skilled in the art, such as but not limited to preparative HPLC, silica gel column chromatography or crystallization from a solvent system.
  • Compound 7 may be dissolved in an organic solvent, such as but not limited to ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide or tetrahydrofiiran, and treated with an aqueous solution of an inorganic base, such as but not limited to sodium carbonate, sodium bicarbonate, sodium hydroxide or sodium phosphate.
  • an organic solvent such as but not limited to ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide or tetrahydrofiiran
  • an inorganic base such as but not limited to sodium carbonate, sodium bicarbonate, sodium hydroxide or sodium phosphate.
  • the resulting system may be treated with BOC anhydride at a temperature ranging from -20 °C to 50 °C ⁇ and progress of the reaction may be followed by a method such as TLC, HPLC or NMR.
  • the reaction mixture may be worked up by adding water and an organic solvent that is not water soluble, such as diethyl ether, tetrahydrofiiran or dichloromethane, to the reaction mixture.
  • the product may be isolated from the organic layer by concentration under vacuum.
  • Compound 8 may be isolated in sufficient purity to be used as is in the next step.
  • Compound 8 may be purified by any purification method known to one skilled in the art, such as but not limited to preparative HPLC, silica gel column chromatography or crystallization from a solvent system.
  • Compound 9 may be prepared by treating Compound 8 with isopropyl isocyanate in an organic solvent, such as but not limited to dichloromethane, tetrahydrofuran or diethyl ether.
  • the reaction may be run in the presence of an organic base, such as sodium ethoxide, sodium methoxide, sodium hydride, potassium hydride and the like.
  • the reaction may run at a temperature ranging from -50 °C to 50 °C, and progress of the reaction may be followed by a method such as TLC, HPLC or NMR,
  • Compound 9 may be prepared in a two-step procedure from Compound 8.
  • Compound 8 may be treated with phosgene, diphosgene, triphosgene, carbonyldiimidazole or para-nitrophenyl- chloro formate in an organic solvent, such as but not limited to dichloromethane, tetrahydrofuran or diethyl ether, to form the corresponding chioro formate (in the case of phosgene, diphosgene, or triphosgene), imidazolyl carbonyl derivative (in the case of carbonyldiimidazole) or para-nttrophenyl carbonate (in the case of p-nitrophenyl- chloroformate).
  • organic solvent such as but not limited to dichloromethane, tetrahydrofuran or diethyl ether
  • imidazolyl carbonyl derivative in the case of carbonyldiimidazole
  • para-nttrophenyl carbonate in the case of
  • para-isopropylaniline in an organic solvent such as but not limited to
  • the reaction may be quenched with an aqueous solution optionally comprising a basic inorganic salt or inorganic base.
  • the product may be extracted with an organic solvent such as dichloromethane or diethyl ether, and isolated by concentration under vacuum,
  • Compound 9 may be isolated in sufficient purity to be used as is in the next step.
  • Compound 9 may be purified by any purification method known to one skilled in the art, such as but not limited to preparative HPLC, silica gel column chromatography or crystallization from a solvent system,
  • Compound 9 may be reacted with hydrogen gas in the presence of a hydrogenation catalyst, such as but not limited to palladium metal on carbon, palladium dihydroxide on carbon, palladium on barium sulfate or platinum metal on carbon,
  • a hydrogenation catalyst such as but not limited to palladium metal on carbon, palladium dihydroxide on carbon, palladium on barium sulfate or platinum metal on carbon
  • Compound 9 may be reacted with a hydrogen transfer reagent in the presence of a catalyst, such as but not limited to ammonium formate or cyclohexadiene in the presence of palladium metal on carbon.
  • the reaction may run at a temperature ranging from -20 °C to 80 °C, and progress of the reaction may be followed by a method such as TLC, HPLC or NMR.
  • the product of the reaction may be isolated by filtration and concentration of the filtrate under vacuum.
  • Compound 10 may be isolated in sufficient purity to be used as is in the next step, in another non-limiting embodiment, Compoimd 10 may be purified by any purification method known to one skilled in the art, such as but not limited to preparative HPLC, silica gel column chromatography or crystallization from a solvent system..
  • Compound 10 may be converted to Compound 1 ((3aS)-3a-methyl- 1 ,2,3,3a,8,8a-hexahydiOpyrrolo[2 J 3-b]indol-5-yl (4-isopropylphenyl)carbamate) by acidic hydrolysis.
  • Compound 10 may be deprotected by treatment with an acid, such as but not limited to trifluoroacetic acid in dichioromethane, trifluoroacetic acid in water, aqueous hydrochloric acid or hydrogen chloride solution in tetrahydrofuran. Progress of the reaction may be followed by a method such as LC-MS, TLC, HPLC or NMR.
  • an acid such as but not limited to trifluoroacetic acid in dichioromethane, trifluoroacetic acid in water, aqueous hydrochloric acid or hydrogen chloride solution in tetrahydrofuran.
  • Progress of the reaction may be followed by a method such as LC-MS, TLC, HPLC or NMR.
  • Compound 10 ( i volume) may be dissolved in dichioromethane (in a non-limiting embodiment, 10 volumes), and the solution may be treated with trifluoroacetic acid (in a non-limiting embodiment, 16 equivalents) at 0-5 °C under stirring.
  • the system may be stirred for 4 hours at 25-30 °C, and the volatiles in the mixture may be distilled, for example, at 44 °C under 2 mm pressure.
  • the resulting system may be treated with one or more of the following solutions: aqueous saturated sodium bicarbonate solution (in a non-limiting embodiment, 16 volumes), dichioromethane (in a non-limiting embodiment, 5.8 volumes), brine (in a non-limiting embodiment, 15.7 volumes) and sodium sulfate (in a non-limiting embodiment, 0.6 w/w).
  • aqueous saturated sodium bicarbonate solution in a non-limiting embodiment, 16 volumes
  • dichioromethane in a non-limiting embodiment, 5.8 volumes
  • brine in a non-limiting embodiment, 15.7 volumes
  • sodium sulfate in a non-limiting embodiment, 0.6 w/w.
  • the system may be allowed to separate phases, and the organic phase may be reserved and concentrated, for example at 44 °C under 600 mm pressure.
  • the resulting residue may be dried, yielding the product.
  • Compound 1 may be converted to Compound 11 (the tartrate salt of (3aS)-3a-methyl-l,2,3,3a,8,8a-hexahydi pynOlo[2,3-b]indol-5-yi-(4-tsopropylphenyl) carbamate) by treatment with tartaric acid.
  • the representation of compound 11 illustrated below does not imply any particular ratio of the Compound 11 and tartaric acid in the compositio
  • compositions and methods of the present invention contemplate and include any salt comprising an acid and Compound 1, wherein the acid and Compound 1 may be present in any particular ratio, wherein the salt is stable (i.e., the salt that does not decompose spontaneously under normal temperature and pressure conditions).
  • Compound 1 may be treated with a solution of tartaric acid in an organic solvent, such as an alcohol.
  • an organic solvent such as an alcohol.
  • alcohols useful within the methods of the invention are methanol, ethanol, 1 -propanol, isopropanol, tert- butanoi, n-butanol or sec-butanol.
  • Compound 1 may be dissolved in isopropanol (in a non-limiting embodiment, 5 volumes) and treated with a solution of L-tartaric acid in isopropanol (in a non-limiting embodiment, 5 volumes) at 55 °C under stirring. The resulting system may be stirred at 45-75 °C for one hour, and then filtered. The solid isolated may be washed with isopropanol (in a non-limiting embodiment, 3 volumes) and then dried at 40 °C for 4 hours.
  • the residue may be stirred with a solvent system comprising DMSO (in a non-limiting embodiment, 10 volumes) and water (in a non-limiting embodiment, 12 volumes), at 0-10 °C for 1 hour, and then filtered.
  • the residue may be dried at 44 °C for 96 hours.
  • the residue may be stirred in acetonttrile (in a non-limiting embodiment, 1 1 volumes) at 25-30 °C for 3 hours, and then filtered.
  • the residue may be freeze-dried or spray-dried to afford Compound 11.
  • the compounds described herein may form salts with acids or bases, and such salts are included in the present invention.
  • the salts are pharmaceutically acceptable salts.
  • the term "salts" embraces addition salts of free acids or free bases that are compounds of the invention.
  • the ratio between the acid and the base in the salt may be any positive number and is not necessary a ratio between integers (i,e., the salt contemplated within the compositions and methods of the invention may be stoichiometric or non-stoichiometric).
  • pharmaceutically acceptable salt refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications, Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention,
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenes ulfonic, pantothenic, trifiuorome
  • Examples of pharmaceutically unacceptable acid addition salts include, for example, perch lorates and tetrafhioroborates.
  • Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metai and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, ⁇ , ⁇ '- dibenzylethyiene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • ranges such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from I to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2,7, 3, 4, 5, 5,3, and 6. This applies regardless of the breadth of the range.
  • Methyl iodide (1 , 162 liters; i 8,499 mmol) was added to the solution dropwise over a period of 80.0 minutes at 1 5-20 °C with constant stirring. A thick white solid was gradually formed in the reaction mixture. Stirring was continued. The white solid precipitate was filtered through a Buckner funnel. This filtered solid was washed with diethyl ether (2 x 1 ,25 liters). The filtered solid was dried at 30 °C under reduced pressure to afford 1550,0 g white solid powder (96.45 %). A ! H NMR analysis of this solid in CDCi 3 ( Figure 3) confirmed the formation of desired 4.
  • reaction mixture was filtered through Buckner funnel.
  • the filtered solid was washed with dichloromethane (5 x 1 ,0 liter).
  • the total filtrate liquid was concentrated under vacuum at 40 °C to afford 756,0 g black semi solid compound.
  • Potassium carbonate (89.39 g; 0.646 mol) was added to the solution portionwise over a period of 10 minute at 30 °C. The reaction mixture was stirred for 45 minutes. Di-tert-butyl dicarbonate (Boc anhydride; 122.08 g; 0.559 mol) was added to the system dropwise over a period of 30 minutes maintaining the temperature at 30 °C. The reaction mass was stirred for 4 hours,
  • reaction mixture was quenched by dropwise addition of cold water (-150.0 mL). Further 2,000 mL cold water were then added to the system with constant stirring. Diethyl ether (10.0 liters) was added to it and stirred for further 30 minutes. The upper organic layer was collected, and the aqueous layer was again extracted by diethyl ether (2 x 2.5 liters). The combined organic layers were washed with water (3.0 liters) and brine (5.0 liters), dried over Na 2 S04 and concentrated at 30 °C under reduced pressure to afford 253.0 g crude (101%) product.
  • FIG. 21 A representative HPLC trace of the reaction mixture is illustrated in Figure 21.
  • 1 mL of the reaction mixture was treated with saturated sodium bicarbonate solution. After 1 mL of dichioroniethane was added and the system was shaken thoroughly, the lower organic layer was used for TLC spotting ( Figure 21).
  • a ⁇ NMR spectrum of the crude trifluoroacetate salt is illustrated in Figure 22.
  • the reaction mixture was concentrated under vacuum at 44 °C, yielding 450 mg crude brown oil.
  • the crude brown oil was dissolved in

Abstract

La présente invention concerne un nouveau procédé de préparation de N1,N8-bisnorcymsérine. Elle concerne également un procédé de préparation de 1:1 sel de (--)-N1,N8-bisnorcymsérine avec un acide.
PCT/US2011/056415 2010-10-28 2011-10-14 Nouveau procédé de préparation de bisnorcymérine et ses sels WO2012058031A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40774310P 2010-10-28 2010-10-28
US61/407,743 2010-10-28

Publications (2)

Publication Number Publication Date
WO2012058031A2 true WO2012058031A2 (fr) 2012-05-03
WO2012058031A3 WO2012058031A3 (fr) 2014-04-10

Family

ID=45994656

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/056415 WO2012058031A2 (fr) 2010-10-28 2011-10-14 Nouveau procédé de préparation de bisnorcymérine et ses sels

Country Status (1)

Country Link
WO (1) WO2012058031A2 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1349858B1 (fr) * 2000-11-02 2008-08-27 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Agents permettant la reduction de la proteine precurseur amyloide et le traitement de la demence et procede d'utilisation de tels agents
US7662816B2 (en) * 2003-08-08 2010-02-16 Schering Corporation Cyclic amine BACE-1 inhibitors having a benzamide substituent

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1349858B1 (fr) * 2000-11-02 2008-08-27 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Agents permettant la reduction de la proteine precurseur amyloide et le traitement de la demence et procede d'utilisation de tels agents
US7662816B2 (en) * 2003-08-08 2010-02-16 Schering Corporation Cyclic amine BACE-1 inhibitors having a benzamide substituent

Also Published As

Publication number Publication date
WO2012058031A3 (fr) 2014-04-10

Similar Documents

Publication Publication Date Title
KR101539561B1 (ko) 목시플록사신 염산염의 합성방법
KR101020399B1 (ko) 퀴놀린 유도체 및 5-ｈｔ6 리간드로서의 그의 용도
FI104174B (fi) Menetelmä terapeuttisesti käyttökelpoisten, 1,4-dihydro-4-okso-3-kinoliinikarboksyylihapon 7-£S,S|-2,8-diatsabisyklo£4.3.0|nonaani-isomeeriven valmistamiseksi
KR101630884B1 (ko) 모르폴린 유도체의 제조
IL230027A (en) A process for making solipanacin and its salts
EP1866308B1 (fr) Preparation d'une quinoxaline substituee de haute purete
EP2861582B1 (fr) Procédé de fabrication de composés de cyclopentylpyrimidine hydroxylée
EP3077375B1 (fr) Procédé pour la production de 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1h-indole dimesylate monohydrate à grande échelle
EP0646583A1 (fr) Dérivés d'imidazol-4-yl-pipéridine, leur préparation et leur application en thérapeutique
HU224914B1 (en) Process for the preparation of nalbuphine having not more then 1% levels of beta-epimer
US20040242556A1 (en) Novel crystalline form of cefdinir
FR2731708A1 (fr) Derives de piperidine, leur procede de preparation et leur application en therapeutique
EP2850064B1 (fr) Procédé de préparation de montélukast sodique
WO2012058031A2 (fr) Nouveau procédé de préparation de bisnorcymérine et ses sels
EP0538314B1 (fr) Carbamates d'indiano-pyrrolidine
FR2719843A1 (fr) Dérivés de 5,6-dihydro-4h-imidazo [2',1':2,3] imidazo-[4,5,1-ij] quinoléine et de 4,5-dihydroimidazo [1,2-a] pyrrolo-[1,2,3-cd] benzimidazole, leur préparation et leur application en thérapeutique.
US6576764B2 (en) Synthesis and crystallization of piperazine ring-containing compounds
US20130096316A1 (en) Novel Method for Preparation of Bisnorcymerine and Salts Thereof
KR100714197B1 (ko) 보글리보스의 제조방법
PL234208B1 (pl) Sposób wytwarzania bursztynianu solifenacyny
JPH09501182A (ja) ナフチリドンカルボン酸塩を製造するための方法および中間体
JPH0597830A (ja) １，２，３−オキサチアゾリジン誘導体およびチエノ［３，２−ｃピリジン誘導体の合成
UA123692C2 (uk) Спосіб одержання піперазинового кільця для синтезу похідних піразинокарбазолу
KR20020001041A (ko) 발기부전 치료에 효과를 갖는 피라졸로피리미디논화합물의 제조방법
CA1334413C (fr) Acides azabicycliques quinolonecarboxyliques pontes a substituants amines, et leurs esters

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11836860

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 11836860

Country of ref document: EP

Kind code of ref document: A2