Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl

Definitions

• the present invention relates to methods for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid and precursors thereto, which are useful in a variety of indications, compositions containing these compounds, and methods of their use.
• U.S. Pat. No. 5,168,103 to Kinney et al. (“the '103 patent”) discloses certain [[2-(Amino-3,4-dioxo-1-cyclobuten-1-yl)amino]alkyl]acid derivatives. These derivatives are disclosed as competitive NMDA antagonists useful to treat certain central nervous system disorders such as convulsions, brain cell damage, and related neurodegenerative disorders.
• perzinfotel is effective in producing antihyperalgesic effects in a variety of preclinical pain models.
• Perzinfotel has also been described as a potent, selective, competitive NMDA antagonist that exhibits a superior therapeutic index for efficacy versus psychotomimetic side effects (Childers et al., Drugs of the Future 27:633-638 (2002)).
• Perzinfotel possesses a bioisosteric squaric acid amide in place of the typical ⁇ -amino acid and is reported to be 10-fold selective for rodent NMDA receptors possessing the NR2A subunit (Sun et al., J.
• Perzinfotel has demonstrated efficacy in animal models of inflammatory pain when administered both intraperitonealy and orally (Brandt et al., J. Pharm. Exp. Ther. 313:1379-1386 (2005)).
• Perzinfotel has also been described as effective in mediating surprisingly robust anesthetic-sparing effects while also providing the surprising additional benefit of improved cardiopulmonary function relative to the anesthetic alone (U.S. Patent Publication No. 2009/0061024). That is, when used in conjunction with an anesthesia regimen, perzinfotel can be used for administering a reduced concentration of anesthetic than would otherwise be required in the absence of perzinfotel, to achieve an equivalent level of anesthesia.
• the present invention provides for an improved process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (perzinfotel), which has Formula I, and derivatives and precursors thereto.
• One embodiment of the invention provides a process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid comprising:
• the reacting 1,3-diaminopropane with dialkylvinylphosphonate step is performed substantially in the absence of exogenous solvent; and/or (b) the reacting the N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester with 3,4-dialkoxy (e.g. diethoxy)-3-cyclobutene-1,2-dione step is performed in an aprotic solvent.
• Another embodiment of the invention provides a process for the preparation of N-(3-aminopropyl)aminoethanephosphonic acid dialkyl (e.g. diethyl) ester comprising:
• Another embodiment of the invention provides a process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester comprising:
• Another embodiment of the invention provides a process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid comprising:
• composition comprising:
• a base one or more of: a base, an acid, a solvent, a hydrogenating agent, a reducing agent, an oxidizing agent, or a catalyst.
• a compound is a reference to one or more compounds and equivalents thereof known to those skilled in the art
• a catalyst refers to one or more catalysts and equivalents thereof known to those skilled in the art, and so forth.
• Alkyl refers to saturated aliphatic hydrocarbyl groups having from 1 to 6 carbon atoms (C 1 -C 6 alkyl), and preferably 1 to 4 carbon atoms (C 1 -C 4 alkyl). This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl(CH 3 —), ethyl(CH 3 CH 2 —), n-propyl (CH 3 CH 2 CH 2 —), isopropyl((CH 3 ) 2 CH—), n-butyl(CH 3 CH 2 CH 2 CH 2 —), isobutyl((CH 3 ) 2 CHCH 2 —), sec-butyl((CH 3 )(CH 3 CH 2 )CH—), and t-butyl((CH 3 ) 3 C—).
• Alkoxy refers to —O-alkyl, where alkyl is defined above.
• “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, aluminum, lithium, zinc, diethanolamine salts, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, besylate, glutamate, methanesulfonate, ethanes
• Perzinfotel or “EAA-090” refers to the compound [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7-en-2-yl)ethyl]phosphonic acid, which has the following chemical structure (formula I):
• the pharmaceutically acceptable salts are prepared by contacting a compound, such as the compound of formula (I) with an acid or salt such as, hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, boric acid, perchloric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, ascorbic acid, sodium iodide and the like.
• a solvent employed may be selected from ketones such as acetone, diethyl ketone, methyl ethyl ketone or their mixtures, methanol, ethanol, n-hexane, ethyl acetate, benzene, diethylamine, formaldehyde, chloroform, dichloromethane or mixture thereof.
• C 1-6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
• the compounds described herein may be formulated for administration to humans and other animals orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, intracisternally, intravaginally, intraperitoneally, bucally, intrathecally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
• Methods of formulation are well known in the art and are disclosed, for example, in Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 21st Edition (2005), incorporated herein by reference.
• Some of the compounds made in the process of the present invention may contain chiral centers and/or tautomers and such compounds may exist in the form of stereoisomers (i.e. enantiomers or diastereomers) or tautomers.
• the present invention includes all such stereoisomers, tautomers and any mixtures thereof including racemic mixtures.
• the compounds of formula I may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purpose of the present invention.
• the compounds of formula I can be synthesized, for example, by the methods described below, or variations thereon as appreciated by the skilled artisan. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.
• step 1 see Scheme 1
• step 2 the new process for the preparation of perzinfotel provided herein offers significant improvements over existing processes.
• step 1 see Scheme 1
• step 2 the material can optionally be used “as is” in subsequent reactions.
• the Step 2 product precipitates from the reaction mixture as a solid with greater than about 95% purity and a yield in the range of 55-70%.
• Unreacted starting materials, dialkylated material (formed from the combination of Step 1 dialkylated product and diethyl squarate) and reaction by products remain in solution.
• step 3 perzinfotel of high purity was obtained directly from the reaction mixture reducing the need for substantial additional work-up nor the treatment of strong acid/base.
• One aspect of the present invention provides a process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid comprising:
• the reacting 1,3-diaminopropane with dialkylvinylphosphonate step is performed in a reaction mixture substantially in the absence of exogenous solvent.
• the reacting 1,3-diaminopropane with dialkylvinylphosphonate step comprises reacting in the presence of excess 1,3-diaminopropane.
• the process further comprises removing excess 1,3-diaminopropane by azeotropic distillation.
• Solvents suitably used in the azeotropic distillation include, among others, 1-butanol and xylenes (ortho, meta and para).
• the reacting N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester with 3,4-dialkoxy-(e.g. diethoxy-)-3-cyclobutene-1,2-dione step is performed in an aprotic solvent.
• the aprotic solvent is n-butyl acetate, iso-butyl acetate, methyl acetate, ethyl acetate, toluene, acetonitrile or a combination thereof, preferably ethyl acetate.
• the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester precipitates out of a liquid phase. More particular still, the liquid phase is cooled to less than about 15° C.
• the process further comprises filtering the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester from the liquid phase.
• the reacting 1,3-diaminopropane with dialkylvinylphosphonate step is performed in a reaction mixture substantially free of solvent;
• the hydrolyzing step is performed in an aprotic solvent, wherein the solvent is acetonitrile or dichloromethane.
• the hydrolyzing step comprises contacting the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester with trimethylsilyl bromide (TMS-Br) or trimethylsilyl iodide (TMS-I).
• TMS-Br trimethylsilyl bromide
• TMS-I trimethylsilyl iodide
• the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid is formed in a reaction medium and the process further comprises contacting the reaction medium with water, wherein the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid precipitates out of the reaction medium. More particularly, the water in the reaction medium is first heated to above 50° C. and then cooled to below 15° C.
• dialkylvinylphosphonate is diethylvinylphosphonate
• N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester is N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester;
• dialkylvinylphosphonate is dimethylvinylphosphonate
• N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester is N-(3-aminopropyl)aminoethanephosphonic acid dimethyl ester
• the 3,4-dialkoxy-3-cyclobutene-1,2-dione is 3,4-diethoxy-3-cyclobutene-1,2-dione.
• Another aspect of the invention provides a process for the preparation of N-(3-aminopropyl)aminoethanephosphonic acid dialkyl (e.g. diethyl) ester comprising:
• the reacting 1,3-diaminopropane with dialkylvinylphosphonate step comprises reacting in the presence of excess 1,3-diaminopropane.
• the process further comprises removing excess 1,3-diaminopropane by azeotropic distillation.
• dialkylvinylphosphonate is dimethylvinylphosphonate
• N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester is N-(3-aminopropyl)aminoethanephosphonic acid dimethyl ester.
• dialkylvinylphosphonate is diethylvinylphosphonate
• the N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester is N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester.
• Another aspect of the invention provides a process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester comprising:
• the aprotic solvent is n-butyl acetate, iso-butyl acetate, ethyl acetate, methyl acetate, toluene, acetonitrile or a combination thereof.
• the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester precipitates out of a liquid phase.
• the liquid phase is cooled to less than about 15° C.
• the process further comprises filtering the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester from the liquid phase.
• N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester is N-(3-aminopropyl)aminoethanephosphonic acid dimethyl ester
• N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester is N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester;
• the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester is [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid diethyl ester.
• the 3,4-dialkoxy-3-cyclobutene-1,2-dione is 3,4-diethoxy-3-cyclobutene-1,2-dione.
• Another aspect of the invention provides a process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid comprising:
• the process further comprises preparing [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester by reacting the N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester with 3,4-dialkoxy-3-cyclobutene-1,2-dione, e.g. by processes described herein, to form [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester.
• the hydrolyzing step comprises contacting the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl (e.g. diethyl) ester with trimethylsilyl bromide (TMS-Br).
• TMS-Br trimethylsilyl bromide
• the aprotic solvent is acetonitrile.
• the aprotic solvent is dichloromethane.
• the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid is formed in a reaction medium and the process further comprises contacting the reaction medium with water, wherein the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid precipitates out of the reaction medium. More particularly, the water in the reaction medium is first heated to above 50° C. and then cooled to below 15° C.
• the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester is [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dimethyl ester.
• the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester is [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid diethyl ester.
• any of the process steps are performed in a polar solvent or a nonpolar solvent. In another embodiment, any of the process steps are performed at or above 25° C.; or include the addition of one or more agents selected from the group consisting of a base, an acid, a solvent, a hydrogenating agent, a reducing agent, an oxidizing agent and a catalyst. In another embodiment, any of the process steps comprises a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.
• any of the process steps comprises an analytical step comprising liquid chromatography (LC), mass spectroscopy (MS), liquid chromatography/mass spectroscopy (LC/MS), gas chromatography (GC), gas chromatography/mass spectroscopy (GC/MS), nuclear magnetic resonance (NMR), thin layer chromatography (TLC), melting point (MP) analysis, optical rotation (OR) or elemental analysis.
• LC liquid chromatography
• MS mass spectroscopy
• LC/MS liquid chromatography/mass spectroscopy
• GC gas chromatography/mass spectroscopy
• NMR nuclear magnetic resonance
• TLC thin layer chromatography
• MP melting point
• OR optical rotation
• Another aspect of the invention provides a composition or compound prepared by the processes described herein.
• the two solutions were simultaneously added drop-wise into the preheated ethyl acetate over 2-3 hours. After the addition was complete, the mixture was cooled to 25° C. and then heated to 35° C. and held for one hour. The mixture was then cooled in an ice bath and held at 0-2° C. for one hour. The product was collected and washed with ethyl acetate (20 mL) and dried under vacuum to yield (23.3 g, 70%) and purity 96.6 w/w %.
• the two solutions were simultaneously added drop wise into the preheated ethyl acetate over 2-3 hours. After the addition was complete, the mixture was cooled to 25° C. and then heated to 35° C. and held for one hour. The mixture was then cooled in an ice bath and held at 0-2° C. for one hour. The product was collected and washed with ethyl acetate (20 mL) and dried under vacuum to yield (37.3 g, 65.6%) and purity 95.5 w/w %.
• ethyl acetate 45 mL was heated to 50-55° C.
• 3,4-diethoxy-3-cyclobutene-1,2-dione (15.5 g, 0.09 mole) was diluted with ethyl acetate to give a total volume of 30 mL and the solution transferred to an addition funnel.
• N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester (25.0 g, 0.105 mole) was mixed with ethyl acetate to give a total volume of 30 mL and transferred to an addition funnel.
• the two solutions were simultaneously added drop-wise into the preheated ethyl acetate over 2-3 hours. After the addition was complete, the mixture was cooled to 25° C. and then heated to 35° C. and held for one hour. The mixture was then cooled in an ice bath and held at 0-2° C. for one hour. The product was collected and washed with ethyl acetate (20 mL) and dried under vacuum to yield (15.8 g, 54.9%) and purity 97.5 w/w %.
• ethyl acetate 45 mL was heated to 50-55° C.
• 3,4-diethoxy-3-cyclobutene-1,2-dione (15.5 g, 0.09 mole) was diluted with ethyl acetate to give a total volume of 30 mL and the solution transferred to an addition funnel.
• N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester (22.5 g, 0.094 mole) was mixed with ethyl acetate to give a total volume of 30 mL and transferred to an addition funnel.
• the two solutions were simultaneously added drop-wise into the preheated ethyl acetate over 2-3 hours. After the addition was complete, the mixture is cooled to 25° C. and then heated to 35° C. and held for one hour. The mixture was then cooled in an ice bath and held at 0-2° C. for one hour. The product was collected and washed with ethyl acetate (20 mL) and dried under vacuum to yield (15.6 g, 54.2%) and purity 96.3 w/w %.
• toluene 50 mL was heated to 50-55° C.
• 3,4-diethoxy-3-cyclobutene-1,2-dione (6.35 g, 0.037 mole) was diluted with toluene to give a total volume of 50 mL and the solution transferred to an addition funnel.
• N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester (8.58 g, 0.036 mole) was mixed with toluene to give a total volume of 50 mL and transferred to an addition funnel.
• acetonitrile 50 mL was heated to 55-60° C.
• 3,4-diethoxy-3-cyclobutene-1,2-dione (6.35 g, 0.037 mole) was dissolved in acetonitrile (50 mL) and the solution transferred to an addition funnel.
• N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester (8.58 g, 0.036 mole) was dissolved in acetonitrile (50 mL) and transferred to an addition funnel.
• ethyl acetate 100 mL was heated to 50-55° C.
• 3,4-diethoxy-3-cyclobutene-1,2-dione 34.63 g, 0.204 mole was dissolved in ethyl acetate (30 mL) and the solution transferred to an addition funnel.
• N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester 50.02 g, 0.192 mole was dissolved in ethyl acetate (15 mL) and 5% toluene (relative to the N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester) added by weight.
• the solution was transferred to an addition funnel.
• the two solutions were simultaneously added drop-wise into the preheated ethyl acetate over 2-3 hours. After the addition was complete, the mixture was cooled to 25° C. and then heated to 35° C. and held for one hour.
• the solution was cooled to room temperature and poured into a vigorously stirred solution of water (81 mL) and acetonitrile (45 ml). During the addition a temperature of 20-25° C. was maintained and a slurry was produced. The slurry was stirred for 0.5 hours and room temperature and then held at 0-2° C. for one hour. The solid was collected and the wet cake was washed with acetonitrile pre-cooled to 0-5° C. (2 ⁇ 90 mL). In a 1000 mL, three-necked flask, equipped with a magnetic stirrer and a dropping funnel, the resulting wet cake (74 g) was suspended in water (270 mL).
• the solution was cooled to room temperature and poured into water (30 mL) and a slurry was produced. The slurry was stirred for 0.5 hours and room temperature and then held at 0-2° C. for one hour. The solid was collected and the wet cake was suspended in water (total volume 140 mL) and heated to 95-100° C. until a clear yellow solution was obtained. The solution was allowed to cool slowly to room temperature and after one hour at room temperature the slurry was cooled and held at 0-2° C. for one hour. The solid was collected and washed with cold water (5 mL) and dried in a vacuum oven at 63-65° C. for twenty-four hours.
• the solution was cooled to room temperature and poured into water (30 mL) and a slurry is produced.
• the slurry was stirred for 0.5 hours at room temperature and then held at 0-2° C. for one hour.
• the solid was collected and the wet cake was suspended in water (total volume 60 mL) and the resulting slurry was heated at 50° C. for one hour.
• the slurry was allowed to cool slowly to room temperature and after one hour at room temperature the slurry was cooled and held at 0-2° C. for one hour.
• the solid was collected and washed with cold water (5 mL) and dried in a vacuum oven at 63-65° C. for twenty-four hours.
• the condenser is set for downward distillation and the methylene chloride collected, As the distillation proceeded, water (45 mL) is added.
• the crude Perzinfotel was now suspended in water (total volume 60 mL) and heated to 80°-85° C. until a thin slurry was obtained.
• the slurry was allowed to cool slowly to room temperature and after one hour at room temperature the slurry was cooled and held at 0-2° C. for one hour.
• the solid was collected and dried in a vacuum oven at 63-65° C. for twenty-four hours.

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