| Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms -> Monitor Keywords |
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Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline formsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Piperidines, Additional Ring ContainingSynthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060205781, Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 11/235,558, filed Sep. 26, 2005, which was a non-provisional of U.S. Provisional Application No. 60/614,014, filed on Sep. 27, 2004, both of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to the fields of medicine and chemistry. More particularly, the present invention relates to N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy-ph- enylmethyl)carbamide, its tartrate salt, and polymorphs and syntheses and uses thereof. [0004] 2. Description of the Related Art [0005] WO 01/66521 describes N-azacycloalkyl-N-aralkyl carbamides and carboxylic acid amides, which constitute, a new class of compounds effective in inhibiting an activity of monoamine receptors, including the serotonin receptor of the 5-HT2A subclass. WO 01/66521 is incorporated herein by reference in its entirety. Examples of disease conditions for which such compounds can be used include, but are not limited to, neuropsychiatric diseases such as schizophrenia and related idiopathic psychoses, depression, anxiety, sleep disorders, appetite disorders, affective disorders such as major depressions, bipolar disorder, depression with psychotic features and Tourette's Syndrome. Other beneficial treatments may be drug-induced psychoses and side-effects of Parkinson's disease as well as psychoses secondary to neurodegenerative disorders such as Alzheimer's or Huntington's Disease, hypertension, migraine, vasospasm, ischemia and the primary treatment and secondary prevention of various thrombotic conditions including myocardial infarction, thrombotic or ischemic stroke, idiopathic and thrombotic thrombocytopenic purpura and peripheral vascular disease. SUMMARY OF THE INVENTION [0006] One embodiment disclosed herein includes a method for the preparation of a compound of formula I: that includes reacting (4-fluorobenzyl)-(1-methylpiperidin-4-yl)amine of formula II with 4-(2-methylpropyloxy)phenylmethy-isocyanate of formula III [0007] In some embodiments, about 0.9 to about 1.1 equivalents of the (4-fluorobenzyl)-(1-methylpiperidin-4-yl)amine is used per equivalent of the 4-(2-methylpropyloxy)phenylmethy-isocyanate. Some embodiments further include isolating the compound of formula I after the reacting. In some embodiments, the isolating includes adding a salt-forming acid after the reacting, isolating the formed salt by solvent removal, precipitation, or both solvent removal and precipitation, adding the isolated salt to a two phase system comprising an organic solvent phase and an alkaline aqueous phase, and obtaining the compound of formula I from the organic solvent phase. In some embodiments, the salt forming acid is selected from the group consisting of one or more of the following: mineral acids, mono- or dicarboxylic acids, and sulfonic acids. In some embodiments, the pH of the aqueous phase is greater than about 8.5. In one embodiment this pH is obtained by adding an aqueous alkaline metal hydroxide. In some embodiments, the reaction is carried out in the presence of an inert organic solvent. In some embodiments, the solvent is selected from the group consisting of one or more of the following: aliphatic ethers, esters of aliphatic carboxylic acids, alcohols, lactones, halogenated hydrocarbons, and aliphatic C.sub.3-C.sub.8 ketones. In some embodiments, the reaction is carried out at a temperature from about -30.degree. C. to about 60.degree. C. [0008] Another embodiment disclosed herein includes a crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)ph- enylmethyl) carbamide that exhibits a melting point of about 124.degree. C., determined with Differential Scanning Calorimetry (DSC) at a heating rate of 10.degree. C./minute. [0009] Another embodiment disclosed herein includes a crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)ph- enylmethyl) carbamide that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 13.0, about 10.9, about 6.5, about 4.7, about 4.3, about 4.22, and about 4.00. In one embodiment, the crystalline form exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 13.0, about 10.9, about 6.8, about 6.5, about 6.2, about 5.2, about 4.7, about 4.5, about 4.3, about 4.22, about 4.00, about 3.53, about 3.40, about 3.28, about 3.24, about 3.19, about 3.08, about 2.91, and about 2.72. [0010] Another embodiment disclosed herein includes a method for the preparation of the above crystalline form including dissolving a salt of a compound of formula I in water: [0011] adding an amount of an organic aprotic solvent to the aqueous salt solution sufficient to dissolve the compound of formula I; [0012] adjusting the pH of the aqueous salt solution to a value of at least about 8.5 by addition of a base; [0013] removing a part of the organic aprotic solvent; [0014] cooling the remaining organic aprotic solution to less than 15.degree. C.; and [0015] isolating any precipitate formed. [0016] In some embodiments, the salt of the compound of formula I is a hemi-tartrate salt. Some embodiments further include extracting the aqueous solution with the organic solvent and collecting all organic phases prior to removing a part of the organic solvent. In one embodiment, the organic solvent is selected from the group consisting of one or more of the following: hydrocarbons, halogenated hydrocarbons, esters of aliphatic carboxylic acids, alcohols, lactones, ethers, and aliphatic C.sub.4-C.sub.8 ketones. [0017] Another embodiment disclosed herein includes a crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)ph- enylmethyl) carbamide produced by the process that includes dissolving a hemi-tartrate salt of a compound of formula I in water: adding an amount of an organic aprotic solvent to the aqueous salt solution sufficient to dissolve the compound of formula I, adjusting the pH of the aqueous salt solution to a value of at least about 8.5 by addition of a base, extracting the aqueous solution with the organic solvent and collecting all organic phases, removing a part of the organic aprotic solvent, cooling the remaining organic aprotic solution to less than 15.degree. C., and isolating any precipitate formed. [0018] Another embodiment disclosed herein is N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy) phenylmethyl)carbamide hemi-tartrate of formula IV, [0019] Another embodiment disclosed herein includes a method for the preparation of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy) phenylmethyl)carbamide hemi-tartrate, comprising performing the reaction for synthesizing the compound of formula I as described above, adding tartaric acid after the reaction, and isolating the hemi-tartrate salt formed. In one embodiment, the isolating includes obtaining the hemi-tartrate salt from a suspension formed after addition of tartaric acid. In one embodiment, the isolating includes precipitating the hemi-tartrate salt by cooling, solvent removal, adding a non-solvent, or a combination of these methods. [0020] Another embodiment disclosed herein includes a crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)ph- enylmethyl) carbamide hemi-tartrate that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 18.6, about 16.7, about 10.2, about 6.2, about 6.1, about 4.63, about 4.49, about 4.44, and about 3.96. In one embodiment, the X-ray powder diffraction pattern includes peaks having d-values in angstroms of about 18.6, about 16.7, about 10.2, about 8.2, about 7.7, about 7.4, about 6.5, about 6.2, about 6.1, about 5.86, about 5.14, about 5.03, about 4.78, about 4.69, about 4.63, about 4.49, about 4.44, about 4.35, about 4.10, about 3.96, and about 3.66. [0021] In one embodiment, the above crystalline form is prepared by dissolving the compound of formula IV in ethanol or an admixture of ethanol and isopropanol: cooling the solution to a temperature of less than about 20.degree. C., and isolating any resulting precipitated solid. In one embodiment, the temperature during the dissolution step is about 55 to about 90.degree. C. In one embodiment, the cooling rate during the cooling step is about 0.1 to about 3.degree. C./minute. Continue reading about Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms... Full patent description for Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. 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