| Enantiomers of 1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine -> Monitor Keywords |
|
|
  Enantiomers of 1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazineRelated 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 Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The Cyclos, Piperazines (i.e., Fully Hydrogenated 1,4-diazines), Plural Carbocyclic Rings Bonded Directly To The Same Acyclic Carbon Atom Which Is Attached Directly Or Indirectly To The Piperazine Ring By Nonionic BondingThe Patent Description & Claims data below is from USPTO Patent Application 20060229320. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a division of application Ser. No. 09/087,808, filed Jun. 1, 1998, which is a division of application Ser. No. 08/947,859, filed Oct. 9, 1997 (now U.S. Pat. No 5,792,770), which is a division of application Ser. No. 08/460,844, filed Jun. 5, 1995 (now U.S. Pat. No. 5,703,082), which is a division of application Ser. No. 08/207,096, filed Mar. 8, 1994 (now U.S. Pat. No. 5,478,941). [0002] The present invention relates to new compounds, the substantially optically pure levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of the formula to a process for the preparation of these compounds and to their use for the preparation of substantially optically pure levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine. The latter compounds, are valuable intermediates for the preparation of substantially optically pure therapeutically active compounds, in the levorotatory and dextrorotatory forms. [0003] These therapeutically active compounds may be used in the treatment of asthma, allergies, inflammation and anxiety, and as sedative or tranquilizing agents. A property frequently observed with these compounds is their high degree of peripheral and/or central antihistaminic activity, as the basis for their use as a drug. [0004] It is well known that the biological properties of many compounds, such as for example drugs, hormones, herbicides, insecticides or sweetening agents, are influenced by stereochemical factors. The importance of the relationships between the optical activity and the biological properties, has been stressed since 1926 (A. R. CUSHNY, Biological Relations of Optically Isomeric Substances, Williams and Williams Co., Baltimore, 1926). Since that time, many examples abound which have confirmed the now generally accepted principle that a racemic compound and its levorotatory and dextrorotatory enantiomers should be considered as entirely distinct pharmacological entities. The optical activity, which is an image of the asymmetrical structure of an organic compound is one of the important factors which govern the pharmacological activity of this compound and its biological response. Indeed, according to whether the levorotatory or dextrorotatory form of a drug is used, considerable differences in the properties, such as its transport, its distribution in the organism or its elimination can appear. These properties are decisive for the concentration of the drug in the organism or its exposure time at the site of activity. Furthermore, the pharmacological activity of the two isomers can differ considerably. For example, one enantiomer may be much more active than the other or, in a border-line case, this enantiomer could possess alone all the pharmacological activity, the other being totally inactive and serving only as a simple diluent. It can also occur that the pharmacological activities of the two isomers are different, which produces consequently two compounds having distinct therapeutic properties. Moreover, the metabolism and the toxicity can be very different from one isomer to another, so much so that one of the optically active isomers can be more toxic than the other. One of the most striking examples in this field is that of thalidomide, where the two enantiomers possess similar hypnotic effects but only the S enantiomer has teratogenic effects. [0005] Finally, it has also to be added that the optical isomers are useful as probes which are of uttermost importance in the study of chemical interactions with physiological mechanisms (for example, the selectivity of binding to a receptor). [0006] That is the reason why many pharmaceutical laboratories devote much time and efforts to isolate or synthesize the enantiomers of pharmacologically active compounds and to study the therapeutic properties thereof. [0007] A process for the preparation of the enantiomers of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxylacetic acid dihydrochloride, known as a non-sedative antihistamine drug under the generic name of cetirizine, is described in British Patent No. 2,225,321. This process is based on the use of levorotatory or dextrorotatory 1-[(4-chlorophenyl)phenylmethyl]piperazine as starting material. In that patent, the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained by chemical resolution of the racemic form, using conventional methods, in particular, by salt formation with a suitably selected optical isomer of tartaric acid. [0008] The major disadvantages of this process are, on the one hand, that the yield of the resolution step of the racemic 1-[(4-chlorophenyl)phenylmethyl]piperazine is extremely low (only 12.7%) and, on the other hand, that the optical purity of the dextrorotatory and levorotatory enantiomers so obtained is insufficient and does not allow the final product to be prepared with an optical purity greater than 95%. [0009] Consequently, it appears to be very desirable to provide new routes for preparing the enantiomers of 1-[(4-chlorophenyl)phenylmethyllpiperazine with improved optical purity and in better yields and, thereby, to provide excellent starting materials to produce optically active isomers of useful drugs with a very high degree of optical purity. [0010] But, to achieve this object, it is necessary to find precursors having already the correct stereochemical configuration and which, on the one hand, can be themselves prepared relatively simply and economically with satisfactory optical purity, and, on the other hand, which can be converted easily and with high yields into the substantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine. [0011] We have now discovered a new compound, 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl) sulfonyl]piperazine, the levorotatory and dextrorotatory forms of which comply perfectly with this object. [0012] Accordingly, the present invention provides as new compounds, the levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of the formula [0013] According to the present invention, the enantiomers of the compound of formula I are advantageously in a substantially optically pure form. [0014] In the present specification, by "substantially optically pure", is meant an optical purity greater than 98% and this optical purity corresponds to the percent excess of the optically active isomer present in major amount with respect to the optically active isomer present in minor amount, and determined by high performance liquid phase chromatography (HPLC) on a chiral stationary phase. [0015] This optical purity can be defined by the equation described on page 107 of the book of J. MARCH, "Advanced Organic Chemistry", John Wiley & Sons, Inc., New York, 3.sup.rd Edition, 1985: Optical .times. .times. .times. purity .times. .times. ( in .times. .times. % ) = [ ( + ) ] - [ ( - ) ] [ ( + ) ] + [ ( - ) ] .times. 100 Where [ ( + ) ] = .times. concentration .times. .times. of .times. .times. .times. the .times. .times. dextrorotatory .times. .times. enantiomer ; and [ ( - ) ] = .times. concentration .times. .times. of .times. .times. .times. the .times. .times. levorotatory .times. .times. enantiomer . [0016] The present invention further relates to a process for preparing the levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, which comprises reacting an enantiomer of (4-chlorophenyl)phenylmethylamine of the formula with a N,N-diethyl-4-methylbenzenesulfonamide of the formula wherein X is a chlorine, bromine or iodine atom or the (4-methylphenyl)sulfonyloxy or methylsulfonyloxy group, in the presence of 2.2 to 4.4 equivalents of an organic or inorganic base per equivalent of the enantiomer of (4-chlorophenyl)phenylmethylamine and at the boiling point of the reaction mixture. [0017] Bases suitable for use to prepare compounds of formula I include organic bases such as ethyldiisopropylamine, N-ethylmorpholine, 2,4,6-trimethylpyridine or triethylamine, preferably ethyldiisopropylamine, and inorganic bases such as sodium carbonate. [0018] The levorotatory and dextrorotatory enantiomers of (4-chlorophenyl)phenylmethylamine of formula II, used as starting materials are known compounds; they can be prepared by chemical resolution of racemic (4-chlorophenyl)phenylmethylamine by known methods using tartaric acid. These enantiomers can be prepared with an optical purity of at least 98%. [0019] The compounds of formula III used as starting materials are also known products which can be easily obtained starting from bis(2-hydroxyethyl)amine and using known methods. [0020] The present invention further relates to the use of the new levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, for the preparation of the substantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of the formula (IV) [0021] According to the present invention, the levorotatory and dextrorotatory enantiomers of the compound of formula IV are prepared by a process, which comprises subjecting an enantiomer of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I to hydrolysis with hydrobromic acid, in acetic acid medium and in the presence of a phenolic compound, preferably 4-hydroxybenzoic acid. [0022] This hydrolysis is generally carried out at a temperature of between 18 and 100.degree. C., preferably at a temperature of about 25.degree. C. [0023] The advantages resulting from the use of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, in the form of its levorotatory or dextrorotatory enantiomers according to the invention, are numerous. [0024] These advantages appear not only at the level of the route which leads to the enantiomers of the compound of formula I but also at the level of the conversion step of these enantiomers to prepare the substantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV. Continue reading... Full patent description for Enantiomers of 1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Enantiomers of 1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Enantiomers of 1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine or other areas of interest. ### Previous Patent Application: Enantiomers of 1-[(4-chlorophenyl) phenylmethyl)-4-[(4-methylphenyl)sulfonyl] piperazine Next Patent Application: Anhydrous crystalline form of valacyclovir hydrochloride Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Enantiomers of 1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine patent info. IP-related news and info Results in 0.10501 seconds Other interesting Feshpatents.com categories: Medical: Surgery , Surgery(2) , Surgery(3) , Drug , Drug(2) , Prosthesis , Dentistry |
||
