| Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof -> Monitor Keywords |
|
|
 
Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereofRelated Patent Categories: Organic Compounds -- Part Of The Class 532-570 Series, Azo Compounds Containing Formaldehyde Reaction Product As The Coupling Component, Carbohydrates Or Derivatives, Hetero Ring Is Five-membered Having Two Or More Ring Hetero Atoms Of Which At Least One Is Nitrogen (e.g., Selenazoles, Etc.), Tetrazoles (including Hydrogenated), Polycyclo Ring System Having The Diazole Ring As One The Cyclos, Bicyclo Ring System Having The Diazole Ring As One Of The Cyclos, ,Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070185333, Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application claims priority to German Application DE 10 2005 061 623.2 filed Dec. 21, 2005, which is hereby incorporated by reference. BACKGROUND TO THE INVENTION [0002] 1. Technical Field [0003] The invention relates to a process for preparing an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein [0004] (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid and [0005] (b) i) the product thus obtained is hydrogenated and [0006] ii) optionally the amidino group is carbonylated without isolating the intermediate product of the hydrogenation beforehand. [0007] The 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained may subsequently be converted into a salt. [0008] Moreover, the invention relates to a process for preparing a salt of an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein [0009] (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, [0010] (b) the product thus obtained is hydrogenated, and [0011] (c) i) optionally the amidino group is carbonylated and [0012] ii) without prior isolation of the intermediate product of the carbonylation the desired salt is isolated. [0013] 2. Prior Art [0014] Substituted (4-benzimidazol-2-ylmethylamino)-benzamidines, particularly 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzi- midazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide are already known from International Patent Application WO 98/37075 as active substances with a thrombin-inhibiting and thrombin time prolonging activity. [0015] The main types of indication for the compound of chemical formula I are the postoperative prevention of deep vein thrombosis and the prevention of stroke (prevention of stroke due to atrial fibrillation, SPAF for short). [0016] In WO 98/37075 it is proposed that the substituted (4-benzimidazol-2-ylmethylamino)-benzamidines be prepared by reacting the corresponding substituted (4-benzimidazol-2-ylmethylamino)-benzonitriles with ammonia. This process is highly complex from the point of view of production technology and results in a high loading of acids that have to be disposed of. [0017] The aim of the present invention was to indicate an alternative method of preparing the substituted (4-benzimidazol-2-ylmethylamino)-benzamidines, by which this technologically complex step could be avoided. BRIEF SUMMARY OF THE INVENTION [0018] Surprisingly it has now been found that the substituted 4-(benzimidazol-2-ylmethylamino)-benzamidines can be produced in high yields and using inexpensive adjuvants if [0019] (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid and [0020] (b) i) the product thus obtained is hydrogenated, and [0021] ii) optionally the amidino group is carbonylated, preferably with an alkyl halogen formate in the presence of a base, particularly with n-hexylchloroformate, without isolating the intermediate product of the hydrogenation beforehand. [0022] The 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained may subsequently be converted into a salt. [0023] It has also surprisingly been found that the salts of optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidines can be prepared in high yields and using inexpensive adjuvants if [0024] (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, [0025] (b) the product thus obtained is hydrogenated, and [0026] (c) i) optionally the amidino group is carbonylated and [0027] ii) without prior isolation of the intermediate product of the carbonylation the desired salt is isolated. DETAILED DESCRIPTION OF THE INVENTION [0028] A process for preparing an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine of formula (I) is preferred wherein [0029] R.sup.1 denotes a C.sub.1-6-alkyl or C.sub.3-7-cycloalkyl group, [0030] R.sup.2 [0031] (i) denotes a C.sub.1-6-alkyl group, a C.sub.3-7-cycloalkyl group optionally substituted by a C.sub.1-3-alkyl group, while the C.sub.1-3-alkyl group may additionally be substituted by a carboxyl group or by a group which may be converted in vivo into a carboxy group, or [0032] (ii) denotes an R.sup.21NR.sup.22 group, wherein [0033] R.sup.21 denotes a C.sub.1-6 alkyl group which may be substituted by a carboxy, C.sub.1-6 alkoxycarbonyl, benzyloxycarbonyl, C.sub.1-3-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, trifluorosulphonylamino, trifluorosulphonylaminocarbonyl or 1H-tetrazolyl group, a C.sub.2-4-alkyl group substituted by a hydroxy, phenyl-C.sub.1-3-alkoxy, carboxy-C.sub.1-3-alkylamino, C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylamino, N-(C.sub.1-3-alkyl)-carboxy-C.sub.1-3-alkylamino or N-(C.sub.1-3-alkyl)-C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylamino group, while in the above-mentioned groups the carbon atom in the .alpha.-position to the adjacent nitrogen atom cannot be substituted, or [0034] a piperidinyl group optionally substituted by a C.sub.1-3-alkyl group, and R.sup.22 denotes a hydrogen atom, a C.sub.1-6-alkyl group, a C.sub.3-7-cycloalkyl group optionally substituted by a C.sub.1-3-alkyl group, or a C.sub.3-6-alkenyl or C.sub.3-6-alkynyl group, while the unsaturated moiety may not be linked directly to the nitrogen atom of the R.sup.21NR.sup.22 group, a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, by a C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, or a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl group optionally substituted by a C.sub.1-3-alkyl group, or R.sup.21 and R.sup.22 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy or C.sub.1-4-alkoxycarbonyl group, to which additionally a phenyl ring may be fused, and [0035] R.sup.3 denotes a hydrogen atom, a C.sub.1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C.sub.1-3-alkoxycarbonyl, benzoyl, p-C.sub.1-3-alkyl-benzoyl or pyridinoyl group, wherein the ethoxy moiety in the 2 position of the above-mentioned C.sub.1-9-alkoxycarbonyl group may additionally be substituted by a C.sub.1-3-alkylsulphonyl or 2-(C.sub.1-3-alkoxy)-ethyl group, while in step (a) a phenyldiamine of formula (II) [0036] wherein R.sup.1 and R.sup.2 have the meanings given for formula (I), [0037] is reacted with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, the resulting product of formula (III) [0038] wherein R.sup.1 and R.sup.2 have the meanings given for formula (I), [0039] is hydrogenated in step (b)i), and subsequently, without any prior isolation of the hydrogenation product, the compound of formula (I) thus obtained wherein R.sup.3 denotes hydrogen is optionally reacted in step (b)ii) with a compound of formula (IV)R.sup.3--X (IV) [0040] wherein R.sup.3 has the meaning given for formula (I), and [0041] X denotes a suitable leaving group. [0042] The 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained may if desired subsequently be converted into a salt, particularly into a pharmaceutically acceptable salt, in another step (c). [0043] Another preferred process for preparing a salt of an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine of formula (I) wherein R.sup.1 to R.sup.3 are as hereinbefore defined, comprises the following steps: [0044] (a) reacting a phenyldiamine of formula (II) [0045] wherein R.sup.1 and R.sup.2 have the meanings given for formula (I), [0046] with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, [0047] (b) hydrogenating the product of formula (III) thus obtained [0048] wherein R.sup.1 and R.sup.2 have the meanings given for formula (I), and [0049] (c) i) reacting the compound of formula (I) thus obtained wherein R.sup.3denotes hydrogen with a compound of formula (IV)R.sup.3--X (IV) [0050] wherein R .sup.3 has the meaning given for formula (I) and [0051] X denotes a suitable leaving group, and [0052] ii) precipitating the desired salt of the compound of formula (I) thus obtained, without previously isolating the carbonylation product. [0053] Particularly preferred are the processes according to the invention for preparing the compounds of formula (I) or the salts thereof, wherein [0054] R.sup.1 denotes a C.sub.1-3-alkyl group, [0055] R.sup.2 denotes an R.sup.21NR.sup.22 group, wherein [0056] R.sup.21 denotes a C.sub.1-3 alkyl group which may be substituted by a carboxy, C.sub.1-3 alkoxycarbonyl, and [0057] R.sup.22 denotes a hydrogen atom, a C.sub.1-3-alkyl group, a pyridinyl group optionally substituted by a C.sub.1-3-alkyl group, and [0058] R.sup.3 denotes a hydrogen atom, a C.sub.1-8-alkoxycarbonyl group. [0059] Most preferred are the processes according to the invention for preparing the compound of formula (I) or the salts thereof, wherein [0060] R.sup.1 denotes a methyl group, [0061] R.sup.2 denotes an R.sup.21NR.sup.22 group, wherein [0062] R.sup.21 denotes an ethyl group which is substituted by an ethoxycarbonyl group, and [0063] R.sup.22 denotes a pyridin-2-yl group, and [0064] R.sup.3 denotes an n-hexyloxycarbonyl group. [0065] Preferred salts are the methanesulphonate, chloride, maleate, tartrate, salicylate, citrate and malonate of the compound of formula (I). A particularly preferred salt is the methanesulphonate. [0066] The following embodiments (A) to (F) of the process according to the invention are preferred: Continue reading about Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof... Full patent description for Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof 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 Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof or other areas of interest. ### Previous Patent Application: Process for the synthesis of imidazoles Next Patent Application: Process for producing 5-hydroxy-4-thiomethylpyrazole compound Industry Class: Organic compounds -- part of the class 532-570 series ### FreshPatents.com Support Thank you for viewing the Process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof patent info. IP-related news and info Results in 0.35909 seconds Other interesting Feshpatents.com categories: Tyco , Unilever , Warner-lambert , 3m 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
