AU2004240716A1 - Method for synthesising heterocyclic compounds from thiourea derivatives - Google Patents

Method for synthesising heterocyclic compounds from thiourea derivatives Download PDF

Info

Publication number
AU2004240716A1
AU2004240716A1 AU2004240716A AU2004240716A AU2004240716A1 AU 2004240716 A1 AU2004240716 A1 AU 2004240716A1 AU 2004240716 A AU2004240716 A AU 2004240716A AU 2004240716 A AU2004240716 A AU 2004240716A AU 2004240716 A1 AU2004240716 A1 AU 2004240716A1
Authority
AU
Australia
Prior art keywords
alkyl
radicals
formula
hydrogen
atoms
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
AU2004240716A
Inventor
Uwe Heinelt
Hans-Jochen Lang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Sanofi Aventis Deutschland GmbH
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 Sanofi Aventis Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Publication of AU2004240716A1 publication Critical patent/AU2004240716A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
    • C07C335/08—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/14—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/18—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/20—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/EP2004/004955 RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and German languages, is a true and correct translation of the PCT Application filed under No. PCT/EP2004/004955 Date: 2 September 2005 C. E. SITCH Deputy Managing Director - UK Translation Division For and on behalf of RWS Group Ltd WO 2004/103976 PCT/EP2004/004955 Method for synthesising heterocyclic compounds The invention provides the process illustrated in scheme 1 for synthesizing the heterocyclic compounds of the formula I. 5 R10 Rl1 R11 R10 R11 R10 R11 R15 S R15 R15 R14 HI NCS H 2 mT R4 Rso2 R R14 A N N m H-X 0H H A-N H R17 Base 16 H-X R17 X 0 R17 R12 R13 R16 R16 R12 R13 R12 R13 SIII IV I Scheme 1 10 In the process, the isothiocyanate of the formula II is initially reacted with the primary amine of the formula III to give the thiourea of the formula IV. Subsequently, the thiourea of the formula IV is converted to the heterocycle of the formula I using a base and a sulfonyl chloride. 15 The construction of basic heterocyclic structures is one of the most important synthetic steps in organic chemistry. The resulting heterocyclic compounds are of great significance, inter alia, as intermediates in the synthesis of active pharmaceutical ingredients and active crop protection ingredients or else directly as such active ingredients. In addition, the rapid 20 synthesis, which is particularly important in the preparation of screening substances, of analogs which are sometimes quite diverse in structural terms places high demands on synthesis planning. Central building blocks which allow direct access to a multitude of diverse heterocycles under similar or ideally identical reaction conditions are therefore particularly 25 valuable and of great significance, in particular for robot-assisted syntheses. The synthesis of heterocycles starting from thioureas has been known for some time. However, the methods have limitations in the substrate 30 selection or disadvantages in reaction control, workup, by-product removal or in the cost of reagents. For instance, 1-(2-hydroxyethyl)-3-arylthioureas can be cyclized by heavy metal derivatives such as mercury(ll) oxide or -2 lead oxide to give oxazolidin-2-ylidenarylamines (Jen, et al., J. Med. Chem. 1975 (18), 90). Acid catalysis of the same reactants affords the corresponding arylthiazolidin-2-ylidenamines (Jen, et al., J. Med. Chem. 1975 (18), 90). However, the use of heavy metals is disadvantageous, 5 since they are unwanted in the product, even only in traces. The acid catalyzed conversion to the thiazolidine again proceeds satisfactorily only at elevated temperature and in the presence of high acid concentrations. These drastic conditions are not tolerated by some functionalities such as esters, nitriles or ketals. 10 Syntheses starting from 1-(2-aminoethyl)-3-arylthioureas to imidazolidin-2 ylidenaryl derivatives succeed in the presence of methyl iodide (Synthesis 1974, 41-42) or carbodiimide derivatives (Synthesis 1977, 864). A disadvantage in the case of methyl iodide is the competing reaction which 15 occurs on other nucleophilic centers in the. molecule and its danger potential in the event of unintentional release. In the case of carbodiimide derivatives, the removal of the ureas formed is frequently problematic and time-consuming. More recent carbodiimide derivatives such as EDC (N'-(3 dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride) or solid phase 20 bound DCC (dicyclohexylcarbodiimide), used in a relatively large amount, are again very expensive. The synthesis method of the present invention leads, starting from isothiocyanates and amino alcohols, amino mercaptans and diamines, via 25 the thioureas formed as intermediates, to the desired heterocycles of variable ring size, by cyclizing the intermediate derivatives in the presence of sulfonyl chloride and of a base. These reagents are inexpensive, easy to handle and require no drastic reaction conditions, and their subsequent products are easy to remove by simple washings, so that this synthetic 30 process is suitable, for example, for reactions on the gram and kilogram scale. However, it can also be employed for parallel and robot syntheses which are usually carried out on the milligram scale, especially owing to the simple reaction control. Of particular interest for these synthetic methods which.are generally employed on a relatively small scale is the use of 35 polymer-bound sulfonyl chloride, which enables the isolation of the reaction products by filtration and evaporation steps which are simple from an apparatus point of view. In the literature, a similar process method is to be found quite specifically -3 for the reaction of phenyl or methyl isothiocyanates with 2-hydroxyethyl amines to give oxazolidin- or thiazolidin-2-ylidenamines (Tetrahedron Letters 40 (1999), 8201; Tetrahedron 57 (2001), 7137; Bull. Korean Chem. Soc. 2002 (23), 19). 5 It has now been possible to show, surprisingly, that under these conditions, not only can five-membered rings such as oxazolidines or thiazolidines be formed, but also that ring size and degree of substitution are much more flexible and the synthesis method is not restricted to the use of 2-hydroxy 10 ethylamines. The restriction to thiourea intermediates which bear at least one aryl substituent on one of the thiourea nitrogens, results in the ring closure proceeding very selectively and affording, with the loss of the thiourea sulfur, generally only one cyclization product. 15 The present invention thus relates to a process for preparing heterocycles of the formula I R10 Ril H R15 N R14 A-N < X OR R17 R12 R13 20 where: X is sulfur, oxygen or NR5 where R5 is hydrogen or (C1-C4)alkyl; m and o are each independently zero, 1 or 2; 25 A is phenyl, naphthyl or heteroaryl, all of which may be substituted by 1,2, 3, 4 or 5 R11 radicals where R11 is in each case independently selected from the group of (C1-C4)alkyl, F, CI, Br, I, CN, NO 2 , OH, O(C1-C4)alkyl, COO(C1-C4)alkyl, and some or all of 30 ' the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; or -4 (Cl-C4)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl where these radicals may each independently be substituted by (C1-C4)alkyl or (C3-C6)cycloalkyl, and 5 some or all of the hydrogen atoms of the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals may be replaced by fluorine atoms, R14, R15, R16 and R17 are each independently hydrogen, F or (C1-C4)alkyl, 10 where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; or R14 and R16 together are a bond, 15 and R15 and R17 with the two carbon atoms to which they are bonded are an aromatic six-membered carbocycle in which one or two carbon atoms may be replaced by nitrogen, or a thiophene ring, 20 where the aromatic six-membered carbocycle and the thiophene ring may be substituted by 1, 2, 3 or 4 R7 radicals, where R7 is in each case independently selected from the group of (C1-C4)alkyl, F, CI, Br, I, CN, NO 2 , OH, O(C1-C4) alkyl and COO(C1-C4)alkyl, and some or all of the hydrogen 25 atoms of the alkyl radicals may be replaced by fluorine atoms; or R14 and R16 are each independently hydrogen or (C1-C4)alkyl, where some or all of the hydrogen atoms of the alkyl radicals 30 may be replaced by fluorine atoms; and R15 and R17 with the two carbon atoms to which they are bonded are a saturated 5-, 6-, 7- or 8-membered carbocycle in which one or two carbon 35 atoms may each independently be replaced by O, S, NH and N(C1 C4)alkyl and may be substituted by 1, 2, 3, 4, 5 or 6 R8 radicals where R8 is in each case independently selected from the group of (C1-C4)alkyl, O(C1-C4)alkyl, COO(C1-C4)alkyl, and -5 some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; R10, R11, R12 and R13 are each independently hydrogen, F or (C1-C4)alkyl, 5 where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; where either A or the ring formed from R15 and R17 together, where m is zero, is an aromatic ring system, or both are aromatic ring systems; and 10 excluding compounds in which A is unsubstituted phenyl or (C1-C4)alkyl, X is oxygen, R14 and R15 are each independently hydrogen, (C1-C4)alkyl or benzyl, R16 and R17 are each hydrogen, and m and o are each zero; and their tautomers and their salts; which comprises, as shown in scheme 1, R10 R11 R R11 R10 R11 R10 R11 R15 S R15 R15 HN R14 H NR ,NCS HN R AN R14 R6SO 2 C R14 A Hx H H A-N H R17 Base R16 H.X R17 X o R17 R12 R13 R16 R 16 R12 R13 R12 R13 II IIl IV I 15 Scheme 1 a) reacting an isothiocyanate of the formula II with a primary amine of the formula Ill to give a thiourea of the formula IV, and b) converting the thiourea of the formula IV using a sulfonyl chloride 20 R6SO2CI in the presence of a base to the compound of the formula I, where, in the compounds of the formulae II, Ill and IV, A, X, n, m and R10 to R17 are each as defined in formula I and R6 is (C1-C4)alkyl, trifluoromethyl or phenyl which is unsubstituted or substituted by methyl, trifluoromethyl, F, CI, Br or a polymeric 25 support. A further embodiment of the present invention relates to a process for preparing heterocycles of the formula la, -6 Ar\ H R2 N N R1 X Ia R4 R3 where: X is sulfur, oxygen or NR5, 5 where R5 is hydrogen or (C1-C4)alkyl; n is zero, 1, 2 or 3; Ar is phenyl, naphthyl or heteroaryl which may be substituted by 1, 2, 3, 4 or 5 R11 radicals where R 1 is in each case independently selected from the 10 group of (C1-C4)alkyl, F, CI, Br, I, CN, NO 2 , OH, O(C1-C4) alkyl, COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; R1, R2, R3 and R4 are each independently hydrogen, F or (C1-C4)alkyl 15 where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; or R1 and R3 together are a bond, 20 and R2 and R4 with the two carbon atoms to which they are bonded are an aromatic six-membered carbocycle in which one or two carbon atoms may be replaced by nitrogen and the aromatic six-membered ring may be 25 substituted by 1, 2, 3 or 4 R7 radicals, where R7 is in each case independently selected from the group of (CI-C4)alkyl, F, CI, Br, I, CN, NO 2 , OH, O(C1-C4) alkyl, COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms, 30 where n = 0; or R1 and R3 are each independently hydrogen or (C1-C4)alkyl and 35 R2 arid R4 -7 with the two carbon atoms to which they are bonded are a saturated 5-, 6-, 7- or 8-membered carbocycle in which one or two carbon atoms may be replaced by O, S, NH and N(C1-C4)alkyl and may be substituted by 1, 2, 3, 4, 5 or 6 R8 radicals 5 where R8 is in each case independently selected from the group of (C1-C4)alkyl, O(C1-C4)alkyl, COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms, where n = 0; 10 excluding compounds in which Ar is unsubstituted phenyl, X is oxygen or sulfur, R1 and R2 are each independently hydrogen, (C1-C4)alkyl or benzyl, R3 and R4 are each hydrogen and n is zero, and their tautomers and their salts, which comprises, as shown in scheme 2 15 R2 H R H H R2 Ar H R2 N I I Ri R6SO 2 C N N R1 NNCS + -/ 1 N N R R6SOC R3 n S X Base X ,X R4 R3 H R3R4 Ila Ilia IVa la Scheme 2 20 a) reacting an aromatic isothiocyanate of the formula Ila with a primary amine of the formula lila to give thiourea of the formula IVa, and b) converting the thiourea of the formula IVa using a sulfonyl chloride R6SO 2 CI in the presence of a base to the compound of the formula la, where, in the compounds of the formulae Ila, Illa and IVa, 25 Ar, X, n and R1 to R4 are each as defined in formula la and R6 is phenyl which is unsubstituted or substituted by methyl, trifluoromethyl, F, Cl or Br. The compounds of the formula la are encompassed by the compounds of 30 the formula 1; similarly the compounds of the formulae Ila, lila, and IVa are encompassed by the compounds of the formulae II, III, and IV. Process step a) may be effected continuously or batchwise. The reaction of the isothiocyanate of the formula II with the primary amine of the formula Ill -8 may be carried out in the presence of a solvent or diluent, or without the addition of a solvent. Preference is given to carrying it out in the presence of a solvent. It is possible to use various solvents, for example aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, for example methylene 5 chloride, esters, for example ethyl acetate, alcohols or ethers. Preference is given to using ethers as the solvent, for example tetrahydrofuran, dioxane or ethylene glycol ethers such as ethylene glycol dimethyl ether, especially when the overall reaction is carried out as a one-pot reaction. It is also possible to use mixtures of two or more solvents. The temperature for the 10 reaction in process step a) is preferably from 0OC to the boiling point of the solvent used, more preferably from 200C to 600C, for example about room temperature. The isothiocyanate of the formula II and the primary amine of the formula Ill are used, for example, in a molar ratio of from 1 : 1.1 to 1 : 0.9, preferably in about equimolar amounts. However, it is also possible to 15 use an excess of the amine of the formula Ill, for example when X is NR5, in order to prevent side reactions. Process step b) may be effected continuously or batchwise. In general, the conversion of the thiourea of the formula IV to the compound of the 20 formula I may be carried out in the presence of a solvent or diluent. It is possible to use various solvents, for example esters or ethers, preferably ethers, for example tetrahydrofuran, dioxane or ethylene glycol ethers such as ethylene glycol dimethyl ether. The solvent used may also, for example, be water. It is also possible to use mixtures of two or more solvents, for 25 example mixtures of water and one or more organic solvents, for example mixtures of water and one of the ethers mentioned. The reaction may proceed as a monophasic reaction or as a biphasic reaction. The temperature for the reaction in process step b) is preferably from 00C to 350C, more preferably about room temperature. The thiourea of the formula 30 IV and the sulfonyl chloride R6SO2CI01 are used, for example, in a molar ratio of from 1 : 1.4 to 1 : 0.9, preferably in a ratio of from 1 : 1 to 1 : 1.2, for example in the ratio of about 1 : 1.1. When polyer-bound sulfonyl chloride is used, the ratio may be from 1:1 to 1:4, preferably from 1:1.5 to 2.5. The molar ratio of the thiourea of the formula IV to the base in process step b) 35 is, for example, from 1 : 4 to 1 : 1, preferably in a ratio of from 1 : 3 to 1 : 2, for example in the ratio of about 1 : 2.5. The base used in process step b) may be various inorganic or organic compounds, for example basic alkali metal compounds or alkaline earth metal compounds, in particular the metal hydroxides, or amines or ammonium hydroxides. Preference is given -9 to using basic sodium compounds or potassium compounds as the base, for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. It is advantageous to use an aqueous solution of sodium hydroxide or potassium hydroxide, for example having a hydroxide 5 concentration of the solution of from 0.1 to 10 molar, preferably about 1 molar. The reaction mixture may be worked up after each of the two process steps a) and b). However, the compounds of the formula I by the process 10 according to the invention may also be synthesized in a one-pot reaction without isolating the thiourea of the formula IV formed in step a), and a workup carried out only after the completion of both process steps. The products are worked up and, if desired, purified by the customary methods such as extraction, filtration, pH separation, chromatography or 15 crystallization and the customary dryings. The starting compounds of the formulae II and Ill are commercially available or can be prepared according to, or in a similar manner to, processes which are described in the literature and familiar to those skilled 20 in the art. The starting compounds may also contain functional groups in protected form or in the form of precursors, and these may then be converted to the desired groups in the compounds of the formula I prepared by the process according to the invention. Appropriate protecting group techniques are known to those skilled in the art. For example, in 25 compounds of the formula Ill in which X is NR5, the NHR5 group may be protected by an acetyl, trifluoroacetyl or trityl group and be deprotected before carrying out process step b). X is preferably NR5 or oxygen, more preferably NR5, most preferably NH. 30 The A radicals, when A is aromatic, and Ar are preferably phenyl or a monocyclic heteroaromatic, more preferably phenyl or a five-membered heteroaromatic, for example thiophene or isoxazole, and all of these radicals may be unsubstituted or substituted. Substituents on the aromatic 35 A and Ar radicals are preferably each independently selected from the group of (C1-C4)alkyl, F, Cl, Br and O(C1-C4)alkyl, where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms. Particularly preferred substituents on the Ar and aromatic A radical are in each case independently methyl, Cl or Br.
- 10 When A is nonaromatic, it is preferably (C1-C4)alkyl, (C2-C5)alkenyl, (C3-C5)cycloalkyl, (C4-C8)cycloalkenyl, more preferably (C1-C4)alkyl or (C3-C5)cycloalkyl, and some or all of the hydrogen atoms of all radicals 5 may be replaced by fluorine atoms. A substituent on the nonaromatic A radicals is preferably (C1-C4)alkyl. n, m and o are preferably in each case independently zero or 1, more preferably zero. 10 R14, R15, R16 and R17 are preferably each independently hydrogen or methyl, more preferably hydrogen, or R14 and R16 together form a bond and R15 and R17 form an aromatic six-membered ring, preferably a benzene ring, or a thiophene ring, and the aromatic six-membered ring and 15 the thiophene ring may be unsubstituted or substituted by 1, 2, 3 or 4 mutually independent R7 radicals, or R14 and R16 are each independently hydrogen or methyl, and R15 and R17 form a saturated 5- or 6-membered ring, preferably a cyclopentane or cyclohexane ring, and the ring may be substituted by a 1, 2, 3, 4, 5 or 6 mutually independent R8 radicals. 20 In compounds of the formulae I, III or IV, it is always the case that either A is aromatic or m is zero and R15 and R17 together with the two carbon atoms to which they are bonded form an aromatic six-membered carbocycle in which one or two carbon atoms may be replaced by nitrogen, 25 or a thiophene ring, or both A and R15 and R17 together with the two carbon atoms to which tney are bonded each form aromatic ring systems. R1, R2, R3 and R4 are preferably each independently hydrogen or methyl, more preferably hydrogen, or R1 and R3 together form a bond and R2 and 30 R4 form an aromatic six-membered ring, preferably a benzene ring, and the aromatic six-membered ring may be unsubstituted or substituted by 1, 2, 3 or 4 mutually independent R7 radicals, or R1 and R3 are each independently hydrogen or methyl and R2 and R4 are a saturated 5- or 6 membered ring, preferably a cyclopentane or cyclohexane ring, and the 35 rirng may be substituted by 1, 2, 3, 4, 5 or 6 mutually independent R8 radicals. R5 is preferably hydrogen or methyl, more preferably hydrogen.
-11 R7 is preferably in each case independently selected from the group of (C1-C4)alkyl, F, CI, Br, OH or O(C1-C4)alkyl, where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; the R7 substituents are more preferably each independently FI, CI, methyl, 5 methoxy, CF3 or OH. R8 is preferably in each case independently selected from the group of (C1-C4)alkyl or O(C1-C4)alkyl, where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms. 10 R10, R11, R12 and R13 are preferably each independently hydrogen, methyl or ethyl, more preferably hydrogen. The base is preferably an aqueous base, triethylamine or diisopropylethyl 15 amine, more preferably an aqueous metal hydroxide solution, in particular a sodium hydroxide or potassium hydroxide solution. The sulfonyl chloride R6SO 2 CI is an unsubstituted or substituted benzene or alkylsulfonyl chloride where R6 is preferably methyl, phenyl, p-tolyl or 20 polymer-bound phenyl. Polymer-bound sulfonyl chloride is generally an aromatic sulfonyl chloride, for example benzenesulfonyl chloride, which is substituted on the phenyl radical by a polymeric support, for example polystyrene, especially 25 crosslinked polystyrene. For example, sulfonylchoride polystyrene from Novabiochem can be used. In this case, the benzenesulfonic acid is bound to copoly(styrene-1%DVB), 100-200 mesh. The compounds of the formula I may be isolated in the form of their salts. 30 These are obtained by the customary methods by reacting with acids or bases. Useful acid addition salts include, for example, halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, benzenesulfonates, p-toluene sulfonates, adipates, fumarates, gluconates, glutamates, glycerol 35 phosphates, maleates, benzoates, oxalates and pamoates and trifluoroacetates; in the case of the preparation of active ingredients, preferably physiologically acceptable salts. When the compounds contain an acid group, they may form salts with bases, for example alkali metal salts, preferably sodium or potassium salts, or ammonium salts, for -12 example as salts with ammonia or organic amines or amino acids. They may also be present as a zwitterion. The compounds of the formula I may also be present as tautomers or as a 5 mixture of tautomeric structures, for example as the following tautomers: R10 R11 R10 R11 R10 R11 H R15 R15 H R15 N R R14 H N R R14 H N R 5814 A-N <N / ,N i X R R17 A X R1R17 A X R17 16 R16 R1 6 R12 Ri3 R12 R13 R12 R13 only when X = N A B C When the compounds of the formula I are present in the tautomeric form A, they may be present as double bond isomers or as a mixture of double 10 bond-isomeric structures. R10 R1I R10 R11 H R15 H R1iS N R14 A N R14 N m A X R17 X R R17 R16 R116 R12 R13 R12 R13 When the compounds of the formula I contain one or more centers of 15 asymmetry, these may each independently have either S or R configuration. The compounds may be present as optical isomers, as diastereomers, as cis/trans isomers, as racemates or as mixtures thereof in any ratios. 20 When m, n or o = 0, there is a direct bond between the two adjacent atoms in each case. Alkyl radicals may be straight-chain or branched. This is also true when they bear substituents or occur as substituents of other radicals, for 25 example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl radicals - 13 are methyl, ethyl, n-propyl, isopropyl (= 1-methylethyl), n-butyl, isobutyl (= 2-methylpropyl), sec-butyl (= 1-methylpropyl) and tert-butyl (= 1,1 dimethylethyl). Preferred alkyl radicals are methyl, ethyl and isopropyl. In alkyl radicals, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9, hydrogen 5 atoms may be substituted by fluorine atoms. Examples of such fluoroalkyl radicals are trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, heptafluoroisopropyl. Substituted alkyl radicals may be substituted in any positions, for example by fluorine, by alkyl, for example methyl, ethyl, propyl, butyl, or by cycloalkyl, for example cyclopropyl, cyclobutyl, 10 cyclopentyl or cyclohexyl. Alkenyl radicals may be straight-chain or branched. This is also true when they bear substituents, for example in fluoroalkenyl radicals. The alkenyl radicals may be unsaturated and also polyunsaturated in different 15 positions. Examples of alkenyl radicals are ethenyl, n-prop-1-enyl, n-prop 2-enyl, isoprop-1-enyl (= 1-methylethenyl), n-but-1-enyl, n-but-2-enyl, n-but-3-enyl, n-buta-1,3-dienyl, isobut-l-enyl (= 2-methylprop-1l-enyl), isobut-2-enyl (= 2-methylprop-2-enyl), sec-but-1-enyl (= 1-methylprop-1 enyl) and pentenyl. Preferred alkenyl radicals are ethenyl, n-prop-1-enyl, 20 n-prop-2-enyl, n-but-1-enyi, n-but-2-enyl, n-pentenyl, n-pentadienyl, isopentenyl, tert-pentenyl and neopentenyl. In alkenyl radicals, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9, hydrogen atoms may be substituted by fluorine atoms. Substituted alkenyl radicals may be substituted in any positions, for example by fluorine, by alkyl, for example 25 methyl, ethyl, propyl, butyl, or by cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Alkynyl radicals may be straight-chain or branched. This is also true when they bear substituents, for example in fluoroalkynyl radicals. The alkynyl 30 radicals may be unsaturated and also polyunsaturated in different positions. Examples of alkynyl radicals are ethynyl, n-prop-l-ynyl, n-prop-2 ynyl, n-but-1-ynyl, n-but-2-ynyl, n-but-3-ynyl, n-buta-1,3-diynyl, sec-but-2 ynyl (= 1-methylprop-2-ynyl), n-pentynyl, n-pentadiynyl, isopentynyl, tert pentynyl and neopentynyl. Preferred alkynyl radicals are n-prop-1-ynyl, n 35 prop-2-ynyl, n-but-1-ynyl and n-but-2-ynyl. In alkynyl radicals, one or more, for example 1, 2, 3, 4, 5, 6 or 7, hydrogen atoms may be substituted by fluorine atoms. Substituted alkynyl radicals may be substituted in any positions, for example by fluorine, by alkyl, for example methyl, ethyl, -14 propyl, butyl, or by cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, 5 cyclohexyl, cycloheptyl or cyclooctyl. Preferred cycloalkyl radicals are cyclopropyl, cyclopentyl and cyclohexyl. In cycloalkyl radicals, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, hydrogen atoms may be substituted by fluorine atoms. Substituted cycloalkyl radicals may be substituted in any positions, for example by fluorine, by alkyl, for 10 example methyl, ethyl, propyl, butyl, or by cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkenyl radicals may be unsaturated in different positions and also polyunsaturated. Examples of cycloalkenyl radicals are cyclobut-1 15 enyl, cyclobut-2-enyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl and cyclooctenyl. Preferred cycloalkylene radicals are cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl. In cycloalkenyl radicals, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, hydrogen atoms may be substituted by 20 fluorine atoms. Substituted cycloalkenyl radicals may be substituted in any positions, for example by fluorine, by alkyl, for example methyl, ethyl, propyl, butyl, or by cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 25 Aromatic ring systems are phenyl, naphthyl and heteroaryl radicals, and also aromatic six-membered carbocycles in which one or two carbon atoms may be replaced by nitrogen, or thiophene rings. Phenyl radicals may oe unsubstituted or mono- or polysubstituted, for 30 example mono-, di-, tri-, tetra- or pentasubstituted, by identical or different radicals. When a phenyl radical is substituted, it preferably bears one or two identical or different substituents. In monosubstituted phenyl radicals, the substituent may be in the 2-position, the 3-position or the 4-position. Disubstituted phenyl may be substituted in the 2,3-position, 2,4-position, 35 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl radicals, the substituents may be in the 2,3,4-position, 2,3,5 position, 2,4,5-position, 2,4,6-position, 2,3,6-position or 3,4,5-position. Naphthyl radicals may be joined via all positions, for example via the 1- -15 position or 2-position. Naphthyl radicals may likewise be unsubstituted or mono- or polysubstituted, for example mono-, di-, tri-, tetra- or pentasubstituted, by identical or different radicals. Where a naphthyl radical is substituted, it preferably bears one or two identical or different 5 substituents. Heteroaryl radicals are aromatic ring compounds in which 1, 2, 3 or 4 ring atoms are oxygen atoms, sulfur atoms or nitrogen atoms, for example 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a 10 combination of different hetero atoms. The heteroaryl radicals may be mono- or bicyclic. The heteroaryl radicals may be bonded via all positions, for example via the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. Heteroaryl radicals may be unsubstituted or mono- or polysubstituted, for example mono-, di- or 15 trisubstituted, by identical or different radicals. Useful heteroaryl radicals include, for example: ,, N 3 N N N N N NN NN 20 Preferred heteroaryl radicals are monocyclic aromatic ring compounds; particular preference is given to five-membered heteroaryl radicals, for example thiophene and isoxazole. 25 When groups, substituents or variables can be present more than once in the compounds of the formula I, la, II, Ila, Ill, Illa, IV or IVa, they may all each independently be as defined above and may each be identical or different. 30 The present invention further provides a process for preparing a compound of the formula I -16 R10 R11 H R15 N ' R14 A-N m< X o R17 FR16 R12 R13 which comprises converting a thiourea of the formula IV using a sulfonyl chloride R6SO2CI in 5 the presence of a base to the compound of the formula I R10 R11 R10 R11 S R15 H R15 A-N'J N R14 R6SO 2 CI N R14 H H Base A-N__ H'X R R17 X o R6R17 R16 Ri16 R12 R13 R12 R13 IV where 10 A, X, o, m, R6 and R10 to R17 are each as specified for the above process. All definitions and illustrations for the above-described process apply correspondingly to this process. 15 In a further embodiment, the present invention provides a process for preparing compounds of the formula la, Ar\ H R2 N N R1 X la R4 R3 which comprises converting a thiourea of the formula IVa using a sulfonyl chloride R6SO 2 CI 20 in the presence of a base to the compound of the formula la -17 H H R2 Ar . H R2 I I N N R1 N N R1 R6SO2Cr " N NBase X S X, n H R4 R3 R3 R4 IVa la where Ar, X, n, R1 to R4 and R6 are each as defined above. 5 All definitions and illustrations of the above-described process apply correspondingly for this process. The compounds of the formula I obtainable by the process according to the invention are valuable intermediates, for example for the preparation of 10 active pharmaceutical ingredients such as clonidine and its analogs, or are themselves active pharmaceutical ingredients. For example, the applications WO 03101984 and WO 03053434 describe compounds which may be prepared by means of the process described here, and which are suitable as NHE inhibitors, in particular NHE3 inhibitors, for example for 15 treating respiratory disorders and snoring, and also for improving the respiratory drive, or for treating acute or chronic disorders which are induced by ischemic and/or reperfusion events or by proliferative or by fibrotic events. 20 Experimental descriptions and examples: Abbreviations: abs. absolute ESI electrospray ionization 25 rt retention time THF tetrahydrofuran TFA trifluoroacetic acid The retention times (rt) reported below relate to LC-MS measurements with 30 the following parameters: Analytical methods: Method A: stationary phase: Merck Purospher 54 2 x 55 mm -18 mobile phase: 95% H 2 0 (0.05% TFA) - 95% acetonitrile, 3 min; -> 95% acetonitrile, 1.5 min; 0.5 ml/min. Method B: 5 stationary phase: Merck Purospher 3[t 2 x 55 mm mobile phase: 95% H20 (0.08% HCOOH) -+ 95% acetonitrile (0.1% HCOOH), 5 min; - 95% acetonitrile (0.1% HCOOH), 2 min; - 95% H 2 0 (0.1% HCOOH), 1 min; 0.45 ml/min. 10 Method C: stationary phase: YMC J'sphere H80, 4p, 2.1 x 20 mm mobile phase: 96% H 2 0 (0.05% TFA) - 95% acetonitrile, 2 min; -> 95% acetonitrile, 0.4 min; 1 ml/min. 15 Method D: stationary phase YMC J'sphere H80, 4p, 2.1 x 20 mm mobile phase: 95% H20 (0.05% TFA) -+ 95% acetonitrile, 2.3 min; -> 95% acetonitrile, 1 min; 1 ml/min. 20 The preparative HPLC was carried out under the following conditions: stationary phase: Merck Purospher RP18 (10pm) 250 x 25 mm mobile phase: 90% H 2 0 (0.05% TFA)-- 90% acetonitrile, 40 min; 25 ml/min 25 Example 1: Imidazolidin-2-ylidenephenylamine, trifluoroacetic acid salt H N TFA H 30 a) 1-(2-Aminoethyl)-3-phenylthiourea A solution of phenyl isothiocyanate (500 mg) in abs. THF (6 ml) was added dropwise over 20 minutes under argon to a solution of ethylenediamine (5.56 g) in abs. THF (6 ml). Afterwards, the reaction mixture was added to water, acidified with 10% HCI and extracted with ethyl acetate. The 35 aqueous phase was then basified with potassium carbonate and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Subsequently, -19 coevaporation with toluene was effected twice. 650 mg of the desired product remained. LC-MS rt (A): 1.96 min MS (ESI+): 196.2 5 b) Imidazolidin-2-ylidenephenylamine, trifluoroacetic acid salt 1-(2-Aminoethyl)-3-phenylthiourea (50 mg) was dissolved in THF (1.5 ml) under argon and admixed with a solution of sodium hydroxide (25.6 mg) in water (0.6 ml), and a solution of p-toluenesulfonyl chloride (53.7 mg) in 10 THF was added dropwise within five minutes. After a half hour of stirring, the reaction mixture was added to water and extraction was effected with ether six times. Subsequently, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative chromatography, and the product 15 containing fractions were combined, freed of acetonitrile and freeze-dried. After freeze-drying, 20 mrng of the desired product were obtained. LC-MS rt (A): 1.72 min MS (ESI+): 162.2 20 Example 2: [1,3]Oxazinan-2-ylidenephenylamine H N 0 a) 1-(3-Hydroxypropyl)-3-phenylthiourea 25 A solution of phenyl isothiocyanate (200 mg) in abs. THF (2 ml) was added dropwise under argon and with stirring to a solution of 3-amino-1-propanol (114.5 mg) in abs. THF (2 ml). The reaction mixture was stirred at room temperature for two hours. After removing the solvent, the residue was dissolved in aqueous HCI and washed with ether. Subsequently, the 30 aqueous phase was basified with potassium carbonate and extracted three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative chromatography, and the product-containing fractions were combined, freed of acetonitrile, basified and extracted three times 35 with ethyl acetate. The organic phases were combined, dried (MgSO 4 ) and -20 filtered. After removing the solvent, 114 mg of the desired product were obtained. LC-MS rt (B): 1.99 min MS (ESI+): 211.20 5 b) [1,3]Oxazinan-2-ylidenephenylamine A solution of sodium hydroxide (23.8 mg) and water (0.6 ml) was added under argon and with stirring to a solution of 1-(3-hydroxypropyl)-3 phenylthiourea (50 mg) and THF (1.5 ml). Subsequently, a solution of p 10 toluenesulfonyl chloride (49.9 mg) and THF (0.5 ml) was added dropwise over fifteen minutes. After stirring for 30 minutes, the reaction mixture was added to water and extraction was effected three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Chromatography using silica gel (initially 50:1 methylene 15 chloride/methanol, at the end 100:1 methanol/saturated ammonia solution) afforded 27.4 mg of the desired product. NMR (400 MHz, CDCI3): 7.35-7.18 (4H, m), 6.9-7.0 (1H, m), 4.29 (2H, t), 3.43 (2H, t), 1.96 (2H, q) 20 Example 3: (2,6-Dichlorophenyl)(octahydrobenzimidazol-2-yliden)amine CI H a) 1-(2-Aminocyclohexyl)-3-(2,6-dichlorophenyl)thiourea 25 A solution of 1,3-dichloro-2-isothiocyanatobenzene (100 mg) and abs. THF (3 ml) was added dropwise slowly over a half hour to a solution of trans 1,2-diaminocyclohexane (139.9 mg) and abs. THF (3 ml). The solution was stirred at room temperature for a further 90 minutes. The reaction mixture was subsequently added to water, acidified with hydrochloric acid and 30 extracted once with ethyl acetate. Afterwards, the mixture was basified using potassium carbonate and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 128 mg of the desired product were obtained. LC-MS rt (B): 1.88 min 35 MS (ESI+): 318.20 -21 b): (2,6-Dichlorophenyl)(octahydrobenzoimidazol-2-yliden)amine A solution of sodium hydroxide (15.7 mg) and water (0.6 ml) was added under argon to a solution of 1-(2-aminocyclohexyl)-3-(2,6-dichlorophenyl) thiourea (50 mg) and THF (1.5 ml). Subsequently, a solution of p 5 toluenesulfonyl chloride (32.9 mg) and THF (0.5 ml) was added dropwise over fifteen minutes. After stirring for 60 minutes, the reaction mixture was added to water and extracted three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 44 mg of the desired product were obtained. 10 LC-MS rt (B): 1.95 min MS (ESI+): 284.20 Example 4: (5-Fluoro-1 H-benzoimidazol-2-yl)(4-methylthiophen-3-yl)amine hydrochloride 15 F -_ N HCI \-N N H S a) 1-(2-Amino-5-fluorophenyl)-3-(4-methylthiophen-3-yl)thiourea and 1-(2 amino-4-fluorophenyl)-3-(4-methylthiophen-3-yl)thiourea 20 4-Fluoro-o-phenylenediamine (1.5 g) was dissolved in abs. THF (25 ml) and added dropwise with stirring to 3-isothiocyanato-4-methylthiophene (1.8 g) dissolved in abs. THF (25 ml). On completion of addition, the mixture was stirred at room temperature for 3 h, then a little more 3-isothio cyanato-4-methylthiophene was added and stirring was continued for a 25 further hour. After leaving to stand overnight, the THF was removed, the residue was dissolved in ethanol, carbon was added, and the mixture was heated to boiling and hot-filtered. After cooling, 1.8 g of the desired product were precipitated out of the filtrate with ether. 30 b) (5-Fluoro-1lH-benzoimidazol-2-yl)-(4-methylthiophen-3-yl)amine hydro chloride The mixture of 1-(2-amino-5-fluorophenyl)-3-(4-methylthiophen-3-yl) thiourea and 1-(2-amino-4-fluorophenyl)-3-(4-methylthiophen-3-yl)thiourea (1.75 g) was dissolved in THF (50 ml) and admixed with a solution of 35 sodium hydroxide (0.622 g) and water (15 ml). Within 5 min, a solution of p toluenesulfonyl chloride (1.304 g) and THF (10 ml) was added dropwise.
- 22 On completion of addition, the mixture was stirred at room temperature for a half hour. The reaction mixture was poured onto water and the aqueous phase was extracted three times. The combined ether phases were dried with magnesium sulfate, filtered and concentrated. The crude product was 5 dissolved in ethyl acetate and adjusted to pH 2 using ethereal HCI. It was precipitated by adding ether. After drying, 750 mg of the desired product were obtained. LC-MS rt (B): 1.48 min MS (ESI+): 248.11 -23 Starting from commercially available or known starting materials, the following compounds were prepared in a similar manner to the above examples:
LC
MS Exa- Amine Isothio- Product M.p. MS (ESI+, mple cyanate [0C] rt
M+H
+
) [min] C x HCI 5 S N >300 S NH NCS Sx HC H S: CF3 ',,..._"CN/ 194 NH2 H 196 x HCI 8 NH2 F F .%jS >F 296 NCS xHCI 9NH 2 CIS > 7 9 N >310
NH
2 H NCS 8 "k.-l N F 296 NCS x HCI -NH2 . ./C1 N H sa? - 24 LC MS Exa- Amine Isothio- Product M.p. MS S, mple cyanate [°C] rt [min
M+H
+ ) [minH 10 S NH 2 NCS S Hci >0 CI x HCICI SNH - NCS '-C N (. 2 14
NH
2 NCS N C C256 2 N SN N 10.90 12 F' N H 2 C1. H s(C) 268.0 CI S F N2 a NCS F N N 13 N F H 286.0 F -NH 2 Cl H 260 (C x HCI 1N 2 N CI 325 14 \> N FvNH 2 CI H \ 61 32 x HCI
NONH
2 CS N 96 15 s [ \ H eN16 15-NH 2 Cl H 200 -25
LC
MS Exa- Amine Isothio- Product M.p. MS MS Amin Prouct(ESIP mple cyanate [C] rt S[min
M+H
+) [min] 16 N N 240 16
NH
2 Ci H ~ 244 H x HCI 2 N 17 NH S NCS H C 17 s kN-4N 228
NH
2 Ci H H 231 Ci CI x HCI NNCS 18 ,S H C1 276 1-1C1 280.
NH
2 H 1\8 F xHCI NH 2 SN S H CI 0.89 19 s\ -N268.0 N (C) v NH 2 CH S\ NCS 20 HO , NH 2 0.14 164.1 NCS 21 HO,"XNH2 N= N 0.1 N,0
(C)
-26
LC
MS Exa- Amine Isothio- M.p. MS MS Amine Product (ESl* mple cyanate [0C] rt [m] M+H +) [min] NCS HCI H 22 HS NH 2 N0.64 179.1
-
(C) NCS H 23 HO 177.1 N
-
(C) CI HCI H NCS 0 24 HO /i" C N== 1.07 4 H2N ( N H 299.4 ,CI HCI CI HH / H2 N % " CI N 1.04 25 HOH Cl0 (C) 299.3 CI H N__ NCS CI HCI HH cI ,.cI 1.83 26 .2 N 1.83 271.3 HO c 271.3 Cl H CI H
H
2 cs NCS/ HcI H . H2N,,7 CI, C / Ci --- N 1.83 27 --- 0 285.3 HO CH (D) NCS CI HCI H H Cl CI N -- N 1.76 28 285. HO ," - 0 (D) Cl H - 27 Example 29: (2,6-Dichlorophenyl)imidazolidin-2-ylidene amine CI H NI N. N N CI H a) 1-(2-Aminoethyl)-3-(2,6-dichlorophenyl)thiourea 5 A solution of 2,6-dichlorophenyl isothiocyanate (500 mg) and THF (5 ml) was added dropwise under argon within 20 minutes to a solution of ethylenediamine (3.68 g) and abs. THF (4 ml). After stirring for a further 30 min, the mixture was added to water, acidified with 10% HCI and extracted three times with ethyl acetate. The aqueous phase was made 10 basic using saturated potassium carbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, the solvent was removed under reduced pressure and the residue was coevaporated twice with toluene. After drying in high vacuum, the desired product was obtained as a white solid (532 mg). 15 LC-MS rt (C): 0.719 min MS (ESI+): 264.0 b) (2,6-Dichlorophenyl)imidazolidin-2-ylidene amine 1-(2-Aminoethyl)-3-(2,6-dichlorophenyl)thiourea (200 mg) was dissolved 20 under argon in THF (4 ml), admixed with a solution of sodium hydroxide (102 mg) in water (2 ml) and then a slurry of polystyrene-bound toluenesulfonyl chloride (457 mg, 2.9 mmol/g) in THF (4 ml) was added dropwise within five minutes. After stirring at room temperature for 2 h, further polystyrene-bound toluenesulfonyl chloride (65 mg in 2 ml of THF) 25 was added, followed after a further hour by further acid chloride (124 mg in 2 ml of THF). After standing overnight, the reaction mixture was filtered, the resin was slurried twice in dichloromethane and the combined phases were concentrated to dryness. The residue was taken up in water/dichloromethane, the phases were separated and the aqueous 30 phase was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, and the solvent was removed under reduced pressure and subsequently dried under high vacuum. 104 mg of the title compound were obtained. LC-MS rt (C): 0.65 min 35 MS (ESI+): 230.1 -28 In a similar manner to example 29, the following compounds were obtained: MS Exa- Isothio- LC-MS Amine Product (ES
+
, mple cyanate rt [min]
M+H
+ ) NCS N
NH
2 6 1 -N 1.42 30 OH 2 211.1
NH
2 NCS N 31 N 0.95 216.1 v -NH 2 H (C)

Claims (9)

1. A process for preparing heterocycles of the formula I 5 R10 R1l A-N mI X 0R R17 R12 R13 where: X is sulfur, oxygen or NR5 10 where R5 is hydrogen or (C1-C4)alkyl; m and o are each independently zero, 1 or 2; A is phenyl, naphthyl or heteroaryl, all of which may be substituted by 1, 2, 3, 4 or 5 Rll radicals 15 where R11 is in each case independently selected from the group of (C1-C4)alkyl, F, CI, Br, I, CN, NO 2 , OH, O(C1-C4) alkyl, COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; or 20 (Cl-C4)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, where these radicals may each independently be substituted by (C1-C4)alkyl or (C3-C6)cycloalkyl, and some or all of the hydrogen atoms of the alkyl, alkenyl, alkynyl, cycloalkyl and 25 cycloalkenyl radicals may be replaced by fluorine atoms, R14, R15, R16 and R17 are each independently hydrogen, F or (C1-C4)alkyl, where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; 30 or R14 and R16 together are a bond, - 30 and R15 and R17 with the two carbon atoms to which they are bonded are an aromatic six-membered carbocycle in which one or two carbon atoms may be 5 replaced by nitrogen, or a thiophene ring, where the aromatic six-membered carbocycle and the thiophene ring may be substituted by 1, 2, 3 or 4 R7 radicals, where R7 is in each case independently selected from the group of (C1-C4)alkyl, F, CI, Br, I, CN, NO2, OH, O(C1-C4) 10 alkyl and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; or R14 and R16 are each independently hydrogen or (C1-C4)alkyl, 15 where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; and R15 and R17 with the two carbon atoms to which they are bonded are a saturated 20 5-, 6-, 7- or 8-membered carbocycle in which one or two carbon atoms may be replaced in each case independently by O, S, NH and N(C1-C4)alkyl and may be substituted by 1, 2, 3, 4, 5 or 6 R8 radicals where R8 is in each case independently selected from the 25 group of (C1-C4)alkyl, O(C1-C4)alkyl, COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; R10, R11, R12 and R13 are each independently hydrogen, F or (C1-C4)alkyl, 30 where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; where either A or the ring formed from R15 and R17 together, where m is zero, is an aromatic ring system, or both are aromatic ring systems; and 35 excluding compounds in which A is unsubstituted phenyl or (C1-C4)alkyl, X is oxygen, R14 and R15 are each independently hydrogen, (C1-C4)alkyl or benzyl, R16 and R17 are each hydrogen and m and o are each zero; and their tautomers and their salts, which comprises, -31 R10 R11 R0 R11 R10 R11 R10 R11 R15 S R14 R15 H R15 NCS H 2 N R14 A, Nk N m R14 R6SO 2 CI N R14 A- R17 H H B A-N S o R17Base R16 HX oR17 x R17 R12 R13 R16 R16 R12 R13 R12 R13 II III IV I a) reacting an isothiocyanate of the formula II with a primary amine of the formula III to give a thiourea of the formula IV, and 5 b) converting the thiourea of the formula IV using a sulfonyl chloride R6SO2CI in the presence of a base to the compound of the formula I, where, in the compounds of the formulae II, Ill and IV, A, X, n, m and R10 to R17 are each as defined in formula I and R6 is (C1-C4)alkyl, trifluoromethyl or phenyl which is unsubstituted or 10 substituted by methyl, trifluoromethyl, F, CI, Br or, or a polymeric support.
2. The process of claim 1, in which the reaction is carried out as a one-pot reaction. 15
3. The process of claim 1 and/or 2, wherein steps a) and b) are each independently conducted continuously or batchwise.
4. The process of one or more of claims 1 to 3, wherein X is oxygen or 20 NR5.
5. The process of one or more of claims 1 to 4, wherein X is NR5.
6. The process of one or more of claims 1 to 5, wherein A is phenyl, thienyl 25 or isoxazolyl, each of which may be substituted as specified in claim 1.
7. The process of one or more of claims 1 to 6, wherein R6 is phenyl or p methylphenyl. 30
8. The process of one or more of claims 1 to 7, wherein the base used in step b) is sodium hydroxide or potassium hydroxide. - 32
9. A process for preparing a compound of the formula I as defined in claim 1 R10 Ril H R15 N R14 A-N < X 0 17 Ri 6 R12 R13 5 which comprises converting a thiourea of the formula IV using a sulfonyl chloride R6SO 2 CI in the presence of a base to the compound of the formula I R10 R11 R10 R11 SR15 H R15 A N N R R14 R6SO 2 CI N RR14 H H Base A-N H X R 6R17 BX R17 R16 R16 R12 R13 R12 R13 IV I 10 where A, X, o, m, R6 and R10 to R17 are each as defined in claim 1.
AU2004240716A 2003-05-22 2004-05-10 Method for synthesising heterocyclic compounds from thiourea derivatives Abandoned AU2004240716A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10323701A DE10323701A1 (en) 2003-05-22 2003-05-22 Process for the synthesis of heterocyclic compounds
DE10323701.1 2003-05-22
PCT/EP2004/004955 WO2004103976A2 (en) 2003-05-22 2004-05-10 Method for synthesising heterocyclic compounds from thiourea derivatives

Publications (1)

Publication Number Publication Date
AU2004240716A1 true AU2004240716A1 (en) 2004-12-02

Family

ID=33461873

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2004240716A Abandoned AU2004240716A1 (en) 2003-05-22 2004-05-10 Method for synthesising heterocyclic compounds from thiourea derivatives

Country Status (18)

Country Link
EP (1) EP1631552B1 (en)
JP (1) JP2007502311A (en)
KR (1) KR20060013676A (en)
CN (1) CN1795178A (en)
AR (1) AR044544A1 (en)
AU (1) AU2004240716A1 (en)
BR (1) BRPI0410565A (en)
CA (1) CA2526646A1 (en)
CL (1) CL2004001156A1 (en)
DE (1) DE10323701A1 (en)
IL (1) IL172009A0 (en)
MX (1) MXPA05012153A (en)
NO (1) NO20055991L (en)
NZ (1) NZ543692A (en)
RU (1) RU2346936C2 (en)
TW (1) TW200505870A (en)
WO (1) WO2004103976A2 (en)
ZA (1) ZA200508430B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2009CH01478A (en) 2003-06-30 2009-08-21 Sumitomo Chemical Co Asymmetric urea compound and process for producing asymmetric compound by asymmetric conjugate addition reaction with the same as catalyst
WO2008051533A2 (en) * 2006-10-25 2008-05-02 Takeda Pharmaceutical Company Limited Benzimidazole compounds
JP2020511671A (en) * 2017-02-24 2020-04-16 アイロア テクノロジーズ リミテッド ライアビリティ カンパニー IROA Metabolomics Workflow for Improved Accuracy, Identification and Quantification

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10163239A1 (en) 2001-12-21 2003-07-10 Aventis Pharma Gmbh Substituted imidazolidines, process for their preparation, their use as medicaments or diagnostic agents, and medicaments containing them
DE10224892A1 (en) 2002-06-04 2003-12-18 Aventis Pharma Gmbh Substituted thiophenes, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them

Also Published As

Publication number Publication date
MXPA05012153A (en) 2006-08-18
TW200505870A (en) 2005-02-16
BRPI0410565A (en) 2006-06-20
RU2346936C2 (en) 2009-02-20
KR20060013676A (en) 2006-02-13
ZA200508430B (en) 2007-12-27
JP2007502311A (en) 2007-02-08
CA2526646A1 (en) 2004-12-02
WO2004103976A3 (en) 2005-02-10
AR044544A1 (en) 2005-09-21
RU2005140090A (en) 2006-04-20
EP1631552A2 (en) 2006-03-08
CN1795178A (en) 2006-06-28
NZ543692A (en) 2009-04-30
DE10323701A1 (en) 2004-12-23
EP1631552B1 (en) 2013-07-03
IL172009A0 (en) 2011-08-01
CL2004001156A1 (en) 2005-03-28
NO20055991L (en) 2006-02-14
WO2004103976A2 (en) 2004-12-02

Similar Documents

Publication Publication Date Title
US4013678A (en) Process for preparing heterocyclicalkylthioalkyl-n-cyanoguanidines
SE456581B (en) INTERMEDIATES FOR THE PREPARATION OF 3,4-DISUBSTITUTED 1,2,5-THIADIAZOL-1-OXIDES AND -1,1-DIOXIDES WHICH ARE H 71 RECEPTOR ANTAGONISTS
Sugimoto et al. Activation of dithiocarbamate by 2-halothiazolium salts
US11760723B2 (en) Method of preparing a DON prodrug from L-pyroglutamic acid
US3775409A (en) 1,3-thiazines
HU225458B1 (en) Process for the preparation of thiazole derivatives, intermediates and preparation thereof
AU2004240716A1 (en) Method for synthesising heterocyclic compounds from thiourea derivatives
US8653259B2 (en) Process for synthesizing heterocyclic compounds
US4093621A (en) Process for preparing heterocyclicalkylthioalkyl-N-cyanoguanidines and thioureas
KR20000070397A (en) Process for the preparation of thiazole derivatives
CA1201119A (en) Diaza-cyclic derivatives of guanidine
CS207750B2 (en) Method of making the n&#39;-cyano-n&#39;-alcyl-n-2-/5-methyl-1h-imidazol-4-yl/methyl thicethyl guanidines
CA1100146A (en) Derivatives of r,s-[2-(2-hydroxyethylamino)-1- phenyl]-ethylamine, and a process of obtaining them
WO2001021592A1 (en) Processes for the preparation of 4(5)-amino-5(4)-carboxamidoimidazoles and intermediates thereof
CN108610306B (en) Synthetic method of 2H-1, 4-thiazine-3 (4H) -ketone derivative
US7358368B2 (en) Azlactone compound and method for preparation thereof
US3267112A (en) Novel imidazothiazole derivatives and a process for preparation thereof
JPS6360969A (en) Production of imidazole derivative
FI89918C (en) EXAMINATION OF THERAPEUTIC CONTAINING CRYSTALINT 2- (1-PENTYL-3-GUANIDINO) -4- (2-METHYL-4-IMIDAZOLYL) THIAZOLEHYDROCHLORIDE TRIHYDRATE
HU189111B (en) Process for producing thiazol derivatives
SU920056A1 (en) Method of producing r,s-2,3,5,6-tetrahydro-6-phenilimidazo(2,1)-thiazole
KR870001793B1 (en) Process for preparing n-sulfamoyl-3-(2-guanidinothiazole-4-ylmethyltio)propionamide
US20240101547A1 (en) Method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one
Aravinda et al. Quinoline-thioureidopeptides: A new approach for the synthesis of quinoline-isothiocyanate and their peptide linkage
MXPA02000773A (en) Method for producing 4-cyano-2-aminomethylthiazol.

Legal Events

Date Code Title Description
MK4 Application lapsed section 142(2)(d) - no continuation fee paid for the application