Substituted 2-dialkylaminoalkylbiphenyl derivatives

专利摘要:
The present invention relates to substituted 2-dialkylaminoalkylbiphenyl derivatives, methods for their preparation, medicaments containing them and their use for preparing medicaments.
公开号:KR20020022100A
申请号:KR1020027001825
申请日:2000-07-25
公开日:2002-03-23
发明作者:준데르만베른트；쾨겔바벳테-위폰네；부쉬만헬무트
申请人:파퀘스, 파우쓰-베르구스；그뤼넨탈 게엠베하；
IPC主号:

专利说明:

Substituted 2-dialkylaminoalkylbiphenyl derivatives
[1] The present invention relates to substituted 2-dialkylaminoalkylbiphenyl derivatives, methods for their preparation, medicaments containing these compounds and the use of these compounds for the manufacture of medicaments.
[2] Treatment of pain in chronic and obese conditions is of great importance in medicine. There is a broad need for pain treatment with good efficacy. The rapid need for action on pain-related and target-based treatment of chronic and obese conditions, understood to mean successful and satisfactory pain treatment in patients, is a fundamental study of the recently applied analgesic and invasive acceptance. Illustrated by numerous scientific work in the field.
[3] Conventional opioids (eg morphine) work well in treating severe to very severe pain. However, their use is limited due to the occurrence of known side effects (eg, respiratory depression, vomiting, sedation, constipation, intoxication, dependence and tolerance). Thus, they can be administered for a relatively long period of time or at relatively high doses according to special safety precautions, for example according to certain prescription instructions (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990). In addition, they are relatively ineffective in certain conditions of pain, particularly neuropathic pain.
[4] It is an object of the present invention to provide an analgesically active substance suitable for the treatment of pain. In addition, these substances should be as low as possible to the side effects of opioid analgesics (eg nausea, vomiting, dependence, lowered breath or constipation). Another object is to provide active compounds for the treatment of inflammatory and allergic reactions, depression, drug and / or alcohol abuse, gastritis, diarrhea, incontinence, cardiovascular disease, respiratory disease, cough, psychosis and / or epilepsy.
[5] According to the invention, it is suitable for the treatment of inflammatory and allergic reactions, depression, drug and / or alcohol abuse, gastritis, diarrhea, urinary incontinence, cardiovascular disease, respiratory disease, cough, psychosis and / or epilepsy treatment, and further prominent By providing novel substituted 2-dialkylaminoalkylbiphenyl derivatives which have analgesic action.
[6] The present invention therefore provides for substituted 2-dialkylaminoalkylbiphenyl derivatives of formula I in the form of salts of bases and / or physiologically acceptable acids.
[7]
[8] In the above formula,
[9] n is 1 or 2,
[10] The radicals R ¹ , R ² and R ³ are the same or different and H, F, Cl, Br, CN, NO ₂ , CHO, SO ₂ CH ₃ , SO ₂ CF ₃ , OR ⁶ , NR ⁶ R ⁷ , C _{1 -6} alkyl, preferably C _1-3 alkyl, aryl, acetyl, acetamido, or pyridyl radical, or represent benzoyl, C _1-6 alkyl, an aryl radical bonded via an alkylene group, preferably a C _1-3 alkylene Represents an aryl radical bound through a group,
[11] R ¹ and R ² together represent, in each case, a group OCH ₂ O, OCH ₂ CH ₂ O, CH═CHO, CH═C (CH ₃ ) O or CH═CHNH,
[12] The radicals R ⁴ and R ⁵ are the same or different and represent H or C _1-6 alkyl radicals, preferably C _1-3 alkyl radicals,
[13] The radicals R ⁶ and R ⁷ are the same or different and represent H, C _1-6 alkyl, preferably C _1-3 alkyl or aryl radicals, or aryl radicals bonded via a C _1-6 alkylene group, preferably Preferably an aryl radical bound through a C _1-3 alkylene group,
[14] Provided that 2'-dimethylaminomethylbiphenyl-2-carbaldehyde, biphenyl-2-ylmethyldimethylamine, 2'-dimethylaminomethylbiphenyl-2-ol and the corresponding hydrochloride, (2 ', 3 '-Dimethoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride and hydrobromide, (4'-methylbiphenyl-2-ylmethyl) -dimethylamine, (2'-methylbiphenyl-2 -Ylmethyl) -dimethylamine, 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile, (2'-dimethylaminomethylbiphenyl-2-yl) methanol, 2'-dimethylaminomethylbiphenyl -2,3-diol and the corresponding hydrobromide, [2- (3 ', 4'-dimethoxybiphenyl-2-yl) ethyl] -dimethylamine and the corresponding hydrochloride, [2- (2' , 3'-dimethoxy-6'-methylbiphenyl-2-yl) ethyl] -dimethylamine and the corresponding hydrobromide, and biphenyl-2-ylethyldimethylamine are excluded.
[15] Alkyl radicals are also understood to mean hydrocarbons which are at least monosubstituted, preferably by halogen and / or hydroxyl groups, particularly preferably by fluorine and / or hydroxyl groups. If they contain one or more substituents, they may be the same or different. Alkyl radicals methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2, Preference is given to 2-dimethylpropyl, hexyl, 1-methylpentyl, CHF ₂ , CF ₃ or CH ₂ OH.
[16] Aryl radicals are also OH, halogen, preferably F and / or Cl, CF ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _1-7 cycloalkoxy, C _3-7 cycloalkyl, C _2-6 It is understood to mean a phenyl or naphthyl radical at least monosubstituted by an alkylene or phenyl radical. The phenyl radical can also be condensed with other rings.
[17] Particular preference is given to the following substituted 2-dimethylaminoalkylbiphenyl derivatives:
[18] (3'-methoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[19] (4'-chlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[20] 2'-dimethylaminomethylbiphenyl-3-ol and the corresponding hydrochloride,
[21] (2'-methoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[22] (3'-chlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[23] (2'-fluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[24] (3'-fluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[25] (4'-fluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[26] (3'-chloro-4'-fluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[27] (3'-methoxybiphenyl-2-ylethyl) dimethylamine and the corresponding hydrochloride,
[28] Dimethyl- [2- (2-methylbenzofuran-4-yl) benzyl] amine and the corresponding hydrochloride,
[29] 2'-dimethylaminomethylbiphenyl-2-carbaldehyde and the corresponding hydrochloride,
[30] (3'-difluoromethylbiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[31] 2'-dimethylaminomethylbiphenyl-3-carbaldehyde and the corresponding hydrochloride,
[32] Biphenyl-2-ylmethyldimethylamine and the corresponding hydrochloride,
[33] (3 ', 4'-dichlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[34] (3 ', 5'-dichlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[35] Dimethyl- (4'-nitro-3'-trifluoromethylbiphenyl-2-ylmethyl) amine and the corresponding hydrochloride,
[36] (3 ', 4'-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[37] (4'-fluoro-3'-trifluoromethylbiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[38] (4'-chloro-3'-methoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[39] N- (2'-dimethylaminomethyl-3-trifluoromethoxybiphenyl-4-yl) acetamide and the corresponding hydrochloride,
[40] (3'-isopropoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[41] 2 '-(2-dimethylaminoethyl) biphenyl-3-ol and the corresponding hydrochloride,
[42] 4-chloro-2'-dimethylaminomethylbiphenyl-3-ol and the corresponding hydrochloride,
[43] [2- (1H-indol-5-yl) benzyl] dimethylamine and the corresponding hydrochloride,
[44] (4'-methanesulfonylbiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[45] (2 ', 4'-dichlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[46] (2 ', 3'-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[47] (2 ', 5'-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[48] (2-benzo [1,3] -dioxol-5-ylbenzyl) dimethylamine and the corresponding hydrochloride,
[49] 1- [2 '-(2-dimethylaminoethyl) biphenyl-3-yl] ethanone and the corresponding hydrochloride,
[50] [2- (3 ', 4'-dimethoxybiphenyl-2-yl) ethyl] dimethylamine and the corresponding hydrochloride,
[51] [2- (3'-isopropoxybiphenyl-2-yl) ethyl] dimethylamine and the corresponding hydrochloride,
[52] [2- (4'-chloro-3'-methoxybiphenyl-2-yl) ethyl] dimethylamine and the corresponding hydrochloride,
[53] 4-chloro-2 '-(2-dimethylaminoethyl) biphenyl-3-ol and the corresponding hydrochloride,
[54] Dimethyl- (3'-nitrobiphenyl-2-ylmethyl) amine and the corresponding hydrochloride,
[55] 4-amino-2'-dimethylaminomethylbiphenyl-3-ol and the corresponding dihydrochloride,
[56] (3 ', 5'-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[57] (2 ', 5'-dimethoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
[58] 2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-ylamine and the corresponding dihydrochloride and
[59] N- (2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-yl) acetamide and the corresponding hydrochloride.
[60] The present invention also discloses that the compound of formula II is reduced in solution with a reducing agent, preferably lithium aluminum hydride and / or diisobutylaluminum hydride, to obtain a compound of formula III, which is purified and separated by conventional methods. Characterized in the process for the preparation of substituted 2-dialkylaminoalkylbiphenyl derivatives of formula (I).
[61]
[62]
[63] In the above formula,
[64] Y is Cl, Br or I,
[65] m is 0 or 1;
[66] The compound of formula III is reacted with aliphatic C _1-6 aldehyde in the presence of a reducing agent, preferably formic acid and / or sodium borohydride, to give a compound of formula IV, which is purified and separated by conventional methods.
[67]
[68] In the above formula,
[69] R ⁴ and R ⁵ are as defined in formula (I).
[70] The compound of formula IV is preferably converted to a halogen-metal exchange reaction with magnesium and / or butyllithium and then at a temperature below 0 ° C. with a boric acid ester, preferably trialkyl borate, particularly preferably trimethyl borate Reaction gives a compound of formula V, which is isolated and purified by conventional methods.
[71]
[72] In the above formula,
[73] R represents a C _1-6 alkyl radical.
[74] The compound of formula V can be reacted with an aqueous acid, preferably hydrochloric acid, to give a compound of formula VI, which can be purified and separated by conventional methods.
[75]
[76] The compounds of formula (V) or (VI) are transition metal catalysis, preferably as palladium (0) compounds or palladium (II) salts, particularly preferably tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone Aliphatic ethers, preferably 1,4-dioxane and tetrahydrofuran, or hydrocarbons, in a reaction catalyzed by palladium, elemental palladium on activated carbon, palladium (II) chloride and / or palladium (II) acetate Is reacted with a compound of formula (VII) in a toluene or hexane, alcohol, preferably ethanol or isopropanol, chlorinated hydrocarbon, preferably chloroform or methylene chloride, at a temperature of 20 to 150 ° C. in water or a mixture of these solvents The compound of I is obtained, which is purified and separated by conventional methods.
[77]
[78] In the above formula,
[79] X represents Cl, Br, I or OSO ₂ C _p F _{(2p + 1)} ,
[80] The radicals R ¹ to R ³ are as defined in formula (I).
[81] The compounds of formula (VIII) or (IX) are also transition metal catalysis, preferably as palladium (0) compounds or palladium (II) salts, particularly preferably tetrakis (triphenylphosphine) palladium, bis (dibenzyl) Aliphatic ethers, preferably 1,4-dioxane and tetrahydrofuran, or hydrocarbons in a reaction catalyzed by palladium (lidene acetone), palladium on activated carbon, palladium (II) chloride and / or palladium (II) acetate Compounds of formula III or IV at temperatures of 20 to 150 ° C., preferably in toluene or hexane, alcohols, preferably ethanol or isopropanol, chlorinated hydrocarbons, preferably chloroform or methylene chloride, in water or mixtures of these solvents Reaction with to give a compound of formula I, which is purified and separated by conventional methods.
[82]
[83]
[84] The compounds of formula (I) are physiologically acceptable acids in a manner known per se, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid , Citric acid, glutamic acid and / or aspartic acid may be used to convert these salts. Salt formation is preferably carried out in a solvent, for example in diethyl ether, diisopropyl ether, acetic acid alkyl esters, acetone and / or 2-butanone. Trimethylchlorosilane in aqueous solution is also suitable for the preparation of hydrochloride.
[85] Substituted 2-dialkylaminoalkylbiphenyl derivatives of formula (I) according to the invention are physiologically acceptable and are therefore suitable pharmaceutically active compounds.
[86] Accordingly, the present invention includes, as active compound, one or more substituted 2-dialkylaminoalkylbiphenyl derivatives of formula (I), which are in the form of their bases and / or physiologically acceptable acids, and optionally, other active compounds and auxiliary substances. To provide a drug.
[87] The agent is preferably used for the treatment / inhibition of pain, inflammatory and allergic reactions, depression, drug and alcohol abuse, gastritis, diarrhea, incontinence, cardiovascular disease, respiratory disease, cough, psychosis and / or epilepsy.
[88] The invention also provides a base for the manufacture of a medicament for the treatment / inhibition of pain, inflammation and allergic reactions, depression, drugs and alcohol abuse, gastritis, diarrhea, incontinence, cardiovascular disease, respiratory disease, cough, psychosis and / or epilepsy. And / or one or more substituted 2-dialkylaminoalkylbiphenyl derivatives of formula (I) in the form of salts of physiologically acceptable acids.
[89] In order to prepare the corresponding pharmaceutical formulations, in addition to one or more substituted 2-dialkylaminoalkylbiphenyl derivatives of formula (I), carrier materials, fillers, solvents, diluents, dyes and / or binders are used. The choice of auxiliary substances to be used and amounts thereof depends on whether the medicament is administered orally, intravenously, intraperitoneally, intradermal, intramuscularly, intranasally, orally or locally, for example, for infections of the skin, mucous membranes and eyes. It depends. Formulations in the form of tablets, tablets, capsules, granules, drops, juices and syrups are suitable for oral administration, while solutions, suspensions, easily reconstitutable anhydrous formulations and sprays are suitable for parenteral, topical and inhalation administration. Optionally, with the addition of an agent that promotes penetration into the skin, the compounds of formula (I) according to the invention in depots, dissolved forms or patches are suitable for formulations for transdermal administration. Formulation forms that can be used for oral or transdermal administration can release the compounds of formula (I) according to the invention in a sustained release manner.
[90] The amount of active compound to be administered to a patient varies depending on the patient's weight, mode of administration, signs of disease and severity. It is common to administer 0.5 to 500 mg / kg of the 2-dialkylaminoalkylbiphenyl derivative of formula (I).
[91] Example
[92] The following examples illustrate the invention but do not limit the general scope of the invention.
[93] The yield of the compound produced is not optimized.
[94] All temperatures were not calibrated.
[95] Ether mentioned refers to diethyl ether.
[96] Silica gel 60 (0.040 to 0.063 mm) (manufactured by E. Merck, Darmstadt) is used as the stationary phase for column chromatography.
[97] Thin layer chromatography analysis is performed using silica gel 60 F 254 (E. Merck, Darmstadt), an HPTLC precoated plate.
[98] The mixing ratio of all mobile phases for chromatographic analysis is always referred to in volume / volume.
[99] Vol.% Represents volume percent and wt% represents weight percent.
[100] Example 1
[101] (3'-methoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride
[102] Stage 1
[103] 3-methoxybenzeneboronic acid
[104] 41.3 g (220 mmol) of 3-bromoanisole is dissolved in 880 mL of tetrahydrofuran and the solution is cooled to -70 ° C in a cooling bath (ethanol / dry ice). 160 mL of butyllithium solution (1.6 M in hexane) (250 mmol) is added dropwise under nitrogen in such a way that the temperature does not exceed −60 ° C. After 1.5 hours of stirring at −70 ° C., 75 ml (660 mmol) of trimethyl borate are also added dropwise in such a way that the temperature does not exceed −60 ° C. After stirring again for 1 hour, the mixture is warmed to 25 ° C. for 2 hours, 720 ml of hydrochloric acid (1M) is added, and the mixture is stirred at 25 ° C. for 15 hours.
[105] For workup, the mixture is extracted three times with 300 ml of ether each time, the organic phases are combined, washed with water and 100 ml of saturated sodium chloride solution respectively, dried over anhydrous magnesium sulfate and filtered, and the filtrate is rotary evaporator (500 to 500). At 10 mbar). 30.8 g (92.1% of theory) of 3-methoxybenzeneboronic acid are obtained in this manner.
[106] Tier 2
[107] (2-bromobenzyl) dimethylamine
[108] 25.1 g (113 mmol) of 2-bromobenzylamine hydrochloride are dissolved in 26 ml (678 mmol) of formic acid and 52 ml (678 mmol) of formaldehyde solution (36 wt% in water), and the mixture is heated with stirring at 95 ° C. for 6 hours. do. The solution is then cooled to 0 ° C. in an ice bath and 90 g (50% by weight) of cold potassium hydroxide solution are added. The mixture is extracted three times with 100 ml of ether each time at 25 ° C., the organic phases are combined, a small amount of activated carbon is added, the mixture is dried over anhydrous magnesium sulfate and filtered, and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 22.2 g (91.9% of theory) of (2-bromobenzyl) dimethylamine are obtained in this manner.
[109] Tier 3
[110] (3'-methoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride
[111] 1.13 g (7.43 mmol) of 3-methoxybenzeneboronic acid, 1.67 g (7.78 mmol) of (2-bromobenzyl) dimethylamine and 2.62 g (24.7 mmol) of sodium carbonate were added to 50 ml of toluene, 20 ml of water and 10 ml of ethanol. Dissolve in the mixture. 175 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated at 110 ° C. for 16 hours with stirring.
[112] For workup, 75 ml of ether is added and the mixture is extracted three times with 75 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is extracted with 30 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 2.12 g (118% of theory) of the crude base are added and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 1 (v: v) ether / n-hexane gave 0.61 g of base, which was dissolved in 6.0 mL of 2-butanone, 25 μl (1.39 mmol) of water and 350 μl (2.78 chlorotrimethylsilane) mmol) is added sequentially. The mixture is kept at 25 ° C. for 15 hours and the precipitated solid is filtered off, washed with a small amount of ether and dried to constant weight under oil pump vacuum. 0.56 g (27.2% of theory) of (3'-methoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 144 DEG C are obtained in this way.
[113] Example 2
[114] (4'-chlorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[115] 0.88 g (5.65 mmol) of 4-chlorobenzeneboronic acid, 1.27 g (5.93 mmol) of (2-bromobenzyl) dimethylamine (2 stage) prepared according to Example 1, and 2.00 g (18.8 mmol) of sodium carbonate were added to toluene 39 Dissolve in a mixture of ml, 16 ml of water and 8 ml of ethanol. 133 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[116] For workup, 65 ml of ether is added and the mixture is extracted three times with 65 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.30 g (93.8% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 × 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.61 g of base, which was separated by HPLC for further purification. Separation conditions: mobile phase acetonitrile / water [80:20 (v / v) + 0.5 vol.% Isopropylamine], flow rate 10 ml / min, wavelength 254 nm, column Eurogel PRP 100 (Knauer, 250 x 16 mm, with preliminary column). 0.31 g of crude base was obtained from which 0.33 g (4'-chlorobiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 232 DEG C (20.7% of theory) was added to chlorotrimethylsilane in 2-butanone. Obtained according to Example 1 (step 3) using / water.
[117] Example 3
[118] 2'-dimethylaminomethylbiphenyl-3-ol hydrochloride
[119] 0.70 g (2.52 mmol) of (3'-methoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride prepared according to Example 1 (step 3) was dissolved in 10 ml of water, and the base was dissolved in 10 ml of water and sodium hydroxide. 2 ml of a solution (32% by weight) was liberated, the mixture was extracted three times with 20 ml of ether each time, the combined organic extracts were dried over anhydrous magnesium sulfate and filtered, and the filtrate was filtered on a rotary evaporator (500-10 mbar). Concentrate. 0.59 g (2.44 mmol) of this base is heated under reflux (bath temperature: 145 ° C.) with 55 ml of hydrogen bromide solution (48% by weight in water) for 2 hours.
[120] For workup, the mixture is poured into 600 ml of sodium bicarbonate solution (1 M) (pH 7-8), extracted three times with 100 ml of ethyl acetate each time, the combined organic extracts are dried over anhydrous magnesium sulfate and filtered, and the filtrate is filtered. Concentrate on a rotary evaporator (500-10 mbar). 0.61 g (109% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with ether gave 0.51 g of base, from which 0.51 g of 2'-dimethylaminomethylbiphenyl-3-ol hydrochloride having a melting point of 180 ° C. (79.7% of theory) was added to chlorotrimethylsilane in 2-butanone. Obtained according to Example 1 (step 3) using / water.
[121] Example 4
[122] (2'-methoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride
[123] 1.00 g (6.58 mmol) of 4-methoxybenzeneboronic acid, 1.48 g (6.91 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (step 2) and 2.32 g (21.9 mmol) of sodium carbonate were toluene Dissolve in a mixture of 45 ml, 18 ml of water and 9 ml of ethanol. 160 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[124] For workup, 75 ml of ether is added and the mixture is extracted three times with 75 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is extracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.62 g (102% of theory) of crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 2 (v: v) ether / n-hexane gave 0.64 g of base from which 0.31 g of (2'-methoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 163 ° C. (17.1% of theory) is obtained according to example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[125] Example 5
[126] (3'-chlorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[127] 1.00 g (6.39 mmol) of 3-chlorobenzeneboronic acid, 1.44 g (6.71 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (step 2), and 2.26 g (21.3 mmol) of sodium carbonate were toluene 44 Dissolve in a mixture of ml, 17 ml of water and 9 ml of ethanol. 160 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[128] For workup, 75 ml of ether is added and the mixture is extracted three times with 75 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.49 g (94.7% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 1 (v: v) ether / n-hexane afforded 0.62 g of base, from which hydrochloride was used in Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone. Precipitate accordingly. The base was liberated from this with 10 ml of water and 2 ml of sodium hydroxide solution (32% by weight), the mixture was extracted three times with 20 ml of ether each time, the combined organic extracts were dried over anhydrous magnesium sulfate and filtered, and the filtrate Is concentrated in a rotary evaporator (500-10 mbar). The resulting crude base is purified by HPLC. Separation conditions: mobile phase acetonitrile / water [80:20 (v / v) + 0.5 vol.% Isopropylamine], flow rate 10 ml / min, wavelength 254 nm, column eurogel 100 (Knauer, 250 x 16 mm, Preliminary column). 0.32 g of crude base was obtained from which 0.29 g (3'-chlorobiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 169 ° C. (16.3% of theory) was added to chlorotrimethylsilane in 2-butanone. Obtained according to Example 1 (step 3) using / water.
[129] Example 6
[130] (2'-fluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[131] 1.02 g (7.27 mmol) of 2-fluorobenzeneboronic acid, 1.63 g (7.63 mmol) of (2-bromobenzyl) dimethylamine and 2.57 g (24.2 mmol) of sodium carbonate prepared according to Example 1 (Step 2) were toluene. Dissolve in a mixture of 50 ml, 20 ml of water and 10 ml of ethanol. 172 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[132] For workup, 80 ml of ether is added and the mixture is extracted three times with 80 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.73 g (104% of theory) of the crude base are obtained and introduced into a column (3 x 25 cm) packed with silica gel. Elution with 1: 3 (v: v) ether / n-hexane gave 0.13 g of base, from which 0.10 g of (2'-fluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 184 ° C (4.7% of theory) is obtained according to example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[133] Example 7
[134] (3'-fluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[135] 1.03 g (7.39 mmol) of 3-fluorobenzeneboronic acid, 1.05 g (4.93 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (step 2) and 2.61 g (24.6 mmol) of sodium carbonate were toluene Dissolve in a mixture of 50 ml, 20 ml of water and 10 ml of ethanol. 175 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[136] For workup, 80 ml of ether is added and the mixture is extracted three times with 80 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.38 g (122% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.57 g of base, from which 0.53 g of (3'-fluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 183 ° C (41.9% of theory) is obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[137] Example 8
[138] (4'-fluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[139] Toluene 1.00 g (7.15 mmol) of 4-fluorobenzeneboronic acid, 1.02 g (4.76 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (step 2) and 2.52 g (23.8 mmol) of sodium carbonate Dissolve in a mixture of 50 ml, 20 ml of water and 10 ml of ethanol. 170 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[140] For workup, 80 ml of ether is added and the mixture is extracted three times with 80 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.21 g (111% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.56 g of base, from which 0.56 g of (4'-fluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 222 ° C. (44.0% of theory) is obtained according to example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[141] Example 9
[142] (3'-Chloro-4'-fluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[143] 1.12 g (6.41 mmol) of 3-chloro-4-fluorobenzeneboronic acid, 1.44 g (6.73 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (step 2) and 2.26 g (21.4) of sodium carbonate mmol) is dissolved in a mixture of 44 ml of toluene, 18 ml of water and 9 ml of ethanol. 151 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[144] For workup, 70 ml of ether is added and the mixture is extracted three times with 70 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.66 g (98.2% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 1 (v: v) ether / n-hexane gave 0.66 g of base, which was purified by HPLC. Separation conditions: mobile phase acetonitrile / water [80:20 (v / v) + 0.5 vol.% Isopropylamine], flow rate 10 ml / min, wavelength 254 nm, column eurogel PRP 100 (Knauer, 250 x 4.6 mm) , There is a preliminary column). 0.37 g of crude base was obtained from which 0.34 g of (3'-chloro-4'-fluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 205 DEG C (17.6% of theory) was 2-butanone. Obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in water.
[145] Example 10
[146] (3'-methoxybiphenyl-2-ylethyl) dimethylamine hydrochloride
[147] Stage 1
[148] 2- (2-Bromo-phenyl) -ethylamine
[149] 10.0 g (51.0 mmol) of 2-bromophenylacetonitrile are dissolved in 80 ml of ether, and the solution is added dropwise to 5.81 g (153 mol) of lithium aluminum hydride in 230 ml of ether. The mixture is heated under reflux with stirring for 3 hours, cooled, and then slowly added dropwise with 80 ml of potassium hydroxide solution (10% by weight) with vigorous stirring. After stirring overnight, the supernatant was decanted and the residue washed twice with 100 ml of ether each time, then the combined organic phases were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator (500-10 mbar). 9.48 g (93% of theory) of 2- (2-bromo-phenyl) -ethylamine are obtained in this way.
[150] Tier 2
[151] [2- (2-bromophenyl) ethyl] dimethylamine
[152] 9.42 g (47.3 mmol) of 2- (2-bromophenyl) ethylamine are dissolved in 18 mL (473 mmol) of formic acid and 36 mL (473 mmol) of formaldehyde solution (36% by weight in water), and the solution is stirred at 95 ° C for 6 hours. Heat under reflux with stirring for a while. The solution is then cooled to 0 ° C. in an ice bath and 61 g (50% by weight) of cold potassium hydroxide solution are added. The mixture is extracted three times with 40 ml of ether each time at 25 ° C., the organic phases are combined, a small amount of activated carbon is added, the mixture is dried over anhydrous magnesium sulfate and filtered, and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 11.3 g (105% of theory) of slightly contaminated [2- (2-bromophenyl) ethyl] dimethylamine are obtained in this way.
[153] Tier 3
[154] (3'-methoxybiphenyl-2-ylethyl) dimethylamine hydrochloride
[155] 2.0 g (13.2 mmol) of 4-methoxybenzeneboronic acid prepared according to Example 1 (Step 1), 3.15 g (13.8 mmol) of [2- (2-bromophenyl) ethyl] dimethylamine obtained from Step 1 And 4.66 g (43.8 mmol) of sodium carbonate are dissolved in a mixture of 90 ml of toluene, 36 ml of water and 18 ml of ethanol. 312 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[156] For workup, 150 ml of ether is added and the mixture is extracted three times with 150 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 50 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 3.52 g (104% of theory) of the crude base are added and introduced into a column filled with silica gel (4.5 x 33 cm). Elution with 1: 1 (v: v) ether / n-hexane gives 2.24 g of base, which is purified by HPLC. Separation conditions: mobile phase acetonitrile / water [70:30 (v / v) + 0.05 vol. Isopropylamine], flow rate 10 ml / min, wavelength 254 nm, column eurogel PRP 100 (manufacturer: Knauer, 250 x 16 mm , There is a preliminary column). 0.96 g of crude base was obtained from which 0.65 g (3'-methoxybiphenyl-2-ylethyl) dimethylamine hydrochloride having a melting point of 143 DEG C (17.3% of theory) was added to chlorotrimethylsilane in 2-butanone. Obtained according to Example 1 (step 3) using / water.
[157] Example 11
[158] Dimethyl- [2- (2-methylbenzofuran-4-yl) benzyl] amine hydrochloride
[159] Stage 1
[160] 2- (dimethylaminomethyl) benzeneboronic acid
[161] 23.3 g (109 mmol) of (2-bromobenzyl) dimethylamine prepared in Example 1 (Step 2) were dissolved in 400 ml of tetrahydrofuran, and the solution was cooled to -70 DEG C in a cooling bath (ethanol / dry ice). Let's do it. 78 ml (125 mmol) of a butyllithium solution (1.6 M in hexane) are added dropwise under nitrogen in such a way that the temperature does not exceed −65 ° C. After stirring the mixture at −70 ° C. for 1.5 hours, 37 ml of trimethyl borate is added dropwise in such a way that the temperature does not exceed −60 ° C. After stirring for another 1 hour, the mixture is warmed to 25 ° C. for 2 hours, 350 ml of hydrochloric acid (1M) is added and the mixture is stirred at 25 ° C. for 15 hours.
[162] For workup, the mixture was neutralized with 10 ml of sodium hydroxide solution (32% by weight), made alkaline (pH approximately 9) with 3.5 g of sodium carbonate, then extracted three times with 150 ml of ether each time and the organic phases combined After drying over anhydrous magnesium sulfate and filtration, the filtrate is concentrated in a rotary evaporator (500-10 mbar). 9.29 g (47.7% of theory) of 2- (dimethylaminomethyl) benzeneboronic acid are obtained in this manner.
[163] Tier 2
[164] Dimethyl- [2- (2-methylbenzofuran-4-yl) benzyl] amine hydrochloride
[165] 1.00 g (5.59 mmol) of 2- (dimethylaminomethyl) benzeneboronic acid obtained from step 1, 1.24 g (5.86 mmol) of 4-bromo-2-methylbenzofuran and 1.97 g (18.6 mmol) of sodium carbonate were added to 38 ml of toluene. , 15 ml of water and 8 ml of ethanol. 132 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[166] For workup, 75 ml of ether is added and the mixture is extracted three times with 75 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.75 g (124% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.78 g of base from which dimethyl- [2- (2-methylbenzofuran-4-yl) benzyl] amine having a melting point of 217 ° C. 0.64 g (39.5% of theory) of hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[167] Example 12
[168] 2'-dimethylaminomethylbiphenyl-2-carbaldehyde hydrochloride
[169] 1.20 g (7.97 mmol) of 4-formylbenzeneboronic acid, 1.63 g (7.59 mmol) of 2- (bromobenzyl) dimethylamine and 2.68 g (25.3 mmol) of sodium carbonate prepared according to Example 1 (Step 2) Dissolve in a mixture of ml, 21 ml of water and 10 ml of ethanol. 180 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[170] For workup, 85 ml of ether is added and the mixture is extracted three times with 85 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.87 g (98.2% of theory) of the crude base are obtained. The base was dissolved in 50 ml of ether, the solution was extracted three times with 25 ml (5 wt.%) Of hydrochloric acid each time, then the combined acid phases were washed with 10 ml of ether, and 15 ml of sodium hydroxide solution (32 wt.%) Was used. It is made alkaline (pH approximately 11). The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.28 g (70.3% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 1 (v: v) ether / n-hexane gave 0.42 g of base, from which 0.43 g of 2'-dimethylaminomethylbiphenyl-2-carbaldehyde hydrochloride having a melting point of 230 ° C. 20.5%) is obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[171] Example 13
[172] (3'-difluoromethylbiphenyl-2-ylmethyl) dimethylamine hydrochloride
[173] 0.98 g (5.46 mmol) of 2- (dimethylaminomethyl) benzeneboronic acid prepared according to Example 11 (step 1), 1.19 g (5.73 mmol) of 1-bromo-3-difluoromethylbenzene, and 1.93 g of sodium carbonate (18.2 mmol) is dissolved in a mixture of 37 ml toluene, 15 ml water and 8 ml ethanol. 130 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[174] For workup, 60 ml of ether is added and the mixture is extracted three times with 60 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.46 g (103% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.79 g of base from which (3'-difluoromethylbiphenyl-2-ylmethyl) dimethylamine hydro having a melting point of 147 ° C. 0.67 g (40.9% of theory) of chloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[175] Example 14
[176] 2'-dimethylaminomethylbiphenyl-3-carbaldehyde hydrochloride
[177] 1.03 g (6.89 mmol) of 3-formylbenzeneboronic acid, 1.40 g (6.56 mmol) of 2- (bromobenzyl) dimethylamine prepared according to Example 1 (Step 2), and 2.32 g (21.8 mmol) of sodium carbonate were added to toluene 45. Dissolve in a mixture of ml, 18 ml of water and 9 ml of ethanol. 156 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[178] For workup, 75 ml of ether is added and the mixture is extracted three times with 75 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.66 g (100% of theory) of the crude base are obtained. The base was dissolved in 50 ml of ether, the solution was extracted three times with 25 ml (5 wt.%) Of hydrochloric acid each time, then the combined acid phases were washed with 10 ml of ether, and 15 ml (32 wt.%) Of sodium hydroxide solution was used. It is made alkaline (pH approximately 11). The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.08 g (68.7% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.40 g of base, from which 0.31 g of 2'-dimethylaminomethylbiphenyl-3-carbaldehyde hydrochloride having a melting point of 185 ° C (theoretical value) 17.3%) are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[179] Example 15
[180] Biphenyl-2-ylmethyldimethylamine hydrochloride
[181] 1.01 g (8.30 mmol) of benzeneboronic acid, 1.69 g (7.90 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (Step 2), and 2.79 g (26.3 mmol) of sodium carbonate, 54 ml of toluene, water Dissolve in a mixture of 22 ml and 11 ml ethanol. 187 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[182] For workup, 90 ml of ether is added and the mixture is extracted three times with 90 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.64 g (93.3% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.26 g of base, from which 0.28 g of biphenyl-2-ylmethyldimethylamine hydrochloride having a melting point of 189 ° C. (14.2% of theory) Is obtained according to example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[183] Example 16
[184] (3 ', 4'-dichlorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[185] 1.01 g (5.29 mmol) of 3,4-dichlorobenzeneboronic acid, 1.19 g (5.56 mmol) of 2- (bromobenzyl) dimethylamine prepared according to Example 1 (Step 2), and 1.87 g (17.6 mmol) of sodium carbonate It is dissolved in a mixture of 36 ml of toluene, 15 ml of water and 7 ml of ethanol. 125 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[186] For workup, 60 ml of ether is added and the mixture is extracted three times with 60 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.43 g (96.5% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 25 cm). Elution with 1: 3 (v: v) ether / n-hexane yields 0.52 g of base and is separated by HPLC for further purification. Separation conditions: mobile phase acetonitrile / water [90:10 (v / v) + 0.05 vol.% Isopropylamine], flow rate 10 ml / min, wavelength 254 nm, column eurogel PRP 100 (Knauer, 250 x 16 mm) , There is a preliminary column). 0.20 g of crude base was obtained from which 0.19 g (11.4% of theory) of (3 ', 4'-dichlorobiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 219 DEG C was dissolved in 2-butanone. Obtained according to Example 1 (step 3) using chlorotrimethylsilane / water.
[187] Example 17
[188] (3 ', 5'-dichlorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[189] 0.89 g (4.66 mmol) of 3,5-dichlorobenzeneboronic acid, 0.95 g (4.44 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (step 2), and 1.57 g (14.8 mmol) of sodium carbonate were prepared. It is dissolved in a mixture of 30 ml of toluene, 12 ml of water and 6 ml of ethanol. 106 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[190] For workup, 50 ml of ether is added and the mixture is extracted three times with 50 ml of potassium hydroxide solution (0.5 M) each time. The combined aqueous solution is reextracted with 20 ml of ether, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.25 g (95.5% of theory) of the crude base are obtained. The base was dissolved in 50 ml of ether, the solution was extracted three times with 25 ml (5 wt.%) Of hydrochloric acid each time, then the combined acid phases were washed with 10 ml of ether, and 15 ml of sodium hydroxide solution (32 wt.%) Was used. It is made alkaline (pH approximately 11). The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 0.46 g (37.3% of theory) of crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.23 g of base, from which the (3 ', 5'-dichlorobiphenyl-2-ylmethyl) dimethylamine hydro having a melting point of 198 ° C. 0.20 g (14.9% of theory) of chloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[191] Example 18
[192] Dimethyl- (4'-nitro-3'-trifluoromethylbiphenyl-2-ylmethyl) amine hydrochloride
[193] Stage 1
[194] Dimethyl 2- (dimethylaminomethyl) benzeneboronate
[195] 20.2 g (94.2 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (Step 2) were dissolved in 350 ml of tetrahydrofuran, and the solution was -70 ° C in a cooling bath (isopropanol / dry ice). Cool to 68 ml (108 mmol) of a butyllithium solution (1.6 M in hexane) are added dropwise under nitrogen in such a way that the temperature does not exceed −60 ° C. After stirring the mixture for 2 h at −70 ° C., 32 ml (282 mmol) of trimethyl borate are also added dropwise in such a way that the temperature does not exceed −60 ° C. The mixture is warmed to 25 ° C. for 15 h and the solution is concentrated in a rotary evaporator (500-10 mbar) without supply of heat. The residue is dissolved in 200 ml of n-hexane, the mixture is stirred for 1 hour, then filtered on an inert gas frit under nitrogen and the filtrate is concentrated on a rotary evaporator (500-10 mbar) without supply of heat. 12.0 g (61.5% of theory) of dimethyl 2- (dimethylaminomethyl) benzeneborate are obtained in this manner.
[196] Tier 2
[197] Dimethyl- (4'-nitro-3'-trifluoromethylbiphenyl-2-ylmethyl) amine hydrochloride
[198] 1.84 g (8.89 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate prepared according to step 1, 1.20 g (4.44 mmol) of 5-bromo-2-nitrobenzotrifluoride and 1.57 g (14.8 mmol) of sodium carbonate ) Is dissolved in a mixture of 30 ml of toluene, 12 ml of water and 6 ml of ethanol. 105 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[199] For workup, 45 ml of ether is added and the mixture is washed three times with 45 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 17 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 10 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.29 g (89.4% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1:10 (v: v) ether / n-hexane gave 1.05 g of base, from which dimethyl- (4'-nitro-3'-trifluoromethylbiphenyl-2 having a melting point of 240 ° C was obtained. 1.02 g (66.1% of theory) of -ylmethyl) amine hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[200] Example 19
[201] (3 ', 4'-difluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[202] 1.01 g (4.87 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 1.88 g (9.75 mmol) of 3,4-difluorobromobenzene, and 1.72 g of sodium carbonate prepared according to Example 18 (Step 1) 16.2 mmol) is dissolved in a mixture of 33 ml of toluene, 13 ml of water and 7 ml of ethanol. 116 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[203] For workup, 55 ml of ether is added and the mixture is washed three times with 55 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 22 ml (5% by weight) hydrochloric acid each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 13 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 0.67 g (55.3% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1:10 (v: v) ether / n-hexane gave 0.47 g of base from which (3 ', 4'-difluorobiphenyl-2-ylmethyl) dimethylamine with a melting point of 222 ° C. 0.52 g (37.6% of theory) of hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[204] Example 20
[205] (4'-fluoro-3'-trifluoromethylbiphenyl-2-ylmethyl) dimethylamine hydrochloride
[206] 1.02 g (4.91 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 2.38 g (9.81 mmol) of 5-bromo-2-fluorobenzotrifluoride prepared according to Example 18 (step 1), and 1.73 g (16.3 mmol) of sodium carbonate are dissolved in a mixture of 34 ml of toluene, 14 ml of water and 7 ml of ethanol. 117 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[207] For workup, 55 ml of ether is added and the mixture is washed three times with 55 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 22 ml (5% by weight) hydrochloric acid each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 13 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 0.55 g (37.5% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1:10 (v: v) ether / n-hexane gave 0.39 g of base from which 4'-fluoro-3'-trifluoromethylbiphenyl-2-yl having a melting point of 180 ° C. 0.37 g (22.8% of theory) of methyl) dimethylamine hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[208] Example 21
[209] (4'-Chloro-3'-methoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride
[210] 1.52 g (4.87 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 1.08 g (4.88 mmol) of 5-bromo-2-chloromethoxybenzene and 1.72 of sodium carbonate prepared according to Example 18 (Step 1) g (16.3 mmol) is dissolved in a mixture of 33 ml toluene, 13 ml water and 7 ml ethanol. 116 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[211] For workup, 55 ml of ether is added and the mixture is washed three times with 55 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 22 ml (5% by weight) hydrochloric acid each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 13 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.26 g (93.3% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Eluting with 1:20 (v: v) ether / n-hexane to afford 0.44 g of base from which (4'-chloro-3'-methoxybiphenyl-2-ylmethyl) dimethyl having a melting point of 218 ° C. 0.46 g (29.9% of theory) of amine hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[212] Example 22
[213] N- (2'-dimethylaminomethyl-3-trifluoromethoxybiphenyl-4-yl) acetamide hydrochloride
[214] 1.55 g (7.48 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate and 1.49 g (4.99 mmol) of 4-bromo-2- (trifluoromethoxy) acetanilide prepared according to Example 18 (Step 1) ) And 1.76 g (16.6 mmol) of sodium carbonate are dissolved in a mixture of 34 ml of toluene, 14 ml of water and 7 ml of ethanol. 118 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[215] For workup, 55 ml of ether is added and the mixture is washed three times with 55 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 22 ml (5% by weight) hydrochloric acid each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 13 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.72 g (97.6% of theory) of crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1:10 (v: v) ether / n-hexane affords 0.91 g of base. From 0.40 g of the base, 0.39 g (45.5% of theory) of N- (2'-dimethylaminomethyl-3-trifluoromethoxybiphenyl-4-yl) acetamide hydrochloride having a melting point of 182 占 폚 is 2-butanone. Obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in water.
[216] Example 23
[217] (3'-isopropoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride
[218] 1.51 g (7.31 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 1.05 g (4.87 mmol) of 1-bromo-3-isopropoxybenzene, and 1.72 of sodium carbonate prepared according to Example 18 (Step 1) g (16.2 mmol) is dissolved in a mixture of 33 ml of toluene, 13 ml of water and 7 ml of ethanol. 116 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[219] For workup, 55 ml of ether is added and the mixture is washed three times with 55 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 22 ml (5% by weight) hydrochloric acid each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 13 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.25 g (94.8% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1:10 (v: v) ether / n-hexane gave 0.65 g of base from which N- (2'-dimethylaminomethyl-3-trifluoromethoxybiphenyl-4-yl) acetate 0.36 g (24.0% of theory) of amide hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[220] Example 24
[221] 2 '-(2-dimethylaminoethyl) biphenyl-3-ol hydrochloride
[222] 0.89 g (3.49 mmol) of a base of (3'-methoxybiphenyl-2-ylethyl) dimethylamine hydrochloride (10) prepared according to Example 10 (step 2) was added to a hydrobromide solution (48% by weight in water) 89 Heat with reflux (bath temperature: 145 ° C.) for 2 hours.
[223] For workup, the mixture is poured into 1000 ml of sodium bicarbonate solution (1 M) (pH: 7-8), extracted four times with 100 ml of ether each time, the combined organic extracts are dried over anhydrous magnesium sulfate and filtered, Is concentrated in a rotary evaporator (500-10 mbar). 0.32 g (38.5% of theory) of crude base were obtained from which 0.26 g (27.9% of theory) of 2 '-(2-dimethylaminoethyl) biphenyl-3-ol hydrochloride having a melting point of 161 占 폚 was obtained. Obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in butanone.
[224] Example 25
[225] 4-chloro-2'-dimethylaminomethylbiphenyl-3-ol hydrochloride
[226] 0.59 g (2.15 mmol) of a base of (4'-chloro-3'-methoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride (21) prepared according to Example 21 was dissolved in a bromide solution (48% by weight in water) Heat with reflux (bath temperature: 145 ° C.) with 60 ml for 2 hours.
[227] For workup, the mixture was poured into 140 ml of water, the pH was adjusted to 7-8 by addition of sodium bicarbonate solid, then extracted three times with 50 ml of ether each time, the combined organic extracts were dried over anhydrous magnesium sulfate and filtered, The filtrate is concentrated in a rotary evaporator (500-10 mbar). 0.55 g (98.1% of theory) of the crude base were obtained, from which 0.56 g (88.0% of theory) of 4-chloro-2'-dimethylaminomethylbiphenyl-3-ol hydrochloride having a melting point of 194 占 폚 was obtained. Obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in butanone.
[228] Example 26
[229] [2- (1H-indol-5-yl) benzyl] dimethylamine
[230] 4.77 g (23.0 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 3.01 g (15.4 mmol) of 5-bromoindole and 5.42 g (51.1 mmol) of sodium carbonate prepared according to Example 18 (Step 1) were prepared. Dissolve in a mixture of 105 ml toluene, 42 ml water and 21 ml ethanol. 364 mg of tetrakis (triphenylphosphine) palladium (0) are added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[231] For workup, 100 ml of ether is added and the mixture is washed three times with 100 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 45 mL of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 20 mL of ether and then alkaline (pH approximately 12) using 25 mL of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 45 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 2.23 g (58.1% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1: 1 (v: v) ether / n-hexane yields 0.33 g (37.6% of theory) of [2- (1H-indol-5-yl) benzyl] dimethylamine.
[232] Example 27
[233] (4'-methanesulfonylbiphenyl-2-ylmethyl) dimethylamine hydrochloride
[234] 1.59 g (7.69 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 1.21 g (5.13 mmol) of 4-bromophenyl methyl sulfone and 1.81 g (17.1 mmol) prepared according to Example 18 (step 1) ) Is dissolved in a mixture of 35 ml of toluene, 14 ml of water and 7 ml of ethanol. 122 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[235] For workup, 55 ml of ether is added and the mixture is washed three times with 55 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 22 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 13 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 0.67 g (55.3% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1: 1 (v: v) ether / n-hexane gave 0.65 g of base, from which the (4'-methanesulfonylbiphenyl-2-ylmethyl) dimethylamine hydrochloride 0.62 had a melting point of 173 ° C. g (37.2% of theory) is obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[236] Example 28
[237] (2 ', 4'-dichlorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[238] 1.69 g (8.17 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 1.23 g (5.44 mmol) of 2,4-dichlorobenzene bromide and 1.92 g (18.1 mmol) prepared according to Example 18 (step 1) ) Is dissolved in a mixture of 37 ml toluene, 15 ml water and 8 ml ethanol. 129 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[239] For workup, 60 ml of ether is added and the mixture is washed three times with 60 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 24 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 14 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 0.62 g (40.3% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.39 g of base from which (2 ', 4'-dichlorobiphenyl-2-ylmethyl) dimethyl having a melting point of 170 to 171 ° C. 0.25 g (15.2% of theory) of amine hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[240] Example 29
[241] (2 ', 3'-difluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[242] 1.97 g (9.53 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 1.23 g (6.35 mmol) of 2,3-difluorobenzene bromide and 2.24 g of sodium carbonate prepared according to Example 18 (Step 1) 21.2 mmol) is dissolved in a mixture of 43 ml of toluene, 17 ml of water and 9 ml of ethanol. 151 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[243] For workup, 70 ml of ether is added and the mixture is washed three times with 70 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 27 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 16 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 30 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 0.99 g (63.2% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.61 g of base from which (2 ', 3'-difluorobiphenyl-2-ylmethyl) dimethylamine having a melting point of 214 ° C. 0.55 g (34.3% of theory) of hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[244] Example 30
[245] (2 ', 5'-difluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[246] 1.86 g (8.98 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 1.16 g (5.99 mmol) of 2,5-difluorobenzene bromide and 2.11 g of sodium carbonate prepared according to Example 18 (step 1) 19.9 mmol) is dissolved in a mixture of 41 mL toluene, 17 mL water and 8 mL ethanol. 142 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[247] For workup, 65 ml of ether is added and the mixture is washed three times with 65 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 26 mL of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 mL of ether and then alkaline (pH approximately 12) using 15 mL of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 0.66 g (44.4% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 0.40 g of base from which (2 ', 5'-difluorobiphenyl-2-ylmethyl) dimethylamine having a melting point of 165 占 폚. 0.36 g (23.4% of theory) of hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[248] Example 31
[249] (2-benzo [1,3] dioxol-5-ylbenzyl) dimethylamine hydrochloride
[250] 1.71 g (8.24 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate prepared according to Example 18 (step 1), 1.10 g (5.49 mmol) of 4-bromo-1,2- (methylenedioxy) benzene ) And 1.94 g (18.3 mmol) of sodium carbonate are dissolved in a mixture of 38 ml of toluene, 15 ml of water and 8 ml of ethanol. 130 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[251] For workup, 55 ml of ether is added and the mixture is washed three times with 55 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 22 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 13 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.46 g (104% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 x 15 cm). Eluting with 1: 1 (v: v) ether / n-hexane to give 1.17 g of base from which (2-benzo [1,3] dioxol-5-ylbenzyl) dimethyl with a melting point of 181 ° C.) 1.20 g (74.8% of theory) of amine hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[252] Example 32
[253] 1- [2 '-(2-dimethylaminoethyl) biphenyl-3-yl] ethanone hydrochloride
[254] 2.13 g (13.0 mol) of 3-acetylbenzeneboronic acid, 1.98 g (8.68 mmol) of [2- (2-bromophenyl) ethyl] dimethylamine prepared according to Example 10, and 3.06 g (28.9 mmol) of sodium carbonate were toluene Dissolve in a mixture of 60 ml, 23 ml water and 12 ml ethanol. 206 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[255] For workup, 90 ml of ether is added and the mixture is washed three times with 90 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 35 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 20 ml of ether and then alkaline (pH approximately 12) using 20 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 40 ml ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 2.08 g of crude base (89.5% of theory) were obtained from which 1.57 g of 1- [2 '-(2-dimethylaminoethyl) biphenyl-3-yl] ethanone hydrochloride having a melting point of 141 ° C was obtained. 59.6%) is obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[256] Example 33
[257] [2- (3 ', 4'-dimethoxybiphenyl-2-yl) ethyl] dimethylamine hydrochloride
[258] 2.22 g (12.2 mmol) of 3,4-dimethoxybenzeneboronic acid, 1.86 g (8.14 mmol) of [2- (2-bromophenyl) ethyl] dimethylamine prepared according to Example 10, and 2.87 g (27.1 mmol) of sodium carbonate ) Is dissolved in a mixture of 55 ml of toluene, 22 ml of water and 11 ml of ethanol. 193 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[259] For workup, 90 ml of ether is added and the mixture is washed three times with 90 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 35 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 20 ml of ether and then alkaline (pH approximately 12) using 20 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 35 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.82 g (78.0% of theory) of crude base were obtained from which 2.02 g of [2- (3 ', 4'-dimethoxybiphenyl-2-yl) ethyl] dimethylamine hydrochloride having a melting point of 179 ° C (theoretical value) 76.8%) is obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[260] Example 34
[261] [2- (3'-isopropoxybiphenyl-2-yl) ethyl] dimethylamine hydrochloride
[262] Stage 1
[263] Dimethyl 2- (2-dimethylaminoethyl) benzeneboronate
[264] 19.0 g (83.2 mmol) of [2- (2-bromophenyl) ethyl] dimethylamine prepared according to Example 10 (Step 2) was dissolved in 300 ml of tetrahydrofuran, and the solution was cooled in a isopropanol / dry ice. ) To -70 ° C. 60 ml (95.7 mmol) of a butyllithium solution (1.6 M in hexane) are added dropwise under nitrogen in such a way that the temperature does not exceed −60 ° C. After stirring the mixture for 2 h at −70 ° C., 28 ml (250 mmol) of trimethyl borate are also added dropwise in such a way that the temperature does not exceed −60 ° C. The mixture is warmed to 25 ° C. for 15 h and the solution is concentrated in a rotary evaporator (500-10 mbar) without supply of heat. The residue is dissolved in 200 ml of n-hexane, the mixture is stirred for 1 hour, then filtered on an inert gas frit under nitrogen and the filtrate is concentrated on a rotary evaporator (500-10 mbar) without supply of heat. 14.1 g (76.5% of theory) of dimethyl 2- (2-dimethylaminoethyl) benzeneboronate are obtained in this manner.
[265] Tier 2
[266] [2- (3'-isopropoxybiphenyl-2-yl) ethyl] dimethylamine hydrochloride
[267] From step 1, 1.20 g (5.43 mmol) of dimethyl 2- (dimethylaminoethyl) benzeneboronate, 1.75 g (8.14 mmol) of 3-bromoisopropoxybenzene and 1.92 g (18.1 mmol) of sodium carbonate were added to 37 ml of toluene, water Dissolve in a mixture of 15 mL and 8 mL of ethanol. 129 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[268] For workup, 60 ml of ether is added and the mixture is washed three times with 60 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 23 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 14 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate and filtered, and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.32 g (86.0% of theory) of crude base were obtained from which 1.11 g of [2- (3'-isopropoxybiphenyl-2-yl) ethyl] dimethylamine hydrochloride having a melting point of 164 ° C (63.9 of theory) was obtained. %) Is obtained according to example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[269] Example 35
[270] [2- (4'-Chloro-3'-methoxybiphenyl-2-yl) ethyl] dimethylamine hydrochloride
[271] 1.20 g (5.43 mmol) of dimethyl 2- (dimethylaminoethyl) benzeneboronate, 1.80 g (8.14 mmol) of 5-bromo-2-chloroanisole and 1.92 g of sodium carbonate prepared according to Example 34 (Step 1) (18.1 mmol) is dissolved in a mixture of 37 ml toluene, 15 ml water and 8 ml ethanol. 129 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[272] For workup, 60 ml of ether is added and the mixture is washed three times with 60 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 23 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 14 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.43 g (90.7% of theory) of crude base were obtained from which 1.34 g of [2- (4'-chloro-3'-methoxybiphenyl-2-yl) ethyl] dimethylamine hydrochloride having a melting point of 227 ° C was obtained. 75.6% of theory) are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[273] Example 36
[274] 4-chloro-2 '-(2-dimethylaminoethyl) biphenyl-3-ol hydrochloride
[275] 0.58 g (2.01 mmol) of a base of [2- (4'-chloro-3'-methoxybiphenyl-2-yl) ethyl] dimethylamine hydrochloride prepared according to Example 35 was added to a solution of hydrogen bromide (48% by weight in water). ) Under reflux (bath temperature: 145 ° C.) for 2 h with 58 ml.
[276] For workup, the mixture is poured into 700 ml of sodium bicarbonate solution (1 M) (pH: 7 to 8), extracted three times with 100 ml of ether each time, the combined organic extracts are dried over anhydrous magnesium sulfate and filtered, and the filtrate Is concentrated in a rotary evaporator (500-10 mbar). 0.54 g (98.0% of theory) of the crude base were obtained, from which 0.51 g of 4-chloro-2 '-(2-dimethylaminoethyl) biphenyl-3-ol hydrochloride having a melting point of 164 ° C (93.5% of theory) was obtained. ) Is obtained according to example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[277] Example 37
[278] Dimethyl- (3'-nitrobiphenyl-2-ylmethyl) amine hydrochloride
[279] 1.04 g (6.20 mmol) of 3'-nitrobenzeneboronic acid, 1.21 g (5.64 mmol) of (2-bromobenzyl) dimethylamine prepared according to Example 1 (Step 2), and 1.99 g (18.8 mmol) of sodium carbonate were toluene. Dissolve in a mixture of 40 ml, 16 ml water and 8 ml ethanol. 134 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[280] For workup, 65 ml of ether is added and the mixture is washed three times with 65 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 25 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 15 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 714 mg (49.3% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 × 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 330 mg of base, from which dimethyl- (3'-nitrobiphenyl-2-ylmethyl) amine hydrochloride with a melting point of 147 ° C. 262 Mg (15.9% of theory) is obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[281] Example 38
[282] 4-amino-2'-dimethylaminomethylbiphenyl-3-ol dihydrochloride
[283] 2.40 g (6.17 mmol) of a base of N- (2'-dimethylaminomethyl-3-trifluoromethoxybiphenyl-4-yl) acetamide hydrochloride (22) prepared according to Example 22 was dissolved in a hydrobromide solution ( Heated to reflux (bath temperature: 160 ° C.) with 110 ml of 33 wt% glacial acetic acid for 6 h.
[284] For workup, the mixture is poured into 1,000 ml of ether and the supernatant is decanted. The residue was dissolved in water, the solution was washed three times with 20 ml of ether each time, then the pH was 7-8 using sodium bicarbonate solution (1M), extracted three times with 40 ml of ether each time, the combined organic extracts Was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in a rotary evaporator (500-10 mbar). 1.94 g (130% of theory) of the crude base are obtained and introduced into a column (3 x 30 cm) filled with silica gel. Elution with 2: 1 (v: v) ether / n-hexane gave 178 mg of crude base, in addition to 1.72 g of an unchanged adduct, from which 4-amino-2'-dimethyl having a melting point of 120 ° C. 177 mg (7.5% of theory) of aminomethylbiphenyl-3-ol dihydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[285] Example 39
[286] (3 ', 5'-difluorobiphenyl-2-ylmethyl) dimethylamine hydrochloride
[287] 1.71 g (8.26 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 1.06 g (5.51 mmol) of bromo-3,5-difluorobenzene, and 1.94 of sodium carbonate prepared according to Example 18 (Step 1) g (18.3 mmol) is dissolved in a mixture of 38 ml toluene, 15 ml water and 7.5 ml ethanol. 131 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[288] For workup, 60 ml of ether is added and the mixture is washed three times with 60 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 24 mL of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 25 mL of ether and then alkaline (pH approximately 12) using 14 mL of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 25 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 1.19 g (87.6% of theory) of the crude base are obtained and introduced into a column filled with silica gel (3 × 25 cm). Elution with 1: 3 (v: v) ether / n-hexane gave 990 mg of base from which (3 ', 5'-difluorobiphenyl-2-ylmethyl) dimethylamine having a melting point of 190 ° C. 1.06 g (37.2% of theory) of hydrochloride are obtained according to Example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[289] Example 40
[290] (2 ', 5'-dimethoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride
[291] 1.61 g (7.79 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate prepared according to Example 18 (step 1), 1.13 g (5.20 mmol) of 2-bromo-1,4-dimethoxy-benzene, and 1.83 g (17.3 mmol) of sodium carbonate are dissolved in a mixture of 35 ml of toluene, 14 ml of water and 7 ml of ethanol. 123 mg of tetrakis (triphenylphosphine) palladium (0) are added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[292] For workup, 55 ml of ether is added and the mixture is washed three times with 55 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 22 ml of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 10 ml of ether and then alkaline (pH approximately 12) using 13 ml of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 20 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 770 mg (61.0% of theory) of crude base were obtained, from which 777 mg (49.7% of theory) of (2 ', 5'-dimethoxybiphenyl-2-ylmethyl) dimethylamine hydrochloride having a melting point of 169 ° C. Is obtained according to example 1 (step 3) using chlorotrimethylsilane / water in 2-butanone.
[293] Example 41
[294] 2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-ylamine dihydrochloride
[295] 6.24 g (30.1 mmol) of dimethyl 2- (dimethylaminomethyl) benzeneboronate, 5.14 g (20.1 mmol) of 2-bromo-4-trifluoromethoxy-phenylamine prepared according to Example 18 (step 1) And 7.09 g (66.9 mmol) of sodium carbonate are dissolved in a mixture of 140 ml of toluene, 55 ml of water and 27 ml of ethanol. 476 mg of tetrakis (triphenylphosphine) palladium (0) is added under nitrogen and the mixture is heated under reflux (bath temperature: 110 ° C.) for 16 h.
[296] For workup, 220 ml of ether is added and the mixture is washed three times with 220 ml of potassium hydroxide solution (0.5 M) each time. The organic solution was extracted three times with 90 mL of hydrochloric acid (5% by weight) each time, the combined acid phases were washed with 90 mL of ether and then alkaline (pH approximately 12) using 52 mL of sodium hydroxide solution (32% by weight). Make. The mixture is extracted three times with 90 ml of ether each time, the combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated on a rotary evaporator (500-10 mbar). 3.46 g (55.5% of theory) of the crude base are obtained and introduced into a column filled with silica gel (4 x 30 cm). Elution with 1: 1 (v: v) ether / n-hexane yields 1.73 g (27.8% of theory) of the base. According to Example 1 (step 3), 389 mg of 2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-ylamine dihydrochloride having a melting point of 125 DEG C from 316 mg of this base in 2-butanone Obtained with chlorotrimethylsilane / water.
[297] Example 42
[298] N- (2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-yl) acetamide hydrochloride
[299] 1.42 g (4.56 mmol) of a base of 2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-ylamine prepared according to Example 41 were mixed with 80 ml of a hydrogen bromide solution (33% by weight in glacial acetic acid). Together for 24 hours (bath temperature: 140 ° C.).
[300] For workup, the mixture is poured into 800 ml of ether and the supernatant is decanted. The residue was dissolved in water, the solution was washed three times with 50 ml of ether each time, then made alkaline (pH> 12) with potassium hydroxide solution (1M), extracted three times with 50 ml of ether each time, and the combined organic phases. Is dried over anhydrous magnesium sulfate and filtered, and the filtrate is concentrated in a rotary evaporator (500-10 mbar). 1.94 g (130% of theory) of the crude base are obtained and introduced into a column (3 x 30 cm) filled with silica gel. Elution with ether gives 940 mg (85.1% of theory). From 303 mg of the base, 274 mg of N- (2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-yl) acetamide hydrochloride having a melting point of 115 ° C. was obtained according to Example 1 (step 3). Obtained using chlorotrimethylsilane / water in butanone.
[301] Pharmacological research
[302] Torsional Test in Mice
[303] Analgesic activity was observed for phenylquinone induced writhing in mice (modified by I. C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237-240 (1959). Male NMRI mice weighing between 25 and 30 g are used for this. 10 minutes after intravenous administration of test substance to 10 animal groups per substance dose, 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen; 5% ethanol) was added as an intraperitoneal administration, and the water bath at 45 ° C. To prepare a solution) at 0.3 ml per mouse. Each animal is placed in an observation cage. The number of pain induced prolonged movements (so-called torsional response = correction of the body stretched from the limbs back) 5-20 minutes after administration of phenylquinone is measured by a push-button counter. Animals administered only physiological saline are also treated as controls. All materials are tested at a standard dose of 10 mg / kg. The percent inhibition (% inhibition) of the torsional reaction by the substance is calculated according to the following formula:
[304]
[305] For some substances, ED ₅₀ values with a 95% confidence range of torsion reactions are dose-dependent in torsional reactions compared to the phenylquinone control group studied in parallel by regression analysis (Martens EDV Service, Eckental's evaluation program). Calculate from the decrease.
[306] All compounds according to the invention investigated exhibit marked analgesic action. The results are summarized in the table below.
[307]
[308]

权利要求:
Claims (31)
[1" claim-type="Currently amended] Substituted 2-dialkylaminoalkylbiphenyl derivatives of formula (I) in the form of salts of bases and / or physiologically acceptable acids.
Formula I

In the above formula,
n is 1 or 2,
The radicals R ¹ , R ² and R ³ are the same or different and H, F, Cl, Br, CN, NO ₂ , CHO, SO ₂ CH ₃ , SO ₂ CF ₃ , OR ⁶ , NR ⁶ R ⁷ , C _{1 -6 represents an} alkyl, aryl, acetyl, acetamidyl or benzoyl radical, or an aryl radical bound via a C _1-6 alkylene group,
R ¹ and R ² together represent, in each case, a group OCH ₂ O, OCH ₂ CH ₂ O, CH═CHO, CH═C (CH ₃ ) O or CH═CHNH,
The radicals R ⁴ and R ⁵ are the same or different and represent H or a C _1-6 alkyl radical,
The radicals R ⁶ and R ⁷ are the same or different and represent an H, C _1-6 alkyl or aryl radical, or an aryl radical bonded via a C _1-6 alkylene group,
Provided that 2'-dimethylaminomethylbiphenyl-2-carbaldehyde, biphenyl-2-ylmethyldimethylamine, 2'-dimethylaminomethylbiphenyl-2-ol and the corresponding hydrochloride, (2 ', 3 '-Dimethoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride and hydrobromide, (4'-methylbiphenyl-2-ylmethyl) -dimethylamine, (2'-methylbiphenyl-2 -Ylmethyl) -dimethylamine, 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile, (2'-dimethylaminomethylbiphenyl-2-yl) methanol, 2'-dimethylaminomethylbiphenyl -2,3-diol and the corresponding hydrobromide, [2- (3 ', 4'-dimethoxybiphenyl-2-yl) ethyl] -dimethylamine and the corresponding hydrochloride, [2- (2' , 3'-dimethoxy-6'-methylbiphenyl-2-yl) ethyl] -dimethylamine and the corresponding hydrobromide, and biphenyl-2-ylethyldimethylamine are excluded.
[2" claim-type="Currently amended] ^2. Substituted ² according to claim 1, wherein the radicals R ¹ , R ² and / or R ³ represent C _1-3 alkyl radicals and other substituents, and n has the meaning as defined for Formula I -Dialkylaminoalkylbiphenyl derivatives.
[3" claim-type="Currently amended] 3. The radical of claim ¹ , wherein the radicals R ¹ , R ² and / or R ³ represent an aryl radical and other substituents bonded via a C _1-3 alkylene group, and n is as defined for Formula I Substituted 2-dialkylaminoalkylbiphenyl derivative, characterized by having a meaning.
[4" claim-type="Currently amended] The process according to claim 1, wherein the radicals R ⁴ and / or R ⁵ represent C _1-3 alkyl radicals and other substituents, and n has the meaning as defined for formula (I). Substituted 2-dialkylaminoalkylbiphenyl derivatives.
[5" claim-type="Currently amended] The process according to any of claims 1 to 4, characterized in that the radicals R ⁶ and / or R ⁷ represent C _1-3 alkyl radicals and other substituents and n has the meaning as defined for formula (I). Substituted 2-dialkylaminoalkylbiphenyl derivatives.
[6" claim-type="Currently amended] ^{6. The} radical according to claim 1, wherein the radicals R ⁶ and / or R ⁷ represent aryl radicals and other substituents bonded via a C _1-3 alkylene group, and n is as defined for formula (I). Substituted 2-dialkylaminoalkylbiphenyl derivative, characterized by the same meaning.
[7" claim-type="Currently amended] The method of claim 1,
(3'-methoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(4'-chlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
2'-dimethylaminomethylbiphenyl-3-ol and the corresponding hydrochloride,
(2'-methoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(3'-chlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(2'-fluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(3'-fluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(4'-fluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(3'-chloro-4'-fluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(3'-methoxybiphenyl-2-ylethyl) dimethylamine and the corresponding hydrochloride,
Dimethyl- [2- (2-methylbenzofuran-4-yl) benzyl] amine and the corresponding hydrochloride,
2'-dimethylaminomethylbiphenyl-2-carbaldehyde hydrochloride,
(3'-difluoromethylbiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
2'-dimethylaminomethylbiphenyl-3-carbaldehyde and the corresponding hydrochloride,
Biphenyl-2-ylmethyldimethylamine hydrochloride,
(3 ', 4'-dichlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(3 ', 5'-dichlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
Dimethyl- (4'-nitro-3'-trifluoromethylbiphenyl-2-ylmethyl) amine and the corresponding hydrochloride,
(3 ', 4'-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(4'-fluoro-3'-trifluoromethylbiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(4'-chloro-3'-methoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
N- (2'-dimethylaminomethyl-3-trifluoromethoxybiphenyl-4-yl) acetamide and the corresponding hydrochloride,
(3'-isopropoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
2 '-(2-dimethylaminoethyl) biphenyl-3-ol and the corresponding hydrochloride,
4-chloro-2'-dimethylaminomethylbiphenyl-3-ol and the corresponding hydrochloride,
[2- (1H-indol-5-yl) benzyl] dimethylamine and the corresponding hydrochloride,
(4'-methanesulfonylbiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(2 ', 4'-dichlorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(2 ', 3'-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(2 ', 5'-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(2-benzo [1,3] -dioxol-5-ylbenzyl) dimethylamine and the corresponding hydrochloride,
1- [2 '-(2-dimethylaminoethyl) biphenyl-3-yl] ethanone and the corresponding hydrochloride,
[2- (3'-isopropoxybiphenyl-2-yl) ethyl] dimethylamine and the corresponding hydrochloride,
[2- (4'-chloro-3'-methoxybiphenyl-2-yl) ethyl] dimethylamine and the corresponding hydrochloride,
4-chloro-2 '-(2-dimethylaminoethyl) biphenyl-3-ol and the corresponding hydrochloride,
Dimethyl- (3'-nitrobiphenyl-2-ylmethyl) amine and the corresponding hydrochloride,
4-amino-2'-dimethylaminomethylbiphenyl-3-ol and the corresponding dihydrochloride,
(3 ', 5'-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
(2 ', 5'-dimethoxybiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride,
2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-ylamine and the corresponding dihydrochloride,
Substituted 2-dialkylaminoalkylbiphenyl derivatives that are N- (2'-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-yl) acetamide and the corresponding hydrochloride.
[8" claim-type="Currently amended] Reducing the compound of formula II with a reducing agent in solution to afford the compound of formula III, which is purified and separated by conventional methods, or
Reacting a compound of formula III with aliphatic C _1-6 aldehyde in the presence of a reducing agent to afford a compound of formula IV, which is purified and isolated by conventional methods, or
The compound of formula IV is converted to a halogen-metal exchange reaction and then reacted with a boric acid ester at a temperature below 0 ° C. to yield a compound of formula V, which is isolated and purified by conventional methods or without further purification In the reaction stage of,
Reacting a compound of formula V with an aqueous acid to give a compound of formula VI, which is purified and separated by conventional methods, or
The compound of formula (V) or (VI) is reacted with a compound of formula (VII) by a transition metal catalysis reaction in a aliphatic ether, hydrocarbon, alcohol, chlorinated hydrocarbon, water or a mixture of these solvents at a temperature of 20 to 150 ° C. Obtained and purified and separated by conventional methods, or
The compound of formula (VIII) or (IX) is reacted with a compound of formula (III) or (IV) by a transition metal catalysis reaction at a temperature of 20 to 150 ° C. in an aliphatic ether, a hydrocarbon, an alcohol, a chlorinated hydrocarbon, water or a mixture of these solvents. A process for preparing a substituted 2-dimethylaminoalkylbiphenyl derivative of formula I according to any one of claims 1 to 7, characterized in that a compound is obtained, which is purified and separated in a conventional manner.
Formula I

Formula II

Formula III

Formula IV

Formula V

Formula VI

Formula VII

Formula VIII

Formula IX

In the above formula,
The radicals R ¹ to R ⁵ are as defined in claim 1,
X represents Cl, Br, I or OSO ₂ C _p F _{(2p + 1)} ,
Y represents Cl, Br or I,
m represents 0 or 1,
n represents 1 or 2,
R represents an alkyl radical.
[9" claim-type="Currently amended] 9. A method according to claim 8, characterized in that the compound of formula (II) is reduced with lithium aluminum hydride and / or diisobutylaluminum hydride.
[10" claim-type="Currently amended] 10. The process according to claim 8 or 9, wherein the compound of formula III is reacted with aliphatic C _1-6 aldehyde in the presence of formic acid and / or sodium borohydride.
[11" claim-type="Currently amended] The process according to any of claims 8 to 10, wherein the halogen-metal exchange reaction is carried out using magnesium and / or butyllithium.
[12" claim-type="Currently amended] The process according to claim 8, wherein the boric acid ester is a trialkyl borate, preferably trimethyl borate.
[13" claim-type="Currently amended] 13. A process according to any one of claims 8 to 12, wherein the compound of formula V is reacted with hydrochloric acid to give a compound of formula VI.
[14" claim-type="Currently amended] 14. Compounds of formula (V) or (VI) as palladium (0) compounds and / or palladium (II) salts, preferably tetrakis (triphenylphosphine) palladium, bis (Dibenzylideneacetone) palladium, elemental palladium on activated carbon, palladium chloride (II) and / or palladium (II).
[15" claim-type="Currently amended] 14. A compound according to any one of claims 8 to 13, wherein the compound of formula VIII or IX is reacted with a palladium (0) compound and / or a palladium (II) salt, preferably tetrakis (triphenylphosphine) palladium, And a reaction catalyzed by bis (dibenzylideneacetone) palladium, palladium element on activated carbon, palladium (II) chloride and / or palladium (II) acetate.
[16" claim-type="Currently amended] The process of claim 8, wherein the transition metal catalysis is 1,4-dioxane, tetrahydrofuran, toluene, hexane, ethanol, isopropanol, chloroform, methylene chloride, water or a mixture of these solvents. Characterized in that performed in the stomach.
[17" claim-type="Currently amended] As a pharmaceutically active compound, at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1, which is in the form of a salt of a base and / or a physiologically acceptable acid, optionally other active compounds and A medicament comprising an auxiliary substance.
[18" claim-type="Currently amended] The agent according to claim 17, for treating / inhibiting pain, inflammatory and allergic reactions, depression, drug and alcohol abuse, gastritis, diarrhea, incontinence, cardiovascular disease, respiratory system disease, cough, psychosis and / or epilepsy.
[19" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula (I) according to claim 1 in the form of a base and / or a physiologically acceptable salt, for the preparation of a medicament for inhibiting pain.
[20" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1 in the form of a base and / or a physiologically acceptable acid salt for the treatment of an inflammatory response.
[21" claim-type="Currently amended] Use of one or more substituted 2-dialkylaminoalkylbiphenyl derivatives of formula I according to claim 1 in the form of bases and / or physiologically acceptable salts for the preparation of a medicament for the treatment of allergic reactions. .
[22" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1 in the form of a base and / or a physiologically acceptable salt, for the preparation of a medicament for the treatment of depression.
[23" claim-type="Currently amended] One or more substituted 2-dialkylaminoalkylbiphenyls of formula I according to claim 1 in the form of salts of bases and / or physiologically acceptable acids for the preparation of drugs and / or drugs for the treatment of alcohol abuse. Use of derivatives.
[24" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1 in the form of a base and / or a physiologically acceptable acid salt for the preparation of a medicament for the treatment of gastritis.
[25" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1 in the form of a base and / or a physiologically acceptable salt, for the preparation of a medicament for the treatment of diarrhea.
[26" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula (I) according to claim 1 in the form of a base and / or a physiologically acceptable acid salt for the preparation of a medicament for the treatment of urinary incontinence.
[27" claim-type="Currently amended] Use of one or more substituted 2-dialkylaminoalkylbiphenyl derivatives of formula I according to claim 1 in the form of bases and / or physiologically acceptable salts for the preparation of a medicament for the treatment of cardiovascular diseases. .
[28" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1 in the form of a base and / or a physiologically acceptable acid salt for the preparation of a medicament for the treatment of respiratory diseases.
[29" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1 in the form of a base and / or a physiologically acceptable salt, for the preparation of a medicament for the treatment of cough.
[30" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1 in the form of a base and / or a physiologically acceptable acid salt for the preparation of a medicament for the treatment of psychosis.
[31" claim-type="Currently amended] Use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of formula I according to claim 1 in the form of a base and / or a physiologically acceptable acid salt for the preparation of a medicament for treating epilepsy.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-08-09|Priority to DE19937537A

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1999-08-09|Priority to DE19937537.2

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2000-07-25|Application filed by 파퀘스, 파우쓰-베르구스, 그뤼넨탈 게엠베하

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2002-03-23|Publication of KR20020022100A

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2007-06-04|Application granted

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2007-06-04|Publication of KR100723816B1

优先权:

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申请号 | 申请日 | 专利标题

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DE19937537A|DE19937537A1|1999-08-09|1999-08-09|Substituted 2-dialkylaminoalkylbiphenyl derivatives|

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DE19937537.2|1999-08-09|