TW200413327A - Novel process for the preparation of imidazolyl compounds - Google Patents

Abstract

The present invention relates to a method for the preparation of an imidazolyl compound of the general formula, wherein: Ra and Rb each separately are (C1-C6)alkyl, (C1-C6)alkoxyalkyl, optionally substituted aryl or heteroaryl; or wherein Ra and Rb together form a further homocyclic or heterocyclic system comprising one or more rings; Ra' and Rb' each are hydrogen or together form a carbon-carbon double bond, said carbon-carbon double bond optionally being part of an aromatic system; Rc is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxyalkyl or halogen; Rd is hydrogen or (C1-C4)alkyl; Re is hydrogen or (C1-C4)alkyl; m is 1 or 2; and R1 is hydrogen or (C1-C4)alkyl; as well as its acid addition salt; characterized in that a compound of the general formula, is reacted with a compound of the formula, wherein: R is a hydrogen, a (C1-C4)alkyl group optionally substituted with a hydroxygroup or an optionally substituted aryl group, R', R", R'" and R"" each individually are a hydrogen or a (C1-C4)alkyl group; followed by a reaction with a compound of the formula, wherein R1, Rd and Re have the meanings defined above; and optionally followed by a reaction with a suitable acid. De method according to the present invention is especially useful for the preparation of ondansetron and cilansetron.

Description

200413327 (ii) Description of the invention: TECHNICAL FIELD OF THE INVENTION The invention relates to a method for preparing an imidazolyl compound. [Prior art] EP191562 and US4,695,578 disclose 1,2,3,9-tetrahydro-9-methyl-3- [2-methyl-1H-imidazol-1-yl] fluorenyl] _4H-carb Azol-4-one (ondansetron). In these patent publications, a class of compounds including ondansetron and homologues, their preparation and their use as effective "neuronal" serotonin receptor selective antagonists are disclosed, as well as in therapeutic preference Applications in headaches and mental illness. EP-B-029765, EP-B-0601345 and EP-B-768309 disclose (10R) -5,6,9,10-tetrahydro-10-[(2-methyl_1H-imidazol-1- Yl) fluorenyl] -4H-pyrido [3,2, l-jk] -carbazole-11 (8H) -one (Siracetron, 15 (^ 1 & 11361 ^ 〇11) (also known as ( P-(-)-4,5,6,8,9,10_hexahydro-10-[(2-methyl-1H-imidazol-1-yl) methyl] -11H-pyrido [3,2 , L-jk] -carbazole-11-one). In the first patent publication, a class of compounds including silaztron and homologues, their preparation, and their use as serotonin antagonists were disclosed. The second patent publication discloses the selective use of these types of compounds in the treatment of certain diseases, while the third patent discloses the preparation of enantiomerically pure compounds and their hydrochloride monohydrates. The common feature of the above compounds is that they all contain a substituted imidazolyl group which is connected to the α-position of the 8 keto group of the carbazole system with a fluorenyl bridge. Several possibilities for these compounds are disclosed in the above patents A common feature of these synthesis methods is the Mannich reactioni on) The introduction of a substituted imidino group, and then through deamination, an intermediate methylene compound is produced which reacts with the substituted imidazolyl group (for example, see route 1). One disadvantage of this route is that the sequence reaction step The yield is quite low. In US 4,695,578, there is no description of the first step which is usually the lowest and the yield of the younger step (US 4,695,578, Example 7) is 68%. In EP_B_0297651, the first step (EP-B- The yield of Example 1lc) of 0297651 was 53%, and the yield of the second step (Ep. 297651 Example Id) was 87%. In scale-up experiments, it appears that this route resulted in the formation of a considerable amount of tar-like by-products. .

[Inner image of the invention] The object of the present invention is to provide an alternative for preparing imidazolyl compounds. 丨 Ezi operation, and meet one or more of the following: Yield of willow to linden, b) compared with the prior art method This method allows for a short reaction time of 200413327, c) fewer side reactions, d) higher quality of the final product, and e) the use of non-diluted reaction conditions and environmentally acceptable solvents. It has now surprisingly been found that such imidazolyl compounds can be easily prepared using substituted oxazolidine compounds to introduce 5 methylene bridges. Therefore, the present invention relates to a method for preparing an imidazolyl compound and an acid addition salt thereof,

fv ίο where:

Ra and Rb are each independently (CVC6) alkyl, (CrC6) alkoxyalkyl, optionally substituted aryl or heteroaryl;

Or where Ra and Rb together form a carbocyclic or heterocyclic system containing one or more rings; 15 Ra, and Rb, each is hydrogen or together form a carbon-carbon double bond, the carbon-carbon double bond is optionally Part of an aromatic system;

Rc is hydrogen, (CrC6) alkyl, (CrC6) alkoxy, (CrC6) alkoxyalkyl or element;

Rd is hydrogen or (CrC4) alkyl; 20 Re is hydrogen or (CrC4) alkyl; m is 1 or 2; and R! Is hydrogen or (CrC4) alkyl; 10 200413327 is characterized in that the general formula (II A compound of the formula (III) is reacted with a compound of formula (III), 0

(III) (II) 5 wherein: R is hydrogen, (CrC4) alkyl optionally substituted with hydroxy or optionally substituted aryl, and R ', R ", R'" and R "" are each independently hydrogen Or (CVQ) alkyl; then react with a compound of formula (IV),

10

(IV) wherein Ri, Rd and Re have the meanings defined above; and optionally then reacted with a suitable acid. The alkyl group of the present invention includes straight-chain, 15-branched and cyclic alkyl groups containing up to 6 carbon atoms. Suitable alkyl groups can be saturated or unsaturated. Furthermore, the alkyl group may be mono- or poly-substituted by a substituent selected from an aryl group, a prime group, an amino group substituted with a group, a cyano group, or a mono- or dialkyl group. The aryl group of the present invention includes an aryl group containing up to 6 heteroatoms. The aryl group may be optionally mono- or poly-substituted by a substituent selected from the group consisting of aryl, (CVC6) alkyl, halogen, hydroxy, cyano 20 or mono- or di-alkyl, and 11 200413327 which may also be substituted with aryl. Or cycloalkyl radicals are fused. Suitable aryl groups include, e.g., phenyl, naphthyl, tolyl, imidazolyl, iridinyl, iridyl, thienyl, amidinyl, glutenyl, and succinyl. A carbocyclic system refers to a system containing at least one saturated or unsaturated cyclic group containing only carbon atoms and hydrogen atoms.

A heterocyclic system refers to a system containing at least one saturated or unsaturated cyclic group that also contains one or more heteroatoms such as N, O or S. Both carbocyclic and heterocyclic systems are optionally substituted with a substituent selected from alkyl, aryl, cyano, halogen, hydroxy, or mono- or dialkyl-substituted amino. 10 In a preferred embodiment of the present invention, RC is hydrogen or (CVC6) alkyl, Rd is hydrogen or (CVC4) alkyl; Re is hydrogen or (CrQ) alkyl; Ri is hydrogen, fluorenyl, or ethyl base. The reaction of the present invention is particularly useful for preparing compounds of the following formulae,

m is 1 or 2;

Ri is hydrogen, methyl or ethyl; and R5 is (CrC4) alkyl; 20 R6 is hydrogen or (CrC4) alkyl, or R5 and R6 form a 5, 6, or 7-membered ring together with the intermediate atom, optionally 12 200413327 is substituted with one or two substituents selected from Li, via a group, (Ci-c4) alkyl, (Ci-C4) alkyloxy, and (C1-C4) alkyloxy. In the case where the starting compound is a compound of the following formula,

5 (Ila) This compound is also called a carbazolone compound. A preferred compound of the general formula la is a compound in which m = 1, and 115 and 116 together with the intermediate atom form a 6-membered ring, and a compound in which R5 is fluorenyl and R6 is hydrogen. For the first compound, 5,3,9,1,0-10 tetrahydro-4Η-σΛσ and [3,2, l-jk] 峻 Jun-ΐι (8Η) -one and 3_ 嗔 0 sit fire The yield of this method with ethanol as the starting material is 77% (see Example 2), while the overall yield of the method of EP0297651 is 46% (Examples Ic and id). Higher yields can be obtained on a production scale. Among substituted oxazolidines, it is preferred that one of R, and R ,, and one of R ,,, and R ,,,, β 15 is hydrogen, because the disubstituted noise on the same carbon atom is dazzling, For example, the burning of 4,4-difluorenyloxazole gives lower yields in the reaction. The preferred oxazolidines are 3-oxazolidine ethanol and 3-ethyloxazolidine. The most preferred oxazole is 3-umol. The reaction needs to be performed in an acidic medium, and the acidity depends on the activity of the system in which the reaction occurs. In the case of a carbazolone system, the medium should be highly acidic. In the latter case, examples of suitable acids are sulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and t &amp; HCl in an alcohol medium. To obtain a South yield, the reaction solution should contain only a small amount Water. The leech should preferably be lower than 0.6% (v / v), more preferably lower than 0.3% (V / V), and preferably lower than 0.1% (ν / ν). The optimal reaction temperature depends on the starting materials and solvent, and is different in the two reaction steps. The first step of the reaction can be from machine to cutting C. For the carbazole system, the preferred reaction temperature for the first step is 5 ° C to 90 ° C, and the most preferred reaction temperature is about the machine. The second step can generally be performed at 100 C to 140 c. For taste saliva _ System, the preferred reaction temperature for the second step is UGt: to 13G ° C, the most preferred reaction temperature is about 120 ° C. The reaction can be in different solvents, such as dipolar aprotic solvents (such as DMF ) Or alcohol. The preferred solvent is C ^ C7 alcohol and can be selected according to the desired reaction temperature. Examples of suitable alcohols are 1-butanol, 1-hexanol and isoamyl alcohol. Preferred alcohols Yes 丨 Butanol. Mixtures of aromatic hydrocarbons and alcohols, such as a mixture of toluene and alcohol, and a mixture of monochlorobenzene and alcohol are also suitable. The preferred mixture is a mixture of monohydric benzene and methanol. When solvent mixture In order to make the solvent system reach a higher reflux temperature in the second step of the reaction, the lower boiling point solvent can be distilled off before the second step of the reaction. The ratio of the volume of the solvent to the amount of the reactants in the mixture can be in a considerable range. Internal change 'and depends on the solubility of the reactants Generally, the ratio of the amount of the solvent to the amount of the reactant is usually about 1: 1 to 15: 1, where the ratio is expressed as the volume of the solvent relative to the weight of the reactant in the solvent 200413327. Preferably, the ratio is about 1 : 1 to about 10: 1. In the case of the oxazolidone system, the preferred ratio of the solvent volume to the weight of the reactant is about 4: 1 °. The product obtained can be crystallized from different solvents. An example of a solvent is an aromatic hydrocarbon, such as toluene. The hydrochloride can be crystallized, for example, from an alcohol solvent, such as isopropanol or 1-butanol. I: Embodiments The following examples are only used to further illustrate the present invention in detail, so they These examples should be considered to limit the scope of the invention in any way. 10 Example 1: Materials and Methods 5,6,9,10_ Tetrazol-4H-pyrene ratio bite [3,2,1 _jk] ϋ 卡萨_ 11 (8H) -pyridine was prepared according to EP0375045. 3,4-dihydro-1 (2Η) -naphthone was obtained from the market. 1,2,3,9_tetrahydromethyl-4Η_carbazolone Ketones are according to US 3,892,766 and Elz, S. and 15 Heil, W., Warner-Lambert Company, Bioorganic &amp; Medicinal Chemistry Letters 199 5, depleted, prepared from 667-672. Methanesulfonic acid was obtained from the market. NMR spectrum was measured on Varian VXR 200, MS spectrum was measured on Finnigan TSQ 7000. HPLC analysis was performed with Separations 757 detector (250 nm) and 35 ° C Separations Marathon XT column furnace on a 20 HP1050 system. The chromatographic column used was a ZorbaxXDB C8 column, 15x0.3 cm. The eluent was prepared by mixing 2 liters of water, 2 ml of triethylamine and 5 ml of 25% ammonia water, buffering it with formic acid to pH = 4, and adding 0.5 liters of acetonitrile. The flow rate is 1 ml / min. Example la: Preparation of oxazolidine 15 200413327 3-oxazolidine ethanol was prepared as follows: An equimolar amount of diethanolamine and paraformaldehyde in 1-butanol were heated to 70 ° C. After the reaction for 1 hour, the water formed was removed by azeotropic distillation with 1-butanol. 5 3-Ethyl σ-xanthine was prepared according to Heany, H. et al., Tetrahedron 1997, Hir., 14381-96. 4,4-Difluorenyloxazolidine is commercially available and is available as a 75% w / w aqueous solution. The 4,4-dimethyloxazolidine was extracted from the aqueous layer by washing the bar with dichloromethane / saturated NaCl solution. The 10 methylene chloride layer was dried over anhydrous sodium sulfate and then evaporated. Example 2. The reaction of 5,6,9,10-tetrahydro-4H-orthopyrene [3,2, l-jk] weitu-11 (8H) -one with 3_ ^ σ sitting ethanol 5,6,9,10-tetrahydro-4fluorene-pyrido [3,2, l-jk] carbazole-11 (8H) -one (25.00 g tri 111.0 mmol) in 1-butanol (100 ml) Ear) and 曱 15 sulfonic acid (17.06 g = 177.5 millimoles) were heated to 70 ° C. Within 3 minutes, a solution of 3-oxazolidine ethanol (19.49 g = 166.4 mmol) in 1-butanol (39 ml) was added. After 8 (50 minutes of TC reaction, 2-methylimidazole (45.55 g, 3,554.8 millimoles) and 1-butanol (10 ml) were added. After 1.5 hours at 120 ° C, the reaction mixture was partially evaporated until the remaining 30 ml of 1-20 butanol are added. At 70 ° C, 75 ml of toluene and 50 ml of water are added to the residue and the layers are separated. The aqueous layer is extracted with 75 ml of toluene. The combined toluene layers are washed three times with 100 ml of water. The organic layer was evaporated to dryness, and then 125 ml of 1-butanol was added. 16 12.5 ml of 36% m / m hydrochloric acid was added to the served solution. After stirring at room temperature for 2 hours, the formed solid was filtered, And washed with 1-butanol and MTBE. After drying, 30.40 g (77 · 0%) of 5,6,9,10 · tetrahydro · 10 _ [(2_methyl_1Η-imidazolyl) fluorenyl] -4Η-pyridine [3,2, l-jk] carbazole-11 (8H) -one hydrochloride (77.0%) HPLC: 95%. LH NMR [200 MHz, DMSO-d6: CDCl3 4: 1] δ 1.97 ( lH, m), 2.18 (3H, m), 2.68 (3H, s), 2.95 (2H, t), 3.00 (lH, dd), 3.12 (2H, m), 4.13 (2H, m), 4.29 (lH , Dd), 4.66 (lH, dd), 6.97 (lH, d), 7.09 (lH, t), 7.55 (lH, d), 7.68 (lH, d), and 7.71 (lH, d). MS [ESI] MH + = 320 Example 3. Reaction of 5,5,9,10_tetrahydro <4Η_σ than 唆 [3,2, l_jk] Weikou-11 (8H) · ketone and 4,4-dimethyloxazolidine Add 5,6,9,10-tetrahydro_4H_pyrido [3,2, l-jk] carbazole_ll (8H) _one (20.00 g ξ 88.8 mmol) in 1_butanol (60 ml) Mol) and mesylate S complex (13.65 142.0 mmol) were heated to 70 ° C. Within 2 minutes, 4,4-dimethyloxazole (13.47) was added in 1-butanol (10 ml) ge 133.2 mol). After reacting at 80 ° C for 50 minutes, 2-methylimidazole (36.45 g ξ 444.0 mmol) and butanol (10 ml) were added. After 2 hours of reaction at i2 ° C The reaction mixture was partially evaporated until 20 ml of 1-butanol remained. 60 ml of toluene and 40 ml of water were added to the residue at 70 ° C, and the layers were separated. The aqueous layer was extracted with 60 ml of toluene. The combined toluene layers were used with It was washed with 80 ml of water three times. The organic layer was evaporated to dryness, and then 100 ml of butanol was added. To the resulting solution was added 10.0 ml of 36% m / m hydrochloric acid. After stirring at room temperature 200413327 for 2 hours, the formed solid was filtered and washed with 1-butanol and MTBE. After drying, 12.38 g of 5,6,9,10-tetrahydrazone-lO-[(2-methyl-1H · mouth michon-1-yl) methyl] merging [3,2, l_jk] ° card Saliva-11 (8H) -one hydrochloride (39.2%). HPLC: 95%. B NMR and MS: see Example 2. 5 The mother liquor contains 3.45 g (10.9%) of the product. Example 4. The reaction of 5,6,9,10-tetrahydro-4H-pyrido [3,2, l_jk] carbazole-11 (8H) -one with 3-ethyloxazolidine 5,6,9,10_tetrahydro-4H_pyrido [3,2, l-jk] carbazole-11 (8H) _one (20.00 g three 88.8 mmol) in alcohol (60 ml) and Methanesulfonic acid (13.65 142.0 mmol) was heated to 70 ° C. Within 2 minutes, 3-ethylsigma-saliva (13.46 g = 133.2 mmol) was added in 1-butanol (10 ml). After reacting at 80 ° C for 50 minutes, 2-fluorenimidazole (36.45 g = 444.0 mmol) and 1-butanol (! 〇1111) were added. At 120. (: After 2 hours of reaction, the reaction mixture was partially evaporated until 20 ml of 1-butanol remained. 15 At 60 ° C, 60 ml of toluene and 40 ml of water were added to the residue, and the layers were separated. ml toluene extraction. The combined toluene layers were washed three times with 80 ml water. The organic layer was evaporated to dryness, followed by the addition of 100 ml 1-butanol. 10.0 ml 36% was added to the bath obtained. m / m hydrochloric acid. After stirring at room temperature for 2 hours, the formed solid was' filtered and washed with 1-butanol and MTBE. After drying, 22.10 g (70.0%) of 5,6,9,10-tetrahydro_ι was obtained. _ [(2-fluorenyl_1H_imidazole + yl) fluorenyl] -4fluorene-pyrido [3,2, l-jk] carbazole-11 (8H) -one hydrochloride (70 0%) HPLC: 95%. NMR and MS β. See Example 2. 18 Example 5. The reaction of 3,4-dihydro-i (2H) -naphthone with 3-oxazolidine ethanol will be in 1-butanol. (60ml) 3,4-dihydro-1 (2H) -naphthone (12.98 g tri 888.8 mmol) and methanesulfonic acid (13 65 g Ξ 14 2 0 mmol) 50 C. Add a solution of 3 嗤 scorched ethanol (15.59 g ξ 133.1) in 1-butanol (14 ml) in 2 minutes. At 80. (: 50 minutes of reaction 'Add 2 -Methylimidazole (36.45 g = 444.0 mmol) and 1-butanol (10 ml). After 12 (TC reaction for 2 hours, the reaction mixture was partially evaporated until 20 ml of 1-butanol remained. At 70 ° C 'Add 60 ml toluene and 40 ml water to the residue and separate the layers. The aqueous layer was extracted with 60 ml toluene. The combined toluene layer was washed three times with 80 ml water. The organic layer was evaporated to dryness and then 100 ml was added. 1-butanol. To the resulting solution was added 10.0 ml of 36% m / m hydrochloric acid. The resulting solution was evaporated to a final volume of 60 ml. After stirring at room temperature for 2 hours, the formed solid was filtered, and 1-butanol and Wash with MTBE. After drying, 15.28 g (62.2%) of 3,4-dihydro_2 _ [(2_fluorenyl_1H_imidazolyl) methyl] -1 (2H) -naphthone hydrochloride. HPLC: 95 %. lU NMR [200 MHz, DMSO-d6: CDCl3 4: 1] δ 2.00 (2H, m), 2.73 (3H, s), 3.20 (3H, m), 4.27 (lH, dd ), 4.68 (lH, dd), 7.35 (2H, t), 7.55 (2H, m), 7.70 (lH, d), and 7.90 (lH, d). MS [ESI] ΜΗ + = 241. The mother liquor contained 3.28 g (13.3%) of the product. Example 6. The reaction of 3,4-dihydro-1 (2H) -naphthalene) with 4,4-dimethylα. The reaction of 3,4-diamine in 1-butanol (60 ml) Hydrogen-l (2H) -naphthone (12.98 g ξ 88.8 mmol) and methanesulfonic acid (13.65 g ξ 142.0 mmol) were heated to 70 ° C with 200413327. 4, 'Dimethyloxazolidine (13.46 g ξ 133.1 mmol) in ι-butanol (iomi) was added over 2 minutes. After reacting at 80 ° C for 50 minutes, 2-methylimidal (36.45 g ξ 444.0 mmol) and i-butanol (10 ml) were added. After reacting at 120 ° C for 2 hours, the reaction mixture was partially evaporated until 5 ml of 1-butanol remained. 60 ml of toluene and 40 ml of water were added to the residue at 70 C ', and the layers were separated. The aqueous layer was extracted with 60 ml of toluene. The combined toluene layers were washed three times with 80 ml of water. The organic layer was evaporated to dryness and then 100 ml of butanol was added. 10 To the obtained> cereal solution was added 10.0 ml of 36% m / m hydrochloric acid. The resulting solution was evaporated to a final volume of 50 ml. After stirring at 0 ° C for 2 hours, the solid formed was filtered and washed with 1-butanol and MTBE. After drying, 14.13 g (57.5 / ^) of 3,4- qi-2 _ [(2 · fluorenyl _1H-weitu _1_yl) fluorenyl] _1 (2H) _naphthone hydrochloride was obtained. HPLC: 95% · 4 NMR and 15 MS: see Example 5. The mother liquor contained 2.33 g (9.5%) of the product. Example 7. Reaction of 3,4-dihydro-1 (2H) -naphthone with 3-ethyloxazolidine 3,4-dihydro_1 (2H in 1-butanol (60 ml) ) _Naphthone (12.98 g ξ 88.8 mmol) and sulfonic acid (13.65 g g 142.0 mmol) were heated to 50 ° C. Add 3-ethyloxa 20 oxazolidine (13.46 § Ξ 33.1 millimoles) in 1-butanol (10 ml) over 2 minutes. After 50 minutes of reaction at 80 ° C, 2-fluorenimidazole (36.45 g Ξ 444.0 mmol) and 1-butanol (10 ml) were added. After 2 hours of reaction at 120 C, the reaction mixture was partially evaporated until 20 ml of 1-butanol remained. At 70 ° C, 60 ml of toluene and 40 ml of water were added to the residue, and the layers were separated. The aqueous layer was extracted with 60 ml of toluene. The combined toluene layers were washed three times with 80 ml of water. The organic layer was evaporated to dryness, and then 100 ml of 1-butanol was added. To the resulting solution was added 10.0 ml of 36% m / m hydrochloric acid. The resulting solution was evaporated to a final volume of 50 mL. After stirring at 0 ° C for 2 hours, the formed solid was filtered and washed with 1-butanol and MTBE. After drying, 17.30 g of 3,4-dihydro-2-[(2-fluorenyl-1H-weisal-1-yl) fluorenyl] -1 (2H) -naphthone hydrochloride (70.4%) was obtained. HPLC: 95%. 4 NMR and MS: See Example 5. 10 Example 8. The reaction of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with 3-oxazole ethanol was performed in 1 · butanol (45 ml). 1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4_one (13.26 ge 66.5 mmol) and sulfonic acid (10.23 ge 106.4 mmol) were heated to 90 ° C. Over 2 minutes, 11.68 g (99.8 mmol) of 3-oxazolidine ethanol in 1-butanol 15 (11 ml) was added. After 50 minutes of reaction at 80 t, 2-methylimidazole (27.32 g = 332.5 mmol) and 1-butanol (8 ml) were added. After reacting at 120 ° C for 2 hours, at 80 ° C, 180 ml of toluene and 120 ml of water were added and the layers were separated. The aqueous layer was extracted with 180 ml of toluene and 60 ml-butanol. The combined organic layers were washed twice with 240 ml of water. 20 The organic layer was evaporated to dryness, and then 150 ml of 1-butanol and 10.0 ml of 36% m / m hydrochloric acid were added to the residue. Crystals soon appeared at 0 ° C. After 1 hour at 0 ° C, the formed crystals were filtered and washed with 1-butanol and MTBE. 15.39 g (70.1%) of 1,2,3,9-tetrahydro-9-fluorenyl-3-[(2-methyl-1H-imidazole_1-yl) fluorenyl] -4H-carbazole was obtained after drying -4-one hydrochloride. 21 HPLC: 95%. LU NMR [200 MHz? DMSO-d6: CDCl3 4: 1] δ 2.00 (lH, m), 2.20 (lH, m), 3.69 (3H, s), 3.09 (3H, m), 3.75 (3H, s), 4.30 (lH, dd), 4.67 (lH, dd), 7.23 (2H, m), 7.53 (2H, m), 7.69 (lH, d), 8.01 ( 1H, d). MS [ESI] MH + = 294. The mother liquor contains 3.19 g (14.5%) of the product. Example 9. The reaction of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with 4,4-dimethyloxazoline will be in 1-butanol (45 ml ), 1,2,3,9-tetrahydro-9-methyl-4H-carbazone_4-one (13.26 g ξ 66.5 mmol) and methoxanthinic acid (10.23 g ξ Ϊ06.4 mmol) Ear) to 90 ° C. Over 2 minutes, 4,4-dimethyloxazolidine (1.09 g = 99.9 millimoles) in 1-butanol (8 ml) was added. After reacting at 80 C for 50 minutes, 2-fluorimid sigma barrier (27.32 g Ξ 332.5 mmol) and 1-butanol (8 ml) were added. After reacting at 120 ° C for 2 hours, 1801111 toluene and 1201111 water were added at 80 ° C, and the layers were separated. The aqueous layer was extracted with 180 ml of toluene and 60 ml-butanol. The combined organic layers were washed twice with 240 ml of water. The organic layer was evaporated to dryness, and then 150 ml of 1-butanol and 1.0 ml of 36% m / m hydrochloric acid were added to the residue. Crystals soon appeared in the generation. After 1 hour at 0 ° C, the crystals formed were filtered and washed with butanol and MTBE. After drying, 0.02 g (45 7%), 2, 3 9-tetrahydromethyl [(2-pyridyl) sialyl) methyl] were obtained. Carbazodone hydrochloride. The mother liquor contained 2.70 g (12.3%) of the product. HPLC: 95% NMR and MS: See Example 8. Example 10 · Reaction of 1,2,3,9_tetrahydro_9_fluorenyl_4H • carbazole_4_ _ with 3-ethylsulfonium sigma 200413327 will be in 1-butanol (45 ml) 1,2,3,9-tetrahydro_9_methyl-4H-carbazole-4 · one (13.26 g tri-66.5 mmol) and methanesulfonic acid (10.23 g ξ 106.4 mmol) were heated to 90 ° C. Within 2 minutes, add 3-ethylpyrene (10.09 § three 99.9 millimoles) in 1-butanol (8 1111). 5 After reacting at 80 ° C for 50 minutes, 2-methylimidazole (27.32 g tri-332.5 mmol) and 1-butanol (8 ml) were added. After reacting at 120 ° C for 2 hours, at 80 ° C, 180 ml of toluene and 120 ml of water were added, and the layers were separated. The aqueous layer was extracted with 180 ml of toluene and 60 ml-butanol. The combined organic layers were washed twice with 240 ml of water. The organic layer was evaporated to dryness, and then 10 150 ml of 1-butanol and 10.0 ml of 36% m / m hydrochloric acid were added to the residue. Crystals soon appeared at 0 ° C. After 1 hour at 0 ° C, the formed crystals were filtered and washed with 1-butanol and MTBE. 15.67 g (71.4%) of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole after drying -4-one hydrochloride. HPLC: 95%. NMR and MS: See Example 8. Stock 15 contains 2.06 g (9.4%) of the product. tSchematic description 3 (none) [Representative symbol table for the main components of the diagram] (none) 23

Claims (1)

200413327 Patent application scope: 1. A method for preparing an imidazolyl compound of the following formula and an acid addition salt thereof, Wherein: Ra and Rb are each independently (CrC6) alkyl, (CVQ) alkoxyalkyl, optionally substituted aryl or heteroaryl; 10 or wherein Ra and Rb together form one or more rings A carbocyclic or heterocyclic ring system; Ra, and Rb, each being hydrogen or together forming a carbon-carbon double bond, said carbon-carbon double bond optionally being part of an aromatic system; Rc is hydrogen, (CrC6) alkyl, (CrC6) alkoxy, (CrC6) alkoxyalkyl or element; 15 Rd is hydrogen or (CrC4) alkyl; Re is hydrogen or (CrC4) alkyl; m Is 1 or 2; and R! Is hydrogen or (CrC4) alkyl; characterized in that a compound of the general formula (II) is reacted with a compound of the general formula (III), 24 20 200413327 In the general formula (II), Ra, Ra ,, Rb, and Rb have the meanings defined above; in the general formula (II), R is hydrogen, optionally substituted by a hydroxyl group (CrC4) alkyl or optionally substituted Aryl 9 R ', R ", R'" and R "" are each independently hydrogen or (CrC4) alkyl; and then react with a compound of formula (IV), HN Rd R (IV) where Ri, Rd * Re has the meaning defined above; and optionally then reacted with a suitable acid. 15 2. The method according to item 1 of the scope of patent application, wherein Ra, Rb, Ra ,, Rb ,, R, R ,, R ,, R ,, and R ,,,, have the same scope as in the scope of patent application No. 1 Meaning of the item; Rc is hydrogen or (CrCJ alkyl group; Rd is hydrogen or (CrC4) alkyl group; 25 Re is hydrogen or (cvc4) alkyl group, ❿ is 1 or 2; and R1 is hydrogen, methyl or Ethyl. • A method for preparing an imidazolyl compound of the following formula and a pharmaceutically acceptable acid addition salt thereof, Where: ❿ is 丨 or 2; 10 Ri is hydrogen, fluorenyl, or ethyl; and R5 is (CVQ) alkyl; R6 is hydrogen or (Crc4) alkyl, or 15 R5 and R6 together with the intermediate atom form a 5, 6, or 7-membered ring, and is optionally selected from the group consisting of halogen, hydroxyl, (CrC4) alkyl, (CrC4) alkoxyalkyl, and (CrC4) alkoxy Or two substituents; characterized in that the compound of the general formula (Ila), (Ila) 26 200413327 wherein R5, R6 and m have the meanings defined above, and react with a compound of the general formula (III), R, R &quot; R "· 0-, R &quot; &quot; (III) where R, R ,, R", R ", and R '' 'have the meanings described in item 1 of the scope of the patent application, then Reaction with a compound of the formula HN, N (IVa) 10 4. The method according to item 1 or 2 of the scope of patent application, characterized in that R, R, R ", R '" and R "in formula (III) "Are 2-hydroxyethyl, hydrogen, hydrogen, hydrogen and hydrogen respectively. 5. The method according to item 1, 2, 3 or 4 of the scope of patent application, characterized in that m = = 1 and R5 and R6 are in the middle with The atoms together form a 6-membered ring. 15 6. The method according to item 1, 2, 3 or 4 of the scope of patent application, characterized in that R5 is a fluorenyl group and R6 is hydrogen. 7. As the scope of patent application 1 to 1 The method according to any one of 6, characterized in that the reaction is performed in an alcohol solvent. 8. The method according to item 7 of the patent application scope, wherein the alcohol 20 solvent is 1-butanol. 27 200413327 9. The method according to any one of claims 1 to 6, wherein the reaction is performed in a mixture of an alcohol solvent and an aromatic hydrocarbon. The method of item 9, characterized in that the mixture is a mixture of methanol and chlorobenzene 28 200413327 柒. Designated representative map: (1) The designated representative map in this case is: (). (II) Elements of the representative map Brief description of representative symbols: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: ⑴ 7