TWI324595B - Novel process for the preparation of imidazolyl compounds - Google Patents

Description

玖, invention description:

L J^ff Λ J FIELD OF THE INVENTION The present invention relates to a process for the preparation of imidazolyl compounds. EP 191 562 and US Pat. No. 4,695,578 disclose 1,2,3,9-tetrahydro-9-methyl-3-[2-indolyl-1 Η·βm嗤-1-yl]indolyl]-4H·0 4-ketone (Ondansetron 'ondansetron). In these patent publications, a class of compounds including ondansetron and homologous compounds, their preparation and use as effective "neuronal" serotonin receptor selective antagonists and in the treatment of migraine and Application in mental illness. EP-B-029765, EP-B-0601345 and EP-B-768309, disclose (10R)-5,6,9,10-tetrahydro-indole [(2-methyl·ΐΗ-咪嗤-i_) Base) methyl]-4Η-α than pyridine and [3,2,i_jk]_carbazole-11 (official)-nano (Slasite, cilansetmnX also known as (R)·(a)-4,5,6 , 8, 9, 10-hexahydro_10_[(2-methyl-1Η-imidazol-1-yl)methyl]_ιΐΗ_" pyridine [3,2,l-jk]-axanone). In the first patent publication, a class of compounds including silestron and homologous compounds, their preparation and their use as serotonin antagonists are disclosed. The second patent publication discloses the selective use of these types of compounds in the treatment of certain diseases, and the third patent discloses the preparation of the above compounds from enantiomerically pure compounds and their hydrochloride monohydrates. A common feature is that they all contain a substituted imidazolyl group attached to the (X-position) of the keto group of the carbazole system by a methylene bridge. Several possible synthetic methods for these compounds are disclosed in the above patents. A common feature of these synthetic methods is the introduction of a substituted imidazolyl group by the Mannich reaction, followed by degassing to produce an intermediate exomethylene compound which is reacted with a substituted imidazolyl group (see, for example, Route 1). A disadvantage of this route is that the yield of the sequence reaction step is rather low. In US 4,695,578, the first step in which the yield is usually the lowest is not described, and the second step (the example of US 4,695,578) The yield is 68%. In EP-B-0297651, the yield of the first step (Example lc of EP-B-0297651) is 53%, while the second step (Example Id of EP-B-0297651) Production 87%. In amplification experiments, this route seems to lead to a substantial amount of formed tarry byproducts.

[智智明内溶1 J

An object of the present invention is to provide an alternative process for the preparation of a taste-salt compound which can be operated economically and which satisfies one or more of the following requirements: a) relatively high yield, b) compared to prior art processes Short reaction times of 1324595, C) less side reactions, d) higher quality of the final product, and e) use of non-diluted reaction conditions and environmentally acceptable solvents. It has now surprisingly been found that such imidazolyl compounds can be readily prepared using substituted oxazolidine compounds to introduce a methylene bridge. Accordingly, the present invention relates to a process for preparing an imidazolyl compound of the following formula and its acid addition salt,

10 of which:

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

Or a carbocyclic or heterocyclic ring system in which R and Rb together form a ring or rings; 15 Ra, and Rb, each of which is hydrogen or together form a carbon-carbon double bond, said carbon-carbon double bond Selection is part of an aromatic system;

Rc is hydrogen, (CrC6)alkyl, (CVC6) alkoxy, (CVC6) alkoxyalkyl or halogen;

Rd is hydrogen or (CrCO alkyl; 20 Re is hydrogen or (CrC4) alkyl; m is 1 or 2; and I is hydrogen or (CrC4) alkyl; 10 is characterized by a reaction of the formula, Compound of formula (111)

R is hydrogen, optionally substituted by hydroxy (CrC4) alkyl or optionally aryl, substituted

The ruler, 'foot, ', 11, 11, '', are each independently hydrogen or ((4)); and then react with a compound of formula (IV),

(IV)

Wherein Rr, Rd and Re have the meanings defined above; and optionally are then reacted with a suitable acid. The alkyl group of the present invention includes a linear, 15-branched and cyclic alkyl group containing up to 6 carbon atoms. Suitable alkyl groups can be saturated or unsaturated. Moreover, the pendant group may also be substituted with one or more substituents selected from the group consisting of a aryl group, a cycline, a thiol group or a cyano group or a one or a dialkyl group. The aryl group of the present invention includes an aryl group containing up to 6 hetero atoms. The aryl group may be optionally substituted by one or more substituents of an amino group selected from an aryl '(C^C:6)alkyl group, a dentate, a hydroxyl group, a cyano group or a mono or difunctional group, and 11 20 1324595 It may also be fused to an aryl or cycloalkyl ring. Suitable aryl groups include, for example, phenyl, naphthyl, anthracenylphenyl, imidazolyl, pyridyl, pyrrolyl, thienyl, thiol, decyl and fluorenyl. A carbocyclic system means a system containing at least one saturated or unsaturated cyclic group containing only carbon atoms and hydrogen atoms.

A heterocyclic ring system refers to a system containing at least one saturated or unsaturated cyclic group hydrazine further containing one or more heteroatoms such as N, 0 or S. Both the carbocyclic and heterocyclic ring systems are optionally substituted with a substituent selected from the group consisting of an alkyl group, an aryl group, a cyano group, a halogen group, a hydroxyl group or a mono- or dialkyl-substituted amino group. In a preferred embodiment of the invention, Rc is hydrogen or (CrCe)alkyl, Rd is hydrogen or (CVC0 alkyl; Re is hydrogen or (CVC4) alkyl; R, is hydrogen, thiol or B The reaction of the present invention is especially useful for the preparation of compounds of the formula

Wherein: m is 1 or 2; I is hydrogen, methyl or ethyl; and R5 is (CrQ)alkyl; 2〇R6 is hydrogen or (CrC4)alkyl, or R5 and R6 together with an intermediate atom form 5 A 6 or 7 membered ring, optionally 12 1324595, is substituted with one or two substituents selected from the group consisting of dentate 'hydroxyl, (CrC4)alkyl, (CrC4)alkoxyalkyl and (CrC4)alkoxy. In the case where the starting compound is a compound of the following formula, 0

(IIa) This compound is also known as an alpha-carboxamide compound. Preferred compounds of the formula la are compounds wherein the paw = 1 and the uldent 5 and the uldent 6 together with the intermediate atoms form a 6-membered ring, and wherein m=l, the uldent 5 is methyl and the R6 is hydrogen . For the first compound, bite [3,2,1 -jk]»carbazole-oxime (8H)-one and 3-oxazole at a ratio of 5,6,9,1〇10 tetrahydro-4H_° The yield of this process with alkanoethanol as the starting material was 77% (see Example 2), while the overall yield of the process of EP 0297651 was 46% (Example 1 (: and Id). More on the production scale High yield. Among the substituted oxazolidines, one of R' and R" and one of R, „ and R, '" 15 is hydrogen because of the disubstituted oxazole on the same carbon atom. Alkane, such as 4,4-dimethyloxazole, gives a lower yield in the reaction. Preferred oxazolidines are 3-oxazolidinone and 3·ethyloxazolidine. Most preferred The oxazolidine is 3-oxazole ethanol. The reaction needs to be carried out in an acidic medium, and the acidity depends on the activity of the system in which the reaction occurs. In the case of the miso net system, the medium should be acidic. In the latter case, examples of suitable acids are methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and HC1 13 in an alcohol medium. In order to obtain high yields, the reaction solution should only Contains a small amount of water. Better water Less than 0.6% (V/V), more preferably less than 0.3% (V/V) 'most preferably less than 〇%% (v/v). The optimum reaction temperature depends on the starting materials and solvent, and It is different in the two reaction steps. The first step of the reaction can be carried out at 4 〇 (: to 11 ° C. For the oxazolone system, the preferred reaction temperature for the first step is 50 ° C to 90 ° °C, the most preferred reaction temperature is about 70. (: The second step can generally be carried out at 100 ° C to 14 (TC. For the oxazolone system, the preferred reaction temperature for the second step is llOt to 13 (TC, the most preferred reaction temperature is about 120%. The reaction can be carried out in a different solvent, such as a dipolar aprotic solvent (such as DMF) or an alcohol. The preferred solvent is a C4_C7 alcohol, and can be The desired reaction temperature is selected. Examples of suitable alcohols are 丨-butanol, 1-hexanol and isoamyl alcohol. Preferred alcohols are 1-butanol. Mixtures of aromatic hydrocarbons and alcohols, such as mixtures of hydrazine and alcohols And a mixture of a gas and a mixture of alcohols is also suitable. A preferred mixture is a mixture of a gas and a sterol. When a solvent mixture is used, The solvent system reaches a higher reflux temperature in the second step of the reaction, and the solvent of the lower point can be vaporized before the second step of the reaction. The ratio of the volume of the solvent to the amount of the reactant in the mixture can be varied within a relatively wide range. And depending on the solubility of the reactants. Generally the ratio of the amount of solvent to the amount of reactants is usually from about 1:1 to 15:1, wherein the ratio is expressed in terms of the volume of the solvent relative to the weight of the reactant in the solvent, 1324595. Preferably, the ratio is from about 1: 丨 to about 1 〇: 1 β in the case of an oxazolone system, a preferred ratio of solvent volume to reactant weight is about 4:1°. The resulting product can be from a different solvent. Crystallization. An example of a solvent for free crystallization is an aromatic hydrocarbon such as methyl sulfonate hydrochloride, for example, which can be crystallized from an alcohol solvent such as isopropanol or 1-butanol.

I: MODE FOR CARRYING OUT THE INVENTION The following examples are intended to illustrate the invention in further detail, and thus are not to be construed as limiting the scope of the invention in any way. 1 〇 Example 1: Material and method 5,6,9,10-tetrahydro-41^-° ratio bite [3,2,1-』1<;] miso-11(811)-_ according to ΕΡ0375045 Preparation of 3,4-dihydro-1(2Η)-naphthalenone is commercially available. 1,2,3,9·Tetrahydro-9-methyl_4Η- miso sitting-4- _ according to Warner-Lambert Company, US 3,892,766 and Elz, S. and 15 Hcil, W., Bioorganic & Medicinal Chemistry Letters 1995, Shiba, 667_672 preparation. Astrathrone is obtained from the market. NMR spectra were determined on a Varian VXR 200 and MS spectra were determined on a Finnigan TSQ 7000. HPLC analysis was performed on a 2-inch HP1050 system with a Separations 757 detector (250 nm) and a Separations Marathon XT column furnace at 35 °C. The column used was a ZorbaxXDB C8 column, 15 x 0.3 cm. The eluent was prepared by mixing 2 liters of water, 2 ml of triethylamine and 5 ml of 25% aqueous ammonia, buffering it to pH = 4 with formic acid, and adding 5 liters of acetonitrile. The flow rate is 1 ml/min. Example la: Preparation of oxazolidine 15 1324595 3- Oxazole Institute Ethanol was prepared as follows: Equimolar amounts of diethanolamine and oligocarbazone in butanol were heated to 7 (TC. Reaction for 1 hour) Thereafter, the formed water was removed by azeotropic distillation with 1-butanol. 5- 3-ethyl. Emerald was prepared according to Heany, H. et al., Tetrahedron 1997, 11, 1438, 96. 4, 4- Methyloxazolidine is commercially available, and a 75% w/w aqueous solution is commercially available. The 4,4-dimethyloxazole is extracted from the aqueous layer by washing with a di-methane/saturated NaCl solution. The alkane methane 10 layer was dried over anhydrous sodium sulfate and then evaporated. Example 2. 5,6,9,1〇-tetrahydro-4H-pyrido[3,2,l-jk]carbazole- The reaction of 11(8Η)-_ with 3-oxazolidine will bite 5,6,9,10-tetrahydro-4H-° in butanol (1〇〇ml) [3,2, L-jk] 咔Salt-11(8H)-one (25.00 gElll.0 mmol) and 曱15 sulfonic acid (17.06 gs 177.5 mmol) heated to 7 (TC. In 3 minutes, add 3_ evil A solution of oxazolidine (19.49 g = 166.4 mmol) in 1-butanol (39 ml). After 8 rc reaction for 5 min, add 2-methylimidazole (45.55 gs 554.8 mM) and 1-butanol (10 ml). After 1.5 hours of reaction at 12 ° C, the reaction mixture was partially evaporated until 3 0 m 1 _ 20 butanol remained 75 ml of hydrazine and 50 ml of water were added to the residue at 70 C ', and the layers were separated. The aqueous layer was extracted with 75 mi of a solution. The combined benzene layer was washed three times with 1 ml of water. The layer was evaporated to dryness, then 125 ml of 1-butanol was added. 16 12.5 ml of 36% m/m hydrochloric acid was added to the resulting solution. After 2 hours of room temperature mixing, the solid formed was transitioned with 1 · butanol and Mtbe washing. After drying, 30.4 〇g (77. 0%) 5,6,9,10-tetrahydro]indole _[(2-indolyl-1Η·imidazole·1-yl)methyl]-4H- Pyrido[3,2,l-jk]carbazole 5-U(8H)·one hydrochloride (77.0%) 〇 HPLC: 95%. lU NMR [200 MHz, DMS〇-d6:CDCl3 4:1] δ 1.97(lH,m), 2.18 (3H,m), 2.6B(3H,s), 2.95(2H,t), 3.00(lH,dd), 3.I2(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 10 [ESI] MH+ = 320. Example 3. 5, 6, 9, 10 - 4 The reaction of hydrogen-4H-pyrido[3,2,l_jk]carbazole-11 (8H)-- with 4,4-didecyloxazolidine will be 5,6 in 1-butanol (60 ml), 9,10-tetrahydro-4H-° ratio bite [3,2,l-jk]carbazole·ιι(8Η)-ketone (20.00 g = 88.8 mmol) and continuous 15 acid (13·65 gs) 142.0 millimoles) heated to 70 °C. Add 4,4-dimercaptooxazolidine in 1-butanol (10 ml) (13.47 g = 133.2 mmol) after reacting for 5 minutes at 8 ° C for 2 minutes, add 2-A Imidazole (36.45 g ξ 444.0 mmol) and butanol (1 〇 ml) at 120. (: After 2 hours of reaction, the reaction mixture was partially evaporated until 20 ml of 1-butanol remained. 2〇 at 7〇 60 ml of hydrazine and 40 ml of water were added to the residue t, and the layers were separated. The aqueous layer was extracted with 60 ml of benzene. The combined benzene layer was washed three times with 80 ml of water. Then, 100 ml of 1-butanol was added. To the resulting solution was added 1 〇ml of 36% m/m hydrochloric acid. After stirring at room temperature for 17 hours, the formed solid was filtered and washed with 1-butanol and MTBE. After drying, Π.38 g 5,6,9,10-tetrahydro-10-[(2-mercapto-1H-imidazol-1-yl)methyl]-4H-pyridine and P,2,l-jk ]carbazole·11(8Η)-ketohydrochloride (39.2%)· HPLC: 95%. !H NMR and MS: see Example 2. 5 The mother liquor contains 3.45 g (10.9%) of the product. Example 4. 5 ,6,9,10-tetrahydro-4H-pyrido[3,2,l-jk]carbazole-11 (8H)-one and 3-ethyloxazolidine will be reacted in 1-butanol (60 5,6,9,10-tetrahydro-4H-pyrido[3,2,l-jk]indazole-11(8H)-one (20.00 g = 88.8 mmol) and methyl 10 sulfonate in ml) The acid (13.65 142.0 mmol) was heated to 70 ° C. 3-ethyloxazolidine (13.46 g = 133.2 mmol) in 1-butanol (10 ml) was added over 2 min. After reacting at ° C for 50 minutes, 2-methylimidazole (36.45 g = 444.0 mmol) and 1-butanol (l?ml) were added to react at 120 ° C for 2 hours, and then the reaction mixture was partially evaporated until the remainder 20 ml 1-butanol 15 At 60 ° C, 60 ml of hydrazine and 40 ml of water were added to the residue and layered. The aqueous layer was extracted with 60 ml of hydrazine and the combined benzene layer was washed with 80 ml of water. Three times. The organic layer was evaporated to dryness, followed by the addition of 100 ml of 1-butanol. To the obtained solution was added 1 〇ml of 36% m/m hydrochloric acid. After stirring at room temperature for 20 hours, it was filtered. The solid was washed with 1-butanol and MTBE. After drying, 22.10 g (70.0 %) of 5,6,9,10-tetrahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl ]_4H-pyrido[3,2,l-jk]carbazole-11(8H)-one hydrochloride (70.0%). HPLC: 95%. 4 NMR and MS. See Example 2. 18 1324595 Example 5. Reaction of 3,4-dihydro-i(2H)-naphthone with 3-oxazolidine Ethanol 3,4-dihydro-1 in 1-butanol (60 ml) 2H)-naphthone (12.98 g Ξ 88.8 mmol) and hydrazine sulfonic acid (13.65 g ξ 142.0 mmol) were heated to 50 °C. A solution of 3·oxazolidine (15.59 gE 133.1 5 mmol) in hydrazine-butanol (14 ml) was added over 2 minutes. After reacting at 80 ° C for 50 minutes, 2-methylimidazole (36 45 g = 444 mM millimolar) and butanol (10 ml) were added. After reacting at 120 ° C for 2 hours, 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 10 layers were layered. The aqueous layer was extracted with 60 ml of cockroach. The combined toluene layers were washed three times with 80 mi of water. The organic layer was evaporated to dryness, followed by 1 〇〇 ml 丨-butanol. To the resulting solution was added 1 〇.〇 ml of 36% m/m hydrochloric acid. The resulting solution was evaporated to a final volume of 6 〇ml. After stirring at room temperature for 2 hours, 15 formed solid was filtered and washed with 1-butanol and MTBE. After drying, 15.28 g (62·20/〇) 3,4-dihydro-2·[(2-methyl-1H-imidazol-1-yl)methyl]-1(2Η)-naphthalenone hydrochloride was obtained. . 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), 20 7.55 (2H,m), 7.70 (lH,d) and 7.90 (lH,d). MS [ESI] MH+ = 241. The mother liquor contained 3.28 g (13.3%) of the product. Example 6. Reaction of 3,4-dihydro·ι(2Η)-naphthone with 4,4-dimethyloxazolidine 3,4-dihydro-l in butanol (60 ml) (2H)-naphthone (12.98 g = 88.8 mmol) and methanesulfonic acid (13.65 g = 142.0 mmol) plus 19 heat to 70 °C. 4,4-didecyloxazolidine (13.46 133.1 mmol) in 丨-butanol (1 〇mi) was added over 2 minutes. After 8 minutes of rc reaction, 2-methylimidazole (36.45 g Ξ 444.0 mmol) and 1-butanol (10 ml) were added. After reacting at 120 ° C for 2 hours, the reaction mixture was partially evaporated until the remainder. 20 ml of 1-butanol was added. 60 ml of stupid and 4 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 terpene layer was washed three times with 80 ml of water. The organic layer was evaporated to dryness, then 100 ml of 1-butanol was added. To the obtained 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 for 2 hours, the solid formed was filtered and washed with 1-butanol and <RTI ID=0.0>>&&&&&&&&&&&&&&&&&&&&&& Base]-1(2H)-naphthalenone hydrochloride. HPLC: 95%. 4 NMR and MS: see Example 5. The mother liquor contains 2.33 g (9.5%) product. Example 7. 3,4-Dihydro- Reaction of 1(2H)-naphthone with 3-ethyloxazolidine 3,4-Di-argon-1(2H)-naphthalenone in 1-butanol (60 ml) (12.98 g ξ 88.8 mmol) Ear) and methanesulfonic acid (13.65 g ξ 142.0 mmol) heated to 50 C. Add 1-butanol in 2 minutes (10 3 -ethyl in the ml). Oxalin (13.46g ξ 133.1 mmol). After 8 minutes of TC reaction, add 2-methylimidazole (36.45 g ξ 444.0 mmol) and 1-butyl Alcohol (10 ml). After reacting at 120 ° C for 2 hours, the reaction mixture was partially evaporated until 20 ml of 1-butanol remained. At 70 ° C, 60 ml of carbamide and 40 ml of water were added to the residue. The layers were separated, and the aqueous layer was extracted with 60 ml of toluene. The combined toluene layer was washed three times with 8 μm of water. The organic layer was evaporated to dryness, followed by the addition of 100 ml of 1-butanol. 10.0 ml of 36% m/m hydrochloric acid. The obtained solution was evaporated to a final volume of 5 〇ml. After stirring for 2 hours in 〇<>c, the solid formed was filtered, washed with butanol and hydrazine and dried. 17_30 g 3,4-Dihydro-2-[(2-methyl·1Η-imidazolyl)methyl]4(211)_naphthalenone hydrochloride (70.4%). HPLC: 95%. NMR and MS : See Example 5. Example 8. Reaction of 1,2,3,9-tetrahydro-9-methyl-4H-indazol-4-one with 3-oxazolidine Ethanol will be in 1-butanol i,2,3,9-tetrahydro-9-methyl-4H-indazol-4-one (13.26 g Ξ 66.5 mmol) in (45 ml) Methanesulfonic acid (10 23 g Ξ 106.4 Mao mole) was heated to 9 (rc. I168 g (99 8 mmol) of 3-oxazolidine in bubutanol (11 ml) was added over 2 minutes. After 50 minutes of reaction, 2 -methylimidazole (2 * 7.32 g Ξ 3315 mmol) and 1 · butanol (8 ml) were added. After not reacting for 2 hours, at 80. (:, 180 ml of toluene and 12 〇mi of water were added, and the layers were separated. The aqueous layer was extracted with 18 〇 ml of toluene and 6 〇mll_T alcohol. The combined organic layers were washed twice with 24 gml of water. The organic layer was evaporated to dryness' Subsequently, 150 ml of 1·butanol and 10.0 ml of 36% m/m hydrochloric acid were added to the residue. Crystallization occurred quickly in the generation. After 0 c 1 small, the formed crystals were filtered and washed with butanol and MTBE. After that, 15.39 g (70.1%) 1 2 3 9_tetrahydrohydromethylmethyl 3 [(2 methyl-1 Η·β m嗤]-yl)methyl]_纽_味刺冰_HCl was obtained. 1324595 HPLC : 95%. 'H 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+ = 5 294. The mother liquor contained 3.19 g (14.5%) of the product. Example 9.1, 2,3,9-tetrahydro-9-methyl-411-oxazol-4-one and 4,4-dimethyl The reaction of the base "eco sing will be 1,2,3,9-tetraar-9-methyl-4 oxime-oxazol-4-one in 1-butanol (45 ml) (13.26 gs 66.5 mil Mohr) and methanesulfonic acid (10.23 g ξ 10 106.4 house Mo) were heated to 9 ° C. 4,4-dimercaptooxazolidine (10 09 gS99.9 mmol) in ι-butanol (8 ml) was added over 2 minutes. After the reaction at 80 C for 5 minutes, '2-meryl group was added' After reacting with sodium iodide (27.32 ge 332, 5 mmol) and 1-butanol for 2 hours, 180 μm of toluene and 120-claw water were added and layered at 80 ° C. The aqueous layer was treated with 18 〇 15 ml of benzene and 60 ml-butanol extraction. The combined organic layers were washed twice with 24 ml of water. The organic layer was evaporated to dryness, then 150 ml of 1-butanol and 1 〇 〇 36% m/m hydrochloric acid were added to the residue. Crystallization occurred rapidly at 〇 ° C. After 1 hour at 〇 ° C, the formed crystals were filtered and washed with butanol and MTBE. After drying, 10.02 g (45.7%) 1,2,3,9-tetrahydrogen was obtained. Mercaptomethyl-1H-methane. Sodium-1-yl)methyl]-4H-*» card "sit_4__ hydrochloride. The mother liquor contained 2.70 g (12.3%) of the product. HPLC: 95% NMR and MS: see Example 8. Example 10. 1,2'3,9-tetrahydro-9-methyl-4H-carbazole·4· Brewing I and 3_ethyl ° σσ sitting reaction 22 1324595 will be in 1-butanol ( 1,2,3,9-tetrahydro-9-mercapto-4H-indazol-4-one (13.26 g of three 66.5 mmol) and sulfonic acid (10.23 g of three 106.4 mmol) in 45 ml) ) Heat to 90 ° C. 3-ethyloxazolidine (10.09 g = 99.9 mmol) in 1-butanol (8 ml) was added over 2 minutes. 5 After reacting at 80 ° C for 50 minutes, 2-mercaptoimidazole (27.32 g of 332.5 mmol) and 1-butanol (8 ml) were added. After reacting at 120 ° C for 2 hours, 180 ml of terpene and 120 mi of water were added at 80 ° C, and the layers were separated. The aqueous layer was extracted with 180 ml of terpene and 60 ml of butanol. The combined organic layers were washed twice with 240 ml of water. The organic layer was evaporated to dryness, then 10150 ml of 1-butanol and 10.0 ml of 36% m/m hydrochloric acid were added to the residue. Crystallization occurs very quickly at 0 °C. After 1 hour at 〇 °C, the formed crystals were filtered and washed with butanol and MTBE. After drying, 15.67 g (71_4%) 1,2,3,9-tetrahydro-9-mercapto-3-[(2-indolyl-1H-imidazol-1-yl)methyl]-4H-carbazole was obtained. 4-ketone hydrochloride. HPLC: 95%. NMR and MS: see Example 8. The mother 15 solution contained 2.06 g (9.4%) of the product. I: Simple description of the diagram 3 (none) [The main components of the diagram represent the symbol table] (none) 23

Claims (1)

1324595 Where: Patent Application No. 092132041 Applicable Patent Revision Amendment This revision period: August 1998 ~ Application scope: For the year 更 (more) bundle method, Ra and Rb are each independently (CrC6) alkane a (CrC6) alkoxyalkyl group, an optionally substituted aryl group or a heteroaryl group; or wherein Ra and Rb together form a carbocyclic or heterocyclic ring system comprising one or more rings; Ra, and Rb, each Is hydrogen or together form a carbon-carbon double bond, optionally a part of an aromatic system; Rc is hydrogen, (CVCJ alkyl, (CrC6) alkoxy, (CrC6) alkoxyalkane Or a halogen; Rd is hydrogen or (CVCO alkyl; Re is hydrogen or (Q-C4)alkyl; m is 1 or 2; and I is hydrogen or (CrQ)alkyl; The compound of II) is reacted with a compound of the formula (III), 24 1324595 ο I , Ο—^-R, M R"" (ΠΙ) In the formula (II), Ra, Ra, Rb and Rb, and m have the meanings defined above; in the formula (III), R is Hydrogen, (Q-CU) alkyl optionally substituted by hydroxy or optionally substituted aryl, R', R", R'" and R"" are each independently hydrogen or (CrCO alkyl; The compound of (IV) is reacted, HN (IV) wherein Ri, Rd and Re have the meanings defined above; and optionally then reacted with a suitable acid. 2. The method of claim 1, wherein Ra, Rb, Ra, Rb, R, R, R", R,,, and R, ', have the meanings as recited in claim 1; Rc is hydrogen or (CrC6)alkyl; Rd is hydrogen Or (CrC4)alkyl; 25 1324595 Re is hydrogen or (CrC4)alkyl, m is 1 or 2; and Ri is hydrogen, decyl or ethyl. 3. The method of claim 1 or 2, A method for producing an imidazolyl compound of the following formula and a pharmaceutically acceptable acid addition salt thereof, 0 NN wherein: m is 1 or 2; I is hydrogen, fluorenyl or ethyl; and R5 is (cvcoalkyl; is hydrogen or (CrC4)alkyl, or R_5 and R>6 form together with an intermediate atom; a 6 or 7 membered ring, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, (CrC4)alkyl, (CrC4)alkoxyalkyl and (CrC4)alkoxy; a compound of the formula (Ila), H2) 26 1324595 (Ila) wherein R5, R6 and m have the meanings defined above and react with a compound of formula (III), RIN R, Co tR r R,' (in) wherein R, R, R, R, R, and R, ', have the meanings as described in the first paragraph of the patent application, and then react with a compound of the formula (IVa) wherein 1^ has the same meaning as described in the first item of the patent application. 4. The method of claim 1 or 2, wherein R, R', R", R''' and R"'' in the formula (III) are 2-hydroxyethyl, hydrogen, respectively. , hydrogen, hydrogen and hydrogen. 5. The method of claim 1 or 2, wherein m == 1 and R5 and R6 together with the intermediate atoms form a 6-membered ring. 6. The method of claim 3, wherein m = 1 and R5 and R6 together with the intermediate atoms form a 6-membered ring. 7. The method of claim 4, wherein m = 1 and 27 1324595 R5 and R6 together with the intermediate atoms form a 6-membered ring. 8. The method of claim 1 or 2, wherein m = 1, R5 is a fluorenyl group and R6 is hydrogen. 9. The method of claim 3, wherein m = 1, R5 is a methyl group and R6 is hydrogen. 10. The method of claim 1 or 2, wherein the reaction is carried out in an alcohol solvent. 11. The method of claim 10, wherein the alcohol solvent is 1-butanol. 1Z The method of claim 1 or 2, wherein the reaction is carried out in a mixture of an alcohol solvent and an aromatic hydrocarbon. 13. The method of claim 12, wherein the mixture is a mixture of methanol and chlorobenzene. 28