SK16993A3 - Process for preparing 1,2,3,9-tetrahydro-9-methyl-3- -[(2-methyl-1h-imidazole-1-yl)methyl]-4h-carbazole-4-one - Google Patents

Description

The invention relates to a process for the production of 1,2,3,9-tetrahydro-9-

is a synthetic compound that selectively antayonizes the subject matter and exhibits interesting properties .9 as those in chemotherapy, as well as in the treatment of headache, schizophrenia, anxiety, obesity and mania.

The prior art

In the patent rb, > 4ΐ · 4.Ο, the production of 1,2,3,9-tetrahydro-9-, thiomethyl-3- [(b-thio-1 H- imidazol-1-yl) non-phenyl] -4-benzimidazol-1-one by reaction of the caroazolone of formula 111

(III)

wherein Y is a tylene with a halogeno group, 2-methyl midazol.

In the EC patent (1) 1, the preparation of 1,2,3,9-tetrabydro-9-methyl-3-phenylethyl-3-yl-III-nitridin-1-yl-I-1 is described. tyl] - 45,1-carbazol-4-one ox. in the case of corbozol of the general formula IV

In patent ES (393), 1,2,3,9-tetrahydro-9-yl-3 - [(2-methyl-19-nitro) -19-nitro] is described. azazol-1-yl) methyl] -4-

or H or R-, represent ⁰ about that hydrogen.

In the EC patent 290993 / the production of 1,2,3,9-tetrahydro-9-methyl-3 - [(c-methyl-1H-imidozo-1-yl) methyl 1J-4 is described. Deep corazol-4-one by cyclization of the phenylhydrazine derivative

In the EC patent 2030-193, the production of 1,2,3,9-tetrahydro-9-1-methyl-3-methyl-1-hydroxy-1-yl-1-yl is described: 11 Ethyl] -41 ketyl-4-iso-4- Snula by cyclization of an aniline derivative of the general formula

(VII) wherein X. the notion is hydrogen or halogen.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a process for the production of 1,2,3,9-th-methyl-9-methyl-3- (k-2-yl) -yl-1-carboxylic acid. I - i m i d - j z ol - 1 - y l) methyl j - 4 (Carbazol-4-one of formula I)

which comprises 2 - [(2-methyl-1H-imidazol-1-yl) methyl] -4-ylmethylindol-2-yl) butyric acid

(U) cyclizes under conditions of 'Priedel-Crai' ts acylation reaction through activation of the carboxyl group by acidic

Even in an environment of suitable dissolution, the rational product is isolated in a conventional manner.

A k t i v c i. and wherein the carboxylic acid is mixed with the carboxylic acid halide or mixed anhydride and the carboxylic acid anhydride is 1. n o u t r i C1 u ó r. 3-methanesulfonic acid, preferably to the mixed anhydride with the characteristic trifluronic acid.

If the acid catalyst can be used, inorganic crystals may be used, and the acid catalysts may be used. oic, or Lewis acid, such as zinc chloride or aluminum chloride; and.

Phosphorus selins are preferably used.

and converting in an aprotic organic solvent, form. d ichl irine tan. dichloretá

Reaction 5) is a mixture of tetrahydrofuran or acetone tri, preferably in acetonitrile.

Cyklizáeia preferably takes the tapolote in the range of -60 to - »- !? 0 ³ C, preferably at ·. '> ³ C.

Upon completion of the reaction, the desired product is conventionally isolated and recrystallized from an organic solvent, preferably methanol. Chemically pure 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl} -4K-tertbazol-4-one is obtained.

The compound of formula (ii) can be prepared by the reaction of 2'-thiene-i - (- k-box-1-methyl-indol-2-yl) -malic acid in zinc and in L.1. i.

with 2-methylimidazole. The reaction is conveniently carried out at a temperature in the range of from 100 to 2 ° C, preferably at 150 ° C.

The reaction is carried out in a high boiling solvent such as toluene, xylene or thiobenzene or mixtures thereof, or without a solvent. Preferably, the process is carried out without solvent.

Upon completion of the reaction, the desired product is isolated by conventional means and recrystallized from an organic solvent such as methanol, toluene, di-ethoxyotane or methoxyethanol, preferably dimethoxyethane.

The dicarboxylic acid of formula VIII is obtained by hydrolyzing 2-thiene-β- (3-ethoxycarbonyl-1-methyl-indol-2-yl) butyric acid with zinc and X

The lithium compound can then be produced by reacting ethyl 1,2-dihydroxy-1-3-cyclohexyl-1-ol and X (X).

(obtained by the method of John E) phthane, Michael E. Newman, J. Org. Ohern. 54, N-bromoethylacrylic acid of formula XI

Me or, Metal · / i n 4735, 1939) s (XI)

br

OOOH

The invention is illustrated by the following examples. These examples are illustrative only and do not limit the scope of the invention in any respect.

Examples of the invention

-methylene-4- (3-ethoxycyclones-1-o-o-butylamino-2-yl) butter / sec. L i. on a solution of the lithium salt, which was made from 4.34 g (20 mmol) of ethyl 1,2-dioethylindole-3-carboxylate, in 150 ml of tetrahydrofuran, kept at > A solution of 4.99 g (30 mmol) of n-bromomethylacrylic acid in 20 ml of tetrahydrofuran was added over a period of 10 s. ; ;; - the fence should not exceed -50 ° C. After all, he is new. add it at the -9 0 ⁰ C, the solution was poured into a mixture of 400> ·· ír.du, 15 ml of concentrated hydrochloric acid j 2 1) ml. e ty L oco t.át. After partitioning and phase separation, the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried (MgSO 4) and evaporated. The resulting solid was recrystallized from toluene and then from methanol. 3.0 g (50%) of analytically pure title compound are obtained as a white solid.

Melting point: 138 DEG-140 DEG .alpha.: 1-4045 (0001): 1.4 (t, J = 7.1, 34, -0.6% -01), 2.52-2.71

(m, 211 -Cil. -0 = C ), 3.35 » N-CiJ- ₃ ), 4.41 (Q, J = 7.1 111, -0 = 0 4), C, 37 (d, J - i '; 11 Oct 1 trf 5Y) 8,1 ' . ) - c., ZO

J - 1.5, III, 7.25 (m, 21i,

P r x k 1 and d 2

2-Non-thien-4- (3-carboxy-1-methyl-indol-2-yl) butyric acid

To a suspension of 5.7 g (18.9 µmol) of the compound of Example 1 in 15 ml of methanol and 15 ml of water was added 19 g of potassium hydroxide, and the resulting mixture was heated under reflux for 30 minutes. The mixture is then poured into a mixture of 200 g of ice and 200 ml of water and acidified with 30 ml of concentrated hydrochloric acid. The product is filtered off and suspended in 10 ml of toluene. Thereafter, 100 mL of toluene was distilled off from the mixture and after cooling to 20 ° 0 and further filtration, 4.5 g (07 Ί) of the analytically pure title compound was obtained as a white solid.

Melting point: 194-195 ° C ¹ H-NMPS (CDCl 3: 2.40-2.00 (m, 2H, indole-C ^-CHCH)) 3.20 3.00 (m, 2H, indole-) _CLH-CII,. ~), 3.77 (s, 3H, N-CH), 5.59 (d, -C? CH), 5.07 (d, J = 1.5, III, -0 = 0-11), 7.10 aromatic), 7.45-7.4 (m, 1H, aromatic),

7.96 - 8.05 (´i, liiii, mighty ones).

Example 1

- (P-Methyl-1H-imidazol-1-yl) -4- (1-methyl-indol-2-yl) -butyric acid.

A mixture of 2.73 g (10 mmol) of the compound of Example 2 and 2.46 g (30 mmol) of 2-methyl-idazole was heated at 10 ° C for a minute. After cooling to room temperature, the mixture is dissolved in chloroform, applied to a silica column and eluted with methylene chloride / methanol, 7θ:

3 0. i and k. with ? iz 1 s an * ^- ·) y medicines no k 2 the > n 21 g oži t (71 4) of the title compound in the external substance. a k. a v e j j p Heat the heater a: 1 ;> · ζ \ until ). 9 0 p ^L H-6 49 ^ (0001 ^) : 1, 0 ) - 2.00 ( ' -ml, indole-CIĽ-O! ^) 2.27 (s, 3Π, C-C.1-J > 0, 0 y - 2.90 (Ή, 4 i, indole-OH · - and -HOL COOlí), 3.3-3 (s, 3H, M n; J .J ) j 3 o.> - 3, <- ‘Y (m, 21), imidazole-CH., -) δ, lp (s, !14), indole - Π) > υ, 79 i-a, J-i, δ, 1H, imidazole H) 6.60 - 7.10 (m , 30) ) v č e 11 ι- at. 7.06 (d, J = 1.6, 1H, imidazol-1), 7 , 30 - 7 / 1 ) * ’ . (.1., 21! , aromas)

1,2,3,9-tetrahydro-y-ylamino-3 - [(2-methyl-1H-imidrzol-1-yl) methyl] -4H-pyrimidin-4-one

To a suspension of 311 mg of (1? Ml of acetonitrile was added 2 phosphoric acid. The mixture there 35341) - (2.5 mmol) of scrim anhydrides) of 2 of Example 3 in 10 uL c (0, P6 acid was cooled to 0 C and dropwise, ^J to the trifluoroacetic acid dride

I.

T

The mixture was poured into a mixture of 50 ml of ice and 50 ml of saturated aqueous solution for 9 minutes. No carbonate solution and the resultant ^one was extracted ·>'; ty.l.ón much hl> hydride (3 x 13 m ±). the combined organic extract is dried over magnesium sulphate and evaporated. The solid residue was recrystallized from methanol to give 10 mg (552%) of the title compound as an analytically pure white solid.

Melting point: 227 C ³ až'2'28,5

H ^ NmRé'kGDCl ): 1, 70 “2, 03 (m, 1 H, 11-0 (2)), 2.45 (with , 3H, CH,), H-G (3)), 3.72 (with, 3 íl , M-C H · / 4 M _Gly-2), 4.73 (d d, J = 4.1 5, 1H, aromatic), 7.20 - 7.40 (rn, 3H 8, <·. <) - 3.30 ( m, .1.1 J aroma Tekla.

1: 1, HC (2)), 2.13-4.30 (m, 2.75-3.1? (M, 3Π, HC (1) and 10 (dcl, J = 8.15, 1H) .

N-Cr (4), δ, 85-7.05 (m, 21i, imidazole-H and aromatic),

Ρ Λ T E N T.) OVERHEAD Ϊ

L. Jp Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2, 1-yl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 -one of formula 1 or III id

and iso-1-yl) not of formula ii

characterized in that 2 - [(2-notyl-1H-1-hylic acid) - 1 - (1 -) -, 1-indole

It follows the conditions of the Priedel Grafts acylation reaction by activation of the carboxyl group by acid catalysis, in a suitable solvent environment, for which the desired product is isolated in the usual manner.

Claims (4)

i. 10. The method of claim 1, wherein the compound of formula III is activated by forming a mixed anhydride, preferably a mixed anhydride with kyl; r? 1 i no u t r i + 1 u o x · o c t. o v o u. Process according to Claim 1 or 2, characterized in that the cyclization is carried out in a suitable solvent in the presence of an acid catalyst. 4. A process as claimed in claim 1, wherein the reaction medium is a p o u g i. j e 3 pr o t i. c k č h o o r p a n .i. c k h o r o z i s> a 1 and, preferably acetones tri.lu. b. Np of claim 3 it is is that as k use of a high catalyst i is an acid phosphoric acid. - Way of action n i e k t o r o h o n o n o v 1 n ž · !, v y z na- č u j úr; i sa in that the c y k1 i z i a at any temperature v r o z.ifioč 7. í. - Oh up to 50 ° C, preferably at 0 ^J C.