LV10948B - Carbazolone derivatives and process for preparing the same - Google Patents
Carbazolone derivatives and process for preparing the same Download PDFInfo
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Abstract
Invention is attributed to carbazolone derivatives, the formula of which is <IMAGE> (I), where A is a group formula of which is - CH2-R (V) where R is hydroxyl or 2-methyl-1H-imidazole-1-yl group; B is a group formula of which is <IMAGE> (VI), where R1 is hydrogen or a group of methyl or ethyl; or A and B together comprise a group formula of which is <IMAGE> (VII), where R2 is a group of methyl or ethyl; or A and B together comprise a group formula of which is <IMAGE> (VIII). The afore-mentioned compounds are useful intermediate substances in a process of synthesizing an ondansetron formula of which is <IMAGE> (II). Chemical name: 9-methyl-3-/(2-methyl-1H-imidazole-1-yl)-methyl/-1,2,3,9-tetrahydro-4H-carbazol-4-on. Besides that, the invention is attributed to the new production method of the formula (I) compounds where A and B are the same as in the formula (I), but B may be also hydrogen. In the way indicated the new method is also suitable for the production of the ondansetron itself.
Description
LV 10948
CARBAZOLONE DERIVATIVES AND PROCESS FOR PREPARING THE SAME 5
The invention relates to novel carbazolone derivatives of formula 0 10
A B (I), CH3 wherein A stands for a group of formula (V), —ch2-r 20 vherein R means a hydroxyl or 2-methyl-lH-imidazol-l-yl group; B represents a group of formula 25 0 II (VI), -C-COORļ 30 vherein Rļ means hydrogen or a methyl or ethyl group; or A and B together form a group of formula
A 4893-6 ? MR 2
(VII), vherein R2 means a methyl or ethyl group; or A and B together form a group of formula
(VIII).
Furthermore, the invention relates to a process for the preparation of the above compounds.
The compounds of formula (I) are valuable intermediates in the synthesis of 9-methyl—3—[(2-methyl-lH—imidazol—l-yl)-methyl]—1,2,3,9-tetrahydro—4H-carbazol-4-one of formula
(II) (generic name: ondansetron) and its acid addition salts, preferably the hydrochloride dihydrate.
Thus, the invention relates also to a novel process for the preparation of ondansetron of the formula (II) .
Due to its selective 5-HT3 antagonistic effect, ondansetron is an excellent antiemetic drug, inhibiting vomiting and nausea by decreasing the gastric motility, mainly during - 3 - LV 10948 cancer cherootherapy (see GB patent specification No. 2,153,821).
Several processes have been published for the prepara-tion of ondansetron.
According to a process described in the published Euro-pean patent application No. 219,929, the imidazolyl-alkyl side chain is introduced by a three-step synthesis onto the methylene group neighbouring the oxo group of the l,3-cyclo-hexanedione monoenol ether used as starting substance. After that the enol ether group is replaced by a 2-methyl-2-phe-nylhydrazino group and the phenylhydrazone obtained is sub-jected to a Fischer's indole synthesis. The drawbacks of this process, comprising five steps, reside in the use of dangerous and expensive reaģents (butyl lithium, dimethyl-methyleneammonium iodide, l-methyl-l-phenylhydrazine) and technological steps, vhich result a moderate yield and which are difficult to carry out, in some cases, and to increase to industrial scales (c.f. column chromatography, tempera-ture of —70°C). The overall yield of ondansetron is only 9.57%, calculated for 1,3-cyclohexanedione monoenol ether.
According to another method described in the published European patent application No. 221,629, after reacting an imidazolylalkyl-l, 3-cyclohexanedione monoenol ether with 2-—iodoaniline, the enamine obtained is cyclized with palla-dium(II) acetate. The indole-N atom of the product thus formed is methylated in the last step. The drawbacks of this process are the same as those of the former one. The overall yield of ondansetron is at most 1.0%, calculated for 1,3-—cyclohexanedione monoenol ether used as starting substance.
According to the above-said GB patent specification No. 2,153,821 (which is equivalent to the Hungarian patent specif ication No. 193,592), 3-(dimethylaminomethyl)—9—methyl-—1,2,3,9-tetrahydro—4H-carbazol-4-one is used as starting substance, which is heated with 2-methylimidazole to obtain 4 ondansetron. However, the starting tertiary amine is sirai-larly basie in character as ondansetron, which causes separ-ation difficulties in the purification of the final produet.
Another important disadvantage of this process consists therein that no teaching for the preparation and character-ization of the starting tertiary amine compound can be found either in the specification itself or in the literature.
Peculiarly, the above-said patent specification indi-cates this tertiary amine to be known per se and, in addi-tion, ondansetron can be prepared therefrom in an other way, too. After quaternizing the tertiary amine with methyl iodide, trimethylamine is split off from the obtained metho-iodide by Hofmann's elimination reaction to give 9-methyl-3-methylene—1,2,3,9~tetrahydro-4H-carbazol-4-one. The thus-obtained electrophilic conjugated enone is subjected to an addition reaction with 2-methylimidazole (see Example 8 of the specification). The surprisingly moderate yield of 43.2% of the reaction shows that the significance of this simple direct addition, starting from the separated enone, should not be overestimated.
However, the reaction of 2-methylimidazole with the said tertiary amine compound (c.f. Example 7) results in a good yield of ondansetron (100% of crude produet, 82% of recrys-tallized produet) . These data suggest that the reaction mechanism of the last step in the known synthesis of ondansetron is decisively not an elimination-addition reaction in its character but has another type, i.e. N,N'-transamination by direct substitution.
The present invention is aimed at developing a preparation process, in the course of which a pure final produet can be obtained from novel intermediates through selective reactions, being easy to carry out and inerease to an indus-trial scale, whereby the above drawbacks can be eliminated.
The invention is based on the surprising discovery that - 5 - LV 10948 any of the new alkoxalylated 4-carbazolones of formula 0
I 0 ch3 ch2oh C — COORi (ib), vherein Rj. means a methyl or ethyl group, or formula 10 0
(Ic) 15 ch3 can N-monoalkylate 2-methylimidazole of formula 20
(IV) , and the obtained intermediate of formula 25
(Id) , chemically 9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-—1,2,3,9—tetrahydro—4H—carbazol—4—one—3—glyoxylic acid, can be converted into ondansetron of the formula (II) by dealk-oxalylating with a nucleophilic reaģent. 30 6
The surprising character of this solution can be explained as follovs:
It is well-known that the N-acylation of imidazoles can easily be carried out in a non-aqueous roedium by using strong acylating aģents, e.g. reactive esters (Alan E. Kat-ritzky, Charles W. Rees: "Comprehensive Heterocyclic Chem-istry", Vol. 5, p. 390-393). Based on this one could expect that the substituted glioxylic acid esters of the formula (Ib) or the lactone of the formula (Ic), both being strong acylating aģents, would acylate 2-methylimidazole of the formula (IV) to give the following compound: 0
0 0 CH3 ("IX") CH3
In an entirely surprising manner the methylene part of the C-hydroxymethyl group was attached to the nitrogen atom of 2—methylimidazole in an N-alkylation reaction, giving the compound of the formula (Id), being sterically more dense, rather than the N-acylimidazole of the formula ("IX").
Thus, the present invention relates to novel compounds of formula 0
v/herein A stands for a group of formula - 7 - LV 10948 (V), —ch2-r wherein R means a hydroxyl or 2~methyl-lH—imidazol-i-yl group; B represents a group of formula 0 (VI),
II -C-COORļ wherein Rļ means hydrogen or a methyl or ethyl group; or A and B together form a group of formula
(VII), wherein R2 means a methyl or ethyl group; or A and B together form a group of formula
(VIII).
The new compounds are as follows: 3—ethoxalyl—9-methyl—1,2,3,9-tetrahydro-4H-carbazol-4--one, methyl 3—hydroxymethyl-9-methy1-1,2,3,9-tetrahydro-4H--carbazol-4-one—3-glyoxylate, ethyl 3—hydroxymethyl-9-methyl—1,2,3,9—tetrahydro—4H- 8 -carbazol—4-one-3-glyoxy late, 3-hydroxymethyl-9-methyl-l ,2,3,9-tetrahydro-4H-carbazol--4-one—3—glyoxylic acid lactone and 9-methy1-3-( (2-methyl-lH-imidazol-l-yl)methyl]-l, 2,3,9--tetrahydro—4H-carbazol—4-one-3—glyoxylic acid. Further, the invention relates also to a process for the preparation of the partially novel, partially known com-pounds of formula 0
vherein A stands for a group of formula— ch2-R <v>, wherein R means a hydroxyl or 2-methy1-1H—imidazol—l-y1 group; B represents hydrogen or a group of formula 0II — C —C00R1 (VI) , wherein Rļ means hydrogen or A and B together form a group of a methyl or ethyl group; or formula Λ coor2 (VII), - 9 - 5 10 15 wherein R2 means a methyl or ethyl group; or A and B together form a group of formula ^ch2 II0 which comprises a) reacting the ketone of formula 0
LV 10948 (VIII), (III) 20 25 with a di(Ci_2alkyl)oxalate in the presence of a basie aģent in order to obtain a novel compound of the formula
(la) , wherein R2 stands for a methyl or ethyl group; b) reacting a compound of the formula (la), vherein R2 is as defined in step a) above, with formaldehyde in the presence of a basie catalyst in a non-acidic protic solvent in order to obtain a novel compound of the formula (Ib), wherein R^ is a methyl or ethyl group; or reacting a compound of the formula (la), vherein R2 is as defined in step a) above with formaldehyde in the presence of a basie cata- 30 10 lyst in an aprotic solvent in order to obtain the novel com-pound of the formula . (Ic); c) reacting a compound of the formula (Ib), vherein Rļ is as defined in step b) above, or the compound of the for- 5 mula (Ic) with 2-methylimidazole of the formula (IV) in order to obtain the novel compound of the formula (Id) ; d) reacting the compound of the formula (īd) vith a base, preferably an alkali mētai carbonate or hydroxide, in order to obtain ondansetron of the formula (II), 10 and, if desired, converting ondansetron of the formula (II) into its pharmaceutically acceptable acid addition salt.
According to variant b) of the above process, the com-pounds of formula (la), vherein R2 is as defined above, are 15 reacted with 1 to 2 moles, preferably 1.2 to 1.6 moles, of formaldehyde in the presence of not more than 0.2 mole of a basie catalyst, preferably an alkaline mētai carbonate or a trialkyl amine. The reaction is carried out preferably in methanol or ethanol if a compound of the formula (It; is to 20 be prepared. If the compound of the formula (Ic) is to be prepared, the reaction vith formaldehyde is carried out pre-ferably in a dipolar aprotic solvent like acetonitrile or acetone. When in variant c) of the process of the invention a compound of the formula (Ib), wherein Rļ means a methyl or 25 an ethyl group, or the compound of the formula (Ic) is used as starting substance, the oxalyl gro’up is removed by alcoholysis of the C—C bond in the presence of a C1_^alkanol and the group cleaved off is bound by salt formation vith a base being stronger than 2-methylimidazole, preferably vith 30 triethylamine. 2-Methylimidazole is used in an amount of 1.0 to 3.0 moles, preferably 1.5 to 2.0 moles, calculated for a compound of the formula (Ib), vherein R^ means a methyl or ethyl group, or for the compound of the formula (Ic). - 11 - LV 10948
When carrying out variant c) of the process of the invention, a compound of the formula (Ib) or (Ic) is heated with 2-methylimidazole in an aprotic solvent until the reac-tion becomes complete. Then in variant d) the oxalyl group 5 is removed by a nucleophilic aģent to obtain the target com pound of the formula (II).
According to a preferred embodiment of variant c) of the process of the invention, 1.0 to 3.0 moles, preferably 1.5 to 2.0 moles of 2-methylimidazole, 1.0 to 2.0 moles of 10 ethanol and a base stronger than 2-methylimidazole, advan- tageously 1.1 to 1.5 moles of triethylamine, each calculated for 1 mole of a compound of the formula (Ib) or (Ic) , are used in an ether-type solvent such as dioxane, or in a di-polar aprotic solvent, preferably dimethylformamide, di-15 methylsulfoxide or sulfolane. The reaction requiring heating is carried out at a temperature between 70°C and 200°C, pre-ferably between 100°C and 150eC, for 0.25 to 20 hours, advantageously 0.25 to 5 hours, then the product of the formula (II) is precipitated by dilution vith v/ater or by salt 20 formation and isolated by filtration.
The compound of the formula (II) is obtained from the compound of the formula (Id) by using an aqueous alkaline mētai hydroxide or alkaline mētai carbonate solution at a temperature from 20°C to 100°C, preferably a potassium hydr-25 oxide or carbonate solution at 30 to 70°C. The compound of the formula (II) obtained in the free base form may be con-verted into its monohydrochloride dihvdrate in a way known per se.
In comparison to the processes known in the art the 3 0 advantages of the process according to the invention are as follows. a) The process consists of reactions easy to carry out and to increase up to industrial scales. b) The alkoxalyl group proves to be an excellent adju- 12 vant function for the selective introduction of the imidazolylmethyl side chain, which is later easily split off in the form of an oxalate salt, in some cases spontaneously, in situ in the reaction mixture. 5 c) The reactions can be performed in very good yields of 70 to 90% to result in well-isolable and well-charac-terizable crystalline substances in ali cases. d) An additional advantage appears also therein that the intermediates of the reaction sequence do not contain 10 any basie group; therefore, the final product is easy to purify.
Thus, the isolation of a pure final product becomes extremely simple since none of the possible or actual impurities contains a basie group. In contrast, the syn-15 thesis disclosed in the above-cited GB patent specification
No. 2,153,821 proceeds through the intermediate 3—(dimethyl-aminomethyl)-carbazol-4-one, i.e. through a substance basie in its character and difficult to reraove.
The invention is illustrated ir. detail by the foiloving 20 Examples.
Example 1
Preparation of 3-ethoxalyl-9-methyl-l,2,3,9-tetrahydro-4H-—carbazol-4-one [compound of formula (la), wherein R2 means an ethyl group] 25 3.0 g (0.13 mole) of sodium mētai are portionwise added to a stirred mixture containing 19.93 g (0.1 mole) of 9-—methyl—1,2,3,9—tetrahydro—4H-carbazol-4—one of formula (III), 19.0 g (0.13 mole) of diethyl oxalate, 2 g of ethanol and 200 ml of dioxane. The slightly varming reaction mixture 30 is stirred at 40 to 50°C for 4 hours, then 16 g of glacial acetic acid and finally 200 ml of water are added thereto at room temperature. After filtering off the yellow crystalline suspension, the precipitate is washed with water and dried to give the title compound in a yield of 24 g (80.2%), m.p.: - 13 - LV 10948 118-120°C.
The active ingredient content of the product amounts to 98.4% based on potentiometric titration with sodium hydr-oxide solution. IR spectrum (KBr) , ļ'īnax: OH 3600-2000 cm”1 C=0 (ester) 1727 cm-1 0 11 0 0 II n 1590 cm”1 1578 cm"1 C-O-C (ester) 1213 cm”1 =C-OH (enol) 1185 cm”1 Ar-H (bending) 754 cm"1 NMR (DMSO-d6) 6 PPm: CH3-CH2- 1.47 (3H, t) -ch2- 2.75 (2H, t) -ch2- 3.12 (2H, t) CH3-N 3.60 (3H, S) CH-ļ-CH? -0 4.36 (2H, q) Ar-H 7.24 (2H, m) 8.00 (1H, dd) 8.13 (1H, dd)
Example 2
Preparation of 3-ethoxalyl-9-methyl-l/2,3,9—tetrahydro-4H-—carbazol—4—one (compound of formula (la), wherein R2 roeans an ethyl group]
After adding 7.1 g (0.13 mole) of solid sodium nethoxide to a stirred mixture containing 19.93 g of the ketone of formula (III) (for the Chemical name see Example 1), 19 g of diethyl oxalate and 200 ml of 1,2-dimethoxyethane, the process described in Example 1 is followed to obtain 23.1 g (77.2%) of the title compound, m.p.: 117-120°C.
The titrimetrically determined active aģent content of the product is 97.9%.
The spectroscopical data of the product are the same as 14 described in Example 1.
Example 3
Preparation of methyl 3-hydroxymethyl—9-methyl—l,2#3/9—tet-rahydro-4H-carbazol-4-one—3—glyoxylate
After dropvise adding 0.2 g of triethylamine to a stirred suspension of 3.00 g (0.01 mole) of the ethoxalyl compound of formula (la), vherein R2 is an ethyl group (chemically 3-ethoxalyl-9-methyl-l ,2,3,9-tetrahydro-4H-car-bazol-4—one), and 0.45 g of paraformadehyde in 20 ml of methanol, the reaction mixture is heated at 55 to 60°C for 1 hour. After cooling the reaction mixture is filtered off, the precipitate is vashed with methanol and dried to give 2.45 g (78.7%) of the title compound, m.p.: 238-242°C (with decomposition). IR spectrum (KBr) , >'j„ax: 0-H 3350 cm-1 (broad) O II 0 1782 cm-1 (alpha-oxo + ester) 1628 cm”i (alpha-oxo + ester) c-o-c 1137 cm-1 (ester) C-OH 1056 cm“i Ar-H (bending) 744 cm"i iH-NHR (DMS0-d6) 6 ppm: -ch2- 2 , . 1 (1H, m) 2 , .55 (1H, m) -ch2- 2. , 98 (1H, m) 3 . .20 (1H, m) CH3-0- 3 . .25 (3H, s) CH3-N 3. .68 (3H, s) -c-ch2oh 3. .99 (1H, d) 4. .50 (1H, d) Ar-H 7 . .21 (2H, m) 7 . .47 (1H, dd) 8 . , 00 (1H, dd)
Example 4
Preparation o£ ethyl 3-hydroxymethyl-9-methyl-l,2,3/9-tetra-hydro-4H-carbazol-4—one-3-glyoxylate
The process described in Example 3 is folloved, except that ethanol is used instead of methanol. In this way 2.65 g (80.55%) of title compound are obtained, m.p. : 240-245°C (with decomposition). IR spectrura: the characteristic bands are identical with those of the methyl ester. iH-NMR (DMS0-d6) S ppn: ch3ch2- 1 .15 (3H, t) -ch2- 2, .05 (1H, m) 2, .58 (1H, m) ch2- 2. .97 (1H, m) 3 , . 18 (1H, m) °-CH2~CH3 3, .45 (2H, q) ch3-n 3 , . 68 (3H, s) -c-ch2oh 3. ,94 (1H, d) 4 . ,48 (1H, d) Ar-H 7. ,21 (2H, m) 7. ,47 (1H, dd) 8. , 00 (1H, dd)
Example 5
Preparation of 3-hydroxymethyl-9-methyl-l,2,3,9—tetrahydro-—4H-carbazol-4—one-3—glyoxylic acid lactone (compound of formula (Ic)]
After adding 0,1 g of triethylamine to a stirred suspen-sion containing 3.00 g (0.01 mole) of the ethoxalyl compound of the formula (la), vherein R2 means an ethyl group (for the Chemical name see Example 3) in 20 ml of acetone, 1.13 g (0.015 mole) of formol solution are dropvise added to the mixture. The suspension becomes clear within 1 to 2 minūtes and crystals begin to precipitate. After further stirring at 35 to 40°C for one hour, the reaction mixture is cooled down 16 to room temperature, filtered off, the precipitate is vashed with 50% acetone and dried to give 2.10 g (74.2%) of the title compound, m.p.: 242-244°C. IR spectrum (KBr),y nax: 5 O-H 1794 cm-1 (lactone) C=0 1782 cm-3· (alpha-oxo) C=0 1642 cm-1 (carbazol-4 c-o-c 1259 cm"1 Ar (skeleton vibration) 1579 cm-1 10 Ar-H (bending) 755 cm"* lH- •NHR (DMSO -d6) δ ppm: -ch2- 2.4 (1H, m) 2.75 (1H, m) -ch2- 3.09 (1H, m) 15 3.78 (1H, m) ch3-n- 3.75 (3H, s) -c-ch2o 4.53 (1H, d) 5.04 (1H, d) Ar-H 7.22 (2H, m) 20 7.53 (1H, dd) 7.92 (1H, dd)
Example 6
Preparation of 3-hydroxymethyl-9-methyl-l/2,3/9-tetrahydro-—4H-carbazol—4-one-3—glyoxylic acid lactone [compound of 2 5 formula. (Ic) ]
To a suspension containing 29.93 g (0.10 mole) of 3--ethoxalyl-9-methyl-l, 2,3,9-tetrahydro-4H-carbazol-4-one and 10.5 g (0.14 mole) of formol solution in 200 ml of acetonit-rile, 1.0 g (0.0072 mole) of potassium carbonate is added. 30 The reaction mixture is stirred at 30 to 35eC for one hour.
Subsequently, the process described in Example 5 is folloved to obtain 22.46 g (75.04%) of the title compound, m.p.: 240-243 °C.
The spectroscopic data of the product are identical with - 17 - LV 10948 those of the product of Example 5.
Example 7
Preparation of ethyl 3-hydroxymethyl-9-methyl-l/2,3/9-tetra-hydro-4H-carbazol-4-one—glyoxylate
To a mixture containing 0.85 g (0.003 mole) of 3-hydr-oxymethyl-9-methyl-l, 2,3,9—tetrahydro—4H-carbazol-4-one—3-—glyoxylic acid lactone of the formula (Ic) and 18.0 of ethanol, 0.2 g of concentrated sulfuric acid is dropwise added under stirring. The reaction mixture is boiled under reflux for 3 hours, then cooled down and filtered off. The precipitate is washed vith ethanol and dried to give 0.35 g (35.43%) of the title compound, m.p.: 241-245°C (vith decom-position).
The spectroscopic data of the product are identical with those of the product of Example 4.
Example 8
Preparation of ondansetron base (chemically 9-methyl-3—[(2-—methyl-lH-imidazol-l-yl) methyl]—1/ 2,3,9-tetrahidro—4H—car-bazol-4-one) A mixture containing 2.83 g (0.01 mole) of 3-hydroxy-methyl-9-methyl-l ,2,3,9-tetrahydro—4H—carbazol-4-one—3-gly-oxylic acid lactone of the formula (Ic), 15 ml of dioxane, 1.32 g of triethylamine, 1.0 g of ethanol and 1.64 g (0.02 mole) of 2-methylimidazole is boiled under reflux while stirring for 5 hours. Thereafter, the reaction mixture is diluted vith 45 ml of vater and cooled dovn. The precipitate is filtered off, washed with aqueous dioxane ar.d dried to obtain 2.56 g (87.3%) of the title compound, m.p.: 220- 223 °C. IR spectrum (KBr), P nax: n II o 1623 cm"1 Ar (skeleton) 1579 cm-1 n-ch3 1483 1460 cm"^· cm-1 18
HetAr-H (bending) 781 cm-1
Ar-H (bending) 758 cm-1 i-H-NHR (DHSO-d6) 6 ppm: -CH2- 1 .98 (1H, a, 2 .17 (1H, e, ch3-c 2 .67 (3H, s) ”CH2“ 2. .94 (1H, a) 3, .11 (1H, e) -CH- 3 , .10 (1H, m) ch3-n 3. .68 (3H, s) -ch-ch2-n 4. .30 91H, dd) 4 . ,68 (1H, dd) Ar-H 7. 25 (2H, m) 7. ,50 (1H, dd) 8 . 03 (1H, dd) HetAr-H 7. 57 (1H, d) 7. 67 (1H, d) axial) eguatorial)
Example 9
Preparation of ondansetron base A mixture containing 3.29 g (0.01 mole) of ethyl 3—hydr-oxymethyl-9-methyl—1,2,3,9-tetrahydro—4H—carbazol-4-one—3-—glyoxylate of the formulā (Ib), 10 ml of dimethylsulfoxide, 1.32 g of triethylamine, 0.5 g of ethanol and 1.64 g (0.02 mole) of 2-methylimidazole is stirred at 110 to 120°C for 3 hours. After diluting the reaction mixture with 40 ml of water, cooling down and filtering off, the precipitate is vashed with water and dried to obtain 2.20 g (75%) of the title product, m.p.: 219-223°C.
The spectroscopic data of the product are in agreement with those of the product of Example 8.
Example 10
Preparation of ondansetron base a) Preparation of 9— methyl—3— ( (2—methyl—1H— imidazol—1-—yl) methyl]-l ,2,3,9-tetrahydro-4H-carbazol-4-one-glyoxylic 19 LV 10948 acid (compound of formula (Id) ] A mixture containing 2.83 g (0.01 mole) of 3-hydroxy-methyl-9—methy 1-1,2,3,9-tetrahydro-4H-carbazol—4—one-3-gly~ oxylic acid lactone [compound of the formula (Ic)] and 1.64 g (0.02 mole) of 2-methylimidazole in 6.0 ml of sulfolane (tetramethylenesulfone) is heated in an oil bath of 150 to 160°C for 15 minūtes while stirring. After cooling dovn and diluting with 60 ml of acetone the precipitate is filtered off, washed with acetone and dried to give 0.95 g of the title compound, m.p.: 190-200eC (with decomposition). The active aģent content of this product measured by titration with perchloric acid in glacial acetic acid was found to be 96%. In the combined filtrate of the reaction, ondansetron could be detected by thin layer chromatography. The most important characteristics of the title product are as fol-lows: IR spectrum (KBr), )’max: Χ-Η 3440 cm-1 2650 cm-1 2550 cm“i 1973 crn-1 C=0 -C00- Ar-H (bending) 1628 cm-1 (alpha-οχο + carbazol-4-one) 1595 cm_i 763 cm-1 b) Preparation of ondansetron base A suspension containing 0.73 g (0.002 mole) of the product of the formula (Id) prepared in the preceding step a) and 0.40 g (0.0061 mole) of 85% potassium hydroxide in 20 ml of water is stirred at 45 to 50°C for one hour. After cooling down and filtering off the suspension, the precipitate is thoroughly washed with water and dried to give 0.50 g (85.32%) of the title product, m.p.: 223-225°C.
The spectroscopic data of the product are in agreement with those of the product of Example 8. 20
The active aģent content of the product was found to be 97.6% based on the potentiometric titration with hydro-chloric acid.
Example 11 5 Preparation o£ 9-methyl-3-[ (2-methyl-iH-imi<Jazol-i-yl)- methyl]—1/2,3,9-tetrahydro-4H-carbazol—4-one hydrochloride dihydrate
The process described in Example 8 is followed, except that after cooling down the reaction mixture to room tem-10 perature after boiling, 20 ml of 37% aqueous hydrochloric acid are added thereto. Then, the precipitate is filtered off, vashed with isopropanol and dried to obtain 2.40 g (65.6%) of the title salt, m.p.: 178-180°C.
The active aģent content of the product was found to be 15 100.3% based on potentiometric titration with sodium hydr- oxide solution.
The theoretical water content is 9.85% (calculated for C18H19N3O·HCl·2Η2θ). The vater content measured is 10.03%. 20 25 30 LV 10948
What we claim is: 1. Novel compounds of the formula 0
(I) , wherein A stands for a group of formula — ch2-R (v)' wherein R means a hydroxyl or 2-methyl-lH-imidazol—l-yl group; B represents a group of formula 0 II (VI), -C-COORļ wherein Rļ means hydrogen or a methyl or ethyl group; or A and B together form a group of formula
0H Λ coor2 wherein R2 means a methyl or ethyl group; or A and B together form a group of formula (VII), / z^0 C (vni)· '-c^o
II 0 2. A compound selected from the group consisting of 3-ethoxalyl-9-methyl-l,2,3,9-tetrahydro-4H-carbazol-4- -one, methyl 3—hydroxymethyl-9—methyl—1,2,3,9—tetrahydro—4H--carbazol-4-one-3^glyoxylate, ethy 1 3-hydroxymethyl-9-methyl-l ,2,3,9-tetrahydro-4H-—carbazol—4-one-3-glyoxylate, 3—hydroxymethyl—9-methy1—1,2,3,9—tetrahydro-4H—carbazol-—4-one—3—glyoxylic acid lactone and 9-methyl—3-[(2—methyl-lH-imidazol—1—yl)methyl]—1,2,3,9-—tetrahydro—4H-carbazol-4—one—3—glyoxylic acid. 3. A novel process for the preparation of the compounds of the formula 0
A B CH- (I), vherein A stands for a group of formula (V), ch2-r LV 10948 wherein R roeans a hydroxyl or 2-methyl-lH-imidazol—l-yl group; B represents hydrogen or a group of formula 0II— c—COORļ (VI), vherein Rļ means hydrogen or a methyl or ethyl group; or A and B together forir. a group of formula 0H Λcoor2 wherein R2 means a methyl or ethyl group; or A and B together form a group of formula (VII), ,ch2. ‘0 CII 0 :vm: which comprises a) reacting the ketone of formula 0
(III) with a di(C1_2alkyl)oxalate in the presence of a basie aģent in order to obtain a novel compound of the formula (la), wherein R2 stands for a methyl or ethyl group; b) reacting a compound of the formula (la), wherein R2 is as defined in step a) above, with formaldehyde in the 24 presence of a basie catalyst in a non-acidic protic solvent, in order to obtain a novel compound of the formula (Ib) , wherein Rļ is a methyl or ethyl group; or reacting a compound of the formula (la), wherein R2 is as defined in step a) above, with formaidehyde in the presence of a basie cata-lyst in an aprotic solvent in order to obtain the novel compound of the formula (Ic); c) reacting a compound of the formula (Ib), wherein Rļ is as defined in step b) above, or the compound of the formula (Ic) with 2-methylimidazole of the formula (IV) in order to obtain the novel compound of the formula (Id); d) reacting the compound of the formula (Id) with a base, preferably an alkali mētai carbonate or hydroxide, in order to obtain ondansetron of the formula (II), and, if desired, converting ondansetron of the formula (II) into its pharmaceutically acceptable acid addition salt. 4. A process as elaimed in elaim 3, variant b) , which comprises carrying out the reaction of the compound of the formula (la) , wherein R2 is as defined above, with form-aldehyde by using 1 to 2 moles, preferably 1.2 to 1.6 moles of formaldehyde in the presence of not more than 0.2 mole of a basie catalyst, preferably an alkaline mētai carbonate or a trialkylamine. 5. A process as elaimed in elaim 3, variant b) for the preparation of the compounds of the formula (Ib), wherein Rļ is as defined above, which comprises carrying out the reaction with formaldehyde in a Cļ_2alkanol. LV 10948
CARBAZOLONE DERIVATIVES AND PROCESS FOR PREPARING SAME 5
Abstract
The invention relates to carbazolone derivatives of the formula 10 0 15
A B (I), 20 wherein A stands for a group of formula
ch2-R (V) , wherein R means a hydroxyl or 2-methyl-lH-imidazol-l-yl group; B represents a group of formula 25 0 -C-COORļ (VI)' wherein R^ means hydrogen or a methyl or ethyl group; or 30 A and B together form a group of formula
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9203222A HU212934B (en) | 1992-10-14 | 1992-10-14 | Process for producing novel alkoxalylated carbazolone derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LV10948A LV10948A (en) | 1995-12-20 |
| LV10948B true LV10948B (en) | 1996-04-20 |
Family
ID=10982420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LV931096A LV10948B (en) | 1992-10-14 | 1993-09-27 | Carbazolone derivatives and process for preparing the same |
Country Status (3)
| Country | Link |
|---|---|
| HU (1) | HU212934B (en) |
| LT (1) | LT3074B (en) |
| LV (1) | LV10948B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU579132B2 (en) | 1984-01-25 | 1988-11-17 | Glaxo Group Limited | Heterocyclic compounds |
| GB8518742D0 (en) | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
| GB8518741D0 (en) | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
-
1992
- 1992-10-14 HU HU9203222A patent/HU212934B/en unknown
-
1993
- 1993-09-27 LV LV931096A patent/LV10948B/en unknown
- 1993-10-04 LT LTIP1401A patent/LT3074B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| LV10948A (en) | 1995-12-20 |
| HU9203222D0 (en) | 1993-01-28 |
| HU212934B (en) | 1996-12-30 |
| HUT67103A (en) | 1995-02-28 |
| LTIP1401A (en) | 1994-05-15 |
| LT3074B (en) | 1994-11-25 |
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