HU212934B - Process for producing novel alkoxalylated carbazolone derivatives - Google Patents

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

The present invention relates to novel alkoxalylated carbazolone derivatives of formula (I): wherein A is hydroxymethyl;

And B is a group of Formula IV wherein R ₂ is methyl or ethyl

A and B together are a group of formula (ΙΠ) wherein R 1 is methyl or ethyl - or a group of formula (V).

The compounds of the present invention are novel compounds which are not described in the literature.

Particularly important novel compounds of the present invention are: 9-methyl-3-ethoxalyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (in its enol tautomeric form), 9-methyl-3- ( hydroxymethyl) -1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylic acid methyl ester, 9-methyl-3- (hydroxymethyl) -1,2,3,9 -tetrahydro-4H-carbazol-4-one-3-glyoxylic acid ethyl ester, 9-methyl-3- (hydroxymethyl) -1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylic acid lactone .

The present invention is based on the discovery that 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl) is a very advantageous intermediate of the compounds of formula (I) wherein the substituents are as defined above. -1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate, commonly known as Ondansetron. This drug is an excellent antiemetic drug due to its 5-HT ₃ (serotonin-ΠΙ) receptor antagonist activity. (See British Patent No. 2,153,821).

The present invention therefore relates to a process for the preparation of carbazolone derivatives of the formula I wherein A and B are as defined above, by reacting a ketone of the formula II with oxalic acid di-C 1-2 alkyl ester. and reacting in the presence of a basic agent, if desired, to yield the enol tautomeric compound of formula (Ia) wherein R 1 is methyl or ethyl, in the presence of a basic catalyst, formaldehyde in a C 1 -C 2 alkanol, and the resulting compound of formula Ib, wherein R _{2 is} methyl or ethyl, is isolated or, if desired, the ) is reacted with formaldehyde in the corresponding enol form tautomeric compound of basic catalyst, and then isolating the resulting (Ic) compound, or if desired, the compound of formula (Ic) by acid catalyzed alcoholysis (Ib), a compound of formula - wherein R ₂ is as defined above - converted.

According to the literature, it was not expected that a ketone of formula (CH) with lower reactivity than simple cyclic ketones such as cyclohexanone, known from J. Chem. Soc. 1957, 2227-2231 (chemical name: 9-methyl, 2,3,9-Tetrahydro-4H-carbazol-4-one), which is also understood as a vinyl analogue acid amide, can be subjected to simple ester condensation. The condensation with the oxalic acid diethyl ester results in a novel compound of formula (Ia) wherein R is ethyl

-, chemically known as 9-methyl-3-ethoxalyl-1,2,3,9-tetrahydro-4H-carbazol-4-one. This compound is present in the enol tautomeric form by infrared spectroscopic analysis. The formaldehyde reaction of this compound gives the lactone of formula (Ic), chemically known as 9-methyl-3-hydroxymethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylic acid lactone, which has less spontaneous formation. it was expected and obvious that no other derivative of the resulting 2-oxaspiro [4,5] decane-3,4,6-trione skeletal system was found in the literature.

Of formula (Ia) - present in the enol form - ethoxalyl ketone - wherein R, is ethyl - when performed in methanol with formaldehyde C hidroximetilezése the compound of formula (Ib): - wherein R ₂ is methyl - chemical 9-methyl-3- (hydroxymethyl) -3-methoxalyl-1,2,3,9-tetrahydro-4H-carbazol-4-one was formed even at room temperature. Surprisingly, besides C-hydroxymethylation, there is not only a simple transesterification, but also a spontaneous lactone closure following C-hydroxymethylation followed by a secondary methanolytic opening of the compound (Ic) containing the slightly stretched lactone ring.

The foregoing was also experimentally aerated to give 9-methyl-3- (hydroxymethyl) -1,2,3,9-tetrahydro-4H-carbazol-4-one-3-one, chemically described above. The glyoxylic acid lactone compound was heated to methanol or ethanol to convert the corresponding alcohol into the corresponding open hydroxy acid ester, i. e., Ib.

In the oxalic acid diester reaction according to the invention, an equimolar amount of an alkali metal alcoholate is preferably used as the basic agent and the compounds of formula (Ia) are isolated by acidifying the reaction mixture.

In the process of the invention, the formaldehyde reaction of the compounds of formula (Ia) with formaldehyde is carried out in the presence of 1-2 moles, preferably 1.2-1.6 moles, of up to 0.2 moles of basic catalyst, preferably alkali metal carbonate or trialkylamine. The alkali metal carbonate may be potassium or sodium carbonate and the trialkylamine may be triethylamine.

For the preparation of compounds of formula Ib, the formaldehyde reaction is carried out in a C 1 -C 2 alkanol, while for the preparation of compound of formula Ic the reaction of formaldehyde is carried out in a dipolar aprotic solvent.

In one embodiment of the process of the present invention, a solution of the ketone of formula II and the oxalic acid diester in ethereal solvent is added in the presence of solid sodium alcoholate or in the presence of a small amount of anhydrous alcohol. The resulting reaction mixture is acidified, diluted with water, and the precipitated compound of formula (Ia) is converted, after plating, into an organic compound of formula (Ib) or (Ic) in an organic solvent with formaldehyde in the presence of a basic catalyst.

Advantageous results are obtained when 1.0 to 1.6, preferably 1.2 to 1.4 moles, per 1.0 mole of ketone II are obtained.

Oxalic acid diethyl ester and metal sodium or sodium alcoholate are added in a water-miscible anhydrous ethereal solvent, preferably dioxane, 1,2-dimethoxyethane or tetrahydrofuran. The slightly heat-producing reaction is carried out at 20-100 ° C for 1-10 hours, preferably at 4070 ° C for 2-6 hours, followed by acidification, preferably glacial acetic acid. After dilution with water, the compounds of formula (Ia) are isolated by filtration.

The compounds of formula (Ia) thus obtained are prepared in methanol or ethanol at a concentration of 1 to 2 mol, preferably 1.2

Using 1.6 moles of formaldehyde to form a compound of formula Ib at 20-100 ° C, preferably 3060 ° C, while the spirolactone Ic is in an alcohol-free medium, water-miscible aprotic solvents, preferably acetone, acetonitrile, dioxane, 20-60, preferably 30-40 'Con in dimethylformamide, working with the aforementioned excess of formaldehyde.

The catalyst used in the formaldehyde reaction is a weak base, preferably an alkali metal carbonate or a tertiary amine, in an amount of 1 to 20, preferably 3 to 10 mol%.

The advantages of the process according to the invention are as follows:

a) a readily feasible, well-directed reaction for the further conversion of the below-average reactive ketone of formula (II) was obtained and the resulting new intermediates were readily converted to the drug drug Ondansetron;

(b) the inexpensive and commercially available oxalic acid diester has proved to be an ideal and sufficiently active reagent,

c) Oxalic acid diester condensation can occur only once due to the already mentioned enolization of the product formed and formation of the H-chelate, so that formaldehyde reactions are also selective, which is not always adjustable for similar types of condensation, such as Mannich condensation,

d) each reaction according to the invention provides a crystalline product which is well-filterable and manageable, in a yield of more than 70%, by simple processing of the reaction mixture,

(e) all reagents and solvents used, except the ketone of formula (II) known per se, are readily available as inexpensive industrial starting materials.

The invention is illustrated by the following non-limiting examples.

Example I

Preparation of 9-Methyl-3-ethoxalyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (R 1 = ethyl)

19.93 g (0.1 mol) of 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one of formula II, 19.0 g (0.13 mol) of oxalic acid diethyl ester, To a stirred mixture of 2 g of ethyl alcohol and 200 ml of dioxane was added 3.0 g (0.13 g) of sodium metal. The slightly warming reaction mixture was stirred at 40-50 ° C for 4 hours, then 16 g of glacial acetic acid and 200 ml of water were added at room temperature. The yellow crystalline suspension was filtered, and the filtered product was washed with water and dried.

Product: 24 g (80.2%) of the title compound.

M.p. 118-120'C.

Content of material measured by caustic potentiometric titration:

IR: OH 3600-2000 cm ^-1 , C = O (ester) 1727 cm ^-1 ,

O = CC = C 1590 cm -1, 1578 cm ^-1 , COC (ester)

1213 cm ^-1 , = C-OH (enol) 1185 cm ^-1 , Ar-H (def.)

754 cm ^-1 .

H-NMR (DMSO-de): C / 7 CH _{3 2-1.47} (3H, t), -CH ₂ 2.75 (2H, t), -CH _{2 to} 3.12 (2H, t); -CH ₃ -N 3.60 (3H, s), -CH ₃ -CV / 2-O 4.36 (2H, q), Ar -H 7.24 (2H, m), 8.00 (1H, dd), 8.13 (1H, dd).

Example 2

9-methyl-3-ethoxyoxalyl-1,2,3,9-tetrahydro-4H-carbazol-4-one [(Ia): wherein R, _is ethyl group] Preparation of

To a stirred mixture of 19.93 g of ketone II (its chemical name is given in Example 1), 19 g of oxalic acid diethyl ester and 200 ml of 1,2-dimethoxyethane, 7.1 g (0.13 mol) of solid sodium methylate was added. Following the procedure of Example 1, 23.1 g (77.2%) of the title compound are obtained.

Melting point: 117-120 ° C.

The titrimetric content is 97.9%.

The spectroscopic data were identical to that described in Example 1.

Example 3

9-methyl-3- (hydroxymethyl) - 1,2,3,9-tetrahydro-3-methoxalylbiphenyl-4H-carbazol-4-one [compound (Ib), with R ₂ = methyl]

3.00 g (0.01 mol) of the ethoxalyl compound of formula Ia - wherein R 1 is is a stirred suspension of ethyl (chemically known as: 9-methyl-3-ethoxalyl-1,2,3,6,9-tetrahydro-4H-carbazol-4-one) and 0.45 g of paraformaldehyde in 20 ml of methanol, Triethylamine (2 g) was added dropwise and the reaction mixture was heated at 55-60 ° C for 1 hour. The cooled reaction mixture was filtered, and the filtrate was washed with methanol and dried.

Product: 2.48 g (78.7%) of the title compound.

Melting point: 238-242 ° C (dec.).

IR: OH 3350 ^cm-1 (broad), 1782 cm ^-1 C = O (alfaoxo + ester), 1628 cm ^-1 (ester alfaoxo +), COC

1137 cm ^-1 (ester), C-OH 1056 cm ^-1 , Ar-H (def.)

744 cm ^-1 ,

1 H-NMR (DMSO-d ₆ ) -CH ₂ - 2.1 (1H, m), 2.55 (1H, m), -CH ₂ - 2.98 (1H, m), 3.20 (1H, m), -CH ₃ -O 3.25 (3H, s), -CH ₃ -N 3.68 (3H, s), -C-CH, OH 3.99 (1H, d), 4.50 (1H , d), Ar-H 7.21 (2H, m), 7.47 (1H, dd), 8.00 (1H, dd).

Example 4

9-methyl-3- (hydroxymethyl) -3-ethoxalyl -], 2,3,9-tetrahydro-4H-carbazol-4-one [compound (Ib), with R ² = ethyl]

The procedure was the same as in Example 3 except that ethanol was used instead of methanol. Product: 2.65 g (80.55%) of the title compound.

Melting point: 240-245 ° C (decomposed).

IR: characteristic bands identical to methyl ester.

HU 212 934 Β

H-NMR _(DMSO-d6): C7 / ₃ -CH _2-1.15 (3H, t), -CH ₂ 2.05 (1H, m), 2.58 (1H, m), -CH ₂ - 2.97 (1H, m), 3.18 (1H, m), _{O-CH2 -CH3} 3.45 (2H, q) _CH3 -N 3.68 (3H, s), -C -CH ₂ OH 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 9-Methyl-3- (hydroxymethyl) -1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylic acid lactone (1c) 3.0 g (0.01 mol) of ethoxalyl of formula Ia To a suspension of the compound R 1 is ethyl (see Example 3 for its chemical name) is added 0.1 g of triethylamine under stirring in 20 ml of acetone and then 1.13 g (0.015 mol) of formalin is added dropwise. The slurry was clarified within 1-2 minutes and crystallization started. After stirring for 1 hour at 35-40 ° C, the reaction mixture, which was cooled to room temperature, was filtered and the product filtered off was washed with 50% acetone and dried.

Product: 2.10 g (74.2%) of the title compound.

Melting point: 242-244 ° C.

IR: C = O 1794 cm ^-1 (lactone), C = O 1782 cm ^-1 (alpha oxo), C = O 1642 cm ^-1 (carbazol-4-one), COC 1259 cm ^-1 , Ar (backbone). 1579 cm ^-1 , Ar-H (def.) 7.55 cm ^-1 .

1 H-NMR (DMSO-d ₆ ): -CH ₂ - 2.4 (1H, m), 2.75 (1H, m), -CH ₂ - 3.09 (1H, m), 3.78 (1H , m), -CH ₃ -N3.75 (3H, s), -C-CH ₂ O 4.53 (1H, d), 5.04 (1H, d), Ar-H 7.22 (2H, m), 7.53 (1H, dd), 7.92 (1H, dd).

Example 6

Preparation of 9-methyl-3- (hydroxymethyl) -1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylic acid lactone (Ic)

29.93 g (0.10 mol) of 9-methyl-3-ethoxalyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 10.5 g (0.14 mol) of formalin in 200 ml of acetonitrile To this suspension was added potassium carbonate (1.0 g, 0.0072 mol). The resulting reaction mixture was stirred for 1 hour at 30-35 ° C and then proceeded as in Example 5 below.

22.46 g (75.04%) of the title compound are obtained. Melting point: 240-243 ° C.

The spectroscopic data are the same as in Example 5.

Example 7

Preparation of 9-Methyl-3- (hydroxymethyl) -3-ethoxalyl-1,2,3,9-tetrahydto-4H-carbazol-4-one (Compound 1b where R ₂ = ethyl)

To a stirred mixture of 0.85 g (0.003 mol) of 9-methyl-3-hydroxymethyl-1,2,3,9-tetrahydro-4H-carbazol-1-one-3-glyoxylic acid lactone (Ic) in 18.0 ml of ethanol 0 Concentrated sulfuric acid (2 g) was added dropwise, the reaction mixture was refluxed for 3 hours, then cooled, filtered, washed with ethanol and finally dried.

Product: 0.35 g (35.43%) of the title compound.

Melting point: 241-245 ° C (decomposed).

The spectroscopic data are the same as in Example 4.

Claims (4)

PATENT CLAIMS A process for the preparation of a compound of formula (I) wherein: A is a hydroxymethyl group, And B is a group of Formula IV wherein R ₂ is methyl or ethyl A and B together form a group of formula (III) wherein R _t is methyl or ethyl - or a group of formula (V) - wherein the ketone of formula (II) is oxalic acid di (C 1-2 alkyl) ester in the presence of a solvent and a basic agent, optionally reacting the resulting enol tautomeric compound of formula (Ia) wherein R 1 is methyl or ethyl in the presence of a basic catalyst with C 1-2 alkanol with formaldehyde. The compound of formula (Ib), wherein R _{2 is} methyl or ethyl, is isolated or, if desired, the resulting enol tautomeric compound of formula (Ia) is reacted with formaldehyde in the presence of a basic catalyst, and the resulting compound of formula (Ic) is isolated. or, if desired, the compound of formula (Ic) by acid catalyzed alcoholysis (1b) to a compound of the general formula wherein R ₂ is as defined above. 2. A process according to claim 1, wherein the basic agent used in the oxalic acid diester reaction is an equimolar amount of an alkali metal alcoholate and a compound of formula (Ia) wherein R 1 is hydrogen. is methyl or ethyl - isolated by acidifying the reaction mixture. Process according to claims 1 and 2, characterized in that the reaction of the compound of formula (Ia), wherein R 1 is as defined above, with 1 to 2 moles, preferably 1.2 to 1.6 moles, of formaldehyde up to 0 2 moles of basic catalyst, preferably alkali metal carbonate or trialkylamine. A process for the preparation of a compound of formula (Ic) according to claim 1, wherein the compound of formula (Ia) wherein R is a methyl or ethyl formaldehyde reaction in a dipolar aprotic solvent.