HU227040B1 - Process for producing indole-5-carbaldehides - Google Patents

Abstract

Indole-5-carb-aldehyde of general formula (I) (R 1: H atom, 1-6C alkyl group or benzyl group) is prepared from an acetal of general formula (III) (R:1-6C alkyl group, or phenyl(1-4C alkyl group, and where two R groups. together form a 1-6C straight or branched alkyl chain linking two 'O' atoms) and from N,N-dimethyl-formamide-dimethyl-acetal to yield compound. (IV) (R: as before). Compound (IV) is reduced and an indole derivative of general formula (V) is obtained (R: as before). Compound (V) may be treated with a compound., suitable for the introduction of an 1-6C alkyl or a benzyl group The indole compound. of general formula (V) or (VI) is hydrolysed (R and R 1as before) and an indole derivative of formula (I) is obtained. This has a H atom in position R 1. This indole-5-carbaldehyde may be reacted with a suitable alkylating agent for the introduction of a 1-6C alkyl or a benzyl-group.

Description

The present invention relates to a process for the preparation of an indole-5-carbaldehyde of the formula I wherein R ¹ is hydrogen, C 1-6 alkyl or benzyl. The compounds of formula (I) are valuable starting materials for the preparation of pharmaceutically important active compounds, such as naratriptan (N-methyl-3- (1-methyl-4-piperidineacyl) -1H-indole-5-ethanesulfonamide) having anti-migraine activity.

It is known in the literature that indole-5-carbaldehydes are difficult to access and the known methods are unsuitable for industrial applications. The main reason for this is that no indole synthesis has been reported that would directly produce an indole containing a formyl group (or its protected form) at the 5-position of the indole ring. In each case, the formyl group at the 5-position is formed from another functional group in a complex, multiple reaction step that is not commercially feasible. Thus, according to French Patent No. 1,344,579, indole-5-carbaldehyde is prepared by reducing the indole-5-carboxylic acid ester with lithium aluminum hydride to the corresponding alcohol and then oxidizing the alcohol to the aldehyde. Chem. Pharm. Bull. 34, 4116 (1986) reported that 5-hydroxymethylindole is oxidized with manganese (IV) oxide to give the corresponding aldehyde in 92% yield. According to French Patent No. 1,394,371, 5-bromoindole is converted to the corresponding 5-cyanoindole with copper (I) cyanide and the nitrile group is reduced to the aldehyde. J. Org. Chem.

According to the above publication and Hungarian Patent Application HU 204 509, 5-bromoindole is prepared by synthesis in the presence of N, N-dimethylformamide dimethylacetal. The process has several disadvantages. On the one hand, the yield is poor and, on the other hand, they operate at extremely low temperatures (-78 ° C), and extremely flammable reagents (such as diethyl ether, potassium hydride, tertiary butyllithium) are used.

One widely used method for the synthesis of indoles is the Leimgruber-Batcho synthesis, which involves condensation of an ortho-nitrotoluene derivative with Ν, Ν-dimethylformamide dimethylacetal and the reduction of the nitro group of the resulting enamine to an indole derivative ( Scheme 1, wherein X is a substituent) [J. A. Joule, K. Mills: Heterocyclic Chemistry, 357-358. Fourth edition, Blackwell Science Ltd., Oxford, UK, 2000]. Although the Leimburger-Batcho method is widely applicable for the preparation of benzene ring-substituted indole derivatives from appropriately substituted ortho-nitrotoluenes, it is not suitable for the preparation of the 3-methyl-4-nitrobenzaldehyde (I) synthesizing indole-5-carbaldehyde.

The object of the present invention is to overcome the drawbacks of the known processes.

It is an object of the present invention to provide a process for the preparation of indole-5-carbaldehydes which is commercially feasible and in good yield.

Surprisingly, it has been found that using Leimgruber-Batcho synthesis from an acetal of formula (III) wherein R is C 1-6 alkyl or phenyl (C 1-4 alkyl), but the two R groups together are It may also represent a straight-chain or branched C 6 -alkyl chain linking the two oxygen atoms to provide the indole-5-carbaldehyde of formula (I) in good yield and in simple steps.

According to the invention, an acetal of formula (III) is reacted with N, N-dimethylformamide dimethylacetal, the resulting enamine of formula (IV) wherein R is as above is treated with a reducing agent and the resulting compound (V) is obtained. an indole derivative of the formula wherein R is the above alkylating agent, optionally having a C 1 -C 6 alkyl or benzyl group, and then the indole derivative of formula V or the compound of formula VI wherein R and R ¹ are as defined above. , hydrolyze and, if desired, reacting the resulting indole-5-carbaldehyde of formula (I) wherein R ¹ is hydrogen with an alkylating agent for the introduction of a C 1-6 alkyl group or a benzyl group.

In the formula (I), R ¹ is preferably hydrogen or benzyl.

The acetal of formula (III) is prepared by reacting the aldehyde (II) in a manner known per se with the appropriate alcohol or diol in the presence of an acid catalyst, optionally with continuous removal of the resulting water. Preferred are C 1-6 alcohols, C 1-3 straight chain and C 1-6 branched diols, especially ethylene glycol. The reaction may be carried out in the presence of a solvent or the alcohol used may also be used as a solvent. Preferably, the solvent is benzene, toluene, dichloromethane, generally at reflux temperature.

In the process according to the invention, the reaction of the acetal of formula III with the N, N-dimethylformamide dimethylacetal is carried out under the usual conditions of Leimgruber-Batcho synthesis. Preferably, the solvent is Ν, Ν-dimethylformamide and the reaction temperature is generally 100-150 ° C. The resulting enamine (IV), which is optionally a mixture of cis and trans isomers, is generally reduced without purification. In fact, the nitro group is reduced using methods known per se for the reduction of the nitro group, under which the acetal group and the enamine moiety are stable under the reaction conditions. Preferably, the reaction is carried out in a neutral or slightly basic medium, preferably in an inert solvent and in the presence of a noble metal catalyst, from 1 to 20 atm. pressure is reduced with hydrogen. Particularly preferred is the reduction in toluene at 5-15% Pd / C

The reaction was carried out in the presence of a catalyst at atmospheric pressure and at room temperature. When the nitro group is reduced, a ring closure also occurs to give the indole derivative (V).

If desired, the indole derivative of formula (V) is reacted with an alkylating agent for the introduction of a C 1-6 alkyl group or a benzyl group, and the resulting acetal group (VI) is removed by hydrolysis. Alternatively, however, the indole derivative of formula (V) may be directly hydrolyzed and the resulting indole-5-carbaldehyde of formula (I) wherein R ¹ is hydrogen is optionally reacted with an alkylating agent for the introduction of a C 1 -C 6 alkyl group or benzyl group. .

Generally, the alkylating agent is the corresponding alkyl halide such as methyl bromide, dialkyl sulfate such as dimethyl sulfate or benzyl halide such as benzyl chloride and the like. and reaction conditions well known in the art.

Hydrolysis of the acetal group is also a well-known basic organic chemical reaction. The hydrolysis is generally carried out in an acidic aqueous medium, usually in the presence of a mineral acid. The reaction mixture may also contain an organic solvent to promote solubility. Preferably, the hydrolysis is carried out in a mixture of tetrahydrofuran and aqueous hydrochloric acid.

The process of the present invention is simple to carry out and allows the economical preparation of the indole-5-carbaldehyde of formula (I).

The process of the present invention has the advantage that it can be carried out in good industrial scale and does not require the use of flammable reagents or extremely low temperatures. A further advantage is the elimination of the synthesis and further reaction of 5-bromoindoles during synthesis.

The invention is illustrated in detail by the following examples.

Example 1

2- (3-Methyl-4-nitrophenyl) -1,2-dioxolane

A mixture of 16.5 g (0.1 mol) of 3-methyl-4-nitrobenzaldehyde and 17 ml (0.3 mol) of ethylene glycol in the presence of 0.2 g (1 mmol) of p-toluenesulfonic acid was heated at 130 ° C for 2 hours. stir in bath. The internal temperature gradually adjusts to 120 ° C. The mixture was dissolved in dichloromethane (160 mL), extracted with saturated sodium bicarbonate solution (30 mL) and water (2 x 30 mL). The collected organic layer was dried over anhydrous magnesium sulfate and evaporated. This gave 19.6 g (93.7%) of 2- (3-methyl-4-nitrophenyl) -1,2-dioxolane as a slightly yellow oil.

MP: 113-4'C / 0.05 mmHg.

/ R (KBr, cm ^-1 ): 1535, 1355.

¹ H-NMR (CDCl ₃ , 200 MHz) δ: 7.98 (d, J = 9.2 Hz, 1H);

7.46 (s, 1H); 7.44 (dd, J = 9.2; 1.8 Hz, 1H); 5.83 (s,

1H); 4.17-4.01 (m, 4H); 2.61 (s, 3H).

Example 2

5- (1,3-Dioxolan-2-yl) -indole

19.4 g (0.093 mol) of 2- (3-methyl-4-nitrophenyl) -1,3-dioxolane and 26.1 ml (0.185 mol) of 94% N, N-dimethylformamide dimethylacetal were added. A solution of N, N-dimethylformamide (1 ml) in nitrogen was stirred at 140 ° C for 25 hours under nitrogen. The mixture darkens strongly. The reaction mixture was evaporated to dryness in vacuo and the residual dark red oil (25.2 g) dissolved in toluene (220 mL) and reduced under hydrogen (3.6 g Selcat Q (10% Pd / C)). The expected amount of hydrogen is consumed in 4 hours while the solution becomes light yellow. The catalyst was filtered off and washed with dichloromethane (100 mL). The solution was concentrated to 50 ml. The precipitated crystals are filtered off and washed with toluene. There was thus obtained 11.2 g (63.6%) of light yellow 5- (1,3-dioxolan-2-yl) indole. Mp 123-5 ° C. The residue of the toluene filtrate was purified by flash chromatography on 70 g of Kieselgel G on dichloromethane to give an additional 1.5 g (8.5%) of a white crystalline product.

127-128 ° C.

IR (KBr, cm ^-1 ): 3330, 1400.

¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 11.15 (bs, 1H); 7.61 (s, 1H); 7.38 (d, J = 8.5 Hz, 1H); 7.35 (d, 3 = 2.7 Hz,

1H); 7.16 (d, J = 8.5 Hz, 1H); 6.45 (d, J = 2.7 Hz, 1H);

5.76 (s, 1H); 4.11-3.83 (m, 4H).

Example 3 Indole-5-carbaldehyde

To a solution of 5- (1,3-dioxolan-2-yl) -indole (1.89 g, 10 mmol) in tetrahydrofuran (38 mL) was added 10% hydrochloric acid (3.8 mL) under ice-cooling. After stirring for 20 minutes in an ice bath, 6 ml of a saturated aqueous sodium bicarbonate solution are added. The organic solvent was distilled off. The residual aqueous mixture was partitioned between ethyl acetate (50 mL), and the organic layer was washed with water (15 mL) and dried over anhydrous magnesium sulfate. The collected organic phase was evaporated. The residue was 1.43 g (-100%) of indole-5-carbaldehyde, a yellowish white crystalline solid.

99-101 C, Liter. 99-101 C [Chem.

Pharm. Bull., 34, 4123 (1986)]. The product is free of impurities based on its NMR spectrum.

IR (KBr, cm ^-1 ): 1660.

¹ H-NMR (CDCl 3, 200 MHz) δ: 10.04 (s, 1H); 8.95 (bs,

1H); 8.18 (s, 1H); 7.77 (dd, J = 8.4, 1.7 Hz, 1H); 7.48 (d, J = 8.4 Hz, 1H); 7.33 (d, J = 3.2 Hz, 1H); 6.70 (d,

J = 3.2 Hz, 1H).

Example 4

1-Benzyl-5- (1,3-dioxolan-2-yl) indole

A mixture of 5- (1,3-dioxolan-2-yl) -indole (0.19 g, 1 mmol), potassium hydroxide powder (0.10 g, 1.78 mmol) and dichloromethane (1 mL) was stirred for 15 minutes, then benzyl bromide (0.18 mL, 1.5 mmol) was added. The mixture was stirred at room temperature for 5 hours and diluted to 20 ml with dichloromethane. The organic layer was washed with water (2 x 10 mL), dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with hexane and filtered. 0.22 g (78.8%) of 1-benzyl-5- (1,3-dioxolan-2-yl) -indole are obtained. M.p. 89-90 'C.

/ R (KBr, cm ^-1 ): 1460, 1390.

¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 7.63 (s, 1H); 7.53 (d,

J = 2.9 Hz, 1H); 7.44 (d, J = 8.4 Hz, 1H); 7.33-7.14

HU 227 040 Β1 (m, 6H); 6.51 (d, J = 2.9 Hz, 1H); 5.76 (s, 1H); 5.43 (s, 2H); 4.10-3.88 (m, 4H).

Example 5

Benzyl indole-5-carbaldehyde

Method 1

To a solution of 1-benzyl-5- (1,3-dioxolan-2-yl) -indole (1.68 g, 6 mmol) in tetrahydrofuran (30 mL) was added 10% hydrochloric acid (3 mL) under ice-cooling. After stirring for half an hour under cooling, 8 ml of a saturated aqueous solution of sodium bicarbonate were added. The organic solvent was distilled off. To the residue was added ethyl acetate (30 mL), washed with water (3x5 mL). The collected organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with heptane and filtered. 1.34 g (95%) of 1-benzylindole-5-carbaldehyde are obtained.

70-72 ° C (2-propanol).

IR (KBr, cm ^-1 ): 1682.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 10.03 (s, 1H); 8.17 (d,

J = 1.2 Hz, 1H); 7.75 (dd, J = 1.6; 8.6 Hz, 1H); 7.37 (d,

J = 8.5 Hz, 1H); 7.33-7.25 (m, 3H); 7.22 (d,

J = 3.2 Hz, 1H); 7.11 (d, J = 7.4 Hz, 2H); 6.71 (dd,

J = 0.7 3.3 Hz, 1H); 5.36 (s, 2H).

Method 2

A suspension of 0.16 g (1.1 mmol) of indole-5-carbaldehyde and 0.10 g (1.8 mmol) of potassium hydroxide powder in 1 ml of dichloromethane was stirred for half an hour at room temperature and then 0.15 ml (1 Benzyl bromide (25 mmol) was added. The mixture was stirred at room temperature for a further 5 hours and then chromatographed to give 0.19 g (73%) of 1-benzylindole-5-carbaldehyde having the same physical properties as in Method 1.

Claims (1)

Patent Claim Point A process for the preparation of an indole-5-carbaldehyde of formula I wherein R ¹ is hydrogen, C 1-6 alkyl, or benzyl, characterized in that an acetal of formula III wherein R is C 1-6 alkyl or phenyl (C 1 -C 4 alkyl), but the two R groups may together be a C 1 -C 6 straight or branched alkyl chain linking the two oxygen atoms by reaction with Ν, Ν-dimethylformamide dimethylacetal, The resulting enamine (IV), wherein R is as defined above, is treated with a reducing agent, and the resulting indole derivative (V), wherein R is as above, is reacted with an alkylating agent, optionally for the introduction of a C 1-6 alkyl or benzyl group. (V) indole derivative of formula I or the compound of formula (VI) wherein R and R ¹ is the case above, is hydrolysed, and if desired wherein an indole-5-carbaldehyde of formula (I) wherein R ¹ is hydrogen is reacted with an alkylating agent for the introduction of a C 1-6 alkyl group or a benzyl group.