MXPA00009623A - Process for the preparation of 3-acyl-indoles - Google Patents

Abstract

The present invention is concerned with the acylation of indoles, specifically the preparation of 3-acylated indoles which may be further treated to provide indoles having an alternative substituent at the 3-position.

Description

ACTION PROCEDURE The present invention relates to the acylation of indoles, in particular, to the preparation of acylated indices in the 3-position which can be subsequently treated, by providing indoles having an alternative substituent in the 3-position. Up to now, the acylation of indoles in the Position 3 has typically been carried out by the method described, for example, in the international patent application PCT / US91 / 07194, ie, by reacting a magnesium salt of indole with an acid chloride: wherein Z is a halogen and R is, for example, substituted pyrrolidinyl, azetidinyl or piperidinyl. The magnesium salt is prepared by reacting the appropriate indole with an alkyl- or aryl-magnesium halide, preferably ethyl magnesium bromide, in an inert solvent, for example, diethyl ether or tetrahydrofuran, at a temperature of about -30. ° C to 65 ° C, preferably about 25 ° C. The acid chloride is prepared by reacting the corresponding acid, for example, with oxalyl or thionyl chloride, in an inert solvent, for example, methylene chloride, diethyl ether or tetrahydrofuran, at a temperature of -10 ° C to 25 ° C. ° C. Acids having a heterocyclic moiety containing a nitrogen can be protected from the resulting acid chloride by substitution of N with a suitable protecting group, for example, carboxybenzyl (CBZ). A solution of the acid chloride is then slowly added to a stirred solution of the magnesium salt at a temperature of -30 ° C to 50 ° C, preferably about 25 ° C, giving the indole acylated in the desired 3-position. This process for the preparation of acylated indices in position 3, which in fact requires the independent preparation of each of the starting materials, is at the same time laborious and prolonged and does not itself easily lead to an increase in commercial scale. The authors of the present report have therefore developed a new methodology for the preparation of acylated indices in position 3 which eliminates the need to independently prepare the aforementioned starting materials. According to the present invention, it is possible to obtain added alkanes in position 3 in good yields by adding solutions of the acid chloride (protected in N if necessary) and the alkyl- or aryl-magnesium halide separately and simultaneously to a solution of indole at "synchronized" rates of molar addition. Thus, the problem addressed by the present invention is to provide a rapid and economically effective method for preparing acylated indices in position 3 which avoids the unsatisfactory convergent synthesis of the prior art, in particular, the need to prepare and isolate the magnesium salt of the indole As an additional measure to save costs, the process of the present invention only requires a molar equivalent of the expensive indole starting material. This contrasts with the two equivalents required by the prior art process and effectively doubles the performance of acylated material based on the indole starting material. According to the present invention, there is provided a process for preparing acylated buffers in the 3-position, which involves preparing the acid chloride as described and then adding the solutions of (i) the acid chloride and (ii) an alkyl halide - or aryl-magnesium separately and simultaneously to a stirred solution of indole so that (a) the two incoming reactant streams do not come into immediate contact, ie, they are added with some separation to prevent them from reacting to each other in instead of with indole, and (b) the two reactants are added at "synchronized" rates of molar addition. Specifically, the invention provides a process for the preparation of a compound of formula (I) wherein R = C 1 -C 4 alkyl, d-C 1 alkoxy, C 3 -C 7 cycloalkyl, or aryl optionally substituted by one or more of hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoro, fluoro (C 1 -C 4 alkyl) and fluoro (C1-C4 alkoxy) and X is hydrogen or one or more substituents independently selected from cyano, halogen, nitro, Ci-Cß alkyl, Ci-Cβ alkoxy, C3-C7 cycloalkyl and aryl optionally substituted by one or more of cyano, halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoro (C 1 -C 4 alkyl) and fluoro (C 1 -C 4 alkoxy); which comprises adding separately and simultaneously to a stirred solution of an indole of formula (II) where X is as defined above; (i) a solution containing an acid chloride of formula RCOCI, where R is as defined above; and (ii) a solution containing an alkyl- or aryl-magnesium halide in such a way that (a) solutions (i) and (ii) are added with sufficient separation to prevent them from reacting with each other; and (b) solutions (i) and (ii) are added at equivalent molar addition rates. According to the particularly preferred characteristics of the invention, the indole of formula (II) is the indole itself or a 5-haloindole and the magnesium halide is an alkyl- or aryl-magnesium halide, preferably ethyl magnesium bromide. The process of the invention is illustrated with the following Examples.

EXAMPLE 1 Preparation of 3- (N-CBZ-2-pyrrolidinylcarboxy) -5-bromoindole -Bromoindole (3.85 kg, 19.6 moles) was added, followed by methylene chloride (12.3 I) to a freshly dried vessel equipped with overhead stirring and maintained under a nitrogen atmosphere. The resulting mixture was stirred at room temperature until a homogeneous solution was obtained, then cooled to 10-12 ° C. Solutions of CBZ-prolinoyl chloride in methylene chloride (20 moles, 1.02 equivalents) and 1M ethylmagnesium bromide in MTBE (37.7 kg, 39.2 moles, 2 equivalents) were then added simultaneously for 2 to 3 hours in opposite sides of the container while maintaining the temperature at 10-15 ° C. These additions should be made in such a way that the two streams do not mix and so that the molar addition rates of each reactant are continuously synchronized. The resulting suspension was added to a vigorously stirred mixture of concentrated HCl (3 I), demineralized water (28 I) and THF (29 I) for 30 minutes, keeping the temperature below 25 ° C. The resulting biphasic mixture was stirred for 30 minutes, allowed to decant for 20 minutes and then the phases were separated, retaining the upper organic layer. The organic layer was washed with saturated aqueous NaHCO3 (28 I) for 20 minutes at 20-25 ° C, allowed to decant for 20 minutes and then the phases were separated, retaining the upper organic layer. The solvents were then removed under reduced pressure keeping the temperature below 50 ° C; crystallization was observed during the subsequent stages. To the resulting suspension was added ethyl acetate (15.5 I) and hexane (15.5 I) and the resulting mixture was cooled to 0 ° C and granulated at this temperature for one hour. The product was then isolated by filtration, washed with hexane.ethyl ethyl acetate 1: 1 (10 L), then dried overnight under vacuum at 35 ° C providing 6.85 kg (82%) of (R) -3. - (N-carboxybenzoyl-2-pyrrolidinylcarboxy) -5-bromo-1 H-indole in the form of fine white crystals. Calculated: C = 59.03%, H = 4.48%, N = 6.56% Found: C = 59.01%, H = 4.50%, N = 6.58% EXAMPLE 2 Preparation of 3- (N-CBZ-2-pyrrolidinylcarboxy) indole A solution of CBZ-prolinoyl chloride (25 mmol) in 25 ml of MTBE and 50 ml of a 1M solution of ethyl magnesium bromide in MTBE was added simultaneously to a solution of 25 mmole of indole in methylene chloride for 1 hour. (25 ml). The two streams were added on opposite sides of the vessel with effective stirring and the temperature was maintained at 10-15 ° C. After the additions were complete, the reaction was quenched by the addition of aqueous 1.0M HCl (50 ml). After stirring, decanting and separating the phases, the organic phase was washed with brine (50 ml) and the volume reduced by 75% causing crystallization of the product. The product was filtered off, washed with ethyl acetate (approximately 10 ml) and dried under vacuum at 45 ° C. Performance 81%.

EXAMPLE 3 Preparation of 3-benzoyl-5-bromoindole 3-Benzoyl-5-bromoindole was obtained in 94% yield using the procedure described in Example 2.

EXAMPLE 4 Preparation of 3-benzoylindole 3-Benzoylindole was obtained with a yield of 91% using the procedure described in example 2. Those skilled in the art will note that the acylated characters in the 3 position obtained according to the process of the invention can be further treated giving them having an alternative substituent in position 3. So, it is a specific embodiment of the present invention that when R = N-CBZ-2-pyrrolidinyl and X = bromine, the 3- (N-CBZ-2-pyrrolidinylcarboxy) -5-bromoindole of formula (I) thus obtained it can then be reduced by using for example lithium aluminum hydride in tetrahydrofuran, giving 3- (N-methyl-2 (R) -pyrrolidinylmethyl) -5-bromoindole (III) which can be converted in turn using a suitable Heck reaction in 3- (N-methyl-2 (R) -pyrrolidinylmethyl) -5- (2-phenylsulfon-letenyl) -1H-indole (IV) which can be treated by catalytic hydrogenation in turn giving the 3- (N-methyl-2 (R) -pyrrolidinylmethyl) -5- (2-phenylsulfonylethyl) -1H-indole (V): said compound being a 5-HT agonist. known used in the treatment of migraine.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing a compound of formula (I) wherein R = d-Cß alkyl, C-Cβ alkoxy, C 3 -C 7 cycloalkyl, or aryl optionally substituted by one or more of hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoro, fluoro (C 1 -C 6 alkyl) C4) and fluoro (C 1 -C 4 alkoxy) and X is hydrogen or one or more substituents independently selected from cyano, halogen, nitro, d-Cß alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl and aryl optionally substituted by one or more than cyano, halogen, nitro, C 1 -C 4 alkyl, C 1 -C alkoxy, fluoro (C 1 -C alkyl) and fluoro (C 1 -C 4 alkoxy); which comprises adding separately and simultaneously to a stirred solution of an indole of formula (II) where X is as defined above here; (i) a solution containing an acid chloride of formula RCOCI, where R is as defined hereinbefore; and (ii) a solution containing an alkyl- or aryl-magnesium halide such that (a) solutions (i) and (ii) are added with sufficient separation to prevent them from reacting with each other; and (b) solutions (i) and (ii) are added at equivalent molar addition rates.

2. A process according to claim 1, wherein the indole of formula (II) is the indole itself or a 5-haloindole.

3. A process according to claim 1 or 2, wherein the magnesium halide is an alkyl- or aryl-magnesium bromide.

4. A process according to any of claims 1 to 3, wherein the magnesium halide is ethyl magnesium bromide.

5. A process according to claims 1 to 4, wherein R is N-CBZ-2-pyrrolidinyl and X is bromine and the compound of formula (I) thus obtained is

6. - A process according to claim 5, wherein the compound of formula (I) thus obtained is then reduced to give a compound of formula (III)

7. - A process according to claim 6, wherein said reduction is carried out using lithium aluminum hydride in tetrahydrofuran.

8. A process according to claims 6 and 7, wherein the compound of formula (III) thus obtained is subsequently converted into a compound of formula (IV):

9. - A method according to claim 8, wherein said conversion is carried out using a suitable Heck reaction.

10. A process according to claims 8 and 9, wherein the compound of formula (IV) thus obtained is subsequently converted into a compound of formula (V):

11. - A method according to claim 10, wherein said conversion is carried out by catalytic hydrogenation.