The method of acylation

 

(57) Abstract:

The invention relates to a method for the preparation of 3-acylated indoles of formula I

< / BR>
where R1-C6-alkyl, C1-C6-alkoxy, C3-C7-cycloalkyl, aryl, optionally substituted by one or more hydroxy-, WITH1-C4-alkyl, C1-C4-alkoxy, fluorine, fluorine(C1-C4)-alkyl and fluorine(C1-C4)-alkoxy; X is hydrogen or one or more substituents independently selected from CN, G, NO2WITH1-C6-alkyl, C1-C6-alkoxy, C3-C7-cycloalkyl, aryl, which is optionally substituted by one or more cyano-, G, NO2WITH1-C4-alkyl, C1-C4-alkoxy, fluorine(C1-C4)alkyl and fluoro(C1-C4)alkoxy; or R - N-carboxymethyl-2-pyrrolidinyl, and X Is 5-Br. The method includes the separate and simultaneous addition to the mixed solution of the indole of formula II

< / BR>
where X is previously defined, (i) the solution containing the acid chloride acid RCOCl, where R is previously defined, and (ii) the solution containing the alkyl - or arylalkylamine, so that (a) the solutions (i) and (ii) is added with sufficient separation to prevent their usaimage reductive further transformation of compounds with N-carboxybenzoyl-2-pyrrolidinyl group to the compounds of formula III

< / BR>
its transformation in the Heck reaction in compound IV

< / BR>
with subsequent catalytic hydrogenation to the compounds of formula V

< / BR>
The compound obtained V, known as 5-HT1, agonist used in the treatment of migraine. 10 C.p. f-crystals.

The invention relates to the acylation of indoles, in particular, to obtain 3-acylated indoles, which can be subjected to additional treatment to obtain indoles with an alternate substituent in 3-position.

Up to the present time 3-acylation of indoles usually carried out by a method described, for example, in international patent application PCT/US91/07194, i.e. by reacting a magnesium salt of indole with acid chloride acid

< / BR>
where Z is a halogen, and R represents, for example, substituted pyrrolidinyl, azetidine or piperidinyl.

The magnesium salt is produced by interaction of the indole with an alkyl - or arylalkylamines, preferably by ethylmagnesium, in an inert solvent, for example diethyl ether or tetrahydrofuran, at a temperature in the range from -30oWith up to 65oWith, preferably approximately 25oC.

The acid chloride cicloturista, for example, methylene chloride, diethyl ether or tetrahydrofuran, at a temperature in the range -10oWith up to 25oC. In the acid with N-containing heterocyclic fragment may be protected from the obtained carboxylic acid by N-substitution of a suitable protecting group, for example carboxyaniline (CBS).

Then a solution of the carboxylic acid is added slowly to a stirred solution of the magnesium salt at a temperature in the range from -30oWith up to 50oWith, preferably approximately 25oWith, receiving the target 3-acylated indole.

This method of obtaining a 3-acylated indoles, actually requiring independent receiving each of the original substance, is both time-and labor-intensive and is not suitable for easy application on an industrial scale.

Therefore, we developed a new methodology for the preparation of 3-acylated indoles, in which there is no need for independent receiving the above-mentioned starting materials. According to the present invention, 3-acylated indoles can be obtained with a good yield by adding solutions of carboxylic acids (N-protected, if necessary) and alkyl - or arylalkylamine.

Thus, the problem to be solved by the present invention is to provide a fast and cost-effective method of obtaining a 3-acylated indoles, which avoid poor convergent synthesis of the prior art, in particular, the need to obtain and allocate a magnesium salt of indole.

As additional measures of cost saving in the method of the present invention requires only one molar equivalent of an expensive initial substance indole. This is contrasted with two equivalents required in the method of the prior art, and effectively doubles the output acylated substance, based on indole original substance.

In accordance with the present invention is disclosed a method of obtaining a 3-acylated indoles, including the production of chloranhydride acid, as described, and then the addition of solutions of (i) carboxylic acids and (ii) alkyl - or arylalkylamine separately and simultaneously to the stirred solution of indole so that (a) two incoming reagents did not come into direct contact, i.e. they are added separately at a distance, to prevent Iago add.

In particular, the invention provides a method of obtaining compounds of formula (I):

< / BR>
in which R represents a C1-C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl or aryl, optionally substituted by one or more hydroxy, C1-C4the alkyl, C1-C4alkoxy, fluorine, fluorine(C1-C4)alkyl and fluoro(C1-C4)alkoxy, and X represents hydrogen or one or more substituents independently selected from cyano, halogen, nitro, C1-C6of alkyl, C1-C6alkoxy, C3-C7cycloalkyl and aryl, optionally substituted by one or more cyano, halogen, nitro, C1-C4the alkyl, C1-C4alkoxy, fluorine(C1-C4)alkyl and fluoro(C1-C4)alkoxy; including individual and simultaneously add to the mix a solution of indole of the formula (II):

< / BR>
in which X has the values defined above;

(i) a solution containing the acid chloride of the acid of formula RCOC1, in which R has the meaning previously defined; and

(ii) solution containing alkyl - or arylalkylamine,

so that

(a) solutions (i) and (ii) is added with sufficient separation to predotvrashch add.

According to a particularly preferred features of the invention, the indole of formula (II) represents an indole as such, or 5-halogenides, and the magnesium halide is alkyl or arellanobond, preferably by ethylmagnesium.

The method of the present invention is illustrated by the following examples.

Example 1

Obtaining 3-(N-CBZ-2-pyrrolidinylcarbonyl)-5-bromoindole

In a dry reaction vessel equipped with overhead stirrer and maintained under nitrogen atmosphere, add 5-bromoindole (3,85 kg 19,6 mol), then methylene chloride (12.3 l). The resulting mixture was stirred at ambient temperature until a homogeneous solution and then cooled to 10-12oC. Then at the same time, within 2-3 hours from opposite sides of the vessel type solutions CBS-prolinamide in methylene chloride (20 mol, of 1.02 EQ. ) and 1M ethylmagnesium in MTBE (methyl tertiary butyl ether) (37,7 kg, 39,2 mol, 2 equiv.) while maintaining the temperature of 10-15oC. These additions should be carried out so that the two streams do not mix, and that speed molar add each reagent were constantly synchronized.

The resulting suspension is added to the on) (29 l) for 30 minutes, keeping the temperature below 25oC. the Obtained two-phase mixture is stirred for 30 minutes, leave to stand for 20 minutes, then the phases are separated, keeping the upper organic layer. This organic layer was washed with saturated aqueous Panso3(28 l) for 20 minutes at 20-25oWith, leave to settle for about 20 minutes, then the phases are separated, keeping the upper organic layer. Then the solvents are removed under reduced pressure, keeping the temperature below the 50oC; crystallization was observed during the late stages. To the resulting suspension add ethyl acetate (15,5 l) and hexane (15,5 l), cool the mixture to 0oAnd granularit at this temperature for 1 hour. After that, the product produce by filtration, washed with a mixture of 1:1 hexane: ethyl acetate (10 l), then dried overnight in vacuum at 35oWith getting 6,85 kg (82%) of (R)-3-(N-carboxybenzoyl-2-pyrrolidinylcarbonyl)-5-bromo-1H-indole in the form of fine white crystals.

Calculated,%: 59,03%, N 4,48%, N 6,56%

Found,%: C 59,01%, N 4,50%, N 6.58 PERCENT

Example 2

Obtaining 3-(N-CBZ-2-pyrrolidinylcarbonyl)indole

To a solution of 25 mmol of indole in methylene chloride (25 ml) was simultaneously added dropwise within 1 chaplet from opposite sides of the vessel with efficient stirring and while maintaining the temperature at 10-15oC. Upon completion of addition the reaction is quenched by addition of 1.0 M aqueous model HC1 (50 ml). After mixing, settling and separation of the phases the organic phase is washed with brine (50 ml) and then reduced in volume by 75%, causing crystallization of the product. The product is filtered, washed with ethyl acetate (~10 ml) and dried in vacuum at 45oC. The Yield 81%.

Example 3

Obtaining 3-benzoyl-5-bromoindole

3-Benzoyl-5-bromoindole get with 94% yield using the procedure described in example 2.

Example 4

Obtaining 3-benzoindole

3-Benzoindole get with 91% yield using the procedure described in example 2.

The specialist will be clear that the 3-acylated indoles obtained in accordance with the method of the invention can be further processed to obtain indoles with 3-position alternate Deputy.

Thus, a special variant of the invention is the case when R= N-CBZ-2-pyrrolidinyl, and X=bromine, thus obtained 3-(N-CBZ-2-pyrrolidinylcarbonyl)-5-bromoindole formula (I)

< / BR>
you can then restore using, for example, socialogical in tetrahydrofuran, getting 3-(N-methyl-2(R)-pyrrolidinyloxy)-5-bromoindole-pyrrolidinyloxy)-5-(2-phenylsulfonyl)-lH-indole (IV)

< / BR>
which, in turn, can be subjected to catalytic hydrogenation, getting 3-(N-methyl-2(R)-pyrrolidinyloxy)-5-(2-phenylsulfonyl)-lH-indole (V)

< / BR>
the connection, which is known as 5-HT1agonist used in the treatment of migraine.

1. The method of obtaining the compounds of formula (I)

< / BR>
in which R is C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl or aryl, optionally substituted by one or more hydroxy-, WITH1-4the alkyl, C1-4alkoxy, fluorine, fluorine(C1-4)alkyl and fluoro(C1-4)alkoxy;

X is hydrogen or one or more substituents independently selected from cyano, halogen, nitro, C1-6of alkyl, C1-6alkoxy, C3-7cycloalkyl and aryl, optionally substituted by one or more cyano, halogen, nitro, C1-4the alkyl, C1-4alkoxy, fluorine(C1-4)alkyl and fluoro(C1-4)alkoxy;

or R - N-carboxymethyl-2-pyrrolidinyl and X - 5-bromo,

includes separate and simultaneous addition to the mixed solution of the indole of formula (II)

< / BR>
in which X has the meaning previously defined,

(i) a solution containing the acid chloride of the acid of formula RCOCl, in which R has the meaning defined wound sufficient separation to prevent their interaction with each other (b) solutions (i) and (ii) add at equivalent speeds molar add.

2. The method according to p. 1, in which the indole of formula (II) represents an indole as such or 5-halogenides.

3. The method according to p. 1 or 2, in which the magnesium halide is alkyl or arellanobond.

4. The method according to any of paragraphs. 1-3, in which the magnesium halide is ethylmagnesium.

5. The method according to any of paragraphs. 1-4, in which the thus obtained compound of formula (I) is a

< / BR>
6. The method according to p. 5, in which the thus obtained compound then restore with obtaining the compounds of formula (III)

< / BR>
7. The method according to p. 6, in which the specified restoration carried out using lydialydia in tetrahydrofuran.

8. The method according to PP. 6 and 7, in which the thus obtained compound of the formula (III) is then converted into the compound of the formula (IV)

< / BR>
9. The method according to p. 8, in which the specified transformation is performed with the use of suitable for the Heck reaction.

10. The method according to PP. 8 and 9, in which the thus obtained compound of the formula (IV) is then converted into the compound of the formula (V)

< / BR>
11. The method according to p. 10, in which the specified transformation is carried out by catalytic hydrogenation.

 

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10 cl, 2 tbl, 39 ex

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