HU190658B - Process for producing hexqhydro-indolo-carboxylic acids - Google Patents

Abstract

The present invention relates to a process for the preparation of the hexahydroindole carboxylic acids of the formula (I) wherein the hydrogen atoms at positions 3a and 7a are in the cis configuration and the CO2W group at the carbon atom in position 2 is exo or endo-linked to the bicyclic ring. and W is hydrogen or C 1-6 alkyl by converting a Schiff base after acylation to a diene and cyclizing it into a mixture of stereoisomers of hexahydroindole carboxylic acids, optionally after separation to the pre-enantiomers, diastereomeric pairs or racemates , Saponification of a compound of formula (I) wherein W is hydrogen and optionally converted to a compound of formula (I) wherein W is C 1-6 alkyl. The compounds of the present invention are intermediates for the production of therapeutic bicyclic amino acids. H C02W 190658 -1-

Description

The present invention relates to a process for the preparation of a novel hexahydroindole carboxylic acid of formula (I) wherein the 3a and 7a hydrogen atoms are in a cis configuration relative to one another and the 2-position -CO2W group is exo or bicyclic. endo-W is hydrogen or C 1-6 alkyl.

The compounds of formula (I) according to the invention are prepared by incorporating into a Schiff base of formula (II):

R is a C 1-6 alkyl group, with an acylating agent introduced into the -COR ¹ group in which

R ¹ is phenyl, cyclized to give the diene amide of formula (III) wherein R and R ¹ are a stereoisomeric mixture of the above hexahydroindole carboxylic acid derivatives of formula (IV)

R ¹ and R ¹ are as defined above and the hydrogen atoms on the bridgehead carbon atoms are in the cis configuration and the resulting stereoisomeric mixture in which, depending on whether the compounds of formula II are R

Starting from a mixture of S-configuration or racemic, diastereomeric pairs of formulas IVb and IVd, or IVa and IVc, or mixtures thereof may occur, optionally after prior separation of the enantiomers, diastereomeric pairs or racemates (I ), wherein W is hydrogen, and optionally esterified to give a compound of formula I wherein W is (C 1 -C 6) -alkyl.

Synthesis of the compounds of formula (II) should be based on the allyl glycine ester of formula (V):

R is C 1-6 alkyl,

The allyl glycine ester can be used as a racemic compound or in optically pure R or S forms. The synthesis of racemic allyl glycine is described in Monatshefte dér Chemie, 1954, 85, 1071; R and S compounds a

J. Bioi. Chem. 223, 40 (1955). The esterification is carried out according to the usual methods of organic chemistry. The preparation of ethyl ester is described in the cited Monatshefte hoar Chemie.

The compound of formula (V) is converted to the Schiff base of formula (II) by crotonaldehyde in an organic solvent during the course of the isolation. The reaction is carried out at a temperature of -40 ° C to +80 ° C, preferably +20 ° C. The organic solvent used is aprotic solvents such as benzene, toluene, carbon tetrachloride or chloroform. The reaction water is removed from the reaction mixture with a water-binding agent such as MgSO 4, Nu 2 SO 2, molecular sieve or organic auxiliary agent, for example, butyric acid ester or azeotropic removal.

Preferably, the Schiff base is acylated in an aprotic solvent such as methylene chloride, chloroform, toluene or dimethylformamide in the presence of a base such as triethylamine, pyridine or other amines to an diene of formula (III) with an acylating agent such as an acid chloride. The reaction is carried out at a temperature of -80 to +40. Preferably, it is started at -80 ° C and completed at 20 ° C.

In the acylating agent transferring the -COR * group, R ¹ is phenyl. Preferably, the compound of formula (III) is heated in a high boiling organic solvent and cyclized to the bicyclic amino acid derivative of formula (IVa-d) by intramolecular Diels-Alder reaction, which forms as a stereoisomeric mixture. Suitable solvents are those having a boiling point of from 80 to 250 ° C, such as toluene, xylene or dichlorobenzene. Thermolysis can also be carried out under reduced pressure in a solvent. Preferably, the thermolysis is carried out at a temperature of 100-180 ° C under normal pressure. Optionally, bis-trimethylsilyl-acetamide or other conventional deactivating agent can be used to deactivate the glass surface of the reaction vessel, or an acid scavenger and radical scavenger such as tert-butyl catechol may be added to suppress the radical side reactions.

The endo-cis compounds IVa and IVb and the exocis compounds IVc and IVd are always present as racemates when the allyl glycine esters of formula V are used. Use of the S-configuration allyl glycine ester as starting material gives the cis-endo-S configuration IVa and cis exconfiguration IVc, where the S configuration is at the 2-position carbon atom It applies. Using the R-configuration alb1-glycine ester yields the R-configuration amino acid derivative of formula (IVb) and (IVd). Racerates (IVa) (IVb) and (IVc) (IVd) and diastereomers (IVa) and (IVc) and (IVb) and (IVd) can be separated by conventional means, for example, by fractional crystallization or by column chromatography on Kiesel gel. Further reactions are carried out using the racemate or the optically pure diastereomers.

Acidic or basic saponification gives amino acids of formula I wherein W is hydrogen. The amino acids may optionally be esterified. The preferred tert-butyl ether (W-tert-butyl group) of amino acids of formula (I) is prepared, for example, by reaction of an acid with isobutylene in an inert organic solvent (e.g. dioxane) in the presence of an acid (e.g. sulfuric acid).

Particularly preferred is the following process: The corresponding amino acid is optionally cleaved with a base such as methylsulfonylethoxycarbonyl [MSC; Tesser, Balvert-Geers: Int J Pepi. Protein Sl., 7, 295 (1975)]. The carboxylic acid is converted to the corresponding tert-butyl ester in a neutral or slightly basic pH range with tert-butanol in an organic solvent such as pyridine in the presence of propyl phosphonic acid anhydride. The MSC protecting group is cleaved in a strongly alkaline medium with an alkali in an aqueous solvent to give the tert-butyl ester of formula (I) (W = tert-butyl).

In the reaction described above for the preparation of the compounds of formula I, the intermediates retain their configuration at the bridgehead carbon atoms 3a and 7a.

The compounds of formula (I) obtained by the above process may be obtained in the form of mixtures which may be separated, for example, by crystallization or chromatography.

The compounds of formula I can be obtained as racemates. However, pure enantiomers may also be prepared by separating the racemates into optical antipodes by conventional means such as salt formation with optically active acids or bases. However, pure enantiomers can be directly produced by this process.

The compounds of formula (I) of the present invention may be used in the synthesis of bicyclic amino acid derivatives having intense antihypertensive activity.

The following examples further illustrate the process of the invention, but are not intended to limit the invention thereto.

The ¹ H-NMR data given in the examples was measured in CDCl 3 and is expressed in ppm.

Example 1

Cis-2,3,3a, 4,5,7-hexahydro [lH] indole-2-R, S-endo-carboxylic acid

a) N-Benzoyl-N- (butadiene-1,3-yl) -R, S-allyl-glycine ethyl ester

28.6 g of R, S-allylglycine ethyl ester are dissolved in 140 ml of toluene and 14.0 g of crotonaldehyde are added. After addition of 30 g of anhydrous magnesium sulfate, the mixture is stirred at room temperature for 3 hours. The magnesium sulfate is then filtered off and the toluene is filtered off with suction. The residue was 44.4 g of an oil. 750 ml of methylene chloride were cooled to -70 ° C and 44.4 g of triethylamine and 28.1 g of benzoyl chloride were added. To this is added 44.4 g of the above Schiff base. The reaction mixture was stirred at -75 ° C for 2 hours, then allowed to warm to 0 ° C. The solvent was filtered off with suction at room temperature in a rotary evaporator. The residue is taken up in toluene, washed with water, dried and the toluene is suctioned off again in a rotary evaporator. The residue was filtered through a short column of Kiesel gel (500 mL). The eluent is methylene chloride. Evaporation of the methylene chloride afforded 49 g of N-bonzoyl-N- (butadien-1,3-yl) -R, S-nnylylglycine ethyl ester.

<1> H NMR: 1.1-1.4 (t, 311), 2.7-3.1 (in

211), 4.0-4.5 (in, 311), 4.8-6.8 (m, 8H), 7.3-7.6 (ή 511)

b) N-Benzoyl-ethyl-2,3,3a, 4,5,7a-hexahydro [11] indole-2-R, 5-endo-carboxylic acid ethyl ester g N-Benzoyl-N- (butadiene-1). 3-yl) -R, Sallylglycine ethyl ester is dissolved in 1000 ml xylene and 0.1 g tert-butyl catechol and 5 drops of cis-trimethylsilylacetanide are added. The reaction mixture was refluxed under nitrogen for 6 hours, after which additional 0.1 g of tert-butyl catechol and 5 drops of bis-trimethylsilylacetamide were added after 3 hours. The xylene is then filtered off with suction in a rotary evaporator to give 43 g of an oily residue. The oil (70 g) was chromatographed on silica gel with a 4: 1 mixture of loluene / ethyl acetate. 53 g of ethyl N-benzoyl-cis-2,3,3a, 4,5,7a-hexahydro- [11'-indole-2-R, 5-endo-carboxylic acid (Rf: 0]) are obtained in the form of an oil and 7.5 g. Ethyl N-benzoyl-cis-2,3,3a, 4,5,7a-hexahydro [1H] indole-2-R, 5-exo-carboxylic acid (Rf 0.26, mp 96-98 ° C). ).

Both compounds can be obtained as racemates.

c) cis-2,3,3a, 4,5,7a-Hexahydro [1 H] indole-2-R, 5-endo-nbronic acid

Ethyl N-benzoyl-cis-2,3,3a, 4,5,7a-hexa-1-indol-2-endo-R, S-carboxylic acid (1.5 g) was dissolved in ethanol (10 ml). To this is added 0.35 g of potassium hydroxide in 5 ml of aqueous solution. The reaction mixture was stirred at room temperature for 2.5 hours, diluted with water and extracted with ethyl acetate. After drying and evaporation in a rotary evaporator, 9 g of N-benzoyl-cis-2,3,3a, 4,5,7a-hexahydro [1H] indole-2-endo-carboxylic acid are obtained, m.p. 153-154 ° C.

13.4 g of N-benzoylcarboxylic acid are dissolved in a mixture of 200 ml of 2N hydrochloric acid and 67 ml of ethanol and the solution is heated at 110 ° C for 22 hours under a nitrogen atmosphere. The alcohol is filtered off with suction and the aqueous phase is extracted with methylene chloride. The pH was then adjusted to 7.0 with concentrated sodium hydroxide and evaporated to dryness in vacuo. The residue is taken up in methylene chloride / methanol, the salt is filtered off, the solution is evaporated and the residue is recrystallized from ethanol / ether. Yield: 7.0 g, m.p. 220 ° C (dec.).

Example 2 Cis-2,3,3a, 4,5,7a-Hexahydro-1H] -indole-2-R, 5-endo-carboxylic acid tert-butyl ester

3.35 g of cis-2,3,3a, 4,5,7a-hexahydro [III] indole-2-R, 5-endo-carboxylic acid in 50 ml of dimethyl-37

-formamide, add 5.3 g of methylsulfonylethylsuccinimido carbone and

2.3 g of ethyl morpholine. The reaction mixture was allowed to stand at room temperature for 12 hours. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution was partitioned between saturated sodium bicarbonate solution, adjusted to pH 3.6 with 2N hydrochloric acid and extracted several times with ethyl acetate. The combined ethyl acetate solutions were evaporated after drying. 8.5 g of N-methylsulfonylethyloxycarbonylcis-2,3,3a, 4,5,7a-hexahydro [1H-indole-2-R, 5-endocarboxylic acid are obtained, which is dissolved in 10 ml of pyridine. At 0 ° C, 10 ml of tert-butanol and 12 ml of a 50% solution of propyl phosphonic anhydride in methylene chloride are added. After stirring for 6 hours at 40 ° C, 200 ml of ethyl acetate are added and the mixture is adjusted to pH 3.5 with potassium hydrogen sulfate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate solution was washed with water, dried and evaporated in vacuo. The residual oil was purified on silica gel with ethyl acetate as eluent. The tert-butyl ester was obtained as an oil.

1 H NMR: 1.4 (s, 9H), 10-2.8 (m, 1H), 2.9 (s, 3H), 3.1-3.5 (m, 2H), 3.7 -4.8 (m, 4H), 5.65.9 (m, 2H)

1.35 g of tert-butyl ester are dissolved in 15 ml of methanol and 1.5 ml of water. The solution was adjusted to pH 13 with 2N sodium hydroxide and stirred at room temperature for 2 hours. It is then neutralized with 2N hydrochloric acid, the methanol is evaporated in vacuo, the aqueous phase is extracted with ethyl acetate, the ethyl acetate solution is washed with water, dried and evaporated. The oily residue was purified on silica gel with ethyl acetate as eluent. 0.3 g of cis-2,3,3a, 4,5,7a-hexahydro [1H] indole-2-R, 5-endo-carboxylic acid tert-butyl ester are thus obtained in the form of an oil.

1 H-NMR: 1.4 (s, 9H), 1.0-2.7 (m, 8H),

3.2-4.9 (m, 2H), 5.8 (d, 2H)

Example 3 Cis-2,3,3a, 4,5,7a-Hexahydro [1H] indole-2-R, S-exo-carboxylic acid

This compound can be prepared from the ethyl ester of N-benzoyl-cis-2,3,3a, 4,5,7a-hexahydro [1H] -indole-2-R, S-exo-carboxylic acid (see Example 1b). in the same manner as in Example. ¹ H-NMR data (after H / D exchange): 1.6-2.5 (m, 3H), 4.4 (s, 1H), 4.8 (m, 1H), 5.4 (m, H), 5.8 (m, H)

Example 4 Cis-2,3,3a, 4,5,7a-Hexahydro [1H] indole-2-R, S-exo-carboxylic acid tert-butyl ester

This compound is shown in Figure 3a. Example 2 may be prepared as described in Example 2.

1 H-NMR: 1.1-2.8 (m, 8H), 1.4 (s, 9H),

3.3-4.9 (m, 2H), 5.8 (in, 2H)

Example 5 Cis-2,3,3a, 4,5,7a-Hexanhydro [1H] indole-2-S-endo-carboxylic acid

a) S-allyl glycine ethyl ester

For its preparation see Monatshefte der Chemie 85, 1071 (1954).

b) N-Benzoyl-N- (butadiene-1,3-yl) -S-allylglycine

This compound is la. prepared as described in Example 1b.

1 H-NMR: 1.1-1.4 (tr, 3H), 2.7-3.1 (m, 2H), 4.0-4.5 (ni, 3H), 4.8-6 , 8 (m, 811), 7.3-7.6 (β, 5H)

c) ethyl N-benzoyl-cis-2,3,3a, 4,5,7a-hexahydro [1H-indole-2-S-endo-carboxylic acid and N-benzoyl-cis-2,3,3a, 4,5 7a-Hexahydror-1-Linoline-2-S-exo-carboxylic acid ethyl ester

This ε diastereomeric mixture can be prepared from the oil of the compound of Example 5 by the method of Example 1b. in the same manner as in Example. The mixture was separated on a silica gel with 4: 1 U-toluene / ethyl acetate, endo-compound Rf: 0.18, exo-compound Rf: 0.26.

1 H-NMR: 0.8-2.8 (m, 10H), 3.8-4.8 (m, 411), 5.5-5.9 (broad s, 2H), 7.4 ( s, 5H)

d) cis-2,3,3a, 4,5,7a-Hexahydro [1H-indole-2-s-end o-carboxylic acid

This is ε. compound 5c. The compound of Example 1b can be prepared. in the same manner as in Example.

1 H NMR (DaO): 1.1-2.9 (m, 711), 3.9-4.4 (in, 2H), 5.5-6.4 (τη, 2H)

Example 6 Cis-2,3,3a, 4,5,7a-Hexahydro [1H] indole-2-S-endo-carbonic acid tert-butyl ester

This compound can be prepared from the compound of Example 5 as described in Example 2.

1 H NMR: 1.4 (s, 9H), 1.0-2.7 (m, 811), 3.2-4.9 (n, 211), 5.8 (d, 211)

Example 7 Cis -2,3,3a, 4,5,7a-Exahyde <> [1H] in <li> 1-2-S-exoates

This compound can be prepared from the exo compound of Example 5. in the same manner as in Example.

1 H NMR: D 2 O: 1.0-2.8 (m, 1H), 3.6-4.4 (in, 211), 5.5-6.4 (in, 2H)

EXAMPLE 8 tert-Butyl Ester of c18-2,3,3a, 4,5,7a-Hexanhydro-1H] -indole-2-S-exo-carboxylic acid

This compound can be prepared from the compound of Example 7 as described in Example 7.

1 H NMR: 1.4 (s, 9H), 0.9-2.8 (ni, 811),

3.3-4.9 (m, 2H), 5.4-5.8 (m, 2H)

Claims (1)

Claims A process for the preparation of the hexahydroindole carboxylic acids of formula I wherein the 3a and 7a hydrogen atoms are in the ciBz configuration and the -CO2W group at the 2-carbon is exo or endo-edged relative to the bicyclic ring, and W is hydrogen or (C 1 -C 6) -alkyl, characterized in that a Schiff R is a C 1 -C 6 alkyl group with an acetylating agent for the introduction of a group -COR ¹ , wherein R ¹ is phenyl, thus converted to the dienamide of formula (ΙΠ) R and R ¹ are as defined above and are cyclized to a stereoisomeric mixture of the hydroxy hydro-iridole carboxylic acid derivatives of formula (IV) R and R ¹ are as defined above and the hydrogen atoms on the bridgehead carbon atoms are cis, this stereoisomeric mixture starting from the R, S configuration or the racemic compound of formula (IIb) ) and diastereomeric pairs of formulas IVd, IVa and IVc, or mixtures thereof R and R ¹ are saponified to form a compound of formula (I) after separation of the above, optionally prior enantiomers, di20 stereoisomeric pairs or racemates, wherein W is hydrogen and is optionally of general formula (I) 25 to form a compound of formula W is C 1-6 alkyl.