MXPA99005741A - Method of preparation of physostigmine carbamate derivatives from eseroline ethers - Google Patents

Abstract

The present invention relates to a novel process for the preparation of physostigmine carbamate derivatives and to pharmaceutically acceptable salts thereof. The present invention further relates to a novel process for the preparation of eseroline derivatives and to pharmaceutically acceptable salts thereof.

Description

METHOD FOR THE PREPARATION OF CARBAMATE DERIVATIVES FROM FISOSTIGMI NA TO PARTIR OF ÉTERES DE ESEROLI NA BACKGROUND OF THE INVENTION The present invention relates to a novel process for the preparation of physostigmine carbamate derivatives and pharmaceutically acceptable salts thereof. The present invention also relates to a novel process for the preparation of eseroline derivatives and pharmaceutically acceptable salts thereof. The physostigmine carbamate derivatives encompassed by the compounds of formula (1) below are useful as memory enhancing and analgesic agents as described in the U.S. Patent. , No. 4,791, 107, issued December 13, 1988; the Patent of E. U. , No. 5, 187, 165, issued February 19, 1993; the Patent of E. U. , No. 5,541, 216, issued July 30, 1996; and the Patent of E. U. , No. 5,547,977, issued August 20, 1996. The eseroline derivatives encompassed by the compounds of the formula (11) are useful as memory enhancing and analgesic agents as described in the U.S. Patent. , No. 5, 541, 216, issued July 30, 1996; Canadian Patent No. 1, 137,489, issued December 14, 1982; and as useful intermediates to make additional memory enhancing and analgesic agents. Various methods are known for the preparation of physostigmine carbamate derivatives. See, for example, Hamer et al., Patent of E. U. , No. 3,791, 107; Brufani et al., Patent of E.

U., No. 4,831,155; Wong et al., Patent of E. U., No. 5,302,721; and Wong et al., U.S. Patent No. 5,455,354. There remains a need, however, for processes that provide higher yields, ecologically permitted reagents and / or less expensive means of obtaining these compounds. An objective of the present invention, therefore, is to provide novel methods for the economic preparation of physostigmine carbamate derivatives and for eseroline derivatives without the need for ecologically unfavorable halogenated organic solvents. BRIEF DESCRIPTION OF THE INVENTION This application refers to a novel process for the preparation of a product of the formula wherein 20 R is lower alkyl; Ri is hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkyl lower alkyl, lower bicycloalkyl, aryl or aryl lower alkyl; R2 is lower alkyl, lower cycloalkyl, lower cycloalkyl "> S lower alkyl, lower bicycloalkyl, aryl, or aryl lower alkyl; Ri and R2 taken together with the nitrogen atom to which they are attached form a group of the formula (la): wherein Y is hydrogen or lower alkyl and Z is hydrogen, lower alkyl, halogen, lower alkoxy or hydroxy; X is lower alkyl, lower alkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; which process comprises (a) contacting a compound of the formula (I I): wherein R, X, and m are as defined above and R3 is lower alkyl, with aqueous hydrogen bromide and lithium halide to give a compound of the formula (11): wherein R, X, and m are as defined above; (b) contacting the reaction mixture containing the compound of the formula (III) with any: (1) with an isocyanate of the formula R-iNCO and isolating a product of the formula (I) wherein R2 is hydrogen; or (2) with a compound of the formula (IV): wherein R 4 is hydrogen or lower alkyl to give a compound of the formula (V): wherein R. R4, X and m are as above; (c) contacting the reaction mixture containing the compound of the formula (V) obtained in step (b) with a compound of the formula wherein Ri and R2 are as before in the presence of a carboxylic acid of the formula RsCOOH wherein Rs is lower alkyl; and form and isolate the product of the formula (I) - This application also provides a novel process for the preparation of a product of the formula (11): wherein R is lower alkyl; X is lower alkyl, lower alkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; which comprises contacting a compound of the formula (I I): (ID wherein R, X and m are as defined above and R3 is lower alkyl, with aqueous hydrogen bromide and lithium halide to give a compound of the formula (11).

BRIEF DESCRIPTION OF THE DIAMETERS Figure 1 shows the effect of lithium bromide (LiBr) on aqueous hydrogen bromide (H Br) (ac) on the O-dealkylation of eserotole. Figure 2 shows the effect of acid strength on O-dealkylation of eserotol. Figure 3 shows the effect of water on the O-dealkylation of eserotol. Figure 4 shows the effect of the relative proportion of lithium bromide / hydrogen bromide on O-dealkylation of eserotol.

DETAILED DESCRIPTION OF PREFERRED MODALI DADES Unless stated or indicated to the contrary, the term "lower alkyl" means a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of alkyl include methyl, ethyl, N-propyl, isobutyl, pentyl, hexyl, and the like. Unless stated or indicated to the contrary, the term "lower bicycloalkyl" means a group having two saturated rings containing from 7 to 11 carbons and the rings are linked together through two carbons. Unless stated or indicated to the contrary, the term halogen means fluorine, chlorine, bromine or iodine.

Unless stated or indicated to the contrary, the term halide means fluoride, chloride, bromide or iodide. Unless stated or indicated to the contrary, the term "aryl" means an unsubstituted aromatic phenyl or heterocyclic group; or a phenyl or aromatic heterocyclic group substituted with 1, 2 or 3 substituents each of which independently being lower alkyl, lower alkoxy, halogen, hydroxy, trifluoromethyl, phenoxy or benzyloxy. The term "pharmaceutically acceptable salts" refers to acid addition salts. The term "pharmaceutically acceptable acid addition salts" is intended to be applied to any non-toxic organic or inorganic acid addition salt of the compounds of the formula (I). Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and metal salts of acid such as monohydrogen sodium orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di-, and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymalonic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- acids. phenoxybenzoic, and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid and 2-hydroxyethane sulfonic acid. Such salts may exist in any substantially hydrated or anhydrous form.

Other methods for the preparation of physostigmine carbamate derivatives are known. See, for example, Hamer et al., Patent of E. U. , No. 3,791, 107; Brufani et al., Patent of E. U. , No. 4,831, 155; Wong et al., Patent of E. U. , No. 5,302,721; and Wong et al., U.S. Patent No. 5,455,354. However, a need persists for processes that provide higher yields, ecologically allowed reagents and / or less expensive means to obtain these compounds. The process of this invention has the following major advantages over previously known methods: • Aqueous hydrobromic acid is used as a dealkylating agent, together with lithium halide, as well as the reaction solvent. This reagent is less expensive than other previously used dealkylating agents such as boron tribromide or aluminum fluoride. • Non-halogenated solvents are used. Halogenated solvents such as dichloromethane or dichloroethane are environmentally undesirable and are not allowed by government regulations in many countries. • Purification of column chromatography preparation is not required. Preparative column chromatography is expensive, of labor intensive and limiting in production of greater scale. • Environmental emission control is more effective since the lithium halide can be recycled. • Diluted acidic medium and mild reaction conditions reduce the risk of erythrocyte.

The compounds of this invention are prepared using the synthetic steps described below. Throughout the description of the synthesis steps, the substituents "X", "Hal", "m", "R", "R", "R2", "R3", "R4" and "R5" shall have the respective meanings given above unless otherwise indicated. In structural formulas representing the compounds of this invention, the thick lines (-) leaving the carbon-3a and carbon-8a of the ring system of 1, 2, 3, 3a, 8, 8a-hexahydro-pyrrolo [2, 3-v ] indole means that the two substituents are above the average plane of the three-ring system, while dotted lines (* > tm) mean that the two substituents are below the average plane of the three-ring system, and wavy lines ( / vww) mean that the two substituents are either above said plane or below said plane. Due to the conformation constraints, the two substituents at positions 3a- and 8a- must both be above said average plane or both below said average plane. Thus, in the formula (I) the substituents at positions 3a- and 8a- are s. since they are on the same side of the three-ring system. Where said substituents are both above the average plane of the three-ring system, the configuration will be referred to as 3aS-cis and where both substituents are below the average plane of the ring, the configuration will be referred to as 3aR-cis. These two types of configurations are represented below.

Both of said cis isomers, namely, the 3aS-cis isomer and the 3aR-cis isomer are encompassed by each given compound name or structural formula containing wavy lines mentioned above. In addition, all mixtures of the 3aS-cis and 3aR-cis isomers including the racemic mixture (1: 1 ratio of 3aS-cis: 3a R-cis) are encompassed.

SCHEME (Saw) In step a, the compound of the formula (I I) is contacted with aqueous hydrogen bromide and lithium halide at room temperature. The reaction is then heated to a temperature ranging from 80 ° C-100 ° C, preferably 90-95 ° C, for a period of time ranging from 1 to 5 hours, preferably from 3 to 4 hours. The reaction is then cooled, diluted with water and neutralized with a suitable base, for example, 10% lithium hydroxide or 20% potassium hydroxide. The appropriate compound of formula (11) is then extracted in an organic solvent such as butyl acetate or ethyl acetate and the resulting solution is dried with a drying agent such as potassium carbonate or molecular sieves. In this application, the term "aqueous hydrogen bromide" is intended to encompass concentrations of hydrogen bromide from about 20% to about 50%. Preferably, the concentration of hydrogen bromide is 48% hydrogen bromide, which is commercially available, and more preferably the concentration of hydrogen bromide is in the range of about 25% to about 30%. Minor concentrations of hydrogen bromide can be obtained from 48% hydrogen bromide by dissolving with water. In this application, the term "lithium halide" is intended to encompass lithium bromide, lithium chloride and lithium iodide with lithium bromide being the preferred. In step b1, the compound of formula (11) is contacted with either an alkyl isocyanate or a substituted alkyl isocyanate. to form a compound of formula (I) wherein R-es is hydrogen, as represented by structure (I b) above. In this case, the reaction temperature is generally between about 0 ° C and about 25 ° C, preferably about 5 ° C to about 10 ° C. The reaction is monitored and the pH is maintained between about 9 and 10 by the addition of a base such as, for example, potassium t-butoxide or an acid such as, for example, acetic acid. In step b2, the compound of formula (III) is contacted with the carbonyldiimidazole compound of formula (IV) to provide the imidazole carbamate product of structure (V). In this case, the addition is carried out from about 0 ° C to about 25 ° C, preferably at about 20 ° C. In step c, the reaction is typically conducted by sequentially adding a carboxylic acid, such as, for example, acetic acid, and an amine such as tetrahydroisoquinoline to the solution obtained above. The pH of the acid solution can be optionally acidified to a pH of about 4.5 to about 6 with an acid, such as acetic acid, before contact with the appropriate amine. The addition of the amine is generally carried out from about -15 ° C to about 25 ° C, preferably from about -10 ° C to about 20 ° C. Examples of compounds made by the process of this invention include those listed below as well as the isomers 3aR-cis thereof and mixtures of the 3aS-cis and 3aR-cis isomers including the racemic mixtures: (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1,2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-methyl-1,2,3,4-tetrahydroxyquinol inyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1 -eti I- 1,2, 3, 4-tetrah idroisoquinol and I) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] ndol-5-ol, (1-prop i I- 1,2, 3, 4-tetrah idroisoquinol in i I) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-butyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-chloro-1,2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-chloro-1,2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] ndol-5-ol, (6-cl-1-methyl-1,2,3,4-tetrahydroquinoline isoquinol in i I) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-chloro-1-methyl-1, 2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-hydroxy-1,2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cys) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-h id roxy- 1,2, 3, 4-tetrah id roisoquinolinyl) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-hydroxy-1-methyl-1 , 2, 3, 4-tetrah idroisoquinoliniI) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1, 3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-h id roxi- 1 -meti I- 1, 2, 3, 4-tetrah id roi soquolioli and I) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, cyclohexyl carbamate ester; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, 3-chlorophenyl carbamate ester fumarate; (3aS-cis) -1, 2,3,3aI8) 8a-hexahydro-l3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, 3-chlorophenyl carbamate ester; and (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, 1- (phenyl) ethyl carbamate ester.

Thus according to the process of this invention in one of the preferred embodiments, the substituents R and R3 are both alkyl of Ci-Ce and X is hydrogen. In a more preferred form of this embodiment, the substituents R and R3 are both methyl. In a most preferred form of this embodiment, the compound of the formula (I I) is (-) - eseretol. In yet another preferred embodiment, the substituent R is C 1 -C alkyl, X is hydrogen and R 1 and R 2 together with the nitrogen to which they are attached form a 1, 2, 3, 4-tetrahydroisoquinoline group or a group 1 - methyl- 1, 2, 3, 4-tetrahydroisoquinoline. In a most preferred form of this embodiment, the substitute R is methyl.

The following examples are presented for the purpose of illustrating the invention and are not to be construed as limiting the invention in any way.

EJ EM PLO 1 Preparation of Salicylic Eseroline Salt Dissolve LiBr (72 g) in water (36 μL) and H Br ac, 48% (40 mL). Cool the clear solution in an ice bath. To this cold solution add thatretol (20 g, 81.22 mmol). Warm the mixture and heat in an oil bath at 90-100 ° C for 3-5 h. Cool the mixture to room temperature and pour it into ice water (600 mL). Neutralize the acid solution with LiOH (10%) and extract with ethyl acetate (2x200 mL). Dry the combined extracts over potassium carbonate (40 g) and filter under nitrogen. The filtrate, which contains eseroline (15.97 g, 90% by H PCL) can be used immediately for the preparation of (3aS-cis) -1, 2, 3,3a, 8, 8a-hexahydro-1, 3a, 8- trimethylpyrrolo [2,3-b] indol-5-ol, (1, 2,3,4-tetrahydroisoquinoline) carbamate. Mix the above solution (20 mL) with salicylic acid (0.55 g, 3.98 mmol, 1.1 eq.) In ethyl acetate (5 mL). Concentrate the clear solution to obtain gray crystals which are recrystallized from ethyl acetate to obtain salicylic salt of pure eseroline. Anal. Caled, for C20H24O N2: 67.40 C 6.79 H 7.86 N Found: 67.50 C 6.77 H 7.86 N EXAMPLE 2 Preparation of (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo r2.3-blindol-5-ol. (1.2, 3.4-tetrah id roi soqu i nol in) carbamate. a) Preparation of Eseroline Add LiBr (80 g) to HBr aq. to 48% (40 mL) and water (40 mL) to make a clear solution. To this solution add) (-) eseretol (21.31 g, 86.63 mmol) at room temperature under nitrogen with stirring. Heat (90-100 ° C) the clear coffee solution with an oil bath for 5.5 hours. Cool the dark greenish brown solution at room temperature and pour it into ice water (240 mL). To this solution was added 20% LiOH to pH 9-10. Extract the mixture with ethyl acetate (2 x 150 mL). Wash the combined ethyl acetate solution with brine, dry over potassium carbonate and filter. Concentrate the filtrate (to 100 mL) to provide a residue containing eseroline (17.76 g, 95% yield, 98.8% purity). This solution was used immediately in the preparation of the title product. b) Preparation of (3aS-cis) -1, 2,3,3a,8,8a-hexahydro-1,3a, 8-trimethylpyrrolo r 2,3-b1indol-5-ol, (1, 2,3, 4-tetrahydroisoquinoline) carbamate. To the solution obtained in Example 2, step (a), add 1,1-carbonyldiimidazole (15.45 g, 95.29 mmol). Shake the reaction solution at room temperature for 15-30 minutes. To the same reaction mixture add acetic acid (15.59 g, 259.89 mmol, 3 equiv.) And 1,2,3,4-tetrahydroisoquinoline (12.69 g, 95.29 mmol, 1.1 equiv.). Leave the mix stir overnight at room temperature under nitrogen. Wash the reddish reaction mixture with water (40 mL). The aqueous solution is then re-extracted with ethyl acetate (40 mL). Extract the combined extracts of ethyl acetate with dilute hydrochloric acid. Neutralize the combined acid extracts with sodium hydroxide to pH 7.0 and extract with cyclohexane (2x129 mL). After drying with potassium carbonate, stir the solution with alumina (25 g), filter and concentrate to give a crystallized residue from cyclohexane to obtain the title product (22.37 g, 68.42%) as a granular white crystalline solid ( 99.5% purity by HPLC); p.f. = 77 ° C. Anal. Caled, for C23H27O2N3: 73.1 8 C 7.21 H 1 1 .13 N Found: 72.97 C 7.12 H 1 1 .05 N EXAM PLO 3 Preparation of (3aS-cis) -1, 2,313a.8,8a-hexahydro-1, 3a.8-trimethylpyrrolo [2,3-b indole-5-ol, (1 .2.3, 4-tetrahydro-i so-i-nol in) carbamate. Prepare by the method of Example 2 by sequentially adding LiBr (36 g) and (-) eseretol (10 g, 40.6 mmol) to a mixture of 18 mL of water and 20 mL of H Br ac. (48%), Heat the solution to 90-100 ° C and hold for 5.5 hours.

Preparation of (3aS-cis) -1, 2.3.3a, 8,8a-hexahydro-1, 3a, 8-trimethylpyrrolo [2,3-b1dol-5-ol, (1,2, 3,4-tetrahydroisoquinolin ) carbamate using lithium iodide To a mixture of Líl (8.08 g), water (2.0 mL) and 2.0 mL of HBr ac. (48%) add this juice (0.5 g): heat the mixture at 88-95 ° C for 7 hours. Pour the reaction mixture into ice water (10 mL) and basify with 50% potassium carbonate until pH 9-10. Extract the mixture with ethyl acetate (2x10 mL). Dry the combined extracts and filter. Prepare the title compound using the filtrate, which contains eseroline (0.406 g, 91.8% purity) according to the method of Example 2.

EXAMPLE 5 Preparation of (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1, 3a, 8-trimethylpyrrolid2,3-b] indole-5-ol, cyclohexyl carbamate ester (-) - eseroline solution (2.2 g, of Example 2), there is added benzene (50 mL) containing cyclohexyl isocyanate (1.2 g) and the mixture is stirred at 25 ° C for 3 hours. The product is isolated by extraction of the solution of butyl acetate with water (200 mL) followed by sodium hydroxide solution (100 ML, 0.5 N) and water (100 mL). The residue is dried over anhydrous sodium sulfate and the butyl acetate solution is concentrated under reduced pressure to give the title compound.

EXAMPLE 6 Preparation of (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1 .3a.8-trimethylpyrrolor-2,3-bindole-5-ol ester fumarate. 3-chlorophenyl carbamate To a solution of (-) - eseroline (2.2 g, of Example 2), there is added isocyanate of 3-chlorophenyl (1.5 g) for 1 hour at 5 ° C and the mixture is mixed.

Stir at 25 ° C for 3 hours. The product is isolated as the fumarate salt followed by washing with water, concentrating under reduced pressure, purification with silica gel chromatography and acidification of the purified free base with fumaric acid (1 equiv.).

EXAMPLE 7 Preparation of the ester of (3aS-cis) -1, 2, 3,3a, 8,8a-hexahydro-1, 3a, 8-trimethylpyrro r 2,3-blindol-5-ol, 3-chlorophenyl carbamate A a solution of (-) - eseroline (2.2 g, of Example 2), 3-chlorophenyl socianate (1.6 g) was added at -5 ° C for 5 minutes. After stirring for 0.25 hours, the title compound was substantially isolated as described in Example 2.

EXAMPLE 8 Preparation of the ester of (3aS-cis) -1, 2, 3, 3a, 8,8a-hexahydro-1, 3a, 8-trimethyl pyrrolo r2.3-bl indole-5-ol. 1 - (phenyl) ethyl carbamate To a solution of (-) - eseroline (2.2 g, of Example 2), (S) - (-) - α-methylbenzyl isocyanate (1.5 g) was added during 1.5 minutes. hours at 10 ° C. The title compound was substantially isolated as described in Example 2. In many cases, O-dealkylation of esters of esters using 48% hydrogen bromide alone is not a suitable method. For example, O-dealkylation requires a very long period of time for completion resulting in serious decomposition of the product. Table 1 describes the O-dealkylation of eseretol and esmetmetol using 48% aqueous hydrogen bromide.

TABLE 1 O-Dealkylation of Esteroline Ethers Using 48% Hydrogen Bromide Only Relative area by HPCL The effects of variable reaction parameters of O-dealkylation of eseretol were studied in such a way that in one package of experiments only one parameter varies while the other parameters remain unchanged. In all these experiments, 1.00 g of eseretol was heated at 95-100 ° C with varying amounts of LiBr, water and H Br ac. while the total volume of the reaction solution was maintained at 4.0 mL. The reaction was monitored by HPLC and the reaction time was represented as the conversion time of 90% of esteretol in order to make comparison easier. It was observed that the reaction rate of the O-dealkylation step increased as the amount of lithium bromide increased (Fig. 1). Table 2 illustrates the information obtained in this O-dealkylation reaction.

TABLE 2 * time (h) for 90% completion with 1.00 g of eseretol, 4.0 mL of H Br (48%) at 95-100 ° C.

Similarly, when the strength of the acid was increased, the reaction rate was increased to a proton concentration of about 4.4. At that point, the reaction rate decreased in level (Fig. 2). In contrast, dissolution with water decreased the reaction rate (Fig. 3). The effect of the proportion with relation of LiBr / H Br on the deprotection of eseretol is illustrated in Fig.4. The relative catalytic effects of various lithium halides compared to other halides are as follows: LiBr »NaBr > KBr; Lil > LiBr > > LiCl. Also, N H4Br, Et3N HBr, and LiCl showed no catalytic effect at all on O-dealkylation when other reaction conditions remained unchanged.

Claims (21)

1. CLAIMS 1. A process for the preparation of a compound of the formula wherein: R is C? -C6 alkyl; Ri is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl, cycloalkyl-d-d-aikyl-d-C?, C7-d? Bicycloalkyl, phenyl, halophenyl or phenyl-C? -C6 alkyl; R2 is C6-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-d6C6 alkyl, C7-Cn bicycloalkyl, phenyl, halophenyl or phenyl-C-? -C6 alkyl; or R-Í and R2 when taken together with the nitrogen atom to which they are attached form a group of the formula (Ia) wherein Y is hydrogen or C? -C6 alkyl and Z is hydrogen, C? -C6 alkyl. halogen, d-C6 alkoxy or hydroxy; X is d-C6 alkyl, d-C6 alkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; whose process comprises: (a) contacting a compound of the formula (I I): where R, X and m are as defined above and R3 is d-C6 alkyl, with aqueous hydrogen bromide and lithium halide to give a compound of the formula (11): wherein R, X and m are as defined above; (b) contacting the reaction mixture containing the compound of the Formula (III) either: (1) with an isocyanate of the formula RICCO and isolating a product of the formula (I) wherein R2 is hydrogen; or (2) with a compound of the formula (IV): wherein R 4 is hydrogen or C alkyl? -C6 to give a compound of the formula (V): wherein R, R, X and m are as before; (c) contacting the reaction mixture containing the compound of the formula (V) obtained from step (b) with a compound of the formula: R? R2N H wherein R ^ and R2 are as before in the presence of a carboxylic acid of the formula: RsCOOH wherein R5 is d-C6 alkyl; and forming and isolating the product of the formula (I).
2. 2. A process according to claim 1 wherein said lithium battery is lithium bromide.
3. 3. A process according to claim 1 wherein said lithium halide is lithium iodide.
4. 4. A process according to claim 1 wherein R and R3 are d-C6 alkyl and X is hydrogen.
5. 5. A process according to claim 4 wherein R is methyl and R3 is methyl.
6. 6. A process according to claim 5 wherein the compound of formula (II) is (-) - eseretol.
7. 7. A process according to claim 1 wherein R is d-C6 alkyl, X is hydrogen and Ri and R2 together with the nitrogen to which they are attached form the 1,2,3,4-tetrahydroisoquinoline group or a group 1-m eti I- 1,2, 3, 4-tetrah idroisoquinol ina.
8. 8. A process according to claim 7 wherein R is methyl.
9. 9. A process according to claim 1 wherein said aqueous hydrogen bromide is hydrogen bromide with a concentration within the range of from about 20% to about 50%.
10. 10. A process according to claim 1 wherein said aqueous hydrogen bromide is hydrogen bromide with a concentration from about 25% to about 30%.
11. 11. A process according to claim 1 wherein the compound of the formula (I) is selected from the group consisting of: (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1,2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-methyl-1, 2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1 -eti I- 1,2, 3, 4-tetrah idroisoquinol ini I) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-propyl-1, 2,3 , 4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-butyl-1, 2, 3, 4-tetrah id roisoquinolin i l) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-chloro-1, 2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-chloro-1, 2,3,4-tetrahydroisoquinolini!) Carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-chloro-1-methyl-1, 2, 3, 4-tetrah idroisoqui nol ini I) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-chloro-1-methi I- 1, 2, 3, 4-tetrahydro isoquinol i nil) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethyl-pyrrolo [2,3-b] indol-5-ol, (6-hydroxy-1, 2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1, 3a, 8-trimethylpyrrolo [2,3-b] 'mdol-5-ol, (7-h id roxi-1, 2, 3, 4-tetrah id roisoquinolin i I) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-hydroxy-1-methyl-1, 2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-h id roxi-1-methyl-1, 2, 3, 4-tetrahydroisoquinol and I) carbamate.
12. 12. A process according to claim 1 wherein said compound of formula (I) is (3aS-cis) -1, 2,3,3a, 8,8a-hexahydro-1, 3a, 8-tri-methyl pyrrolo [ 2, 3-b] indol-5-ol, (1, 2,3,4-tetrahydroisoquinolinyl) carbamate.
13. 13. A process for the preparation of a product of the formula (ll l): wherein R is d-C6 alkyl, X is d-C6 alkyl, d-C6 alkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; which comprises contacting a compound of the formula (I I): wherein R, X and m are as defined above and R 3 is C 1 -C 6 alkyl, with aqueous hydrogen bromide and lithium halide to give a compound of the formula (11). 4.
14. A process according to claim 13 wherein said lithium halide is lithium bromide.
15. 1 5. A process according to claim 13 wherein said lithium halide is lithium iodide.
16. 16. A process according to claim 1 wherein R and R3 are alkyls of C? -C6 and X is hydrogen.
17. 17. A process according to claim 16 wherein R is methyl and R 3 is methyl.
18. 18. A process according to claim 17 wherein the compound of the formula (I I) is (-) - eseretol.
19. 19. A process according to claim 13 wherein the compound of the formula (11) is (-) - eseroline.
20. 20. A process according to claim 13 wherein said aqueous hydrogen bromide is hydrogen bromide with a concentration within the range of from about 20% to about 50%. twenty-one . A process according to claim 13 wherein said aqueous hydrogen bromide is hydrogen bromide at a concentration of about 48%. RESU MEN The present invention relates to a novel process for the preparation of physostigmine carbamate derivatives and pharmaceutically acceptable salts thereof. The present invention also relates to a novel process for the preparation of eseroline derivatives and pharmaceutically acceptable salts thereof.