BG64485B1 - Method for the preparatrion of (-)-galantamine hydrobromide - Google Patents

Abstract

The invention relates to a method for the preparation of (-)-galantamine, wherein diphenol derivatives are subjected to oxidation with phenyliodozo(III)bis(trifluoracetate) in a polar solvent at temperature ranging from 0 to -45 degrees C for 10 to 60 min. The narvedine derivative produced is protected by ethyleneglycol and the intermediate ketal is transformed into (plus minus)-narvedine having high yield by reduction with LiAlH4. Comprehensive conversion of the racemic narvedine into (plus minus)-narvedine is made by making use, as nucleus, of crystals of (-)-narvedin. The produced (-)-narvedin is reduced stereospecifically to (-)-galantamine by means of L-selectride and at subsequent treatment with hydrogen bromide thus producing the hydrogen bromide salts of the (-)-galantamine.

Description

Technical field

The invention relates to a method for the total synthesis of (-) - galanthamine hydrobromide, which is the active substance of the Bulgarian pharmaceutical preparation nivalin.

BACKGROUND OF THE INVENTION

A method for the synthesis of (-) - galanthamine is known in which the yield is less than 1% [1,2]. Other methods [3,4,5] are known to produce a mixture of galanthamine and epigalantamine, which also predetermines the low yield of (-) - galanthamine. Methods for the cyclization of Ν, замест-substituted diphenylethylamine derivatives [6] and electrochemical methods [7,8,9,10] are known. Methods are known [11,12] for the preparation of enantiomerically enriched (-) - galamine from racemic mixtures using crystallization techniques in the presence of germ crystals or asymmetric reduction of the respective precursors [13]. The disadvantages of these methods are that the yields are relatively low (0.5% -50%), the syntheses are multi-step and many by-products are obtained, mainly polymers, which are unusable and lead to the loss of the starting product. There is a known method [14] for the preparation of Norvedine-type enons, which treats only one single step of the complete galantamine production process.

SUMMARY OF THE INVENTION

The invention relates to a convenient and high-yield method for the preparation of optically active galanthamine based on the transformation of racemic narvedin into optically active narvedin.

The process for the preparation of nerve derivatives of the general formula

where A is

A _NR4

D or

X ^ NR, R, in which R ₃ = Br, Cl ₂ , NO ₂ and other substituents,

R ₄ = H, CH ₃ , C ₂ H ₅ and other alkyl substituents, = COCF ₃ , CHO, COOO ₂ H ₅ and other amide derivatives,

R ₅ = HCLO ₄ and similar inorganic and organic acid salts,

X = O, Y = H ₂ or X = H ₂ , Y = O or X = H ₂ , Υ ^, consists in the fact that diphenol derivatives of the general formula

where A is

X

A _NR4

D or

X ^/ ^ NR ₄ R5 g

II in which R ₃ = Br, Cl, NO ₂ and other substituents,

R ₄ = H, CH ₃ , C ₂ H ₅ and other alkyd substituents, = COCF ₃ , CHO, COOO ₂ H ₅ and other similar amide derivatives, R ₅ = HCLO ₄ and other similar salts of inorganic and organic acids, X = H ₂ , Y = O or X = O, Y = H ₂ or X = H ₂ , Y = H ₂ , are subjected to phenolic oxidation and cyclization.

The invention consists in the oxidation of the starting material in a polar solvent (CH ₃ OH, CH ₃ CN, CF ₃ CH ₂ OH, CF ₃ CH ₂ OH, etc.) with phenyldose (III) bis (trifluoroacetate) at 0 ° to -45 ° C for 10-60 min.

The advantages of the process according to the invention are the following: the reaction proceeds in high yield (70-75%); the duration of the process is 10-60 min; operated at a temperature of from 5 0 ° C to -45 ° 0; the unreacted starting product does not change and recovers after the reaction; high yield, soft working conditions, lack of by-products allow the industrial application of the method.

The thus obtained nervevedine derivative 2 was transformed into ethanolglycol (±) -anvedin after high-yield catalysis by reduction with LiAIH ₄ and subsequent deprotection (Scheme 1).

Oh

(±) -narvedin

Scheme 1

The invention has made the total conversion of racemic nervevedine into optically active nervevedine using crystalline (-) - norvedine embryos. The (-) - norvedin thus obtained is stereospecifically reduced by L-electrode to (-) - galanthamine and treated with hydrobromic acid to (-) - galanthamine. HBr (Scheme 2). The optically active galantamine hydrobromide obtained is a white crystalline substance, m.p. 266-267 ° C (lit. 246-247 ° C) [15]. [a] ²⁰ D -92 ° (with 1.5; H2O), (lit. [a] ² ° in -93 ° (with 1.5; H ₂ O) [15].

(-) - gal antamine

Scheme 2

Examples of carrying out the invention

The invention is illustrated by the following examples. Example 1.

To a stirring solution of 2-bromo-

4-Methoxy-5-hydroxy-N- [2- (4-hydroxyphenyl) -ethyl] -N-methylbenzamide 1g (0.0026 mol) in trifluoroethanol (40 ml) was added in portions of phenyldozo (III) -bis (trifluoroacetate) 5

1.35 g (0.0031 mol) at -40 ° C under a nitrogen atmosphere. The solution was stirred for 30 min, then the solvent was distilled off in vacuo and the residue filtered through silica gel on a short column of chloroform / ethyl acetate. Yield of the oxidized product 0.71 g (72%).

Example 2.

A mixture of 42 mg (0.11 mmol) of Norvedin-25 water. After cooling, the mixture was washed with 2,100 mg ethylene glycol and crystalline water, NaHCO ₃ , dried over MgSO _4, and the p-TsOH vacuum was stirred at reflux in 10 ml. Yield: 43 mg (91%) of a yellow oil, toluene for 2 h to remove

Example 3.

(±) -narvedin mg LiAlH ₄ was stirred under argon in 5 ml of dioxane. To these were added dropwise 100 mg of 3 dissolved in 5 ml of dioxane. The mixture was stirred at reflux for 3 h. After cooling, 10 ml of water: dioxane / 1: 1 were added dropwise to the reaction mixture, acidifying the reaction mixture to pH 1 with conc. HCl and stirred for 15 min. The mixture was then basified to pH 12 with NH ₄ OH, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over 5 MgSO, and vacuumed. Yield: 58 mg (86%).

Mp 188-190 ° C (from EtOH

Example 4.

with

NCH ₃ (±) -narvedin (-) - norvedin

298 mg of racemic narvedin were heated at 25 to 80 ° C in 4.8 ml of ethanol: triethylamine / 9: 1 solution. The solution was allowed to slowly cool to 65 ° C, causing turbidity. Crystals of (-) - norvedin (8.02 mg) were added and the mixture continued to cool from 30 to 40 ° C. At this temperature the reaction

Example 5.

the mixture was allowed to stir for 20 h, resulting in a precipitate. Cool to 25 ° C and stir for 3 h. The crystals were filtered and washed with 2 ml of ethanol-triethylamine / 9: 1. Yield: 210 mg (70%) of (-) - norvedin as white crystals. M.P. 190-193 ° C, [] ²⁰ _D -388 ° C (c 1, CHCl ₃ ).

NCH

(-) - norvedine (-) - galanthamine

A solution of (-) - norvedin (152 mg, 0.053 mmol) in tetrahydrofuran (27.4 ml) was added dropwise over 20 minutes to a solution of L-electrode (1.07 ml, IN in THF) in tetrahydrofuran (4, 3 ml) at -78 ° C. After the addition, the mixture was stirred at this temperature for 2 h. (0.22 ml) methanol was added and the temperature was gradually increased to 25 ° C, at which time the temperature was stirred for 15 min. The solution was concentrated and purified by column chromatography eluting with 6% CH ₃ OH / CH ₂ Cl ₂ . Yield: 128 mg (87%). M.P. 121123 ° C (from Et ₂ O); [α] ²⁰ _D -86.1 ° (c 1, CHCl ₃ ).

A solution of (-) - galanthamine (150 mg) in 1.4 ml of 95% ethanol was acidified to pH 1 with a solution of 62% HBr-acid in ethanol (1: 1). Allow to stand at 0 ° C overnight. The separated crystals were filtered off and dried. Yield:

182.9 mg (95%). M.P. 266-267 ° C (from EtOH), (lit. 246 ° -247 ° C) [15]. [α] ²⁰ _β -92 ° (with 1.5; H ₂ O), (lit.

[α] ²⁰ _° -93 ° (c 1.5; H ₂ O) [15].

Claims (14)

A process for the preparation of (-) - galanthamine hydrobromide from diphenolic derivatives of general formula II, which is subjected to oxidation with phenyldose (III) bis (trifluoroacetate) in polar solvent at a temperature of 0 ° C to -45 ° C with the oxidation having a duration of 10 to 60 minutes, converting the resultant nerve derivative into an intermediate ketal, which is transformed into (±) -narvedin by reduction with lithium aluminum hydride, converting (±) -narvedin to (- ) -narvedin using crystal sensors from (-) - norvedin, stereospecific reduction of (-) ) -narvedin using L-electrode and subsequent treatment with hydrobromic acid to the hydroCromide salt of 5 (-) - galanthamine. Literature 1. D. N. R. Barton, G. W. Kirby, Proc. Chem. Soc. 392, 1960. 10 2. D. H. R. Barton, G. W. Kirby, J. Chem. Soc.806, 1962. 3. Kametani et al., J. Chem. Soc. (C), 2602, 1969. 4. Kametani et al., J. Chem., (C), 1043, 15 1971. 5. Kametani et al., J. Org. Chem. 36,1295, 1971. 6. J. Szewczyk et al., J. Heterocyclic Chem., 26, 3765, 1988. 20 7. P. Vlahov, D. Krikoryan, M. Zagorova, M. Khinova, Art. Parushev, Avt. testimony per. No. 41458, 1978 8. R. Vlahov, D. Krikoryan, M. Zagorova, M. Khinova, Art. Parushev, Avt. certificate 25 per. No. 42315, 1978 9. Krikorian et al., Tetrahedron., 25, 2969, 1984. 10. Vlahov et al., Tetrahedron, 45, 3329, 1989. 30 11. US 6,087,495. 12. Chaplin et al., Tetrahedron lett., 39, 6777, 1998. 13. US 6018 043. 14. BG 63434. 35 15. Carroll et al., Bull. Soc. Chim. Fr., 127, 769, 1990.