LV15362B - Method for producing (1s)- and (1r)-enantiomer of 1-(tricyclo[3.3.1.1~3,7~]dec-1-yl)ethanamine hydrochloride - Google Patents

Description

[002] l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hidrohlonds (I, rimantadine hidrohlonds, Ameti-1 -adamantānmetilamīna hydrochloride)

HCl

I is a known antiviral agent that is active against influenza A virus. The antiviral activity of rimantadine is due to the inhibition of the proton permeability of the influenza virus М2 ion channel.

[003] It is well known that the stereochemical structure of a drug is an important factor in determining its pharmacological properties. When the drug molecule binds to an optically active receptor or enzyme, a diastereomeric complex with various chemical and physical properties is formed. Rimantadine has a chiral center and is currently used as a racemate. Solid state NMR studies showed that 1 (tricyclo [3,3, l, l ^3-7] dec-l-yl) ethanamine Λ-enantiomer closely cooperate with the influenza virus М2 ion channel forming stable complexes [1]. Potentially, this may result in a higher antiviral activity of the RU enantiomer of rimantadine compared to the S-enantiomer or racemate. Therefore, a question of l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine pure enantiomers extraction technologies. These extraction methods must be convenient and applicable to production.

[004] The literature a number of known l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine stereoisomers experimental techniques. One way of separating the stereoisomers is to convert the racemic amine into a mixture of diastereomeric diamides using (+) - and (-) - tartranyl by sequential crystallization. Optically active amine is obtained by amide hydrolysis [2]. The yield of the optically active product is low (less than 10%) based on the output racemic amine. The products obtained do not specify the absolute configuration of the chiral center, but only optical rotation.

[005] The literature describes optically active l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine extraction from racemic l- (tricyclo [3,3, l, l ^{3' 7]} dec-l-yl) ethaneamine by crystallization of diastereomeric salts. For this purpose, (5) - and (R) -2-phenoxypropionic acids or other analogous chiral carboxylic acids were used [3,4]. With (S) -2-fenoksipropionskābi authors [4] was given () -l- (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethanamine hydrochloride by erroneously designated by 7? -Isomer. But using (7R) -2-phenoxypropionic acid, the authors obtained (+) - 1- (tricyclo [3.3.1.17 ³⁷ ] dec-1-ylethaneamine hydrochloride, which was mistakenly labeled as the S'-isomer. has a low overall yield.

[006] enantiomerically pure l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine isomers molecules methyl protons replaced by deuterium scored enantioselectively synthesis. 1damantylmethylketone-d3 and chiral (R) -2-methylpropane-2-sulfinamide gave an imine derivative which was then stereoselectively reduced with sodium borohydride to give (R) -1- (ladamantyl ethanamine chloride-d3) or L-selectide The (-) - enantiomer of the deuterated rimantadine was designated by the authors as the S'-isomer and the (+) - enantiomer as the? - isomer. Using the described method, the target products can be obtained from l-adamantylmethylketone-d3. with a yield of 29-A2%, but requires the use of (7R) -2-methylpropane-2-sulfinamide, an expensive reagent.

[007] In the literature known l- (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethanamine hydrochloride pure enantiomers method of obtaining a low product output, and / or they require expensive reagent use. So far, the literature is not unambiguous information about the chiral center the absolute configuration of l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride (-) - and (+) - isomer.

Invention and content of [008] of the invention is to obtain l- (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethanamine hydrochloride in high chiral purity of practical, cost-effective synthesis method which is adaptable for industrial use. We found that (La) -l- (tricyclo [3,3, l, l ^{3 '7]} dec-liljetānamīna hydrochloride (7? - (+) - rimantadine hydrochloride) can be obtained, with a scheme is presented below ( Figure 1):

HCl

R.R-1

Sign 1 Scheme for the preparation of (1T?) - 1- (tricyclo [3.3.1.1 < ³ >] ⁷ -dec-1-yl) ethanamine hydrochloride [009] 1- (Tricyclo [3.3.1.1 < ⁷ >] -1-yl) ethanone (II) reacts with p-phenylethylamine (R-III) in an acidic medium to form (1 R) -1-phenyl-N - [(1 Z) -1- (tricyclo [3 3, l, l ^{3 '7]} dec-l-yl) etilidēn] ethanamine (A-IV). The imine derivative 7? -IV is reduced with sodium borohydride to give the amine (7? -V) as a mixture of stereoisomers in which (1 R) -1-phenyl-N - [(17 R) -1- (tricyclo [3.3] l, l ^{3 '7]} dec-l-yl) ethyl] ethanamine content higher than another stereoisomer content. Intermediates (7? -IV) and (7? -V) may not be isolated from the reaction mixture, but may be used in the next step as a solution. This reduces the number of manipulations and simplifies the synthesis process. The stereoisomeric composition of the amine (2? -V) is enriched to form the corresponding hydrochloride (7?,? - VI) which is crystallized. (l /?) - l-phenyl-N - [(17?) - l (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethyl] ethanamine hydrochloride (7?, /? - VI) hydrogenation to give the objective (l /?) - l (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride (Л-Ι), if necessary, is purified by crystallization.

[010] In analogy to acquire and (15) -l- (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethanamine hydrochloride (5 - (-) rimantadine hydrochloride), the acquisition scheme is shown below (Fig. 2):

NaBH ₄

S.5-I

Sign 2 (lS) -l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride acquisition scheme [Oil] l- (tricyclo [3,3, l, l ^{3' 7]} dec -1-yl) ethanone (II) is reacted with 5-phenylethylamine (5-III) in an acidic medium to form (15) -1-phenyl-N - [(1Z) -1- (tricyclo [3.3.1.1) ^{3 '7]} dec-l-yl) etilidēn] ethanamine (5-IV). The imine (5-1V) is reduced with sodium borohydride to give the amine (5-V) as a mixture of stereoisomers with higher (15) -1-phenyl-N - [(15) -1- (tricyclo [3.3.1] , l ^{3 '7]} dec-l-yl) ethyl] etānamīnasaturs. Intermediates (5-IV) and (5-V) may not be isolated from the reaction mixture but may be used as a solution in the next step. The stereoisomeric composition of the amine (5-V) is enriched to form the corresponding hydrochloride (5.5-VI) which is crystallized. (15) S-phenyl-N - [(15) The effect (tricikIo [3,3, l I ^3.7] dec-l-iI) ethyl] ethanamine hydrochloride (5.5-VI) hydrogenation to give target (15) -l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride (5-1), if necessary, is purified by crystallization.

[012] It will be apparent to one skilled in the chemical art that any suitable reduction catalyst may be used in place of the sodium borohydride in said reduction reactions, or any other suitable hydrogenation catalyst in the chemical field may be used in the hydrogenation reaction. , and such substitution does not exceed the scope of the invention.

To determine the absolute configuration of the chiral center of the products obtained, X-ray structure analysis was performed on the intermediate (7?, 7? -VI) and (5.5-VI) single crystals obtained by slow crystallization of the substance from methanol. Single crystal diffraction data of (?,?, -? - VI) and (5.5-VI) were obtained using a Bruker-Nonius KappaCCD diffractometer (MoKastar, λ = 0.71073 A) equipped with an Oxford Cryostream Plus cooler. The single crystals (7?, 7? -VI) and (5.5-VI) placed in the nitrogen stream were cooled to 110 ° C, thus reducing the thermal oscillation of the atoms and obtaining more accurate results. Two (15) -l-phenyl-N - [(15) -l (tricyclo [3,3, l, l ^37] dec-l-yl) etilļetānamīna hydrochloride and (l /?) - l-phenyl-N- [(l /?) -!

The crystallographic characteristics and crystal structure determination parameters of (tricyclo [3,3,1,1 ^{3 7} ] dec-1-yl) ethyl] ethanamine hydrochloride are summarized in Table 1.

Table 1 l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethyl] ethanamine hydrochloride (1 S) - and (lR) -enantiomer crystallographic characterization

Parameter Value (O-VI) (5.5-VI) Empirical formula C20H29N · HCl C20H29N HCl Molecular weight, g / mol 319.90 319.90 Crystal shape needle needle Crystal size, mm 0.07x0.08x0.37 0.06x0.10x0.41 Crystallographic Singonia monoclinic monoclinic Crystalline lattice parameters: а, А 11.4469 (5) 11.4464 (3) b, A 7.1637 (3) 7.1639 (2) с, А 11.9779 (6) 11.9771 (4) β, ° 113,338 (2) 113,339 (2) Volume of elemental cell V, A ³ 901.85 (7) 901.77 (5) Spatial group P2i P2i Number of molecules per elementary cell, Z 2 2 Density of the substance (calculated) p, g / cm ³ 1,178 1,178 The maximum diffraction angle of 20, ⁰ 58.0 58.0 Total reflexes 4221 3938 Number of independent reflexes with intensity I> 2σ (7) 3306 3437 R-factor 0.0587 0.0420

The quality of the single crystals of the compounds allowed the absolute configuration to be determined using the anomalous diffraction effect.

[014] The synthesis of optically active rimantadine is based on a stereoselective reductive amination reaction. Chiral l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride (I) is obtained with high optical purity (98% ее) 32% ~ 42% outcome per l - (tricyclo [3,3, l, l ^{3 '7} ļdec-liljetanonu (II). the developed three phase synthesis allows to obtain the target compound without the use of expensive reagents is sufficiently simple and effective that the applied production.

EXAMPLES OF THE INVENTION The invention is illustrated but not limited by the following examples.

Example 1. (17?) - l-phenyl-N - [(l /?) - l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethyl] ethanamine hydrochloride (R, R-VI ).

[017] three-necked round-bottomed flask equipped with a stirrer, thermometer, Dean-Stark sleeve and the cooler, pour 25 g (0.140 mol) of l- (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethanone ( II), 200 ml of toluene and 20.5 g (0.169 mol) of Λ-phenylethylamine (Λ-Ш) and 1.2 ml of tetrafluoroboric acid are added with stirring. The reaction mixture is heated to reflux and distilled with water using a Din-Stark coupling. The condensation is carried out for 4-5 hours and, after the reaction is completed, the mixture is cooled to 18-22 ° C. Obtain about 230 ml (17?) - l-phenyl-N - [(LZ) -l- (tricyclo [3,3, l, l ^{3 '7]} decl-yl) etilidēn] ethanamine (7c-IV) toluene solution .

[018] In a three-necked round-bottomed flask equipped with a stirrer, a thermometer and a dropping funnel, pour 100 ml of ethyl alcohol, add 5.0 g (0.132 mol) of sodium borohydride and cool to 10-12 ° C with stirring. The mixture obtained in 1-1.5 hours stirring, add about 230 ml (1 /?) L-phenyl-N - [(LZ) -l- (tricyclo [3,3, l, l ^3,7] dec-l- il) ethylidene] ethanamine in toluene solution at a temperature of 10-20 ° C. The reaction mixture is stirred for a further 8 to 10 hours and then about 60 ml of acetone is added over 1 hour at a temperature not exceeding 30 ° C. After adding, stir for another 1 hour, then add 100 ml of water and stir for 30 minutes. Add approximately 50 ml of concentrated hydrochloric acid to a pH of less than 1, not exceeding 30 ° C, stir for 2-3 hours and filter. Wash the precipitate on the filter with 100 ml water, then 30 ml isopropyl alcohol.

[019] Obtained 30-34 g (67-76% of theoretical) (17?) - l-phenyl-N - [(l /?) - l (tricyclo [3,3, l, l ^{3 '7]} dec-1-yl) ethyl] ethanamine hydrochloride (R, R-VI).

Specific Cutting: [α] D = -28.2 ° (c = 1.0, HCOOH, 20 ° C); mp 302.6 ° C (with decomposition).

1 H-NMR (300 MHz, DMSO-? 7): 8.90 (1 H, s, s); 8.06 (1H, e.g. s); 7.70-7.76 (2 H, m); 7.367.49 (3H, m), 4.35 (1H, m), 2.71 (1H, m); 1.96 (3 H, m); 1.44-1.78 (15H, m); 1.05 (3H, d, J = 6.8 Hz).

¹³ C-NMR (75 MHz, DMSO-t / b): 137.3; 129.0; 128.8; 128.6; 63.4; 58.7; 36.5; 35.9; 34.9; 27.5; 18.7; 12.2.

IS (KBr tablet), cm -1: 3425; 2907; 2847; 2738; 2487; 1596; 1451; 1408; 1377; 1346; 1213; 1090; 1066; 1026; 927; 765; 701; 550.

MS m / z: [M + H] ⁺ 284.

Example 2. (17?) - l- (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethanamine hydrochloride (7? S) acquisition.

290-310 ml of methanol are poured into the autoclave, 25 g of (17R) -1-phenyl-N - [(U) -L- (tricyclo [3.3.1.1 < ³ >] ⁷ ] dec-l- is added. il) ethyl] ethanamine hydrochloride (7?, 7? -VI) and 1.3 g of 5% palladium on carbon catalyst. The reaction mixture is heated to 50 ° C with stirring and hydrogen is fed at 50 atm. pressure. Hydrogenation takes place at 40-55 ° C and 45-50 atm. hydrogen pressure for 8-10 hours. After completion of the reaction, the catalyst is filtered off, washed with 10 ml of methyl alcohol on the filter. Evaporate the filtrate under reduced pressure until no distillate is observed. To the residue is added 30 ml of isopropyl alcohol, the mixture is cooled to 5-10 ° C and stirred for 2-3 hours. The precipitate is filtered off, washed with 10 ml of isopropyl alcohol on a filter. The resulting technical product is dried. Obtained 12-15 g technical (l /?) - l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride (Λ-Ι) (7189% of theoretical).

[022] Technical (LT?) - l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride (13.5 g) if necessary, recrystallized from water. 9-11 g of (1 R) -1- (tricyclo [3.3.1.1 ^{3 7} ] dec1-yl) ethaneamine hydrochloride (R) are obtained (67-81% of theory).

Specific Cutting: [α] σ = + 3.9 ° (c = 1.0, HCOOH, 25 ° C); optical purity 98% ee (HPLC). 1 H-NMR (300 MHz, DMSO-1): 8.04 (3H, s, s); 2.72 (1H, sq.7 = 6.8 Hz); 1.95 (3 H, m); 1.421.72 (12 H, m); 1.11 (3H, d ../= 6.8 Hz).

¹³ C-NMR (75.5 MHz, DMSO-t / e): 55.5; 37.1; 36.2; 34.1; 27.5; 12.7.

IS (KBr tablet), cm ^-1 : 2902; 2028; 1609; 1516; 1450; 1390; 1211; 1077.

MS m / z. [M + H] ⁺ 180.

Example 3. (lS) -l-phenyl-N - [(lS) -l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) etiljetānamīna hydrochloride (S, S-VI) is obtained.

[024] three-necked round-bottomed flask equipped with a stirrer, thermometer, Dean-Stark sleeve and the cooler, pour 25 g (0.140 mol) of l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanone ( II), add 200 ml of toluene and add 25 g (0.202 mol) of S-phenylethylamine (S'-Ш) and 1.2 ml of tetrafluoroboric acid with stirring. The reaction mixture is boiled using a Din-Stark coupling to distil the water. The condensation reaction is carried out for 4 to 5 hours and, at the end of the reaction, is cooled to 18-22 ° C. Obtain about 230 ml (LN) -l-phenyl-N - [(LZ) -l (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) etilidēn] ethanamine (5-IV) toluene solution .

[025] In a triple neck flask fitted with a stirrer, a thermometer and a dropping funnel, pour 100 ml of ethyl alcohol, add 5.0 g (0.132 mol) of sodium borohydride, and cool to 10-12 ° C with stirring. The resulting mixture 1-1.5 hour stirring, add about 230 ml (1 S) l-phenyl-N - [(LZ) -l- (tricyclo [3,3, l, l ^3-7] dec-l-yl) ethylidene] ethanamine in toluene solution maintained at 10-20 ° C. After the addition, the reaction mixture is stirred for a further 8 to 10 hours and about 60 ml of acetone is added over 1 hour at a temperature not exceeding 30 ° C. After adding, stir for another 1 hour, then add 100 ml of water and stir for 30 minutes. Add approximately 50 ml of concentrated hydrochloric acid to a pH of less than 1, not exceeding 30 ° C, stir for 2-3 hours and filter. Wash the precipitate on the filter with 100 ml water, then 30 ml isopropyl alcohol.

[026] Obtained 31-35 g (69-78% of theoretical) (15) -l-phenyl-N - [(15) -l (tricyclo [3,3, l, l ^{3 '7]} dec-l -yl) ethyl] ethanamine hydrochloride (S'.S'-VI).

Specific Cutting: [α] D = +29.0 ° (c = 1.0, HCOOH, 20 ° C); mp 302.5 ° C (decomposition).

1 H-NMR (300 MHz, DMSO-? 7s): 8.72 (1H, pl.s); 7.60-7.80 (3 H, m); 7.38-7.51 (3 H, m); 4.37 (1H, m); 2.78 (1H, m); 1.98 (3 H, m); 1.45-1.75 (15 H, m); 1.08 (3H, d, J = 6.8 Hz).

¹³ C-NMR (75 MHz, DMSO-t / b): 137.3; 129.0; 128.8; 128.6; 63.4; 58.7; 36.5; 35.9; 34.9; 27.5; 18.7; 12.2.

IS (KBr tablet), cm ': 3425; 2907; 2847; 2738; 2487; 1597; 1451; 1408; 1377; 1213; 1066; 927; 765; 701; 550.

MS m / z: [M + H] ⁺ 284.

Example 4. (lS) -l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride (S'-Ι) acquisition.

[028] the autoclave poured 290-310 ml of methanol is added 25 g (lS) -l-phenyl-N - [(lS) -l (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethyl] ethanamine hydrochloride (S, S-VI) and 1.3 g of 5% palladium on carbon catalyst. The reaction mixture is heated to 50 ° C with stirring and hydrogen is fed at 50 atm. pressure. Hydrogenation takes place at 40-55 ° C and 45-50 atm. hydrogen pressure for 8-10 hours. After completion of the reaction, the catalyst is filtered off, washed on a filter with 10 ml of methanol. Evaporate the filtrate under reduced pressure until no distillate is observed. To the residue is added 30 ml of isopropyl alcohol, the mixture is cooled to 5-10 ° C and stirred for 2-3 hours. The precipitate is filtered off, washed with 10 ml of isopropyl alcohol on a filter. The resulting technical product (S'-Ι) is dried. 11-12 g of technical S-rimantadine hydrochloride are obtained (65-71% of theory).

[029] The technical product (11.5 g) is recrystallized from water, if necessary. 8-10 g is obtained (15) -l- (tricyclo [3,3, l, l ^3-7] dec-l-yl) ethanamine hydrochloride (70-87% of theoretical).

Specific Cutting: [α] D = -4.9 ° (c = 1.0, HCOOH, 24 ° C); optical purity 98% ee (HPLC). 1 H-NMR (300 MHz, DMSO-b / b): 8.05 (3H, s, s); 2.71 (1H, sq. Δ = 6.8 Hz); 1.95 (3 H, m); 1.421.71 (12 H, m); 1.11 (3H, d, J = 6.8 Hz).

¹³ C-NMR (75.5 MHz, DMSO-c ₆ ): 55.5; 37.1; 36.2; 34.1; 27.5; 12.7.

IS (KBr tablet), cm ^-1 : 2902; 2028; 1609; 1516; 1450; 1390; 1211; 1077.

MS m / z: [M + H] ⁺ 180.

Literature used

1. J. Amer. Chem. Soc., 2016, Vol. 138, p. 1506-1509

2. J. Med. Chem., 1971, Vol. 14, No. 6, p. 535-543.

3. Acta Cryst., 2008, A64, p. C380.

4. Patent application JP2008024666.

Claims (5)

1) l- (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethanone reacting a chiral counter dryers are laminated obtaining chiral 1 -phenyl-N- [1 - (tricyclo [3.3 1,1 ^3,7] dec-1 -iljetilidēnļetānamīnu; 1. A method of chiral l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride, characterized in that comprises the following successive stages: 2. A method according to claim 1, with a chiral phenylethylamine means that (/?) Enantiomers and the chiral target l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride is (l / ?) - l (tricyclo [3,3, l, l ^3,7] dec-l-yl) ethanamine hydrochloride. 2) The stage 1) reacting a chiral l-phenyl-N- [l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) etilidēn] ethanamine reduction with a suitable reagent reducējušo obtaining chiral l-phenyl N- [l (tricyclo [3,3,1,1 ^37] dec-1-yl) ethyl] ethanamine; 3. A method according to claim 1, with a chiral phenylethylamine means the (S) enantiomer and target chiral l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) ethanamine hydrochloride is (15) - 1 (tric iclo [3,3,1,1 ³⁷ ] dec-1-ylethanamine hydrochloride. 3) Step 2) reacting the chiral l-phenyl-N- [l- (tricyclo [3,3, l, l ^{3 '7]} dec-l-yl) etilletānamīna treatment with HC1 to give a chiral l-phenyl-N- [ l- (tricyclo [3,3, l, l ^{3 '7} ļdec-liljetilļetānamīna hydrochloride The process of claim 1, wherein a suitable reducing agent is sodium borohydride. Hydrogenation of the chiral 1-phenyl-N- [1- (tricyclo [3.3.1.1.7] dec-1-yl) ethyl] ethanamine hydrochloride obtained in Step 3) with hydrogen in the presence of a suitable catalyst - (tricyclo [3.3.1.1.7] dec-1-yl) ethanamine hydrochloride. The process of claim 1, wherein a suitable catalyst is palladium on