JP2012184229A - Process for enantioselective synthesis of landiolol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a process for the enantioselective synthesis of landiolol.SOLUTION: The process for the enantioselective synthesis of landiolol represented by formula (B) uses a compound represented by formula (A) as an intermediate.

Description

  The present invention relates to (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate 3, alkylating agent 4 having an epoxide structure and free base or Landiolol 1, starting from the salt form of 2- (morpholine-4-carboxyamido) ethanamine, ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4- ( (S) -2-Hydroxy-3- (2- (morpholine-4-carboxamido) ethylamino) propoxy) phenyl) propanoate) or its hydrochloride 2.

  According to a particularly preferred embodiment of the present invention, landiolol is (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((R) -3-chloro-2- Prepared from (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate 3 to epichlorohydrin Prepared through kinetic optical resolution.

  Landiolol 1 is a very fast acting potent cardioselective β-blocker and is used as an antiarrhythmic drug in the form of hydrochloride.

  Landiolol 1 was synthesized according to US Pat. No. 5,013,734, Japanese Patent No. 3,302,647, Chinese Patent No. 1,050,814, Japanese Patent No. 2,539,734 and Chemical & Pharmaceutical Bulletin 1992, 40 (6). 1462-1469. The main synthetic route for preparing landiolol is reported in the following scheme:

  Landiolol 1 is synthesized by reacting epoxide 7 with amine 8. Intermediate 7 is synthesized starting from 3 by reaction with a chiral synthon. US Pat. No. 5,013,734 discloses the synthesis of 7 from 3 and (S) -epibromohydrin 10.

  This reagent is very expensive and hardly available on the market. The reaction is carried out under refluxing acetone for 16 hours and the yield is not very high (76.2%). In addition, the yield of landiolol 1 produced by the reaction of 8 and 7 is low (43.3%), after which 1 interconverts to intermediate 9 (total yield from 7 38.4%). In this final stage, chloroform is used as the solvent. Furthermore, both Intermediate 7 and Landiolol 1 require chromatographic purification. Japanese Patent No. 3302647 discloses the same synthesis of Intermediate 7 but uses (S) -glycidyl nosylate 11 instead of (S) -epibromohydrin 10.

  Compound 11 is also very expensive and is hardly available on the market, so that no special advantage is obtained. Furthermore, the reaction to produce 7 is carried out in a dimethylformamide solution of sodium hydroxide at room temperature, i.e. it has caused numerous accidents in the past due to the strong self-heating of the reaction mixture and cannot be scaled up industrially. Not under conditions (Bretherick, 7th edition, 2007, 1671-1673). Again, the yield of Landiolol 1 is low (from 7 to 42.6% of Landiolol 1). In this case, oxalate 6 is used instead of amine 8.

  The resulting intermediate 9 (45.8% yield) is then interconverted to Landiolol 1. CN10176148 discloses a very similar synthesis as described above, and the yield of landiolol oxalate 9 from its 7 and free base 8 is still very low 9 (27.8%). Chinese Patent No. 100506814 discloses another synthesis similar to the above, where (S) -epichlorohydrin (compound of formula 12, where X is chlorine) more readily available on the market. Is used as a chiral synthon.

  However, this reaction is also very expensive and the reaction time is long (16 to 24 hours). Furthermore, the final product Landiolol hydrochloride 2 is obtained by filtration from a water-sodium carbonate-sodium chloride / ether-hexane biphasic mixture, which is not optimal for industrial production. Chemical & Pharmaceutical Bulletin 1992, 40 (6) 1462-1469 describes the synthesis of 7 starting from 3 and similar chiral synthons 13.

  (S) -glycidyl tosylate 13 is also very expensive and hardly available on the market, and the reaction takes a long time (15 hours). Furthermore, again, intermediate 7 and landiolol 1 require chromatographic purification. In Japanese Patent No. 2539734, compound 7 is synthesized according to the following synthetic scheme:

  However, this solution has no special advantage. Furthermore, compound 14 is not commercially available and one of the expensive chiral synthons described above must be used.

  The above process requires isolation of all the intermediates and numerous chromatographic purifications, thus adversely affecting yield and productivity and has a large labor cost impact on the final product. In addition, the reaction from 7 to Landiolol 1 or Landiolol oxalate 9 is often in low yield. Furthermore, the reaction time is very long and in almost all cases the reagents used are very expensive and are hardly available on the market and cannot be reused in the process.

US Pat. No. 5,013,734 Japanese Patent No. 3302647 Specification The specification of the People's Republic of China No. 100506814 Japanese Patent No. 2539734 Specification

Chemical & Pharmaceutical Bulletin 1992, 40 (6) 1462-1469

  It has been found that landiolol 1 and landiolol hydrochloride 2 can be conveniently prepared by a novel synthetic procedure reported herein below:

The process of the present invention includes:
a) (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate 3 and formula 4 wherein X is halogen or C ₁ -C ₃ alkyl Very low cost epoxide alkylating agents, such as sulfonic acid esters or C ₆ -C ₁₀ aryl sulfonic acid esters, in the presence of readily commercially available, very inexpensive and reusable enantioselective catalysts. In a mild and short reaction to obtain Formula 5 (where X is as defined above) with the starting epoxide alkylating agent rich in the (S) isomer of Formula 12;
b) reacting the compound of formula 5 obtained in step a) with 2- (morpholine-4-carboxamido) ethanamine in the form of a free base or a salt thereof in the presence of a base to obtain landiolol 1 in high yield. Obtaining step,
c) obtaining landiolol hydrochloride 2 with high enantiomeric excess by chlorination of landiolol 1;

  In the compound of formula 5, the carbon atom having the secondary alcohol group is R-isomer stereochemically.

  Preferred examples of the compound of formula 4 are epichlorohydrin, epibromohydrin, glycidyl nosylate, glycidyl tosylate and the like.

  A particularly preferred example of a compound of formula 4 is epichlorohydrin.

  The enantioselective catalyst I is preferably a metallic catalyst such as a catalyst based on cobalt, manganese, aluminum, copper, samarium, chromium, vanadium, etc., and has a high optical purity chelating ligand, preferably ( It binds to a salen ligand such as R, R) -bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediamine. Enantioselective catalysts are preferably polar compounds, preferably carboxylic acids, ionic salts or polyfluorinated compounds such as acetic acid, 4-nitrobenzoic acid, cobalt chloride, zinc nitrate, gallium chloride, 3,5-difluorophenol, perfluoro. -Activated by tert-butanol or the like.

  In this case, the synthesis of the compound of formula 5 is carried out in an enantioselective catalyst, preferably (in a preferably aprotic polar organic solvent such as methyl tert-butyl ether (MTBE), dichloromethane, acetonitrile and mixtures thereof. R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt 16, polar activator, preferably 4-nitrobenzoic acid 17 and epoxy It is carried out in the presence of an alkylating agent, preferably epichlorohydrin.

  When epichlorohydrin is used as the compound of formula 4, the compound of formula 5 (wherein X is chlorine), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) Methyl 3- (4-((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate is obtained.

  The synthesis of Landiolol 1 is carried out using 2- (morpholine-4-carboxamido) ethanamine as base or salt thereof, for example oxalate or chloride. The reaction is carried out in an organic polar solvent, for example an alcoholic solvent such as isopropanol and isobutanol or preferably acetonitrile, a base, preferably an inorganic base such as potassium chloride, sodium carbonate, NaOH, KOH, etc., and an ionic, Preferably it is carried out in the presence of an inorganic catalyst such as KI, NaI, KBr, NaBr and the like.

  The chlorination of landiolol hydrochloride 2 is carried out using a chlorinated, preferably inorganic acid such as hydrochloric acid, ammonium chloride or the like. The reaction is carried out in a polar solvent such as isopropanol, acetone, acetonitrile, diisopropyl ether, and mixtures thereof.

  Intermediate 5 (wherein X is chlorine) is novel and is a further object of the present invention.

  According to a preferred embodiment of the invention, the process is carried out as follows:

  Step a

  Typically, (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt is preferably used to activate the salen catalyst. 16 is reacted with 1.0 to 3.0 equivalents of carboxylic acid, preferably 4-nitrobenzoic acid 17, preferably 1.5 to 2.5 equivalents. This reaction is carried out in a polar aprotic catalyst, preferably dichloromethane, at a temperature of 10-40 ° C, preferably 20-30 ° C. Based on the amount of (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt 16 4 to 15 times, preferably Use 7-12 volumes of solvent. After the appearance of a brown color, the solvent is removed, thereby obtaining the catalyst in an active form. This is followed by 10-100 equivalents of starting material (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate 3, preferably 20-50 equivalents Followed by the addition of a polar aprotic solvent, preferably methyl tert-butyl ether (MTBE). 1 to 5 times the amount of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate 3, preferably 2-3 Use double volume of solvent. Thereafter, 2.0 to 3.0 equivalents of a compound of formula 4, typically epichlorohydrin, is added, preferably 2.0 to 2.5 equivalents. The reaction is carried out at a temperature of 10 to 40 ° C., preferably 20 to 30 ° C. The reaction is monitored by UPLC analysis using a C18 column and water / acetonitrile containing 1% formic acid as the eluent phase. After the reaction is complete, water and toluene are added and the phases are separated. The organic phase is then distilled to recover (S) -epichlorohydrin and washed with dilute sodium hydroxide. The organic phase is then concentrated to a small volume, polar solvent, acetonitrile or methanol, preferably acetonitrile is added, concentrated again to a small volume to remove toluene, and finally a polar solvent such as acetonitrile or methanol, preferably acetonitrile is added. Add 5 to 30 times the amount. The suspension is filtered to recover the catalyst and the resulting solution can be used directly in step b or (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3 -(4-((2R) -3-Chloro-2-hydroxypropoxy) phenyl) -propanoate 5 can be isolated as an oil that can be stored at room temperature for several days. To obtain (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate 5 as an oil For example, a decolorizing filter aid is added to a solution in a polar solvent, the resulting suspension is filtered, and the resulting solution is evaporated to dryness.

  (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((2R) -3-chloro-2-hydroxy-propoxy) phenyl) propanoate 5 is obtained as an oil. It is done.

  Step b

  Generally, (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((()) isolated as an oil in step a or obtained directly from a polar solvent solution. 2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate 5 is 1.0 to 6.0 equivalents, 3.0 to 4.0 equivalents of an inorganic base, preferably potassium carbonate, and a catalytic amount ( 0.05-0.20 eq) nonionic inorganic catalyst, preferably in the presence of potassium iodide. Thereafter, 2- (morpholine-4-carboxamido) ethanamine as a base or an oxalate salt or salt thereof such as hydrochloride, preferably oxalate, 1.0-4.0 equivalents, preferably 2.0-3 Add in an amount of 0.0 equivalents. The reaction is carried out in a polar solvent, preferably acetonitrile, at a temperature of 20 to 85 ° C, preferably 60 to 85 ° C. Based on the amount of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((2R) -3-chloro-2-hydroxypropoxy) -phenyl) propanoate 5 The amount is 5 to 30 times, preferably 10 to 20 times. The reaction is monitored by UPLC analysis using a C18 column and water / acetonitrile containing 1% formic acid as the eluent phase. After the reaction is complete, ethyl acetate and water are added and the phases are separated. Subsequently, the organic phase is extracted with water at a pH of 2-5, preferably 3-4. The phases are separated and the organic phase is subsequently extracted again with ethyl acetate at pH 8-13, preferably 9-12. The organic phase solvent can be replaced with 2 to 20 times the amount of polar solvent such as isopropanol and the resulting solution can be used directly in step c or Landiolol 1 can be isolated. For this purpose, the solvent is removed or replaced with a polar solvent, for example diisopropyl ether, to drive solidification, after which the solvent is removed from the resulting suspension, thereby treating Landiolol 1 as an oil that solidifies over time. obtain.

  Process c

  In general, landiolol 1 obtained in step b directly from the polar solvent solution or by dissolution of the isolated product is preferably salified directly with hydrochloric acid to give landiolol hydrochloride 2. Chlorination is carried out in 2 to 20 times, preferably 5 to 10 times the amount of polar solvent, preferably isopropanol, based on the amount of Landiolol 1. After the addition of acid, the solvent is evaporated off and the product is crystallized by adding 1-20 times the amount of polar solvent, preferably acetone. The solid obtained by filtering the suspension is vacuum-dried at 25 to 35 ° C. for 12 hours to obtain landiolol hydrochloride 2. The enantiomeric excess of the final product is analyzed using a Chiralcel OD column and hexane / ethanol as the eluent phase containing diethylamine.

  The process of the present invention is particularly advantageous in that it is effective without isolating any intermediate, intermediate 5 is obtained in very high yield and purity under very mild reaction conditions. Furthermore, starting material 4 (wherein X is chlorine) (epichlorohydrin) is very inexpensive and readily available commercially. The catalyst used is commercially available at low cost and can be easily recovered by simple filtration. Surprisingly, the reaction starting from the new intermediate 5 (where X is chlorine) to produce Landiolol 1 gives significantly higher yields than can be obtained with most processes described in the background of the invention. This is the opposite of starting from intermediate 7. The resulting landiolol 1 can be converted directly to landiolol hydrochloride 2 with good overall yield and requires no further purification or intermediate steps. The resulting landiolol hydrochloride 2 has a very high enantiopurity.

  In addition, the process of the present invention is capable of recovering (S) -epichlorohydrin 12, which can also be used to synthesize Landiolol 1 in the following scheme to prepare compound 3, Is the product:

  The high yield synthesis of intermediate 15 from 12 has been described in numerous publications. Some publications with this disclosure are listed below: Catalysis Communications, 8 (12), 2087-2095; 2007; People's Republic of China Patent No. 100506814; Journal of Molecular Catalysis A: Chemical, 236 (1- 2), 72-76; 2005; Chinese Journal of Chemistry, 23 (9), 1275-1277; 2005; Synthetic Communications, 35 (11), 1441-1445; 2005; Synthetic Communications, 31 (22), 3411-3411 2001; Chemistry Letters, (11), 2019-22; 1990; K; Himiya Geterotsklicicheskih Soedinenii, (1), 33-6; 1991. The synthesis of 3 in high yield starting from 15 and 19 is described in Chinese Patent No. 100506814. A further publication of that disclosure is US Pat. No. 5,013,734. Both publications have already been described in the background art of the present invention for the synthesis of Landiolol 1.

  The invention is illustrated in detail by the following examples.

(S)-(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate (5)

  (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt (16) (50 mg, 0.0828 mmol) suspended in MTBE (1 ml) Acetic acid (10 mg, 0.166 mmol) is added to the suspension. The mixture is left to stir at 20-25 ° C. for 1 hour until a dark color appears. Then (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate (3) (500 mg, 1.78 mmol) followed by epichlorohydrin (A compound of formula 4, wherein X is chlorine) (340 mg, 3.56 mmol) is added thereto. The mixture is left to stir at 20-25 ° C. and monitored by UPLC. After completion of the reaction, water (5 ml) and toluene (5 ml) were added, the phases were separated, and the solvent and (S) -epichlorohydrin were removed from the organic phase under reduced pressure to give 600 mg (90.4%) Obtain a dark oil.

  (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate (5)

  (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt (16) (1,9 g, 3.19 mmol) in dichloromethane (20 ml ) Add 4-nitrobenzoic acid 17 (1.1 g, 6.38 mmol) to the suspension. The mixture is left to stir at 20-25 ° C. for 1 hour until a dark color appears. The solvent was replaced with MTBE (30 ml) followed by (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate (3), (18 g, 63 , 8 mmol) followed by epichlorohydrin (compound of formula 4, where X is chlorine) (13.4 g, 140 mmol). The mixture is left to stir at 20-25 ° C. and monitored by UPLC. After the reaction is complete, toluene (300 ml) and water (150 ml) are added and the phases are separated. The organic phase is evaporated to dryness, whereby concentrated (S) -epichlorohydrin is recovered. Toluene (300 ml) and 10% NaOH (100 ml) are added. The phases are separated and the resulting solution is concentrated to a volume of about 50 ml, 100 ml of acetonitrile is added, concentrated to a volume of 50 ml, and finally 250 ml of acetonitrile is added. Decolorizing filter aid (2.5 g) is added, the mixture is left stirring for 15 minutes and the suspension is filtered. The filtrate is evaporated to dryness to give 23.7 g (99,6%) of a reddish brown oil.

  (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate (5)

  (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt (16) (470 mg, 0.780 mmol) in dichloromethane (5 ml) To the suspension is added 4-nitrobenzoic acid 17 (270 mg, 1.56 mmol). The mixture is left to stir at 20-25 ° C. for 45 minutes until a dark color appears. The resulting solution is concentrated to a volume of about 2 ml, 5 ml MTBE is added, concentrated to a volume of 2 ml, finally 6 ml MTBE, then (S)-(2,2-dimethyl-1,3-dioxolane. -4-yl) methyl 3- (4-hydroxyphenyl) propanoate (3), (5 g, 17.7 mmol) followed by epichlorohydrin (compound of formula 4, wherein X is chlorine) (3.7 g 38.9 mmol). The mixture is left to stir at 20-25 ° C. and monitored by UPLC. After the reaction is complete, toluene (25 ml) and water (25 ml) are added and the phases are separated. The organic phase is evaporated to dryness, whereby concentrated (S) -epichlorohydrin is recovered. Acetonitrile (25 ml) is added and the suspension is filtered, thereby recovering the catalyst. Concentrate the resulting solution to a volume of about 5 ml, add 15 ml of toluene, then concentrate to a volume of 5 ml, and finally add 20 ml of toluene and decolorizing filter aid (20.0 g). The mixture is left stirring for 15 minutes and the suspension is filtered. The filtrate is evaporated to dryness to give 6.1 g (92.4%) of a yellow oil.

  LC-MS (ESI +) [M + H] + = 373

1H-NMR (CDCl3) (chemical shifts are expressed in ppm based on TMS): 1,37 (3H, s, CH3); 1,43 (3H, s, CH3); 2,65 (2H, t , J = 7 Hz, CH2-Ar); 2,83 (1H, bs, OH); 2,91 (2H, t, J = 7 Hz, CH2-CO); 3,66-3, 81 (3H, m, 4.00-4, 25 (6H, m, 4 oxolane CH, CH2-OCO, CH2-OAr and 5 oxolane CH); 4, 25 (1H, m, C H- OH); 6, 84 and 7, 13 (4H, system AA'XX ', aromatic ring).

13C-NMR (CDCl3) (ppm): 25,3 (CH3); 26,6 (CH3); 29,9 (CH2); 35,8 (CH2); 45,9 (CH2-Cl); (CH2); 66,2 (CH2); 68,5 (CH2); 69,7 (CH); 73,4 (CH); 109,7; 114,5 (CH); 129,3 (CH); 133, 1; 156, 7; 172, 6 (COOR).

Elemental analysis: C, 58.3%; H, 6.9%; Cl, 9.3%; O, 25.5%.
(% Calculated: C, 58.0; H, 6.8; Cl, 9.5; O, 25.7).

  FT-IR (UATR, cm-1): 3456, 2987, 2936, 1733, 1612, 1512, 1372, 1241, 1154, 1041, 828, 741, 720.

  Landiolol (1)

  (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate prepared according to Example 3 (5) To a suspension of (0.50 g, 0.00134 mol) in isopropanol (10 ml) was added 2- (morpholine-4-carboxamido) ethaneamino hydrochloride (18) (1.4 g, 0.00670 mol), Heat to 30-35 ° C. and add 30% NaOH dropwise to maintain pH at 10-11. The mixture is left to stir at 35-40 ° C. and monitored by UPLC. After completion of the reaction, ethyl acetate (20 ml) and water (20 ml) are added and the phases are separated. Water (20 ml) is added to the organic phase and adjusted to pH 3-4 with hydrochloric acid. The phases are separated and the resulting aqueous phase is adjusted to pH 10-11 with sodium hydroxide and re-extracted with ethyl acetate (20 m). Subsequently, the solvent was removed by evaporation under reduced pressure to obtain 0.38 g (55.6%) of a pale yellow oil that solidified eventually to become a pale yellow solid.

  Landiolol (1)

  (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate prepared according to Example 3 (5) To a solution of (0.30 g, 0.805 mmol) in acetonitrile (6.0 ml) was added 0.45 g (3.22 mmol) of potassium carbonate and 0.013 g (0.0805 mmol) of KI, followed by refluxing for 2 hours. 2- (morpholine-4-carboxamido) ethaneaminooxalate (6) (0.64 g, 2.42 mmol) is then added. The mixture is stirred at reflux and monitored by UPLC. After completion of the reaction, ethyl acetate (10 ml) and water (10 ml) are added and the phases are separated. Water (10 ml) is added to the organic phase and adjusted to pH 4-5 with hydrochloric acid. The phases are separated and the resulting aqueous phase is adjusted to pH 11-12 with sodium hydroxide and re-extracted with ethyl acetate (10 m). Subsequently, the solvent is removed by evaporation under reduced pressure to give 0.29 g (70.7%) of a pale yellow oil that solidifies over time and becomes a pale yellow solid.

  LC-MS (ESI +) [M + H] + = 510

1H-NMR (CDCl3) (chemical shifts expressed in ppm based on TMS) (assigned based on heterocorrelation HSQC spectrum): 1.36 (3H, s, CH3); 1.42 (3H, s, CH3); 2.63 (2H, t , J = 7Hz, CH2-Ar); 2.75-2.93 (8H, m, CH2-CO, CH-C H2 -NH, CH2-C H2 -NH, NH and OH); 3.35 (6H, m , 2CH2-N morpholine and CH 2 -NH); 3.65 (4H , m, 2CH2-O morpholine), 3.68 (1H, m, 4 oxolane of CH ); 3.94 (2H, bd, CH2-OAr); 4.00-4.20 (4H, m, 4 oxolane CH, CH2-OCO and 5 oxolane CH); 4.25 (1H, m, C H -OH); 5.21 (1 , Bt, NH carbamate); 6.83 and 7.11 (4H, system AA'XX ', aromatic ring).

  13 C-NMR (CDCl 3) (ppm) (duplication assigned by DEPT-135): 25.3 (CH 3); 26.6 (CH 3); 29.9 (CH 2); 35.8 (CH 2); 23.8 (CH2); 43.8 (CH2-N morpholine); 49.2 (CH2); 51.5 (CH2); 64.6 (CH2); 66.2 (CH2); 66.4 (CH2-O) 68.3 (CH); 70.3 (CH2); 73.4 (CH); 109.7; 114.4 (CH); 129.2 (CH); 132.8; 157.0; 158.0; 172.5 (COOR).

  FT-IR (UATR, cm-1): 3350, 2858, 1735, 1626, 1512, 1454, 1371, 1244, 1153, 1115, 1040, 829, 733.

  Landiolol hydrochloride (2)

  To a solution of landiolol (1) (100 mg, 0.196 mmol) prepared according to Example 5 in isopropanol (6.0 ml) is added 18% isopropanolic hydrochloric acid (40 mg, 0.197 mmol). The solvent is evaporated off under reduced pressure and the residue is crystallized from acetone (2 ml). The suspension is filtered and the crystals are dried at 25 ° C. for 12 hours to give 80 mg (74.7%) of a white solid.

  Landiolol hydrochloride (2) from (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate (3)

  (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt (16) (47 mg, 0.0780 mmol) in dichloromethane (1 ml) To the suspension is added 4-nitrobenzoic acid 17 (27 mg, 0.156 mmol). The mixture is left stirring at 20-25 ° C. for 45 minutes until a dark color appears. The resulting solution is concentrated to a volume of about 0.5 ml, 0.5 ml MTBE is added, concentrated to a volume of 0.5 ml, finally 0.5 ml MTBE, followed by (S)-(2, 2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate (3), (0.5 g, 1.77 mmol) followed by epichlorohydrin (in the compound of formula 4 Where X is chlorine) (0.37 g, 3.89 mmol). The mixture is left to stir at 20-25 ° C. and monitored by UPLC. After the reaction is complete, toluene (10 ml) and water (10 ml) are added and the phases are separated. The organic phase is evaporated to dryness, whereby concentrated (S) -epichlorohydrin is recovered, then toluene (10 ml) is added again and washed with 10% NaOH (10 ml). Concentrate the resulting solution to a volume of about 2 ml, add 5 ml of acetonitrile, concentrate to a volume of 2 ml, and finally add 10 ml of acetonitrile. The suspension was filtered to recover the catalyst, and 0.79 g (5.64 mmol) of potassium carbonate and 0.026 g (0.161 mmol) of KI were added to the solution and refluxed for 2 hours, and then 2- (morpholine-4 -Carboxamido) ethaneaminooxalate (6) (1.07 g, 4.03 mmol) is added. The mixture is stirred at reflux and monitored by UPLC. After completion of the reaction, ethyl acetate (20.0 ml) and water (20 ml) are added and the phases are separated. The organic phase is subsequently adjusted to pH 4-5 with hydrochloric acid and extracted with water (20 ml). The phases are separated and the resulting aqueous phase is adjusted to pH 11-12 with sodium hydroxide and re-extracted with ethyl acetate (20 m). The resulting solution is concentrated to a volume of approximately 5 ml, 20 ml of isopropanol is added, concentrated to a volume of 5 ml, and finally 30 ml of isopropanol and then 18% isopropanolic hydrochloric acid (0.24 g, 1.18 mmol) are added. The solvent is evaporated off under reduced pressure and the residue is crystallized from acetone (10 ml). The suspension is filtered and the crystals are dried at 25 ° C. for 12 hours to give 0.48 g (total yield 49.7%, enantiopurity: 99.8%) of a white solid.

  m. p. : 126 ° C (123-127 ° C from literature)

  LC-MS (ESI +) [M + H] + = 510

  FT-IR (UATR, cm-1): 3265, 2941, 2789, 2419, 1723, 1615, 1538, 1515, 1435, 1371, 1260, 1242, 1196, 1118, 1047, 887, 838, 821, 771.

Claims (10)

A process for preparing landiolol hydrochloride with high enantiomeric excess comprising:
a) (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate and a compound of formula 4:
An enantioselective catalyst containing a metal that binds a halogen or a C ₁ -C ₃ alkyl sulfonate ester or a C ₆ -C ₁₀ aryl sulfonate ester to a chelating ligand of high enantiopurity. In the presence of a compound of formula 5:
(Where X is as defined above)
Obtaining with the (S) isomer-rich starting material 4 (wherein X is as defined above);
b) reacting the compound of formula 5 obtained in step a) with N- (2-aminoethyl) morpholine-4-carboxamido) ethanamine as free base or a salt thereof in the presence of a base, Obtaining
c) obtaining landiolol hydrochloride 2 by salification of landiolol 1 obtained in step b);
Including processes. The process of claim 1, wherein the compound of formula 4 is selected from the group consisting of epichlorohydrin, epibromohydrin, glycidyl nosylate, or glycidyl tosylate.
  Process according to claims 1 and 2, wherein the compound of formula 4 is epichlorohydrin.   The process of claim 1, wherein the high enantiopurity chelating ligand of the enantioselective catalyst is a salen ligand.   The enantioselective catalyst is (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt. Process.   Process according to claims 1 and 5, wherein the enantioselective catalyst is activated by a polar compound selected from carboxylic acids, ionic salts or polyfluorinated compounds.   Process according to claim 6, wherein the polar compound is selected from acetic acid, 4-nitrobenzoic acid, cobalt chloride, zinc nitrate, gallium chloride, 3,5-difluorophenol, or perfluoro-tert-butanol.   The compound of formula 4 is epichlorohydrin, and the enantioselective catalyst is (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,2- The process according to any one of claims 1 to 7, which is cyclohexanediaminocobalt and the activated polar compound is 4-nitrobenzoic acid.   9. Process according to any one of claims 1 to 8, wherein the compound of formula 5 and landiolol are not isolated.   A compound of formula 5 as defined in claim 1, wherein X is chlorine, (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4- ((2R) -3-Chloro-2-hydroxy-propoxy) phenyl) propanoate.