KR101862824B1 - Process for the enantioselective synthesis of landiolol - Google Patents

Abstract

상기 방법은 대부분의 중간체를 분리하지 않고 이루어지며, 크로마토그래피를 이용한 정제과정을 요하지 않고, 특히 수율과 생산성 측면에서 이점을 가지고 있다. 게다가, 결과로 얻어진 란디올롤은 특히 순수하고, 높은 거울상체 순도를 가진 란디올롤 히드로클로리드로 용이하게 전환될 수 있다.(S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate as an alkylating agent having an epoxide structure, especially epichlorohydrin, And starting from 2- (morpholine-4-carboximido) ethanamine in the form of the free base or its salt, starting with the Landolol 1, ((S) -2,2-dimethyl- Yl) methyl) -3- (4 - ((S) -2-hydroxy-3- (2- (morpholine-4- carboxamide) ethylamino) propoxy) phenyl) propanoate Way.

The process is carried out without separating most of the intermediates and does not require purification by chromatography, and has particular advantages in terms of yield and productivity. In addition, the resulting Landolol can be readily converted to Landolol Hydrochloride, which is particularly pure and has a high enantiomeric purity.

Description

Process for enantioselective synthesis of landiolol < RTI ID = 0.0 >

Randiolol 1 is a potent cardiac-selective beta-blocker with very fast action and is used as an arrhythmogenic agent in the form of hydrochloride salt.

Synthesis of Landyolol 1 is disclosed in US 5013734, JP 3302647, CN 100506814, JP 2539734 and Chemical & Pharmaceutical Bulletin 1992, 40 (6) 1462-1469. The main synthetic route for the preparation of Landiolol 1 is reported in the following scheme.

The synthesis of Landiolol 1 is carried out by reacting epoxide 7 with amine 8. Intermediate 7 is synthesized in turn starting from 3 by reaction with a chiral synthon. US 5013734 discloses the synthesis of 3 and (S) -epibromohydrin 10 to 7.

This reagent is very expensive and difficult to obtain in the market. The reaction lasts for 16 hours under acetone reflux and the yield is not very high (76.2%). In addition, the reaction between 8 and 7 gives the crude product in low yield (43.3%), then 1 is interconverted to intermediate 9 (overall yield from 7 is 38.4%). In this final step, chloroform is used as the solvent. In addition, both Intermediate 7 and Landolol 1 require purification via chromatography. JP 3302647 discloses the same synthesis of intermediate 7 except that (S) -epibromohydrin 10 is replaced by (S) -glycidylnosylate 11.

Compound 11 is also very expensive and difficult to obtain on the market, so there is no particular advantage. In addition, the reaction for obtaining 7 is carried out with sodium hydride in dimethylformamide at room temperature, not under the conditions that could not be industrially extended because of the strong magnetic heating reaction of the reaction mixture in the past causing many accidents (Bretherick, 7 ^th edition, 2007, 1671-1673). In this case also, the yield of Landolol 1 is low (42.6% from 7 to Landolol 1). In this case the amine 8 is replaced by the oxalate salt 6.

The resulting Intermediate 9 (45.8% yield) is then interconverted to Landiolol 1. CN 101768148 discloses a synthesis substantially similar to the above, wherein the yield of obtaining lanthanoid oxalate 9 from 7 and free base 8 is still very low (27.8%). CN 100506814 discloses another synthesis similar to that described above in which (S) -epichlorohydrin (a compound of Formula 12 where X is chlorine), which is more readily available on the market, is used as the chiral intermediate .

However, the reaction is also very expensive and the reaction is long (16-24 hours). In addition, the final product, randiolol hydrochloride 2, is obtained by filtration from a water-sodium carbonate-sodium chloride / ether hexane two-phase mixture, which is not optimal for industrial production. Chemical & Pharmaceutical Bulletin 1992, 40 (6) 1462-1469 describes the synthesis of 7 starting from 3-like chiral intermediate 13.

(S) -glycidyl Tosylate 13 is also quite expensive, difficult to obtain on the market, and the reaction is time consuming (15 hours). Furthermore, in this case also both intermediate 7 and the raw lanolol 1 require purification by chromatography. In JP 2539734 compound 7 is synthesized according to the following synthesis scheme.

However, this solution has no particular advantage. Furthermore, compound 14 is not commercially available and one of the expensive chiral intermediates as described above should be used.

The above methods have a negative impact on yield and productivity because of the separation of all intermediates and purification using many chromatographs, and have a strong labor cost effect on the final product. Also, in many cases, the reaction from 7 to lanthanide 1 or lanthanolol oxalate 9 provides a low yield. In addition, the reaction time is quite long, above all, the reagents used are very expensive, difficult to obtain on the market, and can not be recirculated in the course of the reaction.

The present invention relates to a process for the preparation of (S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4- hydroxyphenyl) propanoate 3, an alkylating agent 4 having an epoxide structure, Starting from 2- (morpholine-4-carboximido) ethanamine in the form of its salt, Randiolol 1, ((S) -2,2-dimethyl-1,3-dioxolan- Propoxy) phenyl) propanoate) or its hydrochloride salt 2 ((S) -2-hydroxy-3- And a method for producing the same.

 It has now been found that Randiolol 1 and Randiolol Hydrochloride 2 can be easily prepared according to the novel synthetic procedures as reported below.

The method of the present invention comprises:

a) (S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate 3, X is halogen or C ₁ -C ₃ alkyl a monophonic or a C ₆ -C ₁₀ aryl sulfonic acid ester of formula (4) very low epoxide alkylating agent of, easily can be obtained commercially, quite inexpensive, in the presence of a catalyst capable of enantiomers optionally recycled, of the formula 12 (S) isomer Together with an enhanced starting epoxide alkylation agent, wherein X has a mild and fast reaction to obtain a compound of formula 5 as defined above;

b) reacting the compound of formula 5 obtained in step a) with 2- (morpholine-4-carboxamido) ethanamine in the form of the free base or its salt in the presence of a base to obtain Landolol 1 in good yield ;

c) chlorinating the raw lanolol 1 to obtain the crude lanolic hydrocolloid 2 having a high enantiomeric excess.

In the compound of formula 5, the carbon atom having a secondary alcohol group has an R stereochemical structure.

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

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

The enantioselective catalyst I is preferably a metal based catalyst such as a catalyst based on cobalt, manganese, aluminum, copper, samarium, chromium, vanadium etc. based on an enantiopure chelate ligand, preferably (R, R) , 5-di- tert -butylsalicylidene) -1,2-cyclohexanediamine. As butanol, said mirror image selective catalyst is preferably a polar compound, preferably acetic acid, 4-nitrobenzoic acid, cobalt chloride, zinc nitrate, gallium chloride, phenol, 5-difluoro, perfluoro-tert Is activated by the same, carboxylic acid, ionic salt or polyfluorinated compound.

In this case, the synthesis of the compounds of formula 5 are a mirror image selective catalyst, preferably (R, R) -N, N'- bis (3,5-di - tert - butyl salicylate silica den) -1,2-cyclohexane Preferably methyl tert -butyl ether (MTBE), dichloromethane, tetrahydrofuran, dioxane or the like in the presence of diaminocobalt 16, a polar activator, preferably 4-nitrobenzoic acid 17 and an epoxy alkylating agent, preferably epichlorohydrin. ≪ / RTI > acetonitrile, and mixtures thereof.

When epichlorohydrin is used as the compound of formula 4, the compound of formula 5 can be prepared by reacting (S) - (2,2-dimethyl-1,3-dioxolan- - ((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate.

The synthesis of Landiolol 1 is accomplished using 2- (morpholine-4-carboxamido) ethanamine as base or its salt, such as oxalate or chloride. This reaction is carried out in the presence of a base, preferably an inorganic base such as potassium carbonate, sodium carbonate, NaOH, KOH and the like, and an ionic catalyst, preferably an inorganic catalyst such as KI, NaI, KBr, NaBr and the like, In an alcohol solvent such as isopropanol and isobutanol, or preferably in acetonitrile.

The chlorination reaction with lanthanide hydrochloride 2 is carried out using a mineral acid such as a chlorinated acid, preferably hydrochloric acid, ammonium chloride and the like. This reaction takes place in a polar solvent such as isopropanol, acetone, acetonitrile, diisopropyl ether and mixtures thereof.

Intermediate 5 in which X is chlorine is novel and is a further object of the present invention.

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

Step a

Typically, in order to enable the salen catalyst, and preferably (R, R) -N, N'- bis (3,5-di - tert - butyl salicylate silica den) -1,2-cyclohexane-diamino cobalt 16 Reacts with 1 to 3 equivalents of carboxylic acid, preferably 4-nitrobenzoic acid and 17, preferably 1.5 to 2.5 equivalents. The reaction is carried out in a polar aprotic solvent, preferably dichloromethane, and is carried out at a temperature of from 10 to 40 ° C, preferably from 20 to 30 ° C. 4 to 15 parts by volume of a solvent is added to the amount of (R, R) -N, N'-bis (3,5-di- tert -butylsalicylidene) -1,2-cyclohexanediaminocobalt 16, 7 to 12 volumes are used. After dark brown appearance, the solvent is removed to obtain the catalyst in its activated form. Then, 10 to 100 equivalents of the starting material (S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate 3, Preferably 20 to 50 equivalents, is added, followed by the addition of a polar aprotic solvent, preferably methyl tert -butyl ether (MTBE). (S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate 3 is used, Lt; RTI ID = 0.0 > 2-3 < / RTI > Then, 2 to 3 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 캜, preferably 20 to 30 캜. The reaction is monitored by UPLC analysis using a C18 column and water / acetonitrile containing 1% formic acid as the eluent phase. After this reaction, water and toluene are added and the phases are separated. The organic phase is then washed with distilled and diluted sodium hydroxide to recover (S) -epichlorohydrin. The organic phase is then concentrated to a small volume, and a polar solvent, such as acetonitrile or methanol, preferably acetonitrile, is added, again concentrated to a small volume to remove the toluene, and finally acetonitrile or methanol, 5 to 30 parts by volume of a polar solvent such as nitrile is added. This suspension can be filtered to recover the catalyst and the resulting solution can be used directly in step b) or can be used directly in step b) or (S) - (2,2-dimethyl-1,3-dioxolan- (4 - ((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate 5 can be isolated as an oil which can be stored at room temperature for several days. (S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4- ((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate 5 To obtain the oil as an oil, a decolorizing filter aid is added to the 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-hydroxypropoxy) phenyl) propanoate 5 Is obtained as an oil.

Step b

Typically, (S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4- 2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate 5 is reacted with an inorganic base, preferably potassium carbonate, in an amount of 1 to 6 equivalents and 3 to 4 equivalents, Preferably in the presence of potassium iodide, at a catalytic amount (0.05 to 0.20 equivalents). Thereafter, 2- (morpholine-4-carboxamido) ethanamine as the base or its salt, such as oxalate or hydrochloride, preferably oxalate, is reacted with 1 to 4 equivalents, preferably 2 to 3 equivalents, Equivalent amount. The reaction is carried out in a polar solvent, preferably in acetonitrile, at a temperature of 20 to 85 ° C, preferably 60 to 85 ° C. (S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4- ((2R) -3-chloro-2-hydroxypropoxy) phenyl) propanoate 5 5 to 30 parts by volume, preferably 10 to 20 parts by volume of a solvent is used. The reaction was monitored by UPLC analysis using a C18 column and water / acetonitrile containing 1% formic acid as mobile phase. After the reaction is complete, ethyl acetate and water are added and the phases are separated. The organic phase is then extracted with water at pH 2-5, preferably pH 3-4. The phases are separated and the aqueous phase is again extracted with ethyl acetate at pH 8-13, preferably pH 9-12. The organic phase solvent is then replaced with 2 to 20 volumes of a polar solvent such as isopropanol and the resulting solution can be used directly in step c, or the raw lanolol 1 can be separated. For this purpose, the solvent is removed or replaced with a polar solvent, such as diisopropyl ether, to promote solidification, and then the solvent is removed from the resulting suspension to form racemisole 1 .

Step c

Typically, the Randiolol 1 obtained by dissolution of the material directly or from the polar solvent in Step b is directly chlorinated with Randiolol Hydrochloride 2, preferably with hydrochloric acid. The chlorination reaction is carried out in a polar solvent, preferably isopropanol, in an amount of from 2 to 20 parts by volume, preferably from 5 to 10 parts by volume of the solvent, based on the amount of the raw fatty alcohol. After addition of the acid, the solvent is evaporated off and the product crystallized by adding 1-20 volumes of a polar solvent, preferably acetone. The suspension is filtered and the solid is dried in a vacuum at 25-35 [deg.] C for 12 hours to obtain the raw oxidol hydrochloride 2. The enantiomeric excess of the final product is analyzed using Chiralcel OD column and hexane / ethanol containing diethylamine as mobile phase.

  The process of the present invention is particularly advantageous in that it yields results without separating any intermediates. Intermediate 5 is obtained in very high yield with very high purity under very mild reaction conditions. In addition, starting material 4 (epichlorohydrin), where X is chlorine, is very inexpensive and readily commercially available. The catalysts used are commercially available at low cost and can be easily recovered by simple filtration. Surprisingly, the reaction for obtaining Landolol 1 from the novel intermediate 5 in which X is chlorine provides a significantly higher yield than that obtained in most processes starting from Intermediate 7, as mentioned in the Background of the Invention. The resulting Randiolol 1 can be converted directly to Randiolol Hydrochloride 2 in good overall yield without further purification or intermediate steps. The resulting Landiolol Hydrochloride 2 has a very high enantiomeric purity.

In addition, the process of the present invention allows the recovery of (S) -epichlorohydrin 12, which is a high value product that can also be used in the synthesis of Landiolol 1 to prepare Compound 3 according to the following scheme .

The synthesis of very high yields of intermediate 15 from intermediate 12 is described literally in many published documents. Some publications disclosing this are: Catalysis Communications, 8 (12), 2087-2095; 2007; CN 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), 3411-3416, 2001; Chemistry Letters, (11), 2019-22; 1990; Khimiya Geterotsiklicheskikh Soedinenii, (1), 33-6; 1991. Synthesis of high yield 3 starting from 15 and 19 is described in CN 100506814. An additional published document disclosing this is US5013734. Both publications are already mentioned in the Background of the Invention for the synthesis of Landyolol 1.

The present invention is illustrated in detail by the following examples.

Experimental choice

Example  1: (S) - (2,2-dimethyl-1,3- Dioxolane Yl) methyl  3- (4 - ((2R) -3- Chloro Hydroxypropoxy) Phenyl ) Propanoate  (5)

A suspension of (R, R) -N, N'-bis (3,5-di- tert -butylsalicylidene) -1,2-cyclohexanediaminocobalt (16) in MTBE (1 ml) , 0.0828 mmol) was added acetic acid (10 mg, 0.166 mmol). The mixture is allowed to stir at 20-25 ° C for one hour until dark color appears. Thereafter, (3- (4-hydroxyphenyl) propanoate (3) (500 mg, 1.78 mmol) was added to the solution of (S) -2,2-dimethyl- Then, epichlorohydrin (compound of formula 4 where X is chlorine) (340 mg, 3.56 mmol) is added thereto. The mixture is left stirring while being monitored by UPLC at 20-25 ° C. After this 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%).

Example  2: (S) - (2,2-dimethyl-1,3- Dioxolane Yl) methyl  3- (4 - ((2R) -3- Chloro Hydroxypropoxy) Phenyl ) Propanoate  (5)

Dichloromethane (20 ml) of (R, R) -N, N'- bis suspension (1.9 of (3,5-di - - tert-butyl salicylate silica den) -1,2-cyclohexane-diamino cobalt 16 g, 3.19 mmol) was added 4-nitrobenzoic acid 17 (1.1 g, 6.38 mmol). The mixture is allowed to stir at 20-25 ° C for one hour until dark color appears. 3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate (3) was added to a solution of (S) -2,2- (18 g, 63.8 mmol) is added followed by the addition of epichlorohydrin (compound of formula 4 where X is chlorine) (13.4 g, 140 mmol). The mixture is left stirring while being monitored by UPLC at 20-25 ° C. After this reaction, toluene (300 ml) and water (150 ml) are added and the phases are separated. The organic phase is evaporated to dryness and the enriched (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 are added, concentrated to a volume of 50 ml and finally 250 ml of acetonitrile are added. A decolorized 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.

Example  3: (S) - (2,2-dimethyl-1,3- Dioxolane Yl) methyl  3- (4 - ((2R) -3- Chloro Hydroxypropoxy) Phenyl ) Propanoate  (5)

In dichloromethane (5 ml) (R, R ) -N, N'-bis - suspension (470 of (3,5-di- tert-butyl salicylate silica den) -1,2-cyclohexane-diamino cobalt 16 mg, 0.780 mmol) were added 4-nitrobenzoic acid 17 (270 mg, 1.56 mmol). The mixture is allowed to stir for 45 minutes at 20-25 ° C until dark color appears. The resulting solution was concentrated to a volume of about 2 ml, 5 ml of MTBE was added, concentrated to a volume of 2 ml and finally 6 ml of MTBE was added followed by (S) -2,2-dimethyl- 4-yl) methyl 3- (4-hydroxyphenyl) propanoate (3) (5 g, 17.7 mmol) followed by epichlorohydrin (compound of formula 4 where X is chlorine) ) (3.7 g, 38.9 mmol). The mixture is left stirring while being monitored by UPLC at 20-25 ° C. 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 and the enriched (S) -epichlorohydrin is recovered. Acetonitrile (25 ml) is added and the suspension is filtered to recover the catalyst. The resulting solution is concentrated to a volume of about 5 ml, 15 ml of toluene are added, then concentrated to a volume of 5 ml and finally 20 ml of toluene and 20.0 g of decolorized filter aid are added. The mixture is left to stir for 15 minutes and the suspension is filtered. The filtrate is evaporated to dryness to give 6.1 g (92.4%) of yellow oil.

LC-MS (ESI < ⁺ >) [M + H] < ^{+ &}

¹ H-NMR (CDCl ₃ ) (chemical shift expressed in ppm relative to TMS): 1.37 (3H, s, CH ₃ ); _{1.43 (3H, s, CH 3} ); 2.65 (2H, t, J = 7 Hz, CH 2 -Ar); 2.83 (1H, bs, OH); 2.91 (2H, t, J = 7 Hz, CH 2 -CO); 3.66 - 3.81 (3H, m, CH and CH ₂ -Cl in ₄ oxolane); 4.00-4.25 (6H, m, CH in CH 4, CH ₂ -OCO, CH ₂ -OAr and CH in 5oxolane) of 4 oxolane; 4.25 (1H, m, C H -OH); 6.84 and 7.13 (4H, system AA'XX ', aromatics).

_{^{13 C-NMR (CDCl 3)}} (ppm): 25.3 (CH 3); 26.6 (CH _3); 29.9 (CH _2); 35.8 (CH ₂ ); 45.9 (CH ₂ -Cl); 64.6 (CH _2); 66.2 (CH _2); 68.5 (CH ₂ ); 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 as%: C, 58.0; H, 6.8; Cl, 9.5;

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

Example  4: Landy olol  (One)

(S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4- ((2R) -3-chloro- To a suspension (0.50 g, 0.00134 mol) of 2- (hydroxypropoxy) phenyl) propanoate (5) was added 1.4 g (0.00670 mol ), Heating to 30-35 < 0 > C and adding 30% NaOH on ice to maintain the pH at 10-11 do. The mixture is left stirring while being monitored by UPLC at 35-40 < 0 > C. After the reaction is complete, 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 then adjusted to pH 10-11 with sodium hydroxide and re-extracted with ethyl acetate (20 ml). The solvent is then evaporated under reduced pressure to give 0.38 g (55.6%) of a pale yellow oil which solidifies in the course of time to a pale yellow solid.

Example  5: Landy olol  (One)

(S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4 - ((R) -3-chloro- 0.45 g (3.22 mmol) of potassium carbonate and 0.013 g (0.0805 mmol) of potassium iodide were added to a solution (0.30 g, 0.805 mmol) of sodium hydride After refluxing for two hours, 2- (morpholine-4-carboxamide) ethane amino oxalate (6) (0.64 g, 2.42 mmol) is added. The mixture is refluxed while being stirred while being monitored by UPLC. After the reaction is complete, ethyl acetate (10 ml) and water (10 ml) are added and the phases are separated. Water (10 ml) was added to the organic phase and the pH was adjusted to 4-5 with hydrochloric acid, the phases were separated and the resulting aqueous phase was then adjusted to pH 11-12 with sodium hydroxide and extracted with ethyl acetate (10 ml). The solvent is then evaporated under reduced pressure to give 0.29 g (70.7%) of a pale yellow oil which solidifies to a pale yellow solid in the course of time.

LC-MS (ESI < + >) [M + H] < + &

_{^{1 H-NMR (CDCl 3)}} ( the chemical shift expressed in ppm relative to TMS) (Assigned based on a correlation hetero HSQC spectrum): 1.36 (3H, s, CH 3); _{1.42 (3H, s, CH 3} ); 2.63 (2H, t, J = 7 Hz, CH 2 -Ar); 2.75 - 2.93 (8H, m, CH ₂ --CO, CH - C H _{2 -} NH, CH ₂ --C H _{2 -} NH, NH and OH); 3.35 (6H, m, 2CH ₂ -N morpholine and C H ₂ -NH); _{3.65 (4H, m, 2CH 2} -O morpholine), 3.68 (1H, m, 4 octanoic solran CH); _{3.94 (2H, bd, CH 2} -OAr); 4.00 - 4.20 (4H, m, CH2 of ₄ oxolan, CH ₂ -OCO and CH of 5 oxolane); 4.25 (1H, m, C H -OH); 5.21 (1H, bt, NH carbamate); 6.83 and 7.11 (4H, system AA'XX ', aromatics).

¹ C-NMR (CDCl ₃ ) (ppm) (multiplicity assigned by DEPT-135): 25.3 (CH ₃ ); 26.6 (CH _3); 29.9 (CH _2); 35.8 (CH ₂ ); 40.2 (CH _2); 43.8 (CH ₂ -N morpholine); 49.2 (CH _2); 51.5 (CH _2); 64.6 (CH _2); 66.2 (CH _2); 66.4 (CH ₂ -O morpholine); 68.3 (CH); 70.3 (CH ₂ ); 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.

Example  6: Landy olol  Hydrochloride (2)

18% isopropanol hydrochloric acid (40 mg, 0.197 mmol) was added to a solution of Landiolol (1) (100 mg, 0.196 mmol) prepared according to Example 5 in isopropanol (6.0 ml). The solvent is then removed by evaporation under reduced pressure and the residue is crystallized from acetone (2 ml). The suspension is filtered and the crystals are dried at 25 < 0 > C for 12 hours to give 80 mg (74.7%) of a white solid.

Example  7: (S) -2,2-Dimethyl-1,3- Dioxolan Yl) methyl  3- (4- Hydroxyphenyl ) Propanoate (3) from Landy olol Hydrochloride  (2)

(R, R) -N, N'-bis (3,5-di- tert -butylsalicylidene) -1,2-cyclohexanediamine cobalt 16 (47 mg, 0.0780 mol) in dichloromethane (1 ml) mmol) is added 4-nitrobenzoic acid 17 (27 mg, 0.156 mmol). The mixture is allowed to stir for 45 minutes at 20-25 ° C until dark color appears. The resulting solution was concentrated to a volume of about 0.5 ml, added with 0.5 ml of MTBE, concentrated to a volume of 0.5 ml and finally added with 0.5 ml of MTBE, then (S) -2,2-dimethyl Dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate (3) (0.5 g, 1.77 mmol) followed by epichlorohydrin Compound of formula 4) (0.37 g, 3.89 mmol). The mixture is left stirring while being monitored by UPLC at 20-25 ° C. After this reaction, toluene (10 ml) and water (10 ml) are added and the phases are separated. The organic phase is evaporated to dryness and the enhanced (S) -epichlorohydrin is recovered, then added again to toluene (300 ml) and washed with 10% NaOH (10 ml). The resulting solution is concentrated to a volume of about 2 ml, added with 5 ml of acetonitrile, concentrated to a volume of 2 ml and finally added with 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 potassium iodide were added to the solution, and the mixture was refluxed for 2 hours and then 2- (morpholine- Amino) ethanaminoxalate (6) (1.07 g, 4.03 mmol). The mixture is refluxed while being stirred while being monitored by UPLC. After the reaction is complete, ethyl acetate (20.0 ml) and water (20 ml) are added and the phases are separated. The organic phase is then adjusted to pH 4-5 with hydrochloric acid and extracted with water (20 ml). The phases are separated and the resulting aqueous phase is then adjusted to pH 11-12 with sodium hydroxide and re-extracted with ethyl acetate (20 ml). The resulting solution was concentrated to a volume of about 5 ml, 20 ml of isopropanol was added, concentrated to a volume of 5 ml, and finally 30 ml of isopropanol was added followed by 18% isopropanol hydrochloric acid (0.24 g, 1.18 mmol) is added. The solvent is then removed by evaporation under reduced pressure and the residue is crystallized from acetone (10 ml). The suspension is filtered and the crystals are dried at 25 < 0 > C for 12 hours to give 0.48 g of a white solid (49.7% total, 99.8% enantiomeric purity).

Melting point: 126 占 폚 (123-127 占 폚 from the literature)

LC-MS (ESI < ⁺ >) [M + H] < ^{+ &}

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) (S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (4-hydroxyphenyl) propanoate and X is halogen or C ₁ -C ₃ alkyl Lt; RTI ID = 0.0 > C ₆ -C ₁₀ arylsulfonic < / RTI > ester,

With an (S) -isomerically enriched starting compound 4 of formula 12 as defined above, with X being as defined above, with an enantiopure chelate ligand in the presence of a mirror- Lt; RTI ID = 0.0 > 5 < / RTI >

b) reacting the compound of formula 5 obtained in step a) with N- (2-aminoethyl) morpholine-4-carboxamido) ethanamine as a free base or a salt thereof in the presence of a base to obtain Landiolol 1 ;
c) chlorinating the raw diol 1 obtained in step b) to obtain the raw oxidol hydrochloride 2; ≪ / RTI > wherein the crude enantiomeric excess comprises a higher enantiomeric excess. The method of claim 1, wherein the compound of formula 4 is selected from the group consisting of epichlorohydrin, epibromohydrin, glycidyl nosylate, or glycidyl tosylate. The method according to claim 1 or 2, wherein the compound of formula (4) is epichlorohydrin. The method of claim 1, wherein the enantiopure chelate ligand of the enantioselective catalyst is a salen ligand. The method according to claim 1 or claim 4 wherein the enantiomer is a selective catalyst (R, R) -N, N'- bis (3,5-di - tert - butyl salicylate silica Den) of l, 2-cyclohexane diamino-cobalt How it is. The method of claim 1, wherein the enantioselective catalyst is activated by a polar compound selected from a carboxylic acid, an ionic salt, or a multiply fluorinated compound. According to claim 6, wherein said polar compound is acetic acid, 4-nitrobenzoic acid, cobalt chloride, zinc nitrate, gallium chloride, a phenol, or perfluoro-3,5-difluoro-method is selected from the butanol-tert . The method according to claim 6, the compound of formula 4 is epi-chloro Hi gave the enantiomers selective catalyst (R, R) -N, N'- bis (3,5-di - tert - butyl salicylate silica den) -1, 2-cyclohexanediaminocobalt, and the polar compound to be activated is 4-nitrobenzoic acid. The method of claim 1, wherein the compound of formula 5 and the crude oil are not separated. The compound of formula 5 as defined in claim 1, wherein X is chlorine or (S) - (2,2-dimethyl-1,3-dioxolan- Chloro-2-hydroxypropoxy) phenyl) propanoate.