Method for preparing landiolol hydrochloride

Abstract

The invention provides a method for preparing landiolol hydrochloride. According to the method disclosed by the invention, the reaction yield is improved through a potassium salt or sodium salt path in the synthesis process of the compound D; lewis acid or a catalyst similar to the Lewis acid is used for catalysis in the synthesis process of the compound E, the conversion rate is high, reaction conditions are mild, operation is easy, and highly toxic chemicals are not used. Therefore, the method provided by the invention can be used for preparing high-purity landiolol hydrochloride, and has wide application value.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing landiolol hydrochloride. Background Art

[0002] The chemical name of landiolol hydrochloride is ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((S)-2-hydroxy-3-((2-(morpholine-4-carboxamido)ethyl)amino)propoxy)phenyl)propanoate hydrochloride. The English name is ((S)-2,2-dimethyl-1,3-dioxolan-4-y1)methyl3-(4-((S)-2-hydroxy-3-((2-(morpholine-4-carboxamido)ethyl)amino)propoxy)phenyl)propanoate hydrogenchloride. The structural formula is:

[0003]

[0004] Landiolol is a selective β1 receptor blocker with an ultra-broad-spectrum effect. In specific applications, it exists in the form of a hydrochloride. It mainly antagonizes the β1 receptors present in the heart, inhibiting the increase in heart rate caused by catecholamines. The drug was first developed by Ono Pharmaceutical Co., Ltd. of Japan and was first launched in Japan in September 2002 for the emergency treatment of tachycardia-induced arrhythmias (including atrial fibrillation, atrial flutter, and sinus tachycardia) during surgery. In October 2006, a new indication was added in Japan for the emergency treatment of tachycardia-induced arrhythmias (including fine atrial beats, coarse atrial beats, and sinus tachycardia) under dynamic circulatory monitoring after surgery.

[0005] There are several main synthetic routes for landiolol hydrochloride:

[0006] (1): Japan Ono Pharmaceutical Co., Ltd. has disclosed a method for synthesizing landiolol hydrochloride (Japanese Patent Publication No. 05-306281). The synthetic route reported in the literature is mainly as follows:

[0007]

[0008] The problem with this route is that column chromatography is used in multiple steps of the synthesis route, the yield is low, the raw material cost is high and it is not conducive to industrial production.

[0009] (2): Chinese patent (publication number CN101012217A) discloses another synthetic route:

[0010]

[0011] The problem with this route is that the reaction yield of compound A and compound C is very low, and column chromatography is used in the synthesis route, which is costly and not conducive to industrial production.

[0012] (3): Chinese patent (publication number CN114031601B) discloses another synthetic route:

[0013]

[0014] The problem with this route is that the Lewis acid used is relatively expensive, and a large amount of compound H remains after the reaction is completed, which is difficult to remove and is not suitable for commercial production. (4): A Chinese patent (publication number CN1 10483470A) discloses another synthetic route:

[0015]

[0016] The problem with this route is that the raw material I is difficult to prepare and is relatively expensive. The landiolol free base is difficult to purify, and it is not easy to obtain a product of high purity, making it unsuitable for commercial production. Summary of the Invention

[0017] In view of the problems existing in the prior art, the present invention provides a new method for preparing landiolol hydrochloride.

[0018] The present invention provides a method for preparing landiolol hydrochloride, comprising:

[0019]

[0020] Step 1: reacting compound A with sodium alkoxide or potassium alkoxide to produce compound B;

[0021] Step 2: reacting compound B with compound C to generate compound D;

[0022] Step 3: reacting compound D with R-epichlorohydrin to generate compound E;

[0023] Step 4: reacting compound E with compound F to generate compound G;

[0024] Step 5: Compound G is reacted with hydrogen chloride reagent to produce landiolol hydrochloride.

[0025] In one embodiment, step 1 comprises: dissolving compound A in organic solvent 1, adding sodium alcoholate or potassium alcoholate, and reacting at 50-120° C. to obtain compound B.

[0026] Preferably, the sodium alkoxide or potassium alkoxide is selected from at least one of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide and potassium tert-butoxide.

[0027] Preferably, the molar ratio of compound A to sodium alkoxide or potassium alkoxide is 1:1 to 1.5, preferably 1:1 to 1.2.

[0028] Preferably, the organic solvent 1 is selected from at least one of an alcohol solvent and an ether solvent; preferably at least one of methanol, ethanol, isopropanol, tetrahydrofuran, and dioxane.

[0029] Preferably, the reaction temperature is 65-105° C.; and the reaction time is 0.5-6 h.

[0030] Preferably, when adding sodium alkoxide or potassium alkoxide, the temperature of the reaction system is controlled to below 20°C.

[0031] Preferably, after the reaction is completed, the product is filtered and the filter cake is dried to obtain compound B.

[0032] In one embodiment, step 2 comprises: reacting compound B with compound C in the presence of catalyst 2 to form compound D.

[0033] Preferably, step 2 comprises: adding compound B, compound C, and catalyst 2 to organic solvent 2, and reacting at 45-120° C. to obtain compound D.

[0034] Preferably, catalyst 2 is selected from at least one of quaternary ammonium salts and iodized salts; preferably at least one of tetrabutylammonium bromide, tetraethylammonium bromide, hexadecyltrimethylammonium bromide, benzyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, sodium iodide, and potassium iodide.

[0035] Preferably, the mass ratio of compound B to catalyst 2 is 1:0.05-0.3, preferably 1:0.15-0.25.

[0036] Preferably, the molar ratio of compound B to compound C is 1:0.9-1.2, preferably 1:1-1.1.

[0037] Preferably, the organic solvent 2 is selected from at least one of ether solvents, nitrile solvents, and ketone solvents; preferably at least one of dioxane, tetrahydrofuran, acetonitrile, and acetone.

[0038] Preferably, the reaction temperature is 50-105° C. and the reaction time is 2-18 h.

[0039] Preferably, after the reaction is completed, the solvent is evaporated under reduced pressure, water is added, extraction is performed with an extraction solvent, drying, and concentration to obtain a crude product; the crude product is purified to obtain compound D. Further preferably, the extraction solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, toluene, and diethyl ether. The purification includes recrystallization and column chromatography.

[0040] In one embodiment, step 3 comprises: reacting compound D with R-epichlorohydrin in the presence of catalyst 3 to produce compound E. Preferably, step 3 comprises: adding compound D, R-epichlorohydrin, and catalyst 3 to organic solvent 3, and reacting at 70-120° C. to obtain compound E.

[0041] Preferably, the catalyst 3 is selected from at least one of cesium fluoride and cesium carbonate.

[0042] Preferably, the molar ratio of compound D to cesium in catalyst 3 is 1:2-4, preferably 1:2.4-3.6.

[0043] Preferably, the molar ratio of compound D to R-epichlorohydrin is 1:2-10, preferably 1:5-9.

[0044] Preferably, the organic solvent 3 is at least one selected from N,N-dimethylacetamide, N-methylpyrrolidone, toluene, and dimethyl sulfoxide.

[0045] Preferably, the reaction temperature is 85-105° C. and the reaction time is 1-6 h.

[0046] Preferably, after the reaction is completed, water is added, extracted with an extraction solvent, dried, and concentrated to obtain a crude product; the crude product is purified to obtain compound E. Further preferably, the extraction solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, toluene, and diethyl ether. The purification includes recrystallization and column chromatography.

[0047] In one embodiment, step 4 comprises: adding compound E and compound F to organic solvent 4, and reacting at 40-80° C. to obtain compound G.

[0048] Preferably, the molar ratio of compound E to compound F is 1:1-5, preferably 1:2-4.

[0049] Preferably, the organic solvent 4 is selected from at least one of an alcohol solvent and an ether solvent; preferably at least one of methanol, ethanol, isopropanol, tetrahydrofuran, and dioxane.

[0050] Preferably, the reaction temperature is 45-55° C.; and the reaction time is 1-8 h.

[0051] Preferably, after the reaction is completed, water is added, extracted with an extraction solvent, dried, and concentrated to obtain a crude product; the crude product is purified to obtain compound G. Further preferably, the extraction solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, toluene, and diethyl ether. The purification includes recrystallization and column chromatography.

[0052] In one embodiment, step 5 comprises: adding compound G to organic solvent 5, controlling the temperature at 0-10° C., slowly adding hydrogen chloride reagent until the pH of the reaction system is 5-7, and reacting to obtain landiolol hydrochloride.

[0053] Preferably, the organic solvent 5 is selected from at least one of an alcohol solvent and an ether solvent; preferably at least one of methanol, ethanol, isopropanol, tetrahydrofuran, and dioxane.

[0054] Preferably, the hydrogen chloride reagent includes hydrogen chloride gas, a solution of hydrogen chloride in an organic solvent 5, such as a hydrogen chloride isopropanol solution or a hydrogen chloride dioxane solution.

[0055] Preferably, the pH is controlled at 5.5 to 6.5.

[0056] Preferably, the reaction time is 0.5 to 6 hours.

[0057] Preferably, after the reaction is completed, the product is filtered and the filter cake is dried to obtain landiolol hydrochloride.

[0058] In the present invention, the numbers of the catalysts and organic solvents are only used to distinguish the catalysts and organic solvents used in different steps, and do not limit them themselves.

[0059] Beneficial effects

[0060] The present invention provides a process for synthesizing landiolol hydrochloride using 4-hydroxyphenylpropionic acid as a starting material. Compared to existing synthesis processes, this process offers the following advantages: The potassium or sodium salt pathway in the synthesis of Compound D improves reaction yield; and the cesium fluoride and cesium carbonate catalysts used in the synthesis of Compound E are Lewis acids or Lewis acid-like compounds, resulting in high conversion rates, mild reaction conditions, ease of operation, and the absence of highly toxic chemicals. Therefore, the method of the present invention can produce high-purity landiolol hydrochloride and has broad application value. DETAILED DESCRIPTION

[0061] The present invention is described in more detail below to facilitate understanding of the present invention.

[0062] The experimental methods in the following examples are all conventional methods unless otherwise specified. If no specific techniques or conditions are specified in the examples, they were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions.

[0063] The embodiments of the present invention are as follows:

[0064] Step 1:

[0065] Example 1

[0066] Dissolve 10 g of compound A in 60 mL of isopropanol, control the temperature below 20°C, add 6.8 g of potassium tert-butoxide, heat under reflux for 1 hour, cool to room temperature, filter, and vacuum dry the filter cake to obtain 12.2 g of the potassium salt intermediate (yield 99%).

[0067] Example 2

[0068] Dissolve 10g of compound A in 60mL of isopropanol, control the temperature below 20°C, add 5.8g of sodium tert-butoxide, heat under reflux for 1 hour, cool to room temperature, filter, and vacuum dry the filter cake to obtain 12.2g of the sodium salt intermediate (yield 99%).

[0069] Example 3

[0070] Dissolve 10 g of compound A in 60 mL of tetrahydrofuran, control the temperature below 20°C, add 6.8 g of potassium tert-butoxide, heat under reflux for 1 hour, cool to room temperature, filter, and vacuum dry the filter cake to obtain 12.3 g of the potassium salt intermediate (yield 100%).

[0071] Example 4

[0072] Dissolve 10g of compound A in 60mL of dioxane, control the temperature below 20°C, add 5.8g of sodium tert-butoxide, heat under reflux for 1 hour, cool to room temperature, filter, and vacuum dry the filter cake to obtain 12.3g of the sodium salt intermediate (yield 100%).

[0073] Step 2:

[0074] Example 5

[0075] 10 g of the potassium salt of Compound B, 2 g of tetrabutylammonium bromide, and 7.4 g of Compound C were added to 60 mL of dioxane and heated under reflux for 5 hours. The solvent was then removed by distillation under reduced pressure, 50 mL of process water was added, and the mixture was extracted with 50 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 27.5 g of a crude product (yield 200%). Purification by column chromatography (100 g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 5:1) afforded 13.5 g of Compound D (yield 98%).

[0076] Example 6

[0077] 10 g of the potassium salt of Compound B, 2 g of sodium iodide, and 7.4 g of Compound C were added to 60 mL of dioxane and heated under reflux for 5 hours. The solvent was then removed by distillation under reduced pressure, 50 mL of process water was added, and the mixture was extracted with 50 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 26.5 g of a crude product (yield 193%). Purification by column chromatography (100 g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 5:1) afforded 13.4 g of Compound D (yield 97%).

[0078] Example 7

[0079] 10 g of the potassium salt of Compound B, 2 g of tetrabutylammonium bromide, and 7.4 g of Compound C were added to 60 mL of acetonitrile and heated under reflux for 6 hours. The solvent was then removed by distillation under reduced pressure, 50 mL of process water was added, and the mixture was extracted with 50 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated to dryness to obtain 25.5 g of a crude product (yield 185%). Purification by column chromatography (100 g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 5:1) afforded 13.0 g of Compound D (yield 95%).

[0080] Example 8

[0081] 10 g of the potassium salt of Compound B, 2 g of sodium iodide, and 7.4 g of Compound C were added to 60 mL of acetone and heated under reflux for 10 hours. The solvent was then removed by distillation under reduced pressure, 50 mL of process water was added, and the mixture was extracted with 50 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated to dryness to obtain 26.8 g of a crude product (yield 195%). Purification by column chromatography (100 g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 5:1) afforded 12.9 g of Compound D (yield 94%).

[0082] Step 3:

[0083] Example 9

[0084] 20g of compound D and 46.2g of R-epichlorohydrin were dissolved in 100mL of N,N-dimethylformamide, 32.6g of cesium fluoride was added with stirring, and the mixture was heated to 95°C for 2 hours. The mixture was cooled to room temperature, 500mL of water was added, and the mixture was extracted with 500mL of ethyl acetate, washed with 300mL of water, and repeated three times. The ethyl acetate phase was dried over anhydrous magnesium sulfate and spin-dried to obtain 30g of crude oil in a yield of 125%. The crude oil was purified by column chromatography (200g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 5:1) to obtain 19.3g of compound E in a yield of 80%.

[0085] Example 10

[0086] 20g of compound D and 46.2g of R-epichlorohydrin were dissolved in 100mL of N,N-dimethylacetamide, 32.6g of cesium fluoride was added with stirring, and the mixture was heated to 95°C for 2 hours. The mixture was cooled to room temperature, 500mL of water was added, and the mixture was extracted with 500mL of ethyl acetate, washed with 300mL of water, and repeated three times. The ethyl acetate phase was dried over anhydrous magnesium sulfate and spin-dried to obtain 30g of crude oil in a yield of 125%. The crude oil was purified by column chromatography (200g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 5:1) to obtain 19.9g of compound E in a yield of 83%.

[0087] Example 11

[0088] 20g of compound D and 46.2g of R-epichlorohydrin were dissolved in 100mL of N-methylpyrrolidone, 32.6g of cesium fluoride was added with stirring, and the mixture was heated to 95°C for 2 hours. The mixture was cooled to room temperature, 500mL of water was added, and the mixture was extracted with 500mL of ethyl acetate, washed with 300mL of water, and repeated three times. The ethyl acetate phase was dried over anhydrous magnesium sulfate and spin-dried to obtain 30g of crude oil in a yield of 125%. The crude oil was purified by column chromatography (200g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 5:1) to obtain 19.0g of compound E in a yield of 79%.

[0089] Example 12

[0090] 20g of compound D and 46.2g of R-epichlorohydrin were dissolved in 100mL of N,N-dimethylacetamide, 40g of cesium carbonate was added with stirring, and the mixture was heated to 95°C for 2 hours. The mixture was cooled to room temperature, 500mL of water was added, and the mixture was extracted with 500mL of ethyl acetate, washed with 300mL of water, and repeated three times. The ethyl acetate phase was dried over anhydrous magnesium sulfate and spin-dried to obtain 28g of crude oil in a yield of 117%. The crude oil was purified by column chromatography (200g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 5:1) to obtain 18.0g of compound E in a yield of 75%.

[0091] Step 4:

[0092] Example 13

[0093] 10 g of Compound E and 15 g of Compound F were added to 50 mL of isopropanol, heated to 45°C, and stirred for 4 hours. The mixture was cooled to room temperature, added with 300 mL of water, extracted with 300 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give 16 g of a crude product (yield 106%). Purification by column chromatography (300 g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 2:1; ethyl acetate) gave 10.0 g of Compound G (yield 66%).

[0094] Example 14

[0095] 10 g of Compound E and 15 g of Compound F were added to 50 mL of isopropanol, heated to 55°C, and stirred for 4 hours. The mixture was cooled to room temperature, and 300 mL of water was added. The mixture was extracted with 300 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give 14.8 g of a crude product (99% yield). Purification by column chromatography (300 g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 2:1; ethyl acetate) gave 9.2 g of Compound G (61% yield).

[0096] Example 15

[0097] 10 g of Compound E and 15 g of Compound F were added to 50 mL of dioxane, heated to 55°C, and stirred for 4 hours. The mixture was cooled to room temperature, 300 mL of water was added, and the mixture was extracted with 300 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and concentrated to give 13.7 g of a crude product (91% yield). Purification by column chromatography (300 g of 200-300 mesh silica gel, mobile phase: heptane; heptane: dichloromethane = 1:1; dichloromethane: dichloromethane: ethyl acetate = 2:1; ethyl acetate) gave 8.8 g of Compound G (58% yield).

[0098] Step 5:

[0099] Example 16

[0100] Add 10 g of compound G to 50 mL of isopropanol, control the temperature at 0-10°C, slowly introduce hydrogen chloride gas until the reaction system reaches pH 6, and continue the reaction at this temperature for 1 hour. Filter and vacuum dry the filter cake to obtain 8 g of landiolol hydrochloride (yield 75%).

[0101] 1H NMR (400MHz, DMSO-d6) δ9.12 (s, 2H), 7.16 (d, J = 8.2Hz, 2H), 7.10 (t, J = 5.4Hz, 1H), 6.88 (d, J=8.2Hz, 2H), 5.95-5.82 (m, 1H), 4.29-4.18 (m, 2H), 4.09 (dd, J=1 1.5, 4.3Hz, 1H), 4.04-3.90 (m, 4H), 3.64 (dd, J=8.5, 6.1Hz, 1H), 3.55 (t, J=4.8Hz, 4H), 3.41 (q, J=5.6Hz, 2H), 3.32 (t , J=4.8Hz, 4H), 3.20 (dd, J=12.8, 3.1Hz, 1H), 3.11-2.98 (m, 3H), 2.81 (s, 2H), 2.62 (s, 2H), 1.33 (s, 3H), 1.28 (s, 3H). 13 C NMR (100MHz, DMSO-d6) δ172.57, 158.22, 157.20, 133.17, 129.74, 1 14.90, 109.28, 73.58, 70.27, 66.36, 65.93, 65.36, 64.75, 50.14, 48.36, 44.28, 37.11, 35.74, 29.84, 27.01, 25.81.

[0102] Example 17

[0103] Add 10g of compound G to 50mL of isopropanol, control the temperature at 0-10°C, and slowly add 1M hydrogen chloride isopropanol solution dropwise until the reaction system reaches pH 6. Continue the reaction at this temperature for 1 hour. Filter and vacuum dry the filter cake to obtain 8.9g of landiolol hydrochloride (83% yield).

[0104] Example 18

[0105] Add 10g of compound G to 50mL of isopropanol, control the temperature at 0-10°C, and slowly add 1M hydrogen chloride in dioxane solution dropwise until the reaction system reaches pH 6. Continue the reaction at this temperature for 1 hour. Filter and vacuum dry the filter cake to obtain 8.5g of landiolol hydrochloride (yield 79%).

[0106] Although the specific embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that various modifications and substitutions may be made to those details based on all the teachings disclosed, and these changes are all within the scope of protection of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. A method for preparing landiolol hydrochloride, comprising: Step 1: reacting compound A with sodium alcoholate or potassium alcoholate to generate compound B; Step 2: reacting compound B with compound C to generate compound D; Step 3: reacting compound D with R-epichlorohydrin to generate compound E; Step 4: reacting compound E with compound F to generate compound G; Step 5: Compound G is reacted with a hydrogen chloride reagent to produce landiolol hydrochloride.

2. The method according to claim 1, characterized in that The sodium alcoholate or potassium alcoholate in step 1 is selected from at least one of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide and potassium tert-butoxide.

3. The method according to claim 1 or 2, characterized in that: In step 1, the molar ratio of compound A to sodium alkoxide or potassium alkoxide is 1:1-1.5, preferably 1:1-1.

2.

4. The method according to any one of claims 1 to 3, characterized in that: Step 1 comprises: dissolving compound A in an organic solvent 1, adding sodium alcoholate or potassium alcoholate, and reacting at 50-120° C. to obtain compound B.

5. The method according to claim 1 or 2, characterized in that: Step 2 comprises: reacting compound B with compound C in the presence of catalyst 2 to generate compound D; catalyst 2 is selected from at least one of quaternary ammonium salts and iodized salts; preferably at least one of tetrabutylammonium bromide, tetraethylammonium bromide, hexadecyltrimethylammonium bromide, benzyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, sodium iodide, and potassium iodide.

6. The method according to claim 5, characterized in that The mass ratio of compound B to catalyst 2 is 1:0.05 to 0.3, preferably 1:0.15 to 0.

25.

7. The method according to any one of claims 1, 5 and 6, characterized in that: Step 2 comprises: adding compound B, compound C and catalyst 2 into organic solvent 2, and reacting at 45-120° C. to obtain compound D.

8. The method according to claim 1, characterized in that Step 3 comprises: reacting compound D with R-epichlorohydrin in the presence of catalyst 3 to generate compound E; catalyst 3 is selected from at least one of cesium fluoride and cesium carbonate.

9. The method according to claim 8, characterized in that The molar ratio of compound D to cesium in catalyst 3 is 1:2-4, preferably 1:2.4-3.

6.

10. The method according to any one of claims 1, 8 and 9, characterized in that: Step 3 comprises: adding compound D, R-epichlorohydrin and catalyst 3 into organic solvent 3, and reacting at 70-120° C. to obtain compound E.

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