CN106608863A - Preparation method of landiolol hydrochloride - Google Patents

Preparation method of landiolol hydrochloride Download PDF

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CN106608863A
CN106608863A CN201510690951.0A CN201510690951A CN106608863A CN 106608863 A CN106608863 A CN 106608863A CN 201510690951 A CN201510690951 A CN 201510690951A CN 106608863 A CN106608863 A CN 106608863A
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dimethyl
dioxolanes
deca
solution
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和芳
葛泽梅
李润涛
冷朋林
高柏丽
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BEIJING CHUANGLI-KECHUANG PHARMACY TECHNOLOGY DEVELOPMENT Co Ltd
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BEIJING CHUANGLI-KECHUANG PHARMACY TECHNOLOGY DEVELOPMENT Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a preparation method of landiolol hydrochloride. The preparation method utilizes cheap and easily available raw materials. A key reaction utilizes a phase transfer catalysis method so reaction time is shortened. The preparation method has simple processes, improves a yield, and prevents column chromatography purification which is not suitable for industrial production. Through a saturated ammonium chloride solution/dilute hydrochloric acid solution salt forming method, product quality is easy to control, environmental friendliness is obtained, stability is high, repeatability is good and the preparation method is suitable for industrial large-scale production.

Description

A kind of preparation method of hydrochloride landiolol
Technical field
The application belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of hydrochloride landiolol.
Background technology
Hydrochloride landiolol, No. CAS：133242-30-5, trade name：Onoact, Onoact50, Onoact for injection, Chinese chemical name：3- 4- [(2S- hydroxyls-[3- (2- morpholine formamidos) ethyl] ammonia propoxyl group]-phenyl } propanoic acid (2,2- dimethyl -1,3- dioxolanes -4S) methyl ester hydrochloride, English language Chemical name：(-) -3- [4-2 (S)-Hydroxy-3- [2- (morpholinocarboxamido) ethylamino] propoxy] phenyl] propionic acid2,2-dimethyl-1,3-dioxolan-4 (S)-yl ester.Structural formula is：
Hydrochloride landiolol is white or off-white color bulk or powder, has two chiral centres, four optical isomers, the S for clinically using which single, S configurational isomers in molecule.
Hydrochloride landiolol is the indispensable emergency case medicine such as emergency treatment arrhythmia, Post operation dynamic monitoring arrhythmia in peri-operation period, the extremely favor of doctor and patient with operation from after listing.However, the chemical constitution of hydrochloride landiolol is complicated, step of preparation process is loaded down with trivial details, and impurity is wayward, a large amount of to prepare more difficulty, therefore the country does not have producer to form large-scale production at present.But, hydrochloride landiolol is the most complicated compound of structure in aryloxy propanol amine medicine, once solve the problems, such as its production technology, other with this class formation more than 40 plant medicine, such as betaxolol, ranolazine, esmolol, oxprenolol, metoprolol etc., production technology problem will all be readily solved.Therefore hydrochloride landiolol process study has very important using value.
Japanese Patent Laid-Open 5-306281 discloses a kind of hydrochloride landiolol synthetic method, in the synthetic method, the raw material for having used two prices particularly expensive：P-methyl benzenesulfonic acid (2,2- dimethyl-DOX -4S) methyl ester and m-nitrobenzene sulfonic acid ethylene oxidic ester, cause production cost higher；Intermediate compound I, intermediate II, the purification of Landiolol adopt column chromatography method, are unfavorable for industrialized production；Also, needed first to prepare oxalic acid Landiolol before hydrochloride landiolol is prepared, increased synthesis step, also expend the time, production cost also accordingly increases.Synthetic method disclosed in US5013734, EP0397031 is also similar with which.
Chinese patent (CN101012217A) discloses a kind of hydrochloride landiolol synthetic method, in the synthetic method, the use of S- (+)-epoxychloropropane is raw material, through optimization condensation, esterification, the reaction condition being etherified, obtain 3- [4- (2S, 3- glycidoxies) phenyl] propanoic acid (2,2- dimethyl-DOX -4S) methyl ester；Again with the use of carbonyl dimidazoles is that N- (2- aminoethyls) morpholine Methanamide oxalic acid prepared by raw material occurs ring-opening reaction in isopropanol water solution into salt and obtains Landiolol, target product hydrochloride landiolol is obtained by the method directly into salt then.There is following defect when N- (2- aminoethyls) -4- morpholine Methanamide oxalic acid is synthesized in the method：(1) with chloroform as solvent in course of reaction, chloroform has liver toxicity, is difficult production operation；(2) response time is long, needs column chromatography purification, unsuitable industrialization.
Wang Yuanzhong, Li Qingeng (the synthesising process research of hydrochloride landiolol, Medical University Of Chongqing's Master's thesis, 2014) et al. it is also proposed hydrochloride landiolol synthetic method, in synthetic intermediate formula III, ethylenediamine Bis(tert-butoxycarbonyl)oxide monolateral protection is obtained into 2- aminoethyls-tert-butoxy Methanamide, with N, N '-carbonyl dimidazoles and morpholine reaction generate N, N '-carbonyl morpholine imidazoles, N- (2- aminoethyls) morpholine Methanamide is generated with 2- aminoethyls-tert-butoxy formamide again, use trifluoroacetic acid deprotection, again with oxalic acid into salt, generate N- (2- aminoethyls) morpholine Methanamide oxalates.Although column chromatography is not used during the entire process of the method, the ethylenediamine of 20 equivalents during the ethylenediamine for preparing list BOC protections, is needed, Atom economy is very bad.
Cao Zhenyan (alkalescence purples 5, hydrochloride landiolol, the synthesis of three halogen isocyanuric acids and the technological design of lamivudine, Shandong University's master thesis, 2008) method that proposes adopts para hydroxybenzene propanoic acid for raw material, by converting carboxylate groups into ethyl ester, then it is etherified, open loop amination special intermediate 3- of the generation with aryloxy propanol amine structure 4- [(2S- hydroxyls-[3- (2- morpholine formamido groups) ethyl] ammonia propoxyl group]-phenyl } ethyl propionate, Jing saponification after most, ester exchange has obtained Landiolol crude product, it is passed directly into HCl and obtains hydrochloride landiolol.
The major defect of the method is：(1) raw material (2S)-(+)-p-methyl benzenesulfonic acid ethylene oxidic ester for using and p-methyl benzenesulfonic acid (2,2- dimethyl -1,3- dioxy cyclopenta-(4S) base) methyl ester are very expensive；(2) concentrated sulphuric acid has been used, container can have been corroded；(3) hydrogen chloride gas are passed directly into and know from experience a large amount of by-products of generation, yield is low；(4) whole process reactions steps are long, and Yield of final product is not high.
Synthetic method disclosed in patent EP2687521A1 (or KR2012100823) is：Initiation material is intermediate Formulas I and raceme epoxychloropropane, the first step obtains special intermediate 3- { 4- [(2R) the chloro- propoxyl group of -2- hydroxyls -3-]-phenyl } propanoic acid (2 with Jacobsen epoxychloropropane Split Methods, 2- dimethyl -1,3- dioxolanes -4S) methyl ester；This special intermediate obtains Landiolol crude product with intermediate formula IV nucleo philic substitution reaction, then incorporates Landiolol crude product and be obtained in saturation isopropanol solution of hydrogen chloride hydrochloride landiolol.The method Atom economy is good, yield is higher, and resulting compound purity is very high, but first step operation is loaded down with trivial details, and second step will remove oxalates under reflux conditions, not easy to operate.
Therefore, this area remains a need for the novel method for synthesizing for providing hydrochloride landiolol.
The content of the invention
To solve the above problems, present invention offer one is easy to operate, environmental friendliness, the new hydrochloride landiolol synthetic route of high, reproducible, the suitable industrialized great production of stability.
Specifically, the present invention provides hydrochloride landiolol, i.e. 3- 4- [(2S- hydroxyls-[3- (2- morpholine formamidos) ethyl] ammonia propoxyl group]-phenyl } propanoic acid (2,2- dimethyl -1,3- dioxolanes -4S) methyl ester hydrochloride preparation method, the preparation method comprises the following steps：
The present invention provides a kind of preparation method of hydrochloride landiolol, and the preparation method is comprised the following steps：
(1) addition para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate and phase transfer catalyst in DMSO, (2 are instilled afterwards, 2- dimethyl -1,3- dioxolanes -4S) methyl chloride, reaction generates 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester；
(2) by 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester, Anhydrous potassium carbonate, phase transfer catalyst be dissolved in acetone, Deca R- (-)-epoxychloropropane afterwards, reaction generates 4S- (2 shown in Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester；
(3) ethylenediamine is dissolved in into dichloromethane, the dichloromethane solution of Deca TMSIM N imidazole -4- morpholine Methanamides, the methanol solution of rear Deca oxalic acid, reaction generate N- (2- amino-ethyls) -4- morpholine Methanamide oxalic acid shown in formula III；
(4) to Deca sodium hydroxide solution in N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid, reaction generates N- (2- amino-ethyls) -4- morpholino amides shown in formula IV；
(5) N- shown in formula IV (2- amino-ethyls) -4- morpholino amides are dissolved in water-Isopropanol Solvent, 4S- (2 shown in Deca Formula II afterwards, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester aqueous isopropanol, reaction generate Formula V shown in Landiolol；In Landiolol shown in Formula V, add Deca hydrochloric acid after saturated ammonium chloride solution, reaction to generate hydrochloride landiolol shown in Formula IV,
In the step (1), the preparation method of (2,2- dimethyl -1, the 3- dioxolanes -4S) methyl chloride is：By acetone and S- (+)-epoxychloropropane mixing, Deca boron trifluoride diethyl etherate, reaction generate (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride；
Preferably, the preparation method of described (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride is：Under a nitrogen, by acetone and S- (+)-epoxychloropropane mixing, -5～5 DEG C of temperature control, Deca boron trifluoride diethyl etherate, washs by saturated sodium bicarbonate solution, collects supernatant, obtain (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride；
Preferably, the preparation method of described (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride is：Under a nitrogen, by acetone and S- (+)-epoxychloropropane mixing, -5～5 DEG C of ice salt bath temperature control, Deca boron trifluoride diethyl etherate under normal pressure, after be warming up at 40～45 DEG C, reaction 3～6.5 hours, after be cooled to room temperature, washed using saturated sodium bicarbonate solution, collect supernatant, obtain (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride
The step (1) is：Para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, phase transfer catalyst are added in DMSO, it is warming up to 115～120 DEG C, Deca (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride, 7～8h of reaction, extracted with the mixed solution of petroleum ether and ethyl acetate, washed with saturated sodium bicarbonate solution, saturated nacl aqueous solution successively afterwards, concentration, obtain the crude product of 4S- shown in Formulas I (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester；
Preferably, the step (1) is further comprising the steps of：Mixed solution of the petroleum ether with ethyl acetate is added to 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester crude product in, decolourize, filter, obtain 4S- shown in Formulas I (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester；
Preferably, the mixed solution petrochina ether of the petroleum ether and ethyl acetate and the volume ratio of ethyl acetate are 5: 1；
Preferably, in the step (1), the para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, the mol ratio of phase transfer catalyst are 1: 0.98～1.5: 1～2: 0.05～0.2, more preferably 1: 0.98: 1.5: 0.1；
Preferably, in the step (1), the para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, phase transfer catalyst and (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride mol ratio be 1: 0.98～1.5: 1～2: 0.05～0.2: 1～2.5, more preferably 1: 0.98: 1.5: 0.1: 2；
Preferably, in the step (1), the phase transfer catalyst is selected from tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, triethyl benzyl ammonia chloride or PEG400In one or more, preferably tetra-n-butyl ammonium bromide.
The step (2) is：By 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester, and Anhydrous potassium carbonate, phase transfer catalyst are dissolved in acetone, it is warming up to backflow, Deca R- (-)-epoxychloropropane, 6～6.5h of reaction, filter, washed with saturated sodium bicarbonate solution and saturated nacl aqueous solution successively, concentrate, obtain 4S- (2 shown in Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester；
Preferably, in the step (2), 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester, R- (-)-epoxychloropropane, Anhydrous potassium carbonate and phase transfer catalyst mol ratio be 1: 4～5: 2～3: 0.05～0.1, preferably 1: 5: 2: 0.05.
Preferably, in the step (2), the phase transfer catalyst is selected from triethylbenzyl ammonium bromide, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, 4-n-butyl ammonium hydrogen sulfate, PEG400In one or more, preferably triethylbenzyl ammonium bromide.
In the step (3), the preparation method of the TMSIM N imidazole -4- morpholine Methanamides is：By N, after N '-carbonyl dimidazoles are dissolved in dichloromethane, the dichloromethane solution of Deca morpholine, reaction generate TMSIM N imidazole -4- morpholine Methanamides；
Preferably, the preparation method of the TMSIM N imidazole -4- morpholine Methanamides is：By N, after N '-carbonyl dimidazoles are dissolved in dichloromethane, the dichloromethane solution of Deca morpholine stirs 6～6.5h, and water washing, dichloromethane extraction, anhydrous sodium sulfate drying obtain TMSIM N imidazole -4- morpholine Methanamides；
Preferably, the N, N '-carbonyl dimidazoles are 1: 1 with the mol ratio of morpholine.
The step (3) is：Ethylenediamine is dissolved in dichloromethane, the dichloromethane solution of Deca TMSIM N imidazole -4- morpholine Methanamides is warming up to backflow, decompression, temperature control are extremely less than 10 DEG C, the methanol solution of Deca oxalic acid, filter, concentration obtains N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid；
Preferably, the step (3) is：Ethylenediamine is dissolved in dichloromethane, stirring, the dichloromethane solution of Deca TMSIM N imidazole -4- morpholine Methanamides, it is warming up to backflow, 34～38h of reaction, decompression adds dichloromethane after steaming dichloromethane and remaining ethylenediamine, continuing vacuum distillation to without fraction, concentrated residues thing being dissolved using methanol, temperature control is to less than 10 DEG C, the methanol solution of Deca oxalic acid, until when pH value is 4～5, filtering, concentration, ethyl acetate crystallization is added, N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid is obtained；
Preferably, in the step (3), the TMSIM N imidazole -4- morpholines Methanamide is 1: 6 with the mol ratio of the ethylenediamine.
The step (4) is：N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid is dissolved in into water, Deca sodium hydroxide solution at 43～47 DEG C is filtered, concentration obtains N- shown in formula IV (2- amino-ethyls) -4- morpholino amides；
Preferably, the step (4) is：N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid is dissolved in into water, 40% sodium hydroxide solution of Deca at 43～47 DEG C, pH to 10～11.5 is adjusted, 20～30min is stirred, is filtered, concentration, acetone solution is added, anhydrous sodium sulfate drying is added, is filtered, concentration, obtains N- shown in formula IV (2- amino-ethyls) -4- morpholino amides.
The step (5) is：N- shown in formula IV (2- amino-ethyls) -4- morpholino amides are dissolved in water-Isopropanol Solvent, at 40～60 DEG C, 4S- (2 shown in Deca Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester aqueous isopropanol, react 4～6h, obtain Landiolol shown in Formula V；Saturated ammonium chloride solution is added in Landiolol shown in Formula V, it is 4.5～5 that less than 10 DEG C Deca hydrochloric acid make the pH of system, is dried, and concentration obtains hydrochloride landiolol shown in Formula IV；
Preferably, the step (5) is：N- shown in formula IV (2- amino-ethyls) -4- morpholino amides are dissolved in water-Isopropanol Solvent, at 40～60 DEG C, 4S- (2 shown in Deca Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester aqueous isopropanol, 4～6h of reaction, filter, concentration, saturated nacl aqueous solution is added to complete molten, extraction, washing, is dried, and filters, concentration, ethyl acetate dissolving is added, is decolourized, is obtained Landiolol shown in Formula V；Saturated ammonium chloride solution is added in Landiolol shown in Formula V, point liquid, it is 4.5～5 that less than 10 DEG C Deca 0.1～0.3N hydrochloric acid make the pH of system, ammonium chloride is added to saturation, add ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, add ethyl acetate, fluffy solid is separated out, is filtered, rinsed, vacuum drying, obtains hydrochloride landiolol shown in Formula IV；
Preferably, in the step (5), 4S- (2 shown in the Formula II, 2- dimethyl -1,3- dioxolanes -4- bases) mol ratio of-(4- (2S, 3- expoxy propane) phenyl) propyl ester and N- shown in formula IV (2- amino-ethyls) -4- morpholino amides is 1: 2～2.5；Preferably 1: 2.5；
Preferably, in the step (5), in the water-Isopropanol Solvent, the volume ratio of the water and isopropanol is 1: 5～6；Preferably 1: 6.
The preparation method is comprised the following steps：
(1) under 0～25 DEG C and nitrogen protection, acetone and S- (+) - epoxychloropropane, stirring are added; -5～5 DEG C of ice salt bath temperature control; Deca boron trifluoride diethyl etherate under normal pressure, stirring are warming up to 40～45 DEG C and react 3～6.5 hours; it is cooled to room temperature; saturated sodium bicarbonate is washed, and is collected supernatant, is obtained (2; 2- dimethyl -1,3- dioxolanes -4S) methyl chloride；
Under room temperature, the para hydroxybenzene propanoic acid that mol ratio is 1: 0.98: 1.5: 0.1 is added in DMSO, potassium hydroxide, Anhydrous potassium carbonate, tetra-n-butyl ammonium bromide, it is warming up to 115～120 DEG C, stirring, Deca obtained above (2, 2- dimethyl -1, 3- dioxolanes -4S) methyl chloride, under TLC monitoring, 7～8h of reaction, the use of volume ratio is that 5～6: 1 petroleum ether and the mixed solution of ethyl acetate are extracted 3 times, combining extraction liquid, saturated sodium bicarbonate solution is used successively, saturated nacl aqueous solution is washed twice, Jing anhydrous sodium sulfate dryings, it is concentrated under reduced pressure to give 4S- (2 shown in Formulas I, 2- dimethyl -1, 3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester crude product；Volume ratio is added into obtained above crude product with the mixed solution of ethyl acetate for 5: 1 petroleum ether, rising temperature for dissolving, add activated carbon, decolourize, filter, crystallization, vacuum drying, obtain 4S- shown in Formulas I (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester；Wherein, the mol ratio of the para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, phase transfer catalyst and (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride is 1: 0.98: 1.5: 0.1: 2；
(2) take 4S- (2 shown in the Formulas I that mol ratio is 1: 5: 2: 0.05，2- dimethyl -1，3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester、Anhydrous potassium carbonate、Triethylbenzyl ammonium bromide and acetone，By 4S- (2 shown in Formulas I，2- dimethyl -1，3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester、Anhydrous potassium carbonate、Triethylbenzyl ammonium bromide is dissolved in acetone，It is warming up to backflow，Stirring 0.5h，Deca R- (-)-epoxychloropropane，6～6.5h of reaction，Filter，Concentration，Dissolved with ethyl acetate afterwards，2 times are washed with saturated sodium bicarbonate solution and saturated nacl aqueous solution successively，Anhydrous sodium sulfate drying，Filter，Decompression，Concentration，Obtain 4S- (2 shown in Formula II，2- dimethyl -1，3- dioxolanes -4- bases)-(4- (2S，3- expoxy propane) phenyl) propyl ester；
(3) by N, N '-carbonyl dimidazoles are dissolved in dichloromethane, stirring, the dichloromethane solution of constant pressure dropping morpholine, wherein, the N, N '-carbonyl dimidazoles are 1: 1 with the mol ratio of morpholine, and 6～6.5h is stirred at room temperature after being added dropwise to complete, Jing water washings, dichloromethane is extracted, and anhydrous sodium sulfate drying obtains TMSIM N imidazole -4- morpholine Methanamides；Under room temperature, ethylenediamine is dissolved in dichloromethane solution, stirring, the dichloromethane solution of constant pressure dropping TMSIM N imidazole -4- morpholine Methanamides, wherein described TMSIM N imidazole -4- morpholines Methanamide is 1: 6 with the mol ratio of the ethylenediamine, it is warming up to backflow, 34～38h of reaction, decompression adds dichloromethane after steaming dichloromethane and remaining ethylenediamine, continuation vacuum distillation is to without fraction, concentrated residues thing is dissolved using methanol, ice bath temperature control is less than 10 DEG C, it is slowly added dropwise the methanol solution of oxalic acid, until pH value stops Deca when being 4～5, filter, concentration, add ethyl acetate crystallization, obtain N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid；
(4) N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid is dissolved in into water, the sodium hydroxide solution of Deca 40% at 43～47 DEG C, pH to 10～11.5 is adjusted, insulation continues 20～30min of stirring, filter, concentration, adds acetone solution, anhydrous sodium sulfate drying in concentrate, filter, be concentrated to give N- shown in formula IV (2- amino-ethyls) -4- morpholino amides；
(5) N- shown in formula IV (2- amino-ethyls) -4- morpholino amides are dissolved in water-Isopropanol Solvent that volume ratio is 1: 6，Under conditions of 40～60 DEG C，4S- (2 shown in Deca Formula II，2- dimethyl -1，3- dioxolanes -4- bases)-(4- (2S，3- expoxy propane) phenyl) propyl ester aqueous isopropanol，4S- (2 wherein shown in Formula II，2- dimethyl -1，3- dioxolanes -4- bases)-(4- (2S，3- expoxy propane) phenyl) mol ratio of propyl ester and N- shown in formula IV (2- amino-ethyls) -4- morpholino amides is 1: 2.5，Continue 4～6h of reaction after completion of dropping，Filter，Concentration，Saturated nacl aqueous solution is added to complete molten，Jing ethyl acetate is extracted，Jing saturated nacl aqueous solutions are washed and anhydrous sodium sulfate drying，Filter，Concentration，Ethyl acetate dissolving is added afterwards，Add activated carbon，It is heated to reflux decolouring 5min，Filtering and concentrating，Obtain Landiolol shown in Formula V；Landiolol shown in Formula V is added in saturated ammonium chloride solution, 1h is stood, point liquid, after removing oil reservoir, it is 4.5～5 that residual body is tied up to less than 10 DEG C 0.1～0.3N of Deca hydrochloric acid to pH, adds ammonium chloride to saturation, adds ethyl acetate to extract 3 times, combining extraction liquid, Jing anhydrous sodium sulfate dryings, concentration, after add ethyl acetate, be heated to reflux, filter, cooling, separates out solid, filters, ethyl acetate rinse three times, vacuum drying, obtains hydrochloride landiolol shown in Formula IV.
Specifically, the present invention comprises the steps：
(1) synthesis of intermediate Formulas I 3- (4- hydroxy phenyls) propanoic acid-[(S)-(2,2- dimethyl -1,3- dioxolanes bases) -4-] methyl ester：
The first step, synthesis (S) -2,2- dimethyl -1,3- dioxolanes -4- methyl chlorides：0～25 DEG C of temperature control, under the protection of nitrogen, adds acetone and S- (+)-epoxychloropropane; stirring, -5～5 DEG C of ice salt bath temperature control are slowly added dropwise boron trifluoride diethyl etherate under normal pressure; continue stirring, then react 3～6.5 hours at 40～45 DEG C again, stop stirring; it is cooled to room temperature; saturated sodium bicarbonate is washed, and is collected supernatant, is obtained (2; 2- dimethyl -1,3- dioxolanes -4S) methyl chloride；
Second step, synthetic intermediate Formulas I：Under room temperature, the para hydroxybenzene propanoic acid that mol ratio is 1: 0.98: 1.5: 0.1 is added in DMSO, potassium hydroxide, Anhydrous potassium carbonate, tetra-n-butyl ammonium bromide, it is warming up to 115～120 DEG C, stirring, the mol ratio of Deca and para hydroxybenzene propanoic acid is 1.5～2: 1 (S) -2, 2- dimethyl -1, 3- dioxolanes -4- methyl chlorides, TLC monitors extent of reaction, continue 7～8h of reaction, extracted 3 times with the mixed solution of petroleum ether and ethyl acetate, combining extraction liquid, saturated sodium bicarbonate is used successively, saturated nacl aqueous solution is washed, Jing anhydrous sodium sulfate dryings, it is concentrated under reduced pressure to give intermediate compound I crude product；With 5: 1 petroleum ether and the mixed liquor recrystallization of ethyl acetate, it is vacuum dried, obtains white, needle-shaped crystals intermediate compound I；Wherein, the mol ratio of the para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, phase transfer catalyst and (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride is 1: 0.98: 1.5: 0.1: 2.
(2) synthesis of intermediate Formula II 3- (4- (S)-expoxy propane ylmethoxy) benzenpropanoic acid-[(S)-(2,2- dimethyl -1,3- dioxolanes bases) -4-] methyl ester：
By mol ratio for 1: 5: 2: 0.05 intermediate Formulas I, Anhydrous potassium carbonate, triethylbenzyl ammonium bromide dissolve in acetone, be warming up to backflow, stirring 0.5h, Deca R- (-)-epoxychloropropane, 6～6.5h of reaction, filters, concentration, residue with Ethyl acetate dissolves, washed 2 times with saturated sodium bicarbonate and saturated sodium-chloride successively, anhydrous sodium sulfate drying, filtered, concentrating under reduced pressure, you can obtain intermediate Formula II；
(3) synthesis of intermediate formula III N- (2- amino-ethyls) -4- morpholine Methanamide oxalic acid：
The first step, synthesizes TMSIM N imidazole -4- morpholine Methanamides：By N, N '-carbonyl dimidazoles are dissolved in dichloromethane, stirring, the dichloromethane solution of Deca morpholine, wherein, the N, N '-carbonyl dimidazoles are 1: 1 with the mol ratio of morpholine, and 6～6.5h is stirred at room temperature after dripping off, Jing water washings again, dichloromethane is extracted, the step such as anhydrous sodium sulfate drying, obtains TMSIM N imidazole -4- morpholine Methanamides；
Second step, synthetic intermediate formula III：Ethylenediamine is dissolved in dichloromethane, is stirred, the dichloromethane solution of Deca TMSIM N imidazole -4- morpholine Methanamides under room temperature, wherein the TMSIM N imidazole -4- morpholines Methanamide is 1: 6 with the mol ratio of the ethylenediamine,；Then, back flow reaction 35h is warming up to, decompression steams dichloromethane and remaining ethylenediamine, residue methanol dissolves, and the methanol solution of oxalic acid is slowly added dropwise in the case where 10 DEG C of ＜, and it is 4～5 to adjust pH value, filtering and concentrating, adds ethyl acetate crystallization, obtains intermediate formula III；
(4) synthesis of intermediate formula IV N- (2- amino-ethyls) -4- morpholino amides
Will be intermediate formula III soluble in water, the sodium hydroxide solution of Deca 40% under conditions of 43～47 DEG C adjusts pH to 10～11.5, insulation continues stirring 20min, filters, concentration, concentrate adds acetone solution, and anhydrous sodium sulfate drying, filtering and concentrating obtain intermediate formula IV；
(5) synthesis of Formula V Landiolol
Intermediate formula IV is dissolved in water-Isopropanol Solvent that volume ratio is 1: 6，Under conditions of 40～60 DEG C，It is slowly added dropwise the aqueous isopropanol of intermediate Formula II，Wherein intermediate Formula II and the mol ratio of intermediate formula IV are 1: 2～2.5，4S- (2 wherein shown in Formula II，2- dimethyl -1，3- dioxolanes -4- bases)-(4- (2S，3- expoxy propane) phenyl) mol ratio of propyl ester and N- shown in formula IV (2- amino-ethyls) -4- morpholino amides is 1: 2.5，Continue 4～6h of reaction after completion of dropping，Filtering and concentrating，Saturated sodium-chloride is added to complete molten，Ethyl acetate is extracted，Saturated nacl aqueous solution is washed、Anhydrous sodium sulfate drying，Filtering and concentrating，Add ethyl acetate dissolving，Activated carbon decolorizing，Filtering and concentrating，Obtain Formula V Landiolol；
(6) synthesis of Formula IV hydrochloride landiolol
Landiolol shown in Formula V is added in saturated ammonium chloride solution, it is transferred in separatory funnel, 1h is stood, point liquid removes oil reservoir, residual body ties up to less than 10 DEG C be slowly added dropwise 0.1～0.3N hydrochloric acid to be made the pH of system to be 4.5～5, add Sodium Chloride to make system reach saturation, be extracted with ethyl acetate 3 times, combining extraction liquid, anhydrous sodium sulfate drying, is concentrated to give canescence crude product；Ethyl acetate is added, is heated to reflux to whole dissolvings, filtered while hot, slow cooling, is separated out fluffy solid, filter, ethyl acetate rinse three times, vacuum drying obtains final product hydrochloride landiolol.
The synthetic route of the inventive method is as follows：
Compared with prior art, the invention has the advantages that：
(1) raw material is cheaply easily obtained；(2) key reaction uses phase transfer catalysis process, shortens the response time；(3) operation is simplified, yield is improve；(4) the column chromatography purification process for being unsuitable for industrialized production is avoided, is easily controlled using saturated ammonium chloride/dilute hydrochloric acid solution salt forming method product quality.
Description of the drawings
Fig. 1 is hydrochloride landiolol H of the present invention1-NMR；
Fig. 2 is hydrochloride landiolol C of the present invention13-NMR。
Specific embodiment
The present invention is illustrated referring to specific embodiment.It will be appreciated by those skilled in the art that these embodiments are merely to illustrate the present invention, which limits the scope of the present invention never in any form.
Experimental technique in following embodiments, if no special instructions, is conventional method.In following embodiments, medicinal raw material used, reagent material etc., if no special instructions, are commercially available purchase product.
Embodiment 1 ：
(1) synthesis of Formulas I, i.e. 4S- (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester：
20 DEG C of temperature control, under nitrogen protection, acetone 58.08g and (S)-(+)-epoxychloropropane 18.50g is added in dry 250mL there-necked flasks, is stirred ten minutes；0 DEG C of ice salt bath temperature control, is slowly added dropwise 1.42g boron trifluoride diethyl etherate under normal pressure, continue temperature control stirring and be warming up to 40 DEG C after ten minutes, and system gradually turns yellow, and reaction is completed after 6 hours, stops stirring, is cooled to room temperature；By saturation NaHCO3(40mL) solution is slowly added in reaction bulb, and reaction is quenched, and system bubbling gradually becomes clarification, collects supernatant, saturation NaHCO is added in supernatant3(40mL) wash；Supernatant is collected, water white transparency oily thing is concentrated to give, is obtained (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride 28.6g；Under room temperature, 3- (4- hydroxy phenyls) propanoic acid 10.0g, potassium hydroxide 3.3g, Anhydrous potassium carbonate 12.40g, tetrabutyl ammonium bromide 1.93g are sequentially added in 40mLDMSO, above-mentioned thing is placed in 100mL there-necked flasks, 115 DEG C are warming up to, 0.5h is stirred, system blackening, Deca (2,2- dimethyl-DOX -4S) methyl chloride 18.07g, TLC monitors extent of reaction, continues reaction 7～8 hours；After the completion of reaction, filter, collect filtrate, with petroleum ether (v): ethyl acetate (v)=5: 1 (50mL) extracts product totally three times, and united extraction liquid uses saturation NaHCO successively3Solution (110mL × 2), saturation NaCl solution wash (110mL × 2) twice, anhydrous sodium sulfate drying (6g) 1 hour；Filter, concentrating under reduced pressure solvent obtains the crude product (faint yellow) of intermediate Formulas I.Add petroleum ether (v): ethyl acetate (v)=6: in the crude product of 1 (56mL) to intermediate Formulas I, intensification boiling is completely dissolved intermediate Formulas I crude product, add activated carbon 1g, decolourize 3 minutes, filtered while hot, filtrate cooling separate out white, needle-shaped crystals, filter, filter cake is collected, is vacuum dried (at 35 DEG C) and is obtained intermediate Formulas I 14.6g, yield is 85.62%.
(2) synthesis of Formula II, i.e. 4S- (2,2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester：
Intermediate Formulas I 5.60g, Anhydrous potassium carbonate 5.53g, triethyl group butylammonium bromide 272mg are added in 100mL there-necked flasks, add solvent acetone 45mL, it is warming up to backflow, stirring 0.5h, Deca (R)-(-)-epoxychloropropane 9.25g, TLC monitors extent of reaction, continues reaction 6～6.5 hours；Room temperature is cooled to after the completion of reaction, is filtered, saturation NaHCO is used in filter cake a small amount of acetone rinsing (3mL × 3), filtrate concentration, residue with Ethyl acetate dissolving successively3Solution (40mL × 1), saturation NaCl wash solution (40mL × 2) washing, 3g anhydrous sodium sulfate dryings 3 hours；Filter, concentrating under reduced pressure solvent obtains compound shown in intermediate Formula II, and pale yellow oil 6.26g, yield are 93.0%.
(3) synthesis of formula III, i.e. N- (2- amino-ethyls) -4- morpholine Methanamide oxalic acid
Synthesis TMSIM N imidazole -4- morpholine Methanamides：Room temperature, CDI16.21g and 80mL dichloromethane is added in 250mL there-necked flasks, and stirring, dichloromethane (50mL) solution of constant pressure dropping morpholine 8.7g are dripped off for 1 hour or so, and room temperature continues reaction 5～6 hours；Add 60mL water washings, water layer (50mLx3) to be extracted with dichloromethane again after the completion of reaction, merge organic layer, add 5g anhydrous sodium sulfate dryings 3 hours, filter, be concentrated to give white solid TMSIM N imidazole -4- morpholine Methanamide 16.42g, yield is 90.62%；
Compound shown in synthesis formula III：Room temperature, ethylenediamine 18.03g and 50mL dichloromethane is added in 250mL there-necked flasks, and stirring, constant pressure are slowly added dropwise dichloromethane (100mL) solution of -4- morpholine Methanamides of TMSIM N imidazole containing 9.1g, is warming up to backflow, reaction 36h or so；After the completion of reaction, reduced pressure at room temperature steams dichloromethane, 65 DEG C, P≤- 0.07Mpa is decompressed to, steams remaining ethylenediamine, to without fraction, remaining system adds 20mL methanol, continues 65 DEG C, is decompressed to P≤- 0.07Mpa distillations, to without fraction, remaining system adds 20mL dichloromethane, continues 65 DEG C of vacuum distillations, to without fraction；Finally dissolved with methanol 50mL, ice bath temperature control is less than 10 DEG C, is slowly added dropwise the methanol solution of oxalic acid, until pH value stops Deca when being 4～5, filter, filtrate is concentrated into without fraction, adds ethyl acetate 80mL overnight, separates out white solid, filter, filter cake is collected, is vacuum dried (at 35 DEG C) and is obtained intermediate formula III 10.56g, yield is 80.23%；
(4) synthesis of formula IV, i.e. N- (2- amino-ethyls) -4- morpholino amides：
Under room temperature condition, in 100mL reaction bulbs, add compound 15.8g and water 47.4g shown in formula III, stirring to be warming up to 43～47 DEG C of complete molten, 40% sodium hydroxide solutions of agitation and dropping, adjust pH to 10～11.5, insulation continues stirring 20 minutes or so；Room temperature is cooled to, is filtered, filter cake is rinsed with 7.2g water, filtrate proceeds to revolving bottle, under 44～48 DEG C, pressure P≤- 0.07Mpa, is concentrated into and distillates without fraction, residuum is down to room temperature, adds acetone 110g, stirs to residue and be all scattered in acetone, proceeded in the triangular flask of 250mL afterwards, plus anhydrous sodium sulfate 9.48g is dried 3 hours, filters, filtrate proceeds to eggplant shape revolving bottle and is concentrated into without fraction, intermediate formula IV sterling is obtained, pale yellow oil 8.8g, yield are 84.67%.
(5) synthesis of Formula IV, i.e. hydrochloride landiolol
Compound shown in 8.6g formula IVs, 4mL water, 20mL isopropanols are added into 100mL there-necked flasks, stirring is warming up to 50～55 DEG C, it is slowly added dropwise the aqueous isopropanol (aqueous isopropanol is 4mL) of compound shown in 6.7g Formula II, after completion of dropping, it is incubated 50 DEG C and continues reaction 5～5.5 hours；Concentrate less than 45 DEG C after the completion of reaction, to without fraction, remaining system adds 25mL saturated sodium-chlorides, stir to complete molten, after ten minutes, add 25mL ethyl acetate, continue stirring 10min, extraction, divide liquid, collected organic layer, in triplicate, merge organic layer, saturated sodium-chloride (50mL) is added to wash in organic layer 2 times, add 5g anhydrous sodium sulfate dryings, filter, it is concentrated into without fraction, the dissolving of 30mL ethyl acetate is added again, add 1g activated carbons, it is heated to reflux, decolouring 5min or so (or room temperature decolouring 1h), filtered while hot, filtrate is cooled to room temperature, it is concentrated to give the crude product of Landiolol shown in Formula V, yellow oil 9.4g, yield is 92.30%.
The crude product 5.09g of Landiolol shown in Formula V is added in 100mL eggplant type flasks, saturated ammonium chloride 30mL stirring 1h is added, is transferred in the separatory funnel of 125mL, stands 1h or so, point liquid removes the oil reservoir on wall；Remaining system is transferred in the clean eggplant type flasks of 100mL, under ice-water bath, below 10 DEG C of temperature control, being slowly added dropwise 0.2N hydrochloric acid makes pH to 4.5～5 of system or so, a small amount of Sodium Chloride or ammonium chloride is added to make system reach again saturation, 30mL ethyl acetate is added to extract 3 times, 6g anhydrous sodium sulfate dryings are added after combined ethyl acetate layer, it is concentrated to give canescence residue, the ethyl acetate of 35mL is added in residue, it is heated to reflux to White residule all dissolving, filtered while hot is transferred in new 100mL eggplant-shape bottles, slow cooling, separate out fluffy solid, filter, with 5mL ethyl acetate rinses 3 times.Filter cake is put in 35 DEG C of vacuum drying ovens and is dried to constant weight, obtain hydrochloride landiolol 4.60g shown in Formula IV, yield is 84.29%, and purity is 99.6%.
1H NMR (400MHz, CDCl3)：δ 7.13-7.11 (d, J=8.4Hz, 1H), 6.85-6.83 (d, J=8.3Hz, 1H), 5.19 (s, 1H), 4.32-4.27 (m, 1H), 4.19-4.03 (m, 4H), 3.97-3.96 (d, J=4.2Hz, 2H), 3.72-3.66 (m, 5H), 3.41-3.34 (m, 6H), 2.87-2.82 (ddd, J=16.5,13.1,5.6Hz, 8H), 2.67-2.63 (t, J=7.7Hz, 2H), 1.44 (s, 3H), 1.38 (s, 3H).
13C NMR (100MHz, CDCl3)：δ 173.71,159.08,157.54,134.32,129.35,114.57,109.84,73.57,70.38,68.37,66.45,66.32,64.73,51.47,49.29,43.97,40.69,35.89,30.00,26.69,25.39.
Embodiment 2 ：
(1) synthesis of Formulas I, i.e. 4S- (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester：
20 DEG C of temperature control, under nitrogen protection, acetone 58.08g and (S)-(+)-epoxychloropropane 18.50g is added in dry 250mL there-necked flasks, is stirred ten minutes；0 DEG C of ice salt bath temperature control, is slowly added dropwise 1.42g boron trifluoride diethyl etherate under normal pressure, continue temperature control stirring and be warming up to 45 DEG C after ten minutes, and system gradually turns yellow, and reaction is completed after 3 hours, stops stirring, is cooled to room temperature；By saturation NaHCO3(40mL) solution is slowly added in reaction bulb, and reaction is quenched, and system bubbling gradually becomes clarification, collects supernatant, saturation NaHCO is added in supernatant3(40mL) wash；Supernatant is collected, water white transparency oily thing is concentrated to give, is obtained (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride 25.49g；Under room temperature, successively 3- (4- hydroxy phenyls) propanoic acid 10.0g, potassium hydroxide 3.3g, Anhydrous potassium carbonate 16.58g, TBAB 967mg are added in 100mL there-necked flasks in 40mLDMSO, it is warming up to 120 DEG C, stirring 0.5h, system blackening, Deca (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride 18.07g, TLC monitoring extent of reactions, continuation reaction 7～8 hours；After the completion of reaction, filter, collect filtrate, with petroleum ether (v): ethyl acetate (v)=5: 1 (50mL) extracts product totally three times, and united extraction liquid uses saturation NaHCO successively3Solution (110mL × 2), saturation NaCl solution wash (110mL × 2) twice, anhydrous sodium sulfate drying (6g) 1 hour；Filter, concentrating under reduced pressure solvent obtains the crude product (faint yellow) of intermediate Formulas I.Add petroleum ether (v): ethyl acetate (v)=5: in the crude product of 1 (56mL) to intermediate Formulas I, intensification boiling is completely dissolved intermediate Formulas I crude product, add activated carbon 1g, decolourize 3 minutes, filtered while hot, filtrate cooling separate out white, needle-shaped crystals, filter, filter cake is collected, is vacuum dried (at 35 DEG C) and is obtained intermediate Formulas I 11.93g, yield is 70%.
(2) synthesis of Formula II, i.e. 4S- (2,2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester：
Intermediate Formulas I 5.60g, Anhydrous potassium carbonate 5.53g, TEBAB 544mg are added in 100mL there-necked flasks, add solvent acetone 45mL, it is warming up to backflow, stirring 0.5h, Deca (R)-(-)-epoxychloropropane 7.4g, TLC monitors extent of reaction, continues reaction 6～6.5 hours；Room temperature is cooled to after the completion of reaction, is filtered, saturation NaHCO is used in filter cake a small amount of acetone rinsing (3mL × 3), filtrate concentration, residue with Ethyl acetate dissolving successively3Solution (40mL × 1), saturation NaCl wash solution (40mL × 2) washing, 3g anhydrous sodium sulfate dryings 3 hours；Filter, concentrating under reduced pressure solvent obtains compound shown in intermediate Formula II, and pale yellow oil 5.72g, yield are 85.0%.
(3) synthesis of formula III, i.e. N- (2- amino-ethyls) -4- morpholine Methanamide oxalic acid
Synthesis TMSIM N imidazole -4- morpholine Methanamides：Room temperature, CDI16.21g and 80mL dichloromethane is added in 250mL there-necked flasks, and stirring, dichloromethane (50mL) solution of constant pressure dropping morpholine 8.7g are dripped off for 1 hour or so, and room temperature continues reaction 5～6 hours；Add 60mL water washings, water layer (50mLx3) to be extracted with dichloromethane again after the completion of reaction, merge organic layer, add 5g anhydrous sodium sulfate dryings 3 hours, filter, be concentrated to give white solid TMSIM N imidazole -4- morpholine Methanamide 16.42g, yield is 90.62%；
Compound shown in synthesis formula III：Room temperature, ethylenediamine 15.03g and 50mL dichloromethane is added in 250mL there-necked flasks, and stirring, constant pressure are slowly added dropwise dichloromethane (100mL) solution of -4- morpholine Methanamides of TMSIM N imidazole containing 9.1g, is warming up to backflow, reaction 34h or so；After the completion of reaction, reduced pressure at room temperature steams dichloromethane, 65 DEG C, P≤- 0.07Mpa decompressions steam remaining ethylenediamine, and to without fraction, remaining system adds 20mL methanol, continue 65 DEG C, P≤- 0.07Mpa vacuum distillations, to without fraction, remaining system adds 20mL dichloromethane, continue 65 DEG C of vacuum distillations, to without fraction；Finally dissolved with methanol 50mL, ice bath temperature control is less than 10 DEG C, is slowly added dropwise the methanol solution of oxalic acid, until pH value stops Deca when being 4～5, filter, filtrate is concentrated into without fraction, adds ethyl acetate 80mL overnight, separates out white solid, filter, filter cake is collected, is vacuum dried (at 35 DEG C) and is obtained intermediate formula III 9.50g, yield is 72.20%；
(4) synthesis of formula IV, i.e. N- (2- amino-ethyls) -4- morpholino amides：
Under room temperature condition, in 100mL reaction bulbs, add compound 15.8g and water 47.4g shown in formula III, stirring to be warming up to 40% sodium hydroxide solution of agitation and dropping at 43～47 DEG C, adjust pH to 10～11.5, insulation continues stirring 25 minutes or so；Room temperature is cooled to, is filtered, filter cake is rinsed with 7.2g water, filtrate proceeds to revolving bottle, under 44～48 DEG C, P≤- 0.07Mpa, is concentrated into and distillates without fraction, residuum is down to room temperature, adds acetone 110g, stirs to residue and be all scattered in acetone, proceeded in the triangular flask of 250mL afterwards, plus anhydrous sodium sulfate 9.48g is dried 3 hours, filters, filtrate proceeds to eggplant shape revolving bottle and is concentrated into without fraction, intermediate formula IV sterling is obtained, pale yellow oil 8.8g, yield are 84.67%.
(5) synthesis of Formula IV, i.e. hydrochloride landiolol
Compound shown in 6.93g formula IVs, 4mL water, 18mL isopropanols are added in the there-necked flask of 100mL, stirring is warming up to 50～55 DEG C, it is slowly added dropwise the aqueous isopropanol (isopropyl alcohol liquid 4mL) of compound shown in 6.7g Formula II, after completion of dropping, it is incubated 50 DEG C and continues reaction 5～5.5 hours；Concentrate less than 45 DEG C after the completion of reaction, to without fraction, remaining system adds 25mL saturated sodium-chlorides, stir to complete molten, after ten minutes, add 25mL ethyl acetate, continue stirring 10min, extraction, divide liquid, collected organic layer, in triplicate, merge organic layer, saturated sodium-chloride (50mL) is added to wash in organic layer 2 times, add 5g anhydrous sodium sulfate dryings, filter, it is concentrated into without fraction, the dissolving of 30mL ethyl acetate is added again, add 1g activated carbons, it is heated to reflux, decolouring 5min or so (or room temperature decolouring 1h), filtered while hot, filtrate is cooled to room temperature, it is concentrated to give the crude product of Landiolol shown in Formula V, yellow oil 9.07g, yield is 89.04%.
The crude product 5.09g of Landiolol shown in Formula V is added in 100mL eggplant type flasks, saturated ammonium chloride 30mL stirring 1h is added, is transferred in the separatory funnel of 125mL, stands 1h or so, point liquid removes the oil reservoir on wall；Remaining system is transferred in the clean eggplant type flasks of 100mL, under ice-water bath, below 10 DEG C of temperature control, being slowly added dropwise 0.2N hydrochloric acid makes pH to 4.5～5 of system or so, a small amount of Sodium Chloride or ammonium chloride is added to make system reach again saturation, 30mL ethyl acetate is added to extract 3 times, 6g anhydrous sodium sulfate dryings are added after combined ethyl acetate layer, it is concentrated to give canescence residue, the ethyl acetate of 35mL is added in residue, it is heated to reflux to White residule all dissolving, filtered while hot is transferred in new 100mL eggplant-shape bottles, slow cooling, separate out fluffy solid, filter, with 5mL ethyl acetate rinses 3 times.Filter cake is put in 35 DEG C of vacuum drying ovens and is dried to constant weight, obtain hydrochloride landiolol 4.58g shown in Formula IV, yield is 83.88%, and purity is 99.6%.
1H NMR (400MHz, CDCl3)：δ 7.13-7.11 (d, J=8.4Hz, 1H), 6.85-6.83 (d, J=8.3Hz, 1H), 5.19 (s, 1H), 4.32-4.27 (m, 1H), 4.19-4.03 (m, 4H), 3.97-3.96 (d, J=4.2Hz, 2H), 3.72-3.66 (m, 5H), 3.41-3.34 (m, 6H), 2.87-2.82 (ddd, J=16.5,13.1,5.6Hz, 8H), 2.67-2.63 (t, J=7.7Hz, 2H), 1.44 (s, 3H), 1.38 (s, 3H).
13C NMR (100MHz, CDCl3)：δ 173.71,159.08,157.54,134.32,129.35,114.57,109.84,73.57,70.38,68.37,66.45,66.32,64.73,51.47,49.29,43.97,40.69,35.89,30.00,26.69,25.39.
Embodiment 3 ：
(1) synthesis of Formulas I, i.e. 4S- (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester：
20 DEG C of temperature control, under nitrogen protection, acetone 58.08g and (S)-(+)-epoxychloropropane 18.50g is added in dry 250mL there-necked flasks, is stirred ten minutes；0 DEG C of ice salt bath temperature control, is slowly added dropwise 1.42g boron trifluoride diethyl etherate under normal pressure, continue temperature control stirring and be warming up to 40 DEG C after ten minutes, and system gradually turns yellow, and reaction is completed after 4 hours, stops stirring, is cooled to room temperature；By saturation NaHCO3(40mL) solution is slowly added in reaction bulb, and reaction is quenched, and system bubbling gradually becomes clarification, collects supernatant, saturation NaHCO is added in supernatant3(40mL) wash；Supernatant is collected, water white transparency oily thing is concentrated to give, is obtained (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride 27.35g；Under room temperature, successively 3- (4- hydroxy phenyls) propanoic acid 10.0g, potassium hydroxide 3.3g, Anhydrous potassium carbonate 12.40g, TBAB 967mg are added in 100mL there-necked flasks in 40mLDMSO, it is warming up to 115 DEG C, stirring 0.5h, system blackening, Deca (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride 9.04g, TLC monitoring extent of reactions, continuation reaction 7～8 hours；After the completion of reaction, filter, collect filtrate, with petroleum ether (v): ethyl acetate (v)=5: 1 (50mL) extracts product totally three times, and united extraction liquid uses saturation NaHCO successively3Solution (110mL × 2), saturation NaCl solution wash (110mL × 2) twice, anhydrous sodium sulfate drying (6g) 1 hour；Filter, concentrating under reduced pressure solvent obtains the crude product (faint yellow) of intermediate Formulas I.Add petroleum ether (v): ethyl acetate (v)=5: in the crude product of 1 (56mL) to intermediate Formulas I, intensification boiling is completely dissolved intermediate Formulas I crude product, add activated carbon 1g, decolourize 3 minutes, filtered while hot, filtrate cooling separate out white, needle-shaped crystals, filter, filter cake is collected, is vacuum dried (at 35 DEG C) and is obtained intermediate Formulas I 6.82g, yield is 40%.
(2) synthesis of Formula II, i.e. 4S- (2,2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester：
Intermediate Formulas I 5.60g, Anhydrous potassium carbonate 8.29g, TEBAB 272mg are added in 100mL there-necked flasks, add solvent acetone 45mL, it is warming up to backflow, stirring 0.5h, Deca (R)-(-)-epoxychloropropane 9.25g, TLC monitors extent of reaction, continues reaction 6～6.5 hours；Room temperature is cooled to after the completion of reaction, is filtered, saturation NaHCO is used in filter cake a small amount of acetone rinsing (3mL × 3), filtrate concentration, residue with Ethyl acetate dissolving successively3Solution (40mL × 1), saturation NaCl wash solution (40mL × 2) washing, 3g anhydrous sodium sulfate dryings 3 hours；Filter, concentrating under reduced pressure solvent obtains compound shown in intermediate Formula II, and pale yellow oil 4.71g, yield are 70.0%.
(3) synthesis of formula III, i.e. N- (2- amino-ethyls) -4- morpholine Methanamide oxalic acid
Synthesis TMSIM N imidazole -4- morpholine Methanamides：Room temperature, CDI16.21g and 80mL dichloromethane is added in 250mL there-necked flasks, and stirring, dichloromethane (50mL) solution of constant pressure dropping morpholine 10.44g are dripped off for 1 hour or so, and room temperature continues reaction 5～6 hours；Add 60mL water washings, water layer (50mLx3) to be extracted with dichloromethane again after the completion of reaction, merge organic layer, add 5g anhydrous sodium sulfate dryings 3 hours, filter, be concentrated to give white solid TMSIM N imidazole -4- morpholine Methanamide 16.33g, yield is 90.12%；
Compound shown in synthesis formula III：Room temperature, ethylenediamine 18.03g and 50mL dichloromethane is added in 250mL there-necked flasks, and stirring, constant pressure are slowly added dropwise dichloromethane (100mL) solution of -4- morpholine Methanamides of TMSIM N imidazole containing 9.1g, is warming up to backflow, reaction 38h or so；After the completion of reaction, reduced pressure at room temperature steams dichloromethane, 65 DEG C, P≤- 0.07Mpa decompressions steam remaining ethylenediamine, and to without fraction, remaining system adds 20mL methanol, continue 65 DEG C, P≤- 0.07Mpa vacuum distillations, to without fraction, remaining system adds 20mL dichloromethane, continue 65 DEG C of vacuum distillations, to without fraction；Finally dissolved with methanol 50mL, ice bath temperature control is less than 10 DEG C, is slowly added dropwise the methanol solution of oxalic acid, until pH value stops Deca when being 4～5, filter, filtrate is concentrated into without fraction, adds ethyl acetate 80mL overnight, separates out white solid, filter, filter cake is collected, is vacuum dried (at 35 DEG C) and is obtained intermediate formula III 10.53g, yield is 80.0%；
(4) synthesis of formula IV, i.e. N- (2- amino-ethyls) -4- morpholino amides：
Under room temperature condition, in 100mL reaction bulbs, add compound 15.8g and water 47.4g shown in formula III, stirring to be warming up to 40% sodium hydroxide solution of agitation and dropping at 43～47 DEG C, adjust pH to 10～11.5, insulation continues stirring 30 minutes or so；Room temperature is cooled to, is filtered, filter cake is rinsed with 7.2g water, filtrate proceeds to revolving bottle, under 44～48 DEG C, P≤- 0.07Mpa, is concentrated into and distillates without fraction, residuum is down to room temperature, adds acetone 110g, stirs to residue and be all scattered in acetone, proceeded in the triangular flask of 250mL afterwards, plus anhydrous sodium sulfate 9.48g is dried 3 hours, filters, filtrate proceeds to eggplant shape revolving bottle and is concentrated into without fraction, intermediate formula IV sterling is obtained, pale yellow oil 8.5g, yield are 81.78%.
(5) synthesis of Formula IV, i.e. hydrochloride landiolol
Compound shown in 8.6g formula IVs, 4mL water, 20mL isopropanols are added in the there-necked flask of 100mL, stirring is warming up to 40～45 DEG C, the aqueous isopropanol (isopropyl alcohol liquid 4mL) of compound shown in 6.7g Formula II is slowly added dropwise, after completion of dropping, 50 DEG C is incubated and is continued reaction 5～5.5 hours；Concentrate less than 45 DEG C after the completion of reaction, to without fraction, remaining system adds 25mL saturated sodium-chlorides, stir to complete molten, after ten minutes, add 25mL ethyl acetate, continue stirring 10min, extraction, divide liquid, collected organic layer, in triplicate, merge organic layer, saturated sodium-chloride (50mL) is added to wash in organic layer 2 times, add 5g anhydrous sodium sulfate dryings, filter, it is concentrated into without fraction, the dissolving of 30mL ethyl acetate is added again, add 1g activated carbons, it is heated to reflux, decolouring 5min or so (or room temperature decolouring 1h), filtered while hot, filtrate is cooled to room temperature, it is concentrated to give the crude product of Landiolol shown in Formula V, yellow oil 8.64g, yield is 84.87%.
The crude product 5.09g of Landiolol shown in Formula V is added in 100mL eggplant type flasks, saturated ammonium chloride 30mL stirring 1h is added, is transferred in the separatory funnel of 125mL, stands 1h or so, point liquid removes the oil reservoir on wall；Remaining system is transferred in the clean eggplant type flasks of 100mL, under ice-water bath, below 10 DEG C of temperature control, being slowly added dropwise 0.2N hydrochloric acid makes pH to 4.5～5 of system or so, a small amount of Sodium Chloride or ammonium chloride is added to make system reach again saturation, 30mL ethyl acetate is added to extract 3 times, 6g anhydrous sodium sulfate dryings are added after combined ethyl acetate layer, it is concentrated to give canescence residue, the ethyl acetate of 35mL is added in residue, it is heated to reflux to White residule all dissolving, filtered while hot is transferred in new 100mL eggplant-shape bottles, slow cooling, separate out fluffy solid, filter, with 5mL ethyl acetate rinses 3 times.Filter cake is put in 35 DEG C of vacuum drying ovens and is dried to constant weight, obtain hydrochloride landiolol 4.54g shown in Formula IV, yield is 83.14%, and purity is 99.6%.
1H NMR (400MHz, CDCl3)：δ 7.13-7.11 (d, J=8.4Hz, 1H), 6.85-6.83 (d, J=8.3Hz, 1H), 5.19 (s, 1H), 4.32-4.27 (m, 1H), 4.19-4.03 (m, 4H), 3.97-3.96 (d, J=4.2Hz, 2H), 3.72-3.66 (m, 5H), 3.41-3.34 (m, 6H), 2.87-2.82 (ddd, J=16.5,13.1,5.6Hz, 8H), 2.67-2.63 (t, J=7.7Hz, 2H), 1.44 (s, 3H), 1.38 (s, 3H).
13C NMR (100MHz, CDCl3)：δ 173.71,159.08,157.54,134.32,129.35,114.57,109.84,73.57,70.38,68.37,66.45,66.32,64.73,51.47,49.29,43.97,40.69,35.89,30.00,26.69,25.39.
Embodiment 4 ：Phase transfer catalyst is added in the present invention to preparing the impact of intermediate：
Come synthetic compound of formula i and the step (2) to synthesize Formula II compound according to step (1) described in embodiment 1, wherein, the phase transfer catalyst service condition of each group is shown in Tables 1 and 2,
Table 1：Prepare the consumption contrast of phase transfer catalyst in intermediate compound I
Group number Phase transfer catalyst species and consumption Response time (h) Intermediate compound I yield
1 Nothing 15～16 65%
1a Nothing 7～8 40%
2 Tetrabutylammonium iodide (0.10) 7～8 82%
3 Triethyl benzyl ammonia chloride (0.10) 7～8 70%
4 PEG400(0.10) 7～8 70%
5 Tetra-n-butyl ammonium bromide (0.10) 7～8 85%
5a Tetra-n-butyl ammonium bromide (0.20) 7～8 85%
5b Tetra-n-butyl ammonium bromide (0.15) 7～8 85%
5c Tetra-n-butyl ammonium bromide (0.08) 7～8 80%
5d Tetra-n-butyl ammonium bromide (0.05) 7～8 70%
(note：In table 1, the consumption of phase transfer catalyst is its mol ratio with para hydroxybenzene propanoic acid)
As can be seen from Table 1, it is 4S- (2 in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester synthesis in, the response time that phase transfer catalyst is added without in reaction is 15h, and after adding phase transfer catalyst the time foreshorten to 7 hours, and the yield of Formulas I is significantly improved after adding phase transfer catalyst, in all phase transfer catalysts, the catalytic effect of tetra-n-butyl ammonium bromide is optimum.
It is 4S- (2 in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester synthesis in, when para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, tetra-n-butyl ammonium bromide and (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride mol ratio be 1: 0.98: 1.5: 0.1: 2 when, the yield of Formulas I is optimal.
Table 2：The present invention prepares the species contrast of phase transfer catalyst in intermediate II
Group number Phase transfer catalyst species and consumption Response time (h) Intermediate compound I yield
1 -- 20～21 74%
1a -- 6～6.5 30%
2 Tetra-n-butyl ammonium bromide (0.1) 6～6.5 80%
3 Tetrabutylammonium iodide (0.1) 6～6.5 80%
4 Triethyl benzyl ammonia chloride (0.1) 6～6.5 85%
5 Triethylbenzyl ammonium bromide (0.1) 6～6.5 90%
6 Tetra-n-butyl hydrogen sulfate presses (0.1) 6～6.5 80%
7 PEG400(0.1) 6～6.5 80%
8 PEG300(0.1) 6～6.5 80%
9 PEG600(0.1) 6～6.5 80%
5a Triethylbenzyl ammonium bromide (0.15) 6～6.5 84%
5b Triethylbenzyl ammonium bromide (0.12) 6～6.5 90%
5c Triethylbenzyl ammonium bromide (0.05) 6～6.5 90%
5d Triethylbenzyl ammonium bromide (0.03) 6～6.5 85%
(note：In table 2, the consumption of phase transfer catalyst is the mol ratio of phase transfer catalyst and intermediate compound I)
As can be seen from Table 2, it is 4S- (2 in Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester synthesis in, it is shown in Table 2 (numbering 1～9 and 1a), the response time for being added without phase transfer catalyst is 20 hours, the response time for adding phase transfer catalyst is 6.5 hours, and add the yield of phase transfer catalyst to significantly improve, in addition, in all phase transfer catalysts, the catalytic effect of triethylbenzyl ammonium bromide is optimum.
Formula II, that is 4S- (2,2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester synthesis in, when 4S- (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester, R- (-)-epoxychloropropane, Anhydrous potassium carbonate and phase transfer catalyst triethylbenzyl ammonium bromide mol ratio be 1: 5: 2: 0.05 when, yield is optimal.
Embodiment 5 ：The salt forming method adopted in the present invention is affected on the product of hydrochloride landiolol
Carry out synthetic hydrochloric acid Landiolol according to step (5) described in embodiment 1, wherein, each group is shown in Table 3 into salt mode,
Table 3：Screening process of the hydrochloride landiolol of the present invention into salt
As seen from Table 3, in the synthesis that Landiolol Jing salt-forming reactions generate hydrochloride landiolol, it is common into salt mode when selecting, i.e. in organic solvent into salt, then the yield and purity of hydrochloride landiolol be not high, as being passed through dry hydrogen chloride gas in acetone, the yield and purity of hydrochloride landiolol are followed successively by 50%, 60%；
Additionally, as seen from Table 3, when in aqueous into salt, the concentration of hydrochloric acid and the pH changes into system after salt will be had an impact to the yield and purity of hydrochloride landiolol：Concentration of hydrochloric acid is too high, will generate by-product, and when such as using 0.5～2mol/L hydrochloric acid solutions and pH being adjusted to 4.5～6 or so, the yield and purity of hydrochloride landiolol are 70-78% and 85-95%；And when pH being adjusted to 4.5～5 or so using 0.1～0.3mol/L hydrochloric acid solutions, the yield and purity of hydrochloride landiolol are 85% and 99.5%；When pH being adjusted to 6 or so using 0.2mol/L hydrochloric acid solutions, the yield and purity of hydrochloride landiolol are followed successively by 80% and 95%.
From table 3, in saturation NaCl aqueous solution and saturation NH4Into salt in Cl aqueous solutions, when pH being adjusted to 4.5～5 or so with 0.2mol/L hydrochloric acid solutions, the yield and purity of hydrochloride landiolol is higher.
As can be seen from Table 3：Select saturation NH4Cl aqueous solution salifying methods, divide liquid and remove bottle wall grease impurity after standing 1 hour, remaining system extracts a laggard one-step refining, and the yield of its hydrochloride landiolol and purity are optimum.
Specific description of embodiments of the present invention above is not intended to limit the present invention, and those skilled in the art can be variously modified according to the present invention or deform, and without departing from the spirit of the present invention, all should belong to scope of the following claims of the present invention.

Claims (9)

1. a kind of preparation method of hydrochloride landiolol, the preparation method are comprised the following steps：
(1) addition para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate and phase transfer catalyst in DMSO, (2 are instilled afterwards, 2- dimethyl -1,3- dioxolanes -4S) methyl chloride, reaction generates 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester；
(2) by 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester, Anhydrous potassium carbonate, phase transfer catalyst be dissolved in acetone, Deca R- (-)-epoxychloropropane afterwards, reaction generates 4S- (2 shown in Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester；
(3) ethylenediamine is dissolved in into dichloromethane, the dichloromethane solution of Deca TMSIM N imidazole -4- morpholine Methanamides, the methanol solution of rear Deca oxalic acid, reaction generate N- (2- amino-ethyls) -4- morpholine Methanamide oxalic acid shown in formula III；
(4) to Deca sodium hydroxide solution in N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid, reaction generates N- (2- amino-ethyls) -4- morpholino amides shown in formula IV；
(5) N- shown in formula IV (2- amino-ethyls) -4- morpholino amides are dissolved in water-Isopropanol Solvent, 4S- (2 shown in Deca formula II afterwards, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester aqueous isopropanol, reaction generate Formula V shown in Landiolol；In Landiolol shown in Formula V, add Deca hydrochloric acid after saturated ammonium chloride solution, reaction to generate hydrochloride landiolol shown in Formula IV,
2. preparation method according to claim 1, it is characterised in that in the step (1), the preparation method of (2,2- dimethyl -1, the 3- dioxolanes -4S) methyl chloride is：By acetone and S- (+)-epoxychloropropane mixing, Deca boron trifluoride diethyl etherate, reaction generate (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride；
Preferably, the preparation method of described (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride is：Under a nitrogen, by acetone and S- (+)-epoxychloropropane mixing, -5～5 DEG C of temperature control, Deca boron trifluoride diethyl etherate, washs by saturated sodium bicarbonate solution, collects supernatant, obtain (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride；
Preferably, the preparation method of described (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride is：Under a nitrogen, by acetone and S- (+)-epoxychloropropane mixing, -5～5 DEG C of ice salt bath temperature control, Deca boron trifluoride diethyl etherate under normal pressure, after be warming up at 40～45 DEG C, reaction 3～6.5 hours, after be cooled to room temperature, washed using saturated sodium bicarbonate solution, collect supernatant, obtain (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride
3. preparation method according to claim 1 and 2, it is characterised in that the step (1) is：Para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, phase transfer catalyst are added in DMSO, it is warming up to 115～120 DEG C, Deca (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride, 7～8h of reaction, extracted with the mixed solution of petroleum ether and ethyl acetate, washed with saturated sodium bicarbonate solution, saturated nacl aqueous solution successively afterwards, concentration, obtain the crude product of 4S- shown in Formulas I (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester；
Preferably, the step (1) is further comprising the steps of：Mixed solution of the petroleum ether with ethyl acetate is added to 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester crude product in, decolourize, filter, obtain 4S- shown in Formulas I (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester；
Preferably, the mixed solution petrochina ether of the petroleum ether and ethyl acetate and the volume ratio of ethyl acetate are 5: 1；
Preferably, in the step (1), the para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, the mol ratio of phase transfer catalyst are 1: 0.98～1.5: 1～2: 0.05～0.2, more preferably 1: 0.98: 1.5: 0.1；
Preferably, in the step (1), the para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, phase transfer catalyst and (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride mol ratio be 1: 0.98～1.5: 1～2: 0.05～0.2: 1～2.5, more preferably 1: 0.98: 1.5: 0.1: 2；
Preferably, in the step (1), the phase transfer catalyst is selected from tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, triethyl benzyl ammonia chloride or PEG400In one or more, preferably tetra-n-butyl ammonium bromide.
4. preparation method according to any one of claim 1 to 3, it is characterised in that the step (2) is：By 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester, and Anhydrous potassium carbonate, phase transfer catalyst are dissolved in acetone, it is warming up to backflow, Deca R- (-)-epoxychloropropane, 6～6.5h of reaction, filter, washed with saturated sodium bicarbonate solution and saturated nacl aqueous solution successively, concentrate, obtain 4S- (2 shown in Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester；
Preferably, in the step (2), 4S- (2 shown in Formulas I, 2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester, R- (-)-epoxychloropropane, Anhydrous potassium carbonate and phase transfer catalyst mol ratio be 1: 4～5: 2～3: 0.05～0.1, preferably 1: 5: 2: 0.05；
Preferably, in the step (2), the phase transfer catalyst is selected from triethylbenzyl ammonium bromide, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, 4-n-butyl ammonium hydrogen sulfate, PEG400In one or more, preferably triethylbenzyl ammonium bromide.
5. preparation method according to any one of claim 1 to 4, it is characterised in that in the step (3), the preparation method of the TMSIM N imidazole -4- morpholine Methanamides is：By N, after N '-carbonyl dimidazoles are dissolved in dichloromethane, the dichloromethane solution of Deca morpholine, reaction generate TMSIM N imidazole -4- morpholine Methanamides；
Preferably, the preparation method of the TMSIM N imidazole -4- morpholine Methanamides is：By N, after N '-carbonyl dimidazoles are dissolved in dichloromethane, the dichloromethane solution of Deca morpholine stirs 6～6.5h, and water washing, dichloromethane extraction, anhydrous sodium sulfate drying obtain TMSIM N imidazole -4- morpholine Methanamides；
Preferably, the N, N '-carbonyl dimidazoles are 1: 1 with the mol ratio of morpholine.
6. preparation method according to any one of claim 1 to 5, it is characterised in that the step (3) is：Ethylenediamine is dissolved in dichloromethane, the dichloromethane solution of Deca TMSIM N imidazole -4- morpholine Methanamides is warming up to backflow, decompression, temperature control are extremely less than 10 DEG C, the methanol solution of Deca oxalic acid, filter, concentration obtains N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid；
Preferably, the step (3) is：Ethylenediamine is dissolved in dichloromethane, stirring, the dichloromethane solution of Deca TMSIM N imidazole -4- morpholine Methanamides, it is warming up to backflow, 34～38h of reaction, decompression adds dichloromethane after steaming dichloromethane and remaining ethylenediamine, continuing vacuum distillation to without fraction, concentrated residues thing being dissolved using methanol, temperature control is to less than 10 DEG C, the methanol solution of Deca oxalic acid, until when pH value is 4～5, filtering, concentration, ethyl acetate crystallization is added, N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid is obtained；
Preferably, in the step (3), the TMSIM N imidazole -4- morpholines Methanamide is 1: 6 with the mol ratio of the ethylenediamine
7. preparation method according to any one of claim 1 to 6, it is characterised in that the step (4) is：N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid is dissolved in into water, Deca sodium hydroxide solution at 43～47 DEG C is filtered, concentration obtains N- shown in formula IV (2- amino-ethyls) -4- morpholino amides；
Preferably, the step (4) is：N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid is dissolved in into water, 40% sodium hydroxide solution of Deca at 43～47 DEG C, pH to 10～11.5 is adjusted, 20～30min is stirred, is filtered, concentration, acetone solution is added, anhydrous sodium sulfate drying is added, is filtered, concentration, obtains N- shown in formula IV (2- amino-ethyls) -4- morpholino amides.
8. preparation method according to any one of claim 1 to 7, it is characterised in that the step (5) is：N- shown in formula IV (2- amino-ethyls) -4- morpholino amides are dissolved in water-Isopropanol Solvent, at 40～60 DEG C, 4S- (2 shown in Deca Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester aqueous isopropanol, react 4～6h, obtain Landiolol shown in Formula V；Saturated ammonium chloride solution is added in Landiolol shown in Formula V, it is 4.5～5 that less than 10 DEG C Deca hydrochloric acid make the pH of system, is dried, and concentration obtains hydrochloride landiolol shown in Formula IV；
Preferably, the step (5) is：N- shown in formula IV (2- amino-ethyls) -4- morpholino amides are dissolved in water-Isopropanol Solvent, at 40～60 DEG C, 4S- (2 shown in Deca Formula II, 2- dimethyl -1,3- dioxolanes -4- bases)-(4- (2S, 3- expoxy propane) phenyl) propyl ester aqueous isopropanol, 4～6h of reaction, filter, concentration, saturated nacl aqueous solution is added to complete molten, extraction, washing, is dried, and filters, concentration, ethyl acetate dissolving is added, is decolourized, is obtained Landiolol shown in Formula V；Saturated ammonium chloride solution is added in Landiolol shown in Formula V, point liquid, it is 4.5～5 that less than 10 DEG C Deca 0.1～0.3N hydrochloric acid make the pH of system, ammonium chloride is added to saturation, add ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, add ethyl acetate, fluffy solid is separated out, is filtered, rinsed, vacuum drying, obtains hydrochloride landiolol shown in Formula IV；
Preferably, in the step (5), 4S- (2 shown in the Formula II, 2- dimethyl -1,3- dioxolanes -4- bases) mol ratio of-(4- (2S, 3- expoxy propane) phenyl) propyl ester and N- shown in formula IV (2- amino-ethyls) -4- morpholino amides is 1: 2～2.5；Preferably 1: 2.5；
Preferably, in the step (5), in the water-Isopropanol Solvent, the volume ratio of the water and isopropanol is 1: 5～6；Preferably 1: 6.
9. preparation method according to any one of claim 1 to 8, it is characterised in that the preparation method is comprised the following steps：
(1) under 0～25 DEG C and nitrogen protection, acetone and S- (+) - epoxychloropropane, stirring are added; -5～5 DEG C of ice salt bath temperature control; Deca boron trifluoride diethyl etherate under normal pressure, stirring are warming up to 40～45 DEG C and react 3～6.5 hours; it is cooled to room temperature; saturated sodium bicarbonate is washed, and is collected supernatant, is obtained (2; 2- dimethyl -1,3- dioxolanes -4S) methyl chloride；
Under room temperature, the para hydroxybenzene propanoic acid that mol ratio is 1: 0.98: 1.5: 0.1 is added in DMSO, potassium hydroxide, Anhydrous potassium carbonate, tetra-n-butyl ammonium bromide, it is warming up to 115～120 DEG C, stirring, Deca obtained above (2, 2- dimethyl -1, 3- dioxolanes -4S) methyl chloride, under TLC monitoring, 7～8h of reaction, the use of volume ratio is that 5～6: 1 petroleum ether and the mixed solution of ethyl acetate are extracted 3 times, combining extraction liquid, saturated sodium bicarbonate solution is used successively, saturated nacl aqueous solution is washed twice, Jing anhydrous sodium sulfate dryings, it is concentrated under reduced pressure to give 4S- (2 shown in Formulas I, 2- dimethyl -1, 3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester crude product；Volume ratio is added into obtained above crude product with the mixed solution of ethyl acetate for 5: 1 petroleum ether, rising temperature for dissolving, add activated carbon, decolourize, filter, crystallization, vacuum drying, obtain 4S- shown in Formulas I (2,2- dimethyl -1,3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester；Wherein, the mol ratio of the para hydroxybenzene propanoic acid, potassium hydroxide, Anhydrous potassium carbonate, phase transfer catalyst and (2,2- dimethyl -1,3- dioxolanes -4S) methyl chloride is 1: 0.98: 1.5: 0.1: 2；
(2) take 4S- (2 shown in the Formulas I that mol ratio is 1: 5: 2: 0.05，2- dimethyl -1，3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester、Anhydrous potassium carbonate、Triethylbenzyl ammonium bromide and acetone，By 4S- (2 shown in Formulas I，2- dimethyl -1，3- dioxolanes -4- bases) -3- (4- hydroxy phenyls) propyl ester、Anhydrous potassium carbonate、Triethylbenzyl ammonium bromide is dissolved in acetone，It is warming up to backflow，Stirring 0.5h，Deca R- (-)-epoxychloropropane，6～6.5h of reaction，Filter，Concentration，Dissolved with ethyl acetate afterwards，2 times are washed with saturated sodium bicarbonate solution and saturated nacl aqueous solution successively，Anhydrous sodium sulfate drying，Filter，Decompression，Concentration，Obtain 4S- (2 shown in Formula II，2- dimethyl -1，3- dioxolanes -4- bases)-(4- (2S，V- expoxy propane) phenyl) propyl ester；
(3) by N, N '-carbonyl dimidazoles are dissolved in dichloromethane, stirring, the dichloromethane solution of constant pressure dropping morpholine, wherein, the N, N '-carbonyl dimidazoles are 1: 1 with the mol ratio of morpholine, and 6～6.5h is stirred at room temperature after being added dropwise to complete, Jing water washings, dichloromethane is extracted, and anhydrous sodium sulfate drying obtains TMSIM N imidazole -4- morpholine Methanamides；Under room temperature, ethylenediamine is dissolved in dichloromethane solution, stirring, the dichloromethane solution of constant pressure dropping TMSIM N imidazole -4- morpholine Methanamides, wherein described TMSIM N imidazole -4- morpholines Methanamide is 1: 6 with the mol ratio of the ethylenediamine, it is warming up to backflow, 34～38h of reaction, decompression adds dichloromethane after steaming dichloromethane and remaining ethylenediamine, continuation vacuum distillation is to without fraction, concentrated residues thing is dissolved using methanol, ice bath temperature control is less than 10 DEG C, it is slowly added dropwise the methanol solution of oxalic acid, until pH value stops Deca when being 4～5, filter, concentration, add ethyl acetate crystallization, obtain N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid；
(4) N- shown in formula III (2- amino-ethyls) -4- morpholine Methanamide oxalic acid is dissolved in into water, the sodium hydroxide solution of Deca 40% at 43～47 DEG C, pH to 10～11.5 is adjusted, insulation continues 20～30min of stirring, filter, concentration, adds acetone solution, anhydrous sodium sulfate drying in concentrate, filter, be concentrated to give N- shown in formula IV (2- amino-ethyls) -4- morpholino amides；
(5) N- shown in formula IV (2- amino-ethyls) -4- morpholino amides are dissolved in water-Isopropanol Solvent that volume ratio is 1: 6，Under conditions of 40～60 DEG C，4S- (2 shown in Deca Formula II，2- dimethyl -1，3- dioxolanes -4- bases)-(4- (2S，3- expoxy propane) phenyl) propyl ester aqueous isopropanol，4S- (2 wherein shown in Formula II，2- dimethyl -1，3- dioxolanes -4- bases)-(4- (2S，3- expoxy propane) phenyl) mol ratio of propyl ester and N- shown in formula IV (2- amino-ethyls) -4- morpholino amides is 1: 2.5，Continue 4～6h of reaction after completion of dropping，Filter，Concentration，Saturated nacl aqueous solution is added to complete molten，Jing ethyl acetate is extracted，Jing saturated nacl aqueous solutions are washed and anhydrous sodium sulfate drying，Filter，Concentration，Ethyl acetate dissolving is added afterwards，Add activated carbon，It is heated to reflux decolouring 5min，Filtering and concentrating，Obtain Landiolol shown in Formula V；Landiolol shown in Formula V is added in saturated ammonium chloride solution, 1h is stood, point liquid, after removing oil reservoir, it is 4.5～5 that residual body is tied up to less than 10 DEG C 0.1～0.3N of Deca hydrochloric acid to pH, adds ammonium chloride to saturation, adds ethyl acetate to extract 3 times, combining extraction liquid, Jing anhydrous sodium sulfate dryings, concentration, after add ethyl acetate, be heated to reflux, filter, cooling, separates out solid, filters, ethyl acetate rinse three times, vacuum drying, obtains hydrochloride landiolol shown in Formula IV.
CN201510690951.0A 2015-10-23 2015-10-23 Preparation method of landiolol hydrochloride Pending CN106608863A (en)

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CN108752308A (en) * 2018-08-06 2018-11-06 江苏恒瑞医药股份有限公司 A kind of preparation method of hydrochloride landiolol
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CN113480438B (en) * 2021-07-19 2024-05-14 山东安弘制药有限公司 Preparation method of esmolol hydrochloride
CN114195754A (en) * 2021-12-28 2022-03-18 苏州昊帆生物股份有限公司 R-glycerol acetonide intermediate and preparation method thereof
CN114031601A (en) * 2022-01-12 2022-02-11 南京桦冠生物技术有限公司 Preparation method of landiolol hydrochloride
CN114031601B (en) * 2022-01-12 2022-03-18 南京桦冠生物技术有限公司 Preparation method of landiolol hydrochloride
CN118754867A (en) * 2024-09-05 2024-10-11 伊诺药物研究(南京)有限公司 Synthesis method of landiolol hydrochloride

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