CN117865927A - Preparation method of landiolol hydrochloride and intermediate thereof - Google Patents
Preparation method of landiolol hydrochloride and intermediate thereof Download PDFInfo
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- CN117865927A CN117865927A CN202311601573.5A CN202311601573A CN117865927A CN 117865927 A CN117865927 A CN 117865927A CN 202311601573 A CN202311601573 A CN 202311601573A CN 117865927 A CN117865927 A CN 117865927A
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- landiolol
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- hydrochloride
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- WMDSZGFJQKSLLH-RBBKRZOGSA-N landiolol Chemical compound O1C(C)(C)OC[C@H]1COC(=O)CCC(C=C1)=CC=C1OC[C@@H](O)CNCCNC(=O)N1CCOCC1 WMDSZGFJQKSLLH-RBBKRZOGSA-N 0.000 title claims abstract description 91
- 229950005241 landiolol Drugs 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title claims abstract description 62
- FMVSRINQKOORMK-UHFFFAOYSA-N n-(2-aminoethyl)morpholine-4-carboxamide;oxalic acid Chemical compound OC(=O)C(O)=O.NCCNC(=O)N1CCOCC1 FMVSRINQKOORMK-UHFFFAOYSA-N 0.000 title description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940125782 compound 2 Drugs 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 239000012046 mixed solvent Substances 0.000 claims abstract description 14
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 239000005453 ketone based solvent Substances 0.000 claims description 5
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- 238000005755 formation reaction Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000003759 ester based solvent Substances 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 4
- 239000006227 byproduct Substances 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000005809 transesterification reaction Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 208000001871 Tachycardia Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 206010003119 arrhythmia Diseases 0.000 description 3
- 230000006793 arrhythmia Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 230000006794 tachycardia Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- 206010003662 Atrial flutter Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- DLPGJHSONYLBKP-IKGOIYPNSA-N Landiolol hydrochloride Chemical compound Cl.O1C(C)(C)OC[C@H]1COC(=O)CCC(C=C1)=CC=C1OC[C@@H](O)CNCCNC(=O)N1CCOCC1 DLPGJHSONYLBKP-IKGOIYPNSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000007888 Sinus Tachycardia Diseases 0.000 description 2
- -1 [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methyl Chemical group 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000009533 lab test Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- MRQFCJJRLCSCFG-UHFFFAOYSA-N dimethylazanium;formate Chemical compound C[NH2+]C.[O-]C=O MRQFCJJRLCSCFG-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- UMIHKUQVXHVFDJ-UHFFFAOYSA-N n-(2-aminoethyl)morpholine-4-carboxamide Chemical compound NCCNC(=O)N1CCOCC1 UMIHKUQVXHVFDJ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of landiolol hydrochloride and an intermediate thereof. The invention discloses a preparation method of landiolol I, which comprises the following steps: and (3) performing nucleophilic substitution reaction on the compound 2 and SM4 in an organic solvent to obtain the landiolol I, wherein the organic solvent is a mixed solvent formed by one or two of tetrahydrofuran, dioxane and isopropanol. The preparation process of the invention has simple operation, less byproducts, high reaction yield and high purity of the prepared product, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of landiolol hydrochloride and an intermediate thereof.
Background
Landiolol hydrochloride (Landiolol hydrochloride, CAS: 144481-98-1), trade name Onoact, chemical Chinese name: [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methyl 3- [4- [ (2S) -2-hydroxy-3- [2- (morpholin-4-carboxamido) ethylamino ] propoxy ] phenyl ] propanoate hydrochloride, in particular the chemical structure shown below:
landolt hydrochloride is an ultrashort high-selectivity beta 1 receptor blocker, mainly antagonizes beta 1 receptors existing in the heart, and improves tachycardia arrhythmia by inhibiting heart beat increase caused by catecholamine. Developed by the japanese small field pharmaceutical industry company, the first market in japan in 9 months 2002, is clinically used mainly for the urgent treatment of tachycardia arrhythmia (including atrial fibrillation, atrial flutter, sinus tachycardia) at the time of surgery, and for the urgent treatment of tachycardia arrhythmia (including atrial flutter, atrial fibrillation, sinus tachycardia) under dynamic monitoring of the postoperative cycle.
The literature (chem. Pharm. Bull.40 (6) 1462-1469 (1992) reports a process for the preparation of landiolol hydrochloride, the route being as follows:
in the synthetic route, column chromatography purification is carried out in each step of technological process, the yield is low, the operation is complicated, the method is not suitable for industrial production, the product is unstable in the column chromatography process, and a qualified sample with high purity (the purity is more than or equal to 99 percent and the maximum single impurity is less than or equal to 0.10 percent) is difficult to obtain. And the key reaction step for synthesizing landiolol (compound I), the compound 2 and SM4 are both carried out in a solvent isopropanol or isopropanol/water system. However, alcohol solvents, particularly alkyl alcohol, are adopted, transesterification reaction is easy to occur in the reaction process, more transesterification impurities are generated, the target conversion rate is only 45% -55%, the process purification difficulty is high, and the final yield is only 15% -25%.
The transesterified impurities are represented by formula III (R is selected from alkyl groups such as methyl, isopropyl, etc.):
CN104003973a discloses that the compound landiolol is very susceptible to transesterification with alcoholic solvents under alkaline conditions, thereby risking the safety and effectiveness of the drug. CN101012217a discloses that landiolol is highly decomposed in methanol to produce by-products (formula IV), and chooses to avoid using methanol in the process, but still uses isopropanol/water as a reaction solvent for the ring-opening reaction in its synthesis process, or cannot avoid inhibiting the production of isopropyl transesterification impurity (formula V). Because isopropyl ester exchange impurity is larger, the structure of the impurity is similar to that of landiolol, if the impurity is controlled below 0.10% in the bulk drug, the landiolol hydrochloride finished product of related substances meeting the pharmaceutical quality requirement can be obtained through repeated recrystallization, the operation is not complicated, the yield is greatly reduced, the yield is lower, and the cost is higher.
CN104003973a discloses that in the process of synthesizing landiolol, an aqueous solution of sodium hydroxide is used, and N, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide are used as reaction solvents, and the yield is only 45% -55%. However, formamide solvents tend to decompose in aqueous sodium hydroxide solutions, for example, with N, N-dimethylformamide, a series of by-products such as dimethylamine, dimethylamine formate, etc. are decomposed. The dimethyl sulfoxide is also poor in stability to alkali, is easy to decompose and disproportionate to generate thioether, and in addition, the dimethyl sulfoxide has oxidizing property, can influence easily-oxidized groups such as hydroxyl and amino of the landiolol, and generates oxidized impurities such as ketone, oxynitride and other impurities, so that the product quality is influenced.
In addition, CN102232930a discloses that landiolol is susceptible to hydrolysis and isomerization under acidic or basic conditions, and in particular that ester hydrolysis reactions under basic conditions are susceptible to occur, yielding hydrolyzed impurities represented by formula VI, thereby affecting product quality and yield.
In the prior art CN108752308B, dioxane is used as a solvent in the process of synthesizing landiolol, and transesterification impurities are avoided, but in the reaction process, the reaction is carried out under the reaction solvent, the byproducts are more, the target conversion rate is still lower, the process purification difficulty is higher, the final yield is lower (the step yield is 20-25%), and a high-purity qualified sample (the purity is more than or equal to 99% and the maximum single impurity is less than or equal to 0.10%) is difficult to obtain.
Therefore, there is an urgent need to find a synthesis process of landiolol hydrochloride, which has high target conversion rate, few byproducts, high purity of the prepared product, and suitability for industrial production.
Disclosure of Invention
The invention aims to solve the technical problems of more reaction byproducts, high purification difficulty, low yield, low purity of prepared products, high production and raw material cost and the like in the prior art in the synthesis method of the landiolol hydrochloride, and provides a preparation method of the landiolol hydrochloride and an intermediate thereof. The preparation process of the invention has simple operation, less byproducts, high reaction yield and high purity of the prepared product, and is suitable for industrial production.
The invention provides a preparation method of landiolol I, which comprises the following steps: performing nucleophilic substitution reaction on the compound 2 and SM4 in an organic solvent to obtain landiolol I, wherein the organic solvent is a mixed solvent formed by tetrahydrofuran, dioxane and/or isopropanol;
the preparation method of the landiolol I can adopt a conventional method of nucleophilic substitution reaction in the field, and the following reaction conditions are particularly preferred in the invention:
in the preparation method of the landiolol I, the organic solvent is preferably a mixed solvent of tetrahydrofuran and dioxane or a mixed solvent of tetrahydrofuran and isopropanol. When a mixed solvent of tetrahydrofuran and dioxane is used, the volume ratio of the tetrahydrofuran to the dioxane is preferably (1:5) to (20:1), more preferably (1:1) to (10:1), for example, 5:1.
When a mixed solvent of tetrahydrofuran and isopropyl alcohol is used, the volume ratio of the tetrahydrofuran to the isopropyl alcohol is preferably (1:5) to (20:1), more preferably (1:1) to (10:1), for example, 5:1.
In the preparation method of the landiolol I, the volume mass ratio of the organic solvent to the compound 2 is preferably 1 mL/g-30 mL/g, more preferably 2 mL/g-10 mL/g, for example 3mL/g.
In the process for preparing landiolol I, the molar ratio of SM4 to compound 2 is preferably 1 to 5, more preferably 1 to 3, for example 2.
In the process for preparing landiolol 1, the temperature of the nucleophilic substitution reaction is preferably 0 to 100 ℃, more preferably 20 to 60 ℃, and even more preferably 40 to 50 ℃.
In the preparation method of landiolol I, the progress of the nucleophilic substitution reaction can be detected by a method conventional in the art (e.g., HPLC, TLC or NMR), and the disappearance of the compound 2 is generally regarded as the end point of the reaction, and the nucleophilic substitution reaction is preferably carried out for 10 hours to 30 hours, more preferably 15 hours to 24 hours, for example, 20 hours.
The preparation method of the landiolol I preferably comprises the following post-treatment steps: after the reaction is finished, the solvent is removed, and the reaction is directly used for the next reaction for preparing the landiolol hydrochloride without further purification.
The invention also provides a preparation method of the landiolol hydrochloride, which comprises the following steps: in a solvent, carrying out salt formation reaction on the prepared landiolol I and ammonium chloride to obtain the landiolol II hydrochloride;
conventional methods of such salification reactions in the art can be employed in the preparation of landiolol II hydrochloride, with the following reaction conditions being particularly preferred in the present invention:
in the preparation method of the landiolol II hydrochloride, the solvent is preferably a mixed solvent of water and an ester solvent, and the ester solvent is preferably ethyl acetate.
In the preparation method of the landiolol II hydrochloride, the volume-mass ratio of the solvent to the compound I is preferably 1 mL/g-30 mL/g, more preferably 3 mL/g-10 mL/g, for example 6.8mL/g.
In the process for the preparation of landiolol II hydrochloride, the molar ratio of said ammonium chloride to said compound I is preferably from 1 to 50, more preferably from 10 to 30, for example 20.
In the process for preparing landiolol II hydrochloride, the temperature of the salifying reaction is preferably 0 to 40 ℃, more preferably 5 to 35 ℃, and even more preferably 20 to 30 ℃.
In the preparation method of landiolol II hydrochloride, the progress of the salt formation reaction can be detected by a method conventional in the art (e.g., HPLC, TLC or NMR), and the disappearance of the compound I is generally taken as the end point of the reaction, and the time of the salt formation reaction is preferably 1 minute to 5 hours, more preferably 10 minutes to 1 hour, for example 30 minutes or 1 hour.
The preparation method of the landiolol II hydrochloride preferably comprises the following post-treatment steps: after the reaction is finished, removing the solvent, and recrystallizing to obtain the purified landiolol hydrochloride.
The recrystallization preferably employs the following steps: and (3) cooling and crystallizing a solution formed by the crude product of the landiolol hydrochloride and the organic solvent to obtain the purified landiolol hydrochloride. The organic solvent used for the recrystallization is selected from one or more of ether solvents, ester solvents and ketone solvents, preferably ketone solvents. The ketone solvent is preferably acetone.
The temperature of the recrystallization is preferably 40 to 60 ℃, more preferably 45 to 55 ℃. The crystallization temperature is preferably 0 to 20 ℃, and more preferably 5 to 15 ℃.
The preparation method of the landiolol hydrochloride preferably adopts the following route:
the invention has the positive progress effects that: the preparation method has the advantages of few byproducts, high conversion rate, simple post-treatment operation, high purity of the prepared product (chemical purity and chiral purity are both more than 99.50 percent and the maximum single impurity is less than or equal to 0.10 percent), and high total molar yield of more than 80 percent; the chemical purity of the landiolol hydrochloride can be more than 99.80%, other single impurities are less than 0.10%, the chiral purity reaches 99.98%, the grade of bulk drug (API) is achieved, and the method is suitable for industrial production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention.
Related substances and isomer detection conditions:
(1) related substance detection
Laboratory test equipment:
chromatographic column: octadecylsilane chemically bonded silica gel as filler
Detection wavelength: 223nm
Flow rate: 1.0ml/min
Mobile phase a:0.02mol/L sodium dihydrogen phosphate solution
Mobile phase B: acetonitrile
Elution gradients were performed as follows:
| time (minutes) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 93 | 7 |
| 5 | 93 | 7 |
| 25 | 68 | 32 |
| 43 | 45 | 55 |
| 45 | 93 | 7 |
| 60 | 93 | 7 |
(2) Isomer impurity detection
Laboratory test equipment:
chromatographic column: polysaccharide derivative normal phase coating chiral chromatographic column
Detection wavelength: 220nm
Flow rate: 1.0ml/min
Mobile phase: n-hexane-isopropyl alcohol-diethylamine (80:20:0.1)
Run time: 60 minutes
The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1 preparation of Compound 2 (4- [ (2S) -3-Cyclopropoxy ] phenylpropionic acid [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methyl ester
500g of compound 1, 5L of acetone and 620g of potassium carbonate are added into a reaction bottle at room temperature, 600g of compound SM3 is added for nitrogen replacement, the temperature is raised to 60-65 ℃ for 16 hours of reaction, HPLC monitors that the raw materials are completely converted, the temperature is reduced to room temperature, 2.5L of ethyl acetate and 1.5L of saturated sodium bicarbonate aqueous solution are added, stirring and filtering are carried out, the filtrate is kept stand for separating liquid, the aqueous phase is extracted once by 1L of ethyl acetate, the organic phase is combined, then the organic phase is dried by anhydrous sodium sulfate, filtering is carried out, and the obtained product is directly used for the next reaction under the reduced pressure at 45 ℃ to obtain 590g of compound 2 oily matter with the purity of 97.06 percent by HPLC.
EXAMPLE 2 preparation of Compound SM4 (N- (2-aminoethyl) -4-morpholinecarboxamide)
1Kg of N- (2-aminoethyl) -4-morpholinecarboxamide oxalate, 1Kg of anhydrous sodium sulfate, 380g of sodium hydroxide and 7L of dichloromethane are added into a reaction bottle, the temperature is raised to 35-45 ℃, stirring is carried out for 16h, filtration is carried out, a filter cake is washed by 2L of dichloromethane, and the filtrate is concentrated under reduced pressure at 35+/-5 ℃ to obtain 640g of off-white solid SM4, the purity of HPLC is 99.3%, and the yield is 97.3%.
EXAMPLE 3 preparation of landiolol II hydrochloride ([ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methyl 3- [4- [ (2S) -2-hydroxy-3- [2- (morpholine-4-carboxamido) ethylamino ] propoxy ] phenyl ] propanoate hydrochloride
610g (1.81 mol) of Compound 2, 6L of tetrahydrofuran and 1.2L of dioxane were added to the reaction flask at room temperature (20 ℃ C. To 30 ℃ C.), and the solution was stirred. The free 640g (3.69 mol) of SM4 was added to the reaction mixture in portions, the solution was stirred and then heated to 40-50℃for 20 hours. The reaction was controlled by HPLC and starting compound 2 was reacted completely. The reaction solution was concentrated under reduced pressure until substantially no solvent was distilled off, to obtain 876g of a concentrate. Adding 3L of ethyl acetate and 3L of water into the concentrate, stirring for 30min, standing for separating, extracting and washing the water phase with 3L of ethyl acetate once, combining the organic phases, extracting the organic phases with 3L of saturated ammonium chloride aqueous solution for 2 times, stirring for 30min each time, standing for separating, drying the organic phases with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure at 35+/-5 ℃ to obtain an off-white solid. Adding 1.8L of acetone into the solid, heating to 45-55 ℃, dissolving the system, removing the heat, cooling to room temperature of 5-15 ℃, filtering, drying the filter cake at 40+/-5 ℃ to obtain 791g (1.45 mol) of white solid powder, wherein the HPLC purity is 99.91%, the yield is 80.1%, and the chiral HPLC purity is 99.98%.
LCMS：m/z＝510.3[M+H] + 。 1 H-NMR (400 MHz, deuterated DMSO): delta 7.10 (2)
H，d)，6.84(2H，d)，5.09(1H，t)，4.38(1H，q)，4.25(1H，dd)，4.18(1H，dd)，4.05(1H，m)，4.01(1H，dd)，3.93(1H，dd)，3.90(1H，dd)，3.60(1H，dd)，3.60(4H，t)，3.33(2H，q)，3.30(4H，t)，2.85(2H，t)，2.80(1H，dd)，2.82(2H，t)，2.79(1H，dd)，2.65(2H，t)，1.43(3H，s)，1.35(3H，s)。
Example 4 comparison of reactions with different solvents
In order to compare the influence of different reaction solvents on the preparation reaction of the landiolol II hydrochloride, typical experimental operation is adopted to compare the reaction conditions of the process for obtaining the landiolol hydrochloride.
Remarks: the purity was checked by HPLC detection of the relevant substances.
The structures of the formulas IV, V and the compound 2 are shown as follows:
experimental data show that tetrahydrofuran is used as a solvent for reaction, so that byproducts are few, but the reaction rate is particularly slow, and the raw materials cannot be thoroughly converted. The dioxane is used as a solvent, the reaction rate is high, but the byproducts are obviously more, the conversion rate is low, and the yield is low.
Example 5 tetrahydrofuran was prepared as in example 3: dioxane = 5:1 (volume ratio) as reaction solvent the reaction conditions for the preparation of the compound of formula VII in different batches are shown in table 2:
Claims (10)
1. the preparation method of the landiolol I is characterized by comprising the following steps of: performing nucleophilic substitution reaction on the compound 2 and SM4 in an organic solvent to obtain landiolol I, wherein the organic solvent is a mixed solvent formed by tetrahydrofuran, dioxane and/or isopropanol;
2. a process for the preparation of landiolol I according to claim 1, characterized in that:
the organic solvent is one or two of tetrahydrofuran, dioxane and isopropanol, and the mixed solvent is one or two of tetrahydrofuran, dioxane and isopropanol.
3. A process for the preparation of landiolol I according to claim 2, characterized in that:
in the preparation method of the landiolol I, when a mixed solvent of tetrahydrofuran and dioxane is adopted,
the volume ratio of the tetrahydrofuran to the dioxane is (1:5) - (20:1);
and/or the number of the groups of groups,
when a mixed solvent of tetrahydrofuran and isopropanol is used, the volume ratio of the tetrahydrofuran to the isopropanol is (1:5) - (20:1).
4. A process for the preparation of landiolol I as claimed in claim 3, characterized in that:
in the preparation method of the landiolol I, when a mixed solvent of tetrahydrofuran and dioxane is adopted,
the volume ratio of the tetrahydrofuran to the dioxane is (1:1) - (10:1);
and/or the number of the groups of groups,
when a mixed solvent of tetrahydrofuran and isopropanol is used, the volume ratio of the tetrahydrofuran to the isopropanol is (1:1) - (10:1).
5. A process for the preparation of landiolol I according to claim 1, characterized in that:
in the preparation method of the landiolol I, the volume-mass ratio of the organic solvent to the compound 2 is 1-30 mL/g;
and/or the number of the groups of groups,
in the preparation method of the landiolol I, the molar ratio of the SM4 to the compound 2 is 1-5;
and/or the number of the groups of groups,
in the preparation method of the landiolol 1, the temperature of the nucleophilic substitution reaction is 0-100 ℃;
and/or the number of the groups of groups,
in the preparation method of the landiolol I, the nucleophilic substitution reaction time is 10-30 hours;
and/or the number of the groups of groups,
the preparation method of the landiolol I comprises the following post-treatment steps: after the reaction, the solvent was removed and used directly for the reaction for preparing landiolol hydrochloride without further purification.
6. A process for the preparation of landiolol I according to claim 5, characterized in that:
in the preparation method of the landiolol I, the volume-mass ratio of the organic solvent to the compound 2 is 2-10 mL/g;
and/or the number of the groups of groups,
in the preparation method of the landiolol I, the molar ratio of the SM4 to the compound 2 is 1-3;
and/or the number of the groups of groups,
in the preparation method of the landiolol 1, the temperature of the nucleophilic substitution reaction is 20-60 ℃;
and/or the number of the groups of groups,
in the preparation method of the landiolol I, the nucleophilic substitution reaction time is 15-24 hours.
7. The preparation method of the landiolol hydrochloride is characterized by comprising the following steps of: in a solvent, carrying out salt formation reaction on the landiolol I prepared by the preparation method of the landiolol I according to any one of claims 1 to 6 and ammonium chloride to obtain the landiolol II hydrochloride;
8. the method for preparing landiolol II hydrochloride according to claim 7, wherein:
in the preparation method of the landiolol II hydrochloride, the solvent is a mixed solvent of water and an ester solvent;
and/or the number of the groups of groups,
in the preparation method of the landiolol II hydrochloride, the volume-mass ratio of the solvent to the compound I is 1-30 mL/g;
and/or the number of the groups of groups,
in the preparation method of the landiolol II hydrochloride, the molar ratio of the ammonium chloride to the compound I is 1-50;
and/or the number of the groups of groups,
in the preparation method of the landiolol II hydrochloride, the temperature of the salifying reaction is 0-40 ℃;
and/or the number of the groups of groups,
in the preparation method of the landiolol II hydrochloride, the salifying reaction time is 1 minute to 5 hours;
and/or the number of the groups of groups,
the preparation method of the landiolol II hydrochloride comprises the following post-treatment steps: after the reaction is finished, removing the solvent, and recrystallizing to obtain the purified landiolol hydrochloride.
9. A process for the preparation of landiolol I according to claim 1, characterized in that:
in the preparation method of the landiolol II hydrochloride, the ester solvent is ethyl acetate;
and/or the number of the groups of groups,
in the preparation method of the landiolol II hydrochloride, the volume-mass ratio of the solvent to the compound I is 3-10 mL/g;
and/or the number of the groups of groups,
in the preparation method of the landiolol II hydrochloride, the molar ratio of the ammonium chloride to the compound I is 10-30;
and/or the number of the groups of groups,
in the preparation method of the landiolol II hydrochloride, the temperature of the salifying reaction is 5-35 ℃;
and/or the number of the groups of groups,
in the preparation method of the landiolol II hydrochloride, the salifying reaction time is 10 minutes to 1 hour;
and/or the number of the groups of groups,
the preparation method of the landiolol II hydrochloride preferably comprises the following post-treatment steps: after the reaction is finished, removing the solvent, and recrystallizing to obtain the purified landiolol hydrochloride.
10. A process for the preparation of landiolol I according to claim 1, characterized in that: the recrystallization adopts the following steps: cooling and crystallizing a solution formed by the crude product of the landiolol hydrochloride and the organic solvent to obtain purified landiolol hydrochloride;
the organic solvent adopted by the recrystallization is preferably one or more of ether solvents, ester solvents and ketone solvents, and further preferably ketone solvents, wherein the ketone solvents are preferably acetone;
the temperature of the recrystallization is preferably 40-60 ℃, and more preferably 45-55 ℃;
the crystallization temperature is preferably 0 to 20 ℃, and more preferably 5 to 15 ℃.
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