CN114539077B - Synthesis method of levosalbutamol hydrochloride - Google Patents
Synthesis method of levosalbutamol hydrochloride Download PDFInfo
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- OWNWYCOLFIFTLK-YDALLXLXSA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;hydron;chloride Chemical compound Cl.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 OWNWYCOLFIFTLK-YDALLXLXSA-N 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 40
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4h-1,3-dioxine Chemical compound C1OCC=CO1 UCZQXJKDCHCTAI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 22
- -1 [1,3] dioxin-6-yl Chemical group 0.000 claims abstract description 18
- 229940087642 levalbuterol hydrochloride Drugs 0.000 claims abstract description 17
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims abstract description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 15
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000005977 Ethylene Substances 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims abstract description 8
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012425 OXONE® Substances 0.000 claims abstract description 6
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 claims abstract description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 4
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000018044 dehydration Effects 0.000 claims abstract description 3
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 3
- 239000012467 final product Substances 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000005915 ammonolysis reaction Methods 0.000 claims description 4
- 238000006735 epoxidation reaction Methods 0.000 claims description 4
- 239000004408 titanium dioxide Substances 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 3
- 230000035484 reaction time Effects 0.000 claims 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000010494 dissociation reaction Methods 0.000 abstract 1
- 230000005593 dissociations Effects 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 14
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 description 8
- 229950008204 levosalbutamol Drugs 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000005091 airway smooth muscle Anatomy 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000004269 oxiran-2-yl group Chemical group [H]C1([H])OC1([H])* 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- 229940121786 Beta 2 adrenoreceptor agonist Drugs 0.000 description 1
- 102100039705 Beta-2 adrenergic receptor Human genes 0.000 description 1
- 101710152983 Beta-2 adrenergic receptor Proteins 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
Abstract
The invention discloses a method for synthesizing levalbuterol hydrochloride, which takes 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxin-6-yl) ethanol as a starting material, and synthesizes 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxin through dehydration. And then epoxidizing under the combined action of 1,2:4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-diketone-2, 6-pyranose, potassium monopersulfate and potassium hydroxide to obtain (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin. Then the mixture is condensed with tert-butylamine, and the product is salified with D- (+) -malic acid to obtain (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate. Finally, ammonia water is used for dissociation, and the ammonia water reacts with hydrogen chloride ethanol to obtain the final product of the levalbuterol hydrochloride. The method has the advantages of simple and novel route, convenient operation, total yield of 85-90%, undetected isomer content and suitability for large-scale production.
Description
Technical field:
the invention belongs to the field of medicinal chemistry, and particularly relates to a synthesis method of levalbuterol hydrochloride.
The background technology is as follows:
levalbuterol is a β2-adrenoreceptor agonist, which primarily agonizes β2-adrenoreceptors on airway smooth muscle, resulting in activation of adenylate cyclase, increasing intracellular concentration of adenosine 3',5' -cyclic phosphate (cAMP), and thus dilating airway smooth muscle. In vitro studies have shown that the affinity of the levorotatory form of albuterol for the beta receptor is 100 times stronger than that of the dextrorotatory form, and that the physiological effect of the racemate is mostly provided by the levorotatory form. Meanwhile, experiments also prove that the relaxation action strength of the low-dose levalbuterol is equivalent to that of the racemate. Compared with racemate, the levosalbutamol has quick effect, high curative effect and small side effect, so that the application of single enantiomer levosalbutamol has become a necessary trend, and the single enantiomer administration mode has attracted wide clinical attention.
The chemical name of the levalbuterol hydrochloride is (R) -alpha 1 - [ (tert-butylamino) methyl group]-4-hydroxy-1, 3-benzenedimethanol hydrochloride having the structural formula:
the most reported method for synthesizing the levalbuterol is to split and prepare the optical isomer by using the raceme albuterol. The resolution methods have complicated steps, and the biggest disadvantages are low yield (less than 50%) and high cost due to resolution loss. British patent document GB1298494a discloses first the synthesis of levalbuterol, which is carried out by crystallization resolution with D- (+) -dibenzoyltartaric acid, then ester reduction reaction, and then removal of two benzyl protecting groups, to obtain levalbuterol, the process route is as follows:
another more reported method is to obtain levalbuterol in technical scale, better yields and good optical purity by asymmetric hydrogenation reduction of ketones to chiral alcohols, e.g. China patent CN1705634A, using rhodium in combination with chiral bidentate phosphine ligands. The disadvantages are that the reagent has high toxicity and high hydrogenation risk, and the process route is as follows:
in addition, the literature on the use of asymmetric reduction methods also discloses: journal of chinese pharmaceutical chemistry, 2006, 16 (4): 222-225; tetrahedron letters, 1994, 35 (31), 5551-5554, etc. The method has the defects of high reagent toxicity, high risk coefficient and the like.
The invention aims to avoid using reagents such as metal catalysis or organoboron with larger toxicity, and the like, and constructs a chiral framework through asymmetric epoxidation, thereby realizing a novel method for preparing the levalbuterol hydrochloride economically, safely and simply.
Disclosure of Invention
The invention provides a novel synthesis process of levosalbutamol hydrochloride, and develops a novel synthesis method of a key intermediate in the synthesis process, for example, asymmetric epoxidation is used for synthesizing (R) -2, 2-dimethyl-6- (epoxy ethane-2-yl) -4H-benzo [ d ] [1,3] dioxin, the defect of using heavy metal and borane reagent with high toxicity and high-pressure hydrogenation reaction is overcome, and the method is mild in condition and simple and convenient to operate. The amplification test shows that the method is suitable for industrial amplification production and has the characteristics of high total reaction yield, high product purity and low isomer content.
The technical scheme adopted by the invention is as follows: 1) 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxin-6-yl) ethanol and titanium dioxide are taken as starting materials, and a solvent-free system is used for synthesizing 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxin through dehydration.
Then epoxidizing 2, 2-dimethyl-6-vinyl-4H-benzo [ D ] [1,3] dioxin under the combined action of 1,2:4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-dione-2, 6-pyranose (Shi's Catalyst), potassium monopersulfate (Oxone) and potassium hydroxide to obtain (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin.
(R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin and tert-butylamine react and condense in ethanol, and then form salt with D- (+) -malic acid to obtain (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate.
(R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate is subjected to hydro-ammonolysis and reacts with hydrogen chloride ethanol to prepare the levalbuterol hydrochloride.
The invention discovers a novel method for synthesizing the levosalbutamol hydrochloride, and the key intermediate is not novel for epoxidation, and the total yield is between 85 and 90 percent, which is higher than that of the prior method. The process is convenient to operate, the raw materials are economical, and the method is suitable for large-scale industrial production.
Drawings
FIG. 1 is a diagram showing the applicability of the levalbuterol hydrochloride purity detection system of example 4
FIG. 2 is a graph showing the purity of levalbuterol hydrochloride in example 4
FIG. 3 is a diagram showing the systematic applicability of the isomer content system of levalbuterol hydrochloride of example 4
FIG. 4 is a graph showing the isomer content of levalbuterol hydrochloride of example 4
Detailed Description
Example 1 preparation of 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxin
A1000 mL flask was charged with 208g (1.0 mol) of 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxin-6-yl) ethanol accurately weighed, and stirring was started. Then, 16g (0.2 mol) of titanium dioxide was slowly added, a water separator and a return pipe were installed, heating was started to an internal temperature of 120 to 130℃and stirring was carried out for 12 hours. After the reaction is finished, the temperature is reduced to below 50 ℃, the water separator is removed, the vacuum distillation device is changed, and the fraction of 120 ℃ (less than 100 Pa) is collected to obtain 180.7g of 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxin, and the yield is 95%.
Mass spectrometry: EI (m/z): 190; nuclear magnetic resonance hydrogen spectrum: 1 HNMR(400MHz，CDCl 3 )δ7.55(d，J＝4Hz，1H)，7.11(s，1H)，6.87(d，J＝4Hz，1H)，6.65～6.60(m，1H)，5.63～5.60(m，1H)，5.19～5.5(m，1H)，4.59(s，2H)，1.49(s，6H)。
EXAMPLE 2 Synthesis of (R) -2, 2-dimethyl-6- (oxiran-2-yl) -4H-benzo [ d ] [1,3] dioxin
A clean 5000mL three-necked flask was taken, 180.5g (0.95 mol) of 2, 2-dimethyl-6-vinyl-4H-benzo [ D ] [1,3] dioxin, which was the compound obtained in example 1, was added, 2000mL of acetonitrile was added for dissolution, 49.1g (0.19 mol) of 1,2:4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-dione-2, 6-pyranose was then added, 876g (1.43 mol) of potassium monopersulfate (Oxone) was added with stirring, and an appropriate amount of potassium hydroxide was then added after the addition, so that the pH of the system was kept between 10 and 11, and the stirring reaction was continued at 25℃for 8 to 12 hours. After the reaction, slowly pouring the mixture into 2000ml of prepared purified water, fully stirring the mixture for 30min, standing the mixture for layering, and collecting an organic layer. 2000ml of dichloromethane was added for extraction, the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness to give 196g of crude colorless liquid in 100% yield.
Mass spectrometry: EI (m/z): 207 (x, y); nuclear magnetic resonance hydrogen spectrum: 1 HNMR(400MHz，CDCl 3 )δ7.25(s，1H)，7.18(d，J＝4Hz，1H)，6.85(d，J＝4Hz，1H)，4.59(s，2H)，3.85～3.81(m，1H)，2.96～2.71(m，2H)，1.49(s，6H)。
example 3 preparation of (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate
A clean 5000mL three-necked flask was taken, 196g (0.95 mol) of the compound (R) -2, 2-dimethyl-6- (oxiran-2-yl) -4H-benzo [ d ] [1,3] dioxin obtained in example 2 was taken, 1000mL of ethanol was added to dissolve, 80.4g (1.1 mol) of tert-butylamine was then added, stirring was started, and heated to reflux for 3H, and TLC was used to detect the progress of the reaction. After the reaction, 127g (0.95 mol) of D- (+) -malic acid was added in portions, and stirring and refluxing were continued for 2 hours after the addition was completed. Then cooling to 5-15 ℃, a large amount of solid is separated out, stirring for 3 hours, filtering, washing a filter cake with ethanol, collecting the filter cake and drying to obtain 372g of (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate as white solid, wherein the yield is 94.7%.
Mass spectrometry: ESI (m/z): 280.1; nuclear magnetic resonance hydrogen spectrum: 1 HNMR(400MHz，d-DMSO)δ7.25(s，1H)，7.18(d，J＝4Hz，1H)，6.85(d，J＝4Hz，1H)，4.90～4.76(m，2H)，4.59(s，2H)，4.44～4.40(m，2H)，3.65(br，2H)，3.15～2.90(m，2H)，2.77～2.52(m，2H)，2.03(s，1H)，1.50(s，6H)，1.27(s，9H)。
EXAMPLE 4 preparation of Levoalbuterol hydrochloride
372g of the compound (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate obtained in example 3 was added to a 5000mL beaker, 1500mL of purified water was added, the solution was stirred and dissolved, 1500mL of methylene chloride was further added, and the mixture was cooled in an ice bath. Adding a proper amount of strong ammonia water slowly under stirring, adjusting the pH of the water phase to 9-10, continuously stirring for 30min, standing and layering. The organic layer was separated and collected, and the aqueous layer was added with 1000ml of dichloromethane, followed by stirring for 10min and allowed to stand for delamination. The organic layers were separated and collected, the organic layers were combined, 2000ml of saturated sodium chloride solution was added to the organic layers, stirred for 30min, allowed to stand for delamination, the organic layers were collected, dried over a suitable amount of anhydrous sodium sulfate, filtered, washed with dichloromethane, and the filtrate was collected.
The filtrate is concentrated to about 1500mL by rotary evaporation, transferred into a 5000mL three-mouth bottle and placed in an ice bath for cooling to 5-15 ℃. About 110g of 30% hydrogen chloride ethanol solution was added dropwise under stirring, and after the completion of the dropwise addition, 2000mL of methyl tert-butyl ether was added dropwise under stirring, whereby a large amount of white solid was precipitated. After the addition, stirring for 3 hours at the temperature of 5-15 ℃, filtering, washing a filter cake by adding methyl tertiary butyl ether, collecting the filter cake, and drying to obtain 241.5g, wherein the yield is 97.3%. The purity was 99.95% by HPLC analysis, and the isomer content was not detected, see FIGS. 1-4. The total yield of the four-step reaction is 87.5 percent.
Claims (5)
1. The synthesis method of the levalbuterol hydrochloride is characterized by comprising the following steps in sequence:
1) Dehydrating 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxin-6-yl) ethanol by titanium dioxide to synthesize 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxin;
2) 2, 2-dimethyl-6-vinyl-4H-benzo [ D ] [1,3] dioxin is prepared by taking 1,2:4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-dione-2, 6-pyranose, potassium monopersulfate and potassium hydroxide as reaction conditions and performing asymmetric epoxidation reaction to obtain a key intermediate (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin;
3) Reacting and condensing (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin with tert-butylamine, and then salifying with D- (+) -malic acid to obtain (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malic acid;
4) (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malic acid is subjected to ammonolysis and then salified with hydrogen chloride to obtain a final product of levalbuterol hydrochloride;
2. the method for synthesizing levalbuterol hydrochloride according to claim 1, characterized in that the reaction of step 1) is performed under the following conditions: 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxin-6-yl) ethanol is taken as a starting raw material, and 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxin is synthesized by dehydration, wherein the molar ratio of the raw materials is as follows: the mol ratio of 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxin-6-yl) ethanol to titanium dioxide is 1:0.2-1.0, the reaction temperature is 120-150 ℃, and the reaction time is 10-15 hours.
3. The method for synthesizing levalbuterol hydrochloride according to claim 1, characterized in that the reaction of step 2) is performed under the following conditions: synthesis of (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin, using 2, 2-dimethyl-6-vinyl-4H-benzo [ D ] [1,3] dioxin, 1,2:4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-dione-2, 6-pyranose, potassium monopersulfate and potassium hydroxide as raw materials, acetonitrile as solvent, molar ratio of 2, 2-dimethyl-6-vinyl-4H-benzo [ D ] [1,3] dioxin and 1,2:4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-dione-2, 6-pyranose is 1:0.2-0.5,2,2-dimethyl-6-vinyl-4H-benzo [ D ] [1,3] dioxin and molar ratio of potassium monopersulfate is 1:1-3, and the reaction time is kept at pH value of between 10-30 ℃ and 10 at a temperature of 15.
4. The method for synthesizing levalbuterol hydrochloride according to claim 1, characterized in that the reaction of step 3) is performed under the following conditions: the synthesis of (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate takes (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin, tert-butylamine and D- (+) -malic acid as raw materials, ethanol as a solvent, the mol ratio of (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin to tert-butylamine is 1:1.0-3.0, the mol ratio of (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin to D- (+) -malic acid is 1:1.0-3.0, and the reaction temperature of (R) -2, 2-dimethyl-6- (ethylene oxide-2-yl) -4H-benzo [ D ] [1,3] dioxin and the tert-butylamine is at a temperature of between 80 and 3 ℃ is between 80 and 100.
5. The method for synthesizing levalbuterol hydrochloride according to claim 1, characterized in that the reaction of step 4) is performed under the following conditions: the synthesis of levalbuterol hydrochloride is carried out by taking (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate as reaction raw material, taking dichloromethane and purified water as ammonolysis solvent, taking ammonia-solution as ammonolysis reagent, adjusting pH value to 9-10, salifying with hydrogen chloride ethanol for 3-10 hours, reacting at 5-15 ℃.
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| CN1413976A (en) * | 2002-09-13 | 2003-04-30 | 苏州君宁新药开发中心有限公司 | New process for preparing levo-albuterol |
| CN103951568A (en) * | 2014-05-19 | 2014-07-30 | 苏州弘森药业有限公司 | New process for synthesizing salbutamol and sulfate of salbutamol |
| CN104557572A (en) * | 2014-12-30 | 2015-04-29 | 上海默学医药科技有限公司 | Levalbuterol intermediate and levalbuterol hydrochloride synthesis method |
| CN110963929A (en) * | 2019-11-26 | 2020-04-07 | 安徽恒星制药有限公司 | Preparation method of salbutamol hydrochloride suitable for industrial production |
| CN113227113A (en) * | 2018-12-20 | 2021-08-06 | 帝斯曼知识产权资产管理有限公司 | Improved synthesis of epoxidation catalysts |
| CN113801029A (en) * | 2020-06-16 | 2021-12-17 | 盈科瑞（天津）创新医药研究有限公司 | Preparation method of levalbuterol hydrochloride |
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| CN1413976A (en) * | 2002-09-13 | 2003-04-30 | 苏州君宁新药开发中心有限公司 | New process for preparing levo-albuterol |
| CN103951568A (en) * | 2014-05-19 | 2014-07-30 | 苏州弘森药业有限公司 | New process for synthesizing salbutamol and sulfate of salbutamol |
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| CN113227113A (en) * | 2018-12-20 | 2021-08-06 | 帝斯曼知识产权资产管理有限公司 | Improved synthesis of epoxidation catalysts |
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