CN113480438B - Preparation method of esmolol hydrochloride - Google Patents
Preparation method of esmolol hydrochloride Download PDFInfo
- Publication number
- CN113480438B CN113480438B CN202110815504.9A CN202110815504A CN113480438B CN 113480438 B CN113480438 B CN 113480438B CN 202110815504 A CN202110815504 A CN 202110815504A CN 113480438 B CN113480438 B CN 113480438B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- methanol
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- VZTMYLWJKCAXMZ-UHFFFAOYSA-N 2-[(2-chloroquinazolin-4-yl)amino]ethanol Chemical compound C1=CC=C2C(NCCO)=NC(Cl)=NC2=C1 VZTMYLWJKCAXMZ-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960001015 esmolol hydrochloride Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 96
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 13
- MWQPWIHSYNEOQI-UHFFFAOYSA-N methyl hydrogen sulfite hydrochloride Chemical compound Cl.COS(O)=O MWQPWIHSYNEOQI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 44
- 239000002904 solvent Substances 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 238000006266 etherification reaction Methods 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 7
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000005576 amination reaction Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 abstract description 6
- BDUPRNVPXOHWIL-UHFFFAOYSA-N dimethyl sulfite Chemical compound COS(=O)OC BDUPRNVPXOHWIL-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- IIEKQHRBPZWNMR-UHFFFAOYSA-N 4-methylphenol;propanoic acid Chemical compound CCC(O)=O.CC1=CC=C(O)C=C1 IIEKQHRBPZWNMR-UHFFFAOYSA-N 0.000 abstract 1
- RKRICIZSQYMGCP-UHFFFAOYSA-N methyl propanoate;phenol Chemical compound CCC(=O)OC.OC1=CC=CC=C1 RKRICIZSQYMGCP-UHFFFAOYSA-N 0.000 description 13
- RPUSRLKKXPQSGP-UHFFFAOYSA-N methyl 3-phenylpropanoate Chemical compound COC(=O)CCC1=CC=CC=C1 RPUSRLKKXPQSGP-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 7
- 238000001514 detection method Methods 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 229960003745 esmolol Drugs 0.000 description 6
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 description 6
- QOHGMEYPUKSMST-UHFFFAOYSA-N methyl 2-(4-hydroxyphenyl)propanoate Chemical compound COC(=O)C(C)C1=CC=C(O)C=C1 QOHGMEYPUKSMST-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 3
- 229960002216 methylparaben Drugs 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- -1 (S) -glycidyl Chemical class 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 206010003662 Atrial flutter Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000007888 Sinus Tachycardia Diseases 0.000 description 1
- 239000000332 adrenergic beta-1 receptor antagonist Substances 0.000 description 1
- 102000016967 beta-1 Adrenergic Receptors Human genes 0.000 description 1
- 108010014494 beta-1 Adrenergic Receptors Proteins 0.000 description 1
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- GEKNCWBANDDJJL-PFEQFJNWSA-N methyl 3-[4-[(2r)-2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]propanoate;hydrochloride Chemical compound Cl.COC(=O)CCC1=CC=C(OC[C@H](O)CNC(C)C)C=C1 GEKNCWBANDDJJL-PFEQFJNWSA-N 0.000 description 1
- GEKNCWBANDDJJL-UQKRIMTDSA-N methyl 3-[4-[(2s)-2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]propanoate;hydrochloride Chemical compound Cl.COC(=O)CCC1=CC=C(OC[C@@H](O)CNC(C)C)C=C1 GEKNCWBANDDJJL-UQKRIMTDSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/27—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms
- C07D301/28—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms by reaction with hydroxyl radicals
-
- 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
-
- 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
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- 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
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
- C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of esmolol hydrochloride. The method of the invention comprises the steps of: the thionyl chloride reacts with methanol to prepare methyl sulfite chloride; the p-hydroxy benzene propionic acid and methyl sulfite undergo substitution reaction to prepare methyl p-hydroxy benzene propionate; the method has the advantages of easily available raw materials, low cost, simple preparation method, high yield and high purity of target products, and market competitiveness.
Description
Technical Field
The invention relates to a preparation method of esmolol hydrochloride, belonging to the field of pharmaceutical chemistry synthesis.
Background
Esmolol hydrochloride (Esmolol Hydrochloride) is a white or white-like crystalline powder, the chemical name of which is 4- [ 3- [ 1-methylethyl ] amino ] -2-hydroxy ] propoxy } phenylpropionic acid methyl ester hydrochloride, and the structural formula of the esmolol hydrochloride is shown as the following formula I. Esmolol hydrochloride is a beta 1 adrenergic receptor blocker with the characteristics of quick action, short action time and selectivity, and mainly acts on beta 1 adrenergic receptors of cardiac muscle; the beta 2 adrenergic receptor of the smooth muscle of the trachea and the blood vessel also has a blocking effect at a large dose; the device is mainly used for controlling ventricular rate during atrial fibrillation and atrial flutter and treating operation period hypertension and sinus tachycardia.
In the prior art, esmolol hydrochloride or intermediate preparation methods have been reported, for example: chinese patent document CN111620782A discloses a preparation method of esmolol hydrochloride intermediate; reacting p-bromophenol with methyl acrylate in the presence of a palladium catalyst and a phosphine ligand to generate 3- (4-hydroxyphenyl) methyl acrylate; the 3- (4-hydroxyphenyl) methyl acrylate is hydrogenated in the presence of a palladium carbon catalyst to obtain the target product methyl 4-hydroxyphenylpropionate, wherein the total yield is 70 percent and the purity is 99 percent. However, the invention uses palladium-carbon catalyst, and the cost is high; and the reaction selectivity is poor, the side reaction is more, and the yield and purity of the target product are lower.
For another example, chinese patent CN101891636a discloses a method for preparing esmolol hydrochloride optical isomer, dissolving methyl parahydroxybenzoate in anhydrous aprotic polar solvent, adding alkali to prepare phenoxide, then condensing with (S) -glycidyl derivative or (R) -glycidyl derivative to prepare intermediate, then hydrolyzing with isopropylamine to form salt with hydrogen chloride, obtaining optically active esmolol hydrochloride, and refining to obtain pure (S) -esmolol hydrochloride or (R) -esmolol hydrochloride. However, the invention has low yield of target products, and NaH is used in the preparation process, so that the risk is high, and the invention is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of esmolol hydrochloride. The method has the advantages of easily available raw materials, low cost and simple preparation method; the target product has high yield and purity and has market competitiveness.
Description of the terminology:
a compound of formula I: esmolol hydrochloride;
A compound of formula II: p-hydroxy benzene propionic acid;
A compound of formula III: methyl p-hydroxyphenylpropionate;
A compound of formula IV: methyl 3- [4- (2, 3-epoxypropoxy ] phenylpropionate;
a compound of formula V: esmolol.
The compound numbers and the structural formula numbers have the same reference relationship and are based on the structural formula.
The technical scheme of the invention is as follows:
a method for preparing esmolol hydrochloride, comprising the steps of:
(1) The thionyl chloride reacts with methanol to prepare methyl sulfite chloride; the compound of the formula II and methyl sulfite chloride undergo substitution reaction to prepare a compound of the formula III;
(2) In a solvent A, under the action of potassium carbonate and tetrabutylammonium bromide, carrying out etherification reaction on a compound of a formula III and epoxy chloropropane to obtain a compound of a formula IV;
(3) In a solvent B, subjecting a compound of the formula IV and isopropylamine to amination reaction to prepare a compound of the formula V;
(4) In a solvent C, the compound of the formula V and hydrogen chloride are salified to prepare esmolol hydrochloride.
According to the invention, in the step (1), the mass ratio of the methanol to the compound of the formula II is 3-4:1, and the molar ratio of the thionyl chloride to the compound of the formula II is 1.0-1.1:1.
According to a preferred embodiment of the present invention, in the step (1), the reaction temperature of the methanol and thionyl chloride is 0 to 10 ℃. The reaction time is 0.5-3.0h.
According to a preferred embodiment of the invention, in step (1), the substitution reaction temperature of the methyl sulfite chloride and the compound of formula II is 30-40 ℃. The reaction time is 0.5-1.0h.
According to a preferred embodiment of the present invention, in step (1), the thionyl chloride is added dropwise to the methanol.
According to the present invention, in the step (1), the reaction solution obtained by the reaction of thionyl chloride and methanol is directly subjected to the next reaction without being treated.
According to a preferred embodiment of the present invention, in the step (2), the solvent a is one of tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile; preferably, the solvent A is tetrahydrofuran; the mass ratio of the solvent A to the compound of the formula III is 3-4:1.
According to the invention, in the step (2), the molar ratio of potassium carbonate to the compound of the formula III is 1.5-3.0:1, the molar ratio of epichlorohydrin to the compound of the formula III is 1.5-4.0:1, and the mass ratio of tetrabutylammonium bromide to the compound of the formula III is 0.8-1.2:1.
According to a preferred embodiment of the present invention, in the step (2), the etherification reaction temperature is 60 to 65 ℃. The reaction time is 8.0-10.0h.
According to the present invention, in the step (2), the post-treatment step of the reaction liquid obtained by the etherification reaction is preferably as follows: the obtained reaction liquid is decompressed and concentrated, toluene is added into the concentrate and stirred evenly, and then the compound of the formula IV is obtained through water washing, anhydrous sodium sulfate drying and decompression distillation.
Preferably, in step (3), the solvent B is methanol; the mass ratio of the solvent B to the compound of the formula IV is 3-4:1.
According to a preferred embodiment of the invention, in step (3), the molar ratio of isopropylamine to the compound of formula IV is 2.0-2.5:1.
According to a preferred embodiment of the present invention, in the step (3), the amination reaction temperature is 45 to 55 ℃; the reaction time is 4.0-5.0h.
According to the invention, in the step (4), the solvent C is one or a mixture of two of methanol and ethyl acetate; preferably, the solvent C is a mixed solvent of methanol and ethyl acetate, and the mass ratio of the methanol to the ethyl acetate is 1:4-5; the mass ratio of the solvent C to the compound of the formula V is 3.5-4.5:1.
According to the invention, in the step (4), the salt forming reaction temperature is 0-10 ℃, and the pH value of a salt forming system is less than or equal to 2; the reaction time is 1.0-2.0h.
According to a preferred embodiment of the invention, in step (4), hydrogen chloride is introduced as a gas into the mixture of the compound of formula V and the solvent C.
According to a preferred embodiment of the present invention, in the step (4), the reaction mixture obtained by the salt-forming reaction of the compound of formula V with hydrogen chloride is worked up as follows: filtering the obtained reaction liquid, washing with ethyl acetate, and drying to obtain an esmolol hydrochloride crude product; the obtained esmolol hydrochloride crude product is dissolved in a mixed solvent of methanol and ethyl acetate, and then the esmolol hydrochloride is obtained through recrystallization, filtration, washing with ethyl acetate and drying.
Preferably, the mass ratio of the methanol to the esmolol hydrochloride crude product is 0.5-1.0:1, and the mass ratio of the ethyl acetate to the esmolol hydrochloride crude product is 3.0-4.0:1.
The reaction route of the invention is as follows:
The invention has the technical characteristics and beneficial effects that:
1. according to the invention, methyl sulfite is prepared by the reaction of thionyl chloride and methanol, and then the methyl sulfite is subjected to substitution reaction with parahydroxy phenylpropionic acid (II) to prepare methyl parahydroxy phenylpropionate (III), so that the use of a palladium catalyst is avoided, and the cost is low; and the reaction selectivity is high, the conversion rate is high, the side reaction is less, and the purity of the obtained methyl p-hydroxyphenylpropionate (III) is high.
2. The invention prepares 3- [4- (2, 3-epoxypropoxy ] methyl phenylpropionate (IV) by using tetrabutylammonium bromide as a phase transfer catalyst and alkali potassium carbonate, and has high etherification conversion rate.
3. In the salification process of esmolol, hydrogen chloride gas is preferably introduced, so that the salification conversion rate is high, and the product yield is high.
4. The invention preferably uses the mixed solvent of methanol and ethyl acetate to form salt and recrystallize, and has high product yield and high purity.
5. The method has the advantages of low-cost and easily-obtained raw materials, mild technological reaction conditions, simple preparation method and post-treatment, low cost, safe and safe use of dangerous reagents and contribution to industrial production; the reaction selectivity is high, the side reaction is less, the yield and purity of the target product are high, the yield of esmolol hydrochloride can reach 83.7%, and the purity can reach 99.7%.
Drawings
FIG. 1 is a high performance liquid chromatogram of esmolol hydrochloride obtained in example 1;
Fig. 2 is a high performance liquid chromatogram of esmolol hydrochloride obtained in example 2.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The methods described in the examples are conventional, unless otherwise specified; the reagents used are commercially available unless otherwise specified.
The yields in the examples are all molar yields.
Example 1
A method for preparing esmolol hydrochloride, comprising the steps of:
(1) 70.00g of methanol is added into a reaction bottle, the temperature is reduced to 5 ℃ by stirring, 15.00g (0.126 mol) of thionyl chloride is added dropwise at the temperature of 5 ℃ after 0.5h, and the reaction is carried out for 0.5h at the temperature of 5 ℃. Adding 20.00g (0.120 mol) of parahydroxyphenylpropionic acid (II), heating to 35 ℃, controlling the temperature to 35 ℃ for reacting for 0.5-1.0h, detecting that the reaction is complete by TLC, controlling the temperature to 30-40 ℃ and distilling under reduced pressure to obtain 21.62g of light yellow oily substance, wherein the purity is 99.9%, and the molar yield is 99.6% when the parahydroxyphenylpropionic acid methyl ester (III) is converted into 21.60 g;
(2) 70.00g of tetrahydrofuran, 35.00g (0.25 mol) of potassium carbonate, 20.00g of tetrabutylammonium bromide, 35.00g (0.38 mol) of epichlorohydrin and 20.00g (0.11 mol) of methyl p-hydroxyphenylpropionate (III) prepared in the step (1) are added into a reaction bottle, the mixture is stirred and heated to 60 ℃, the temperature is controlled to be 60 ℃ for reaction for 8.0 to 10.0h, TLC detection reaction is complete, the temperature is controlled to be 60 to 65 ℃ for reduced pressure concentration, 50.00g of toluene is added into the concentrate for uniform stirring, then 100ml of water is used for each time for three times of washing, anhydrous sodium sulfate is added for drying, suction filtration and reduced pressure distillation are carried out on the filtrate, so as to obtain light yellow oily matter 25.98g, the purity is 98.8%, and 3- [4- (2, 3-epoxypropoxy ] methyl phenylpropionate (IV) 25.67g is converted, and the molar yield is 97.9%;
(3) 70.00g of methanol, 11.26g (0.19 mol) of isopropylamine and 20g (0.085 mol) of methyl 3- [4- (2, 3-epoxypropoxy ] phenylpropionate (IV) prepared in the step (2) are added into a reaction bottle, the mixture is stirred and heated to 50 ℃, the reaction is carried out for 4.0 to 5.0 hours at the temperature of 50 ℃, the TLC detection reaction is complete, the reduced pressure distillation is carried out at the temperature of 45 to 55 ℃ to obtain 24.76g of light yellow oily matter with the purity of 93.5 percent, 23.15g of converted esmolol (V) and the molar yield of 92.6 percent;
(4) Adding 15.00g of methanol, 70.00g of ethyl acetate and 20g of esmolol (V) prepared in the step (3) into a reaction bottle, stirring and cooling to 5 ℃, introducing dry hydrogen chloride gas at the temperature of 5 ℃ until the pH value of the system is less than or equal to 2, stopping introducing the hydrogen chloride gas after the pH value reaches the requirement, stirring and reacting for 1.5h, carrying out suction filtration, leaching a filter cake by using 20.00g of ethyl acetate, and drying the filter cake to obtain 21.82g of esmolol hydrochloride crude product with the molar yield of 97.1% and the purity of 99.4%;
(5) Adding 15.00g of methanol, 70.00g of ethyl acetate and 20g of esmolol hydrochloride crude product into a reaction bottle, stirring and heating to 55-65 ℃ for dissolution, cooling to 0-10 ℃ for crystallization after solution clearing, stirring and crystallization at 0-10 ℃ for 1.0-2.0h, carrying out suction filtration, leaching a filter cake by using 20.00g of ethyl acetate, and drying the filter cake to obtain 19.12g of esmolol hydrochloride, wherein the molar yield is 95.6%, the purity is 99.7%, and a high-phase liquid chromatogram of a final product is shown in a figure 1; the total yield of esmolol hydrochloride is 83.7%.
Example 2
A method for preparing esmolol hydrochloride, comprising the steps of:
(1) Methyl parahydroxybenzoate (III) was prepared as in example 1;
(2) 70.00 g (0.25 mol) of acetonitrile, 35.00g (0.25 mol) of potassium carbonate, 20.00g (tetrabutylammonium bromide), 35.00g (0.38 mol) of epichlorohydrin and 20.00g (0.11 mol) of methyl p-hydroxyphenylpropionate (III) prepared in the step (1) are added into a reaction bottle, the mixture is stirred and heated to 60 ℃, the temperature is controlled to be 60 ℃ for reaction for 8.0 to 10.0h, TLC detection reaction is complete, the temperature is controlled to be 60 ℃ to 65 ℃ for reduced pressure concentration, 50.00g of toluene is added into the concentrate and stirred uniformly, then 100ml of water is used for each time for three times, the washed oil is dried by adding anhydrous sodium sulfate, suction filtration is carried out, and the filtrate is distilled under reduced pressure, thus obtaining light yellow oily matter 25.77g, the purity of 3- [4- (2, 3-epoxypropoxy) methyl phenylpropionate (IV) is converted into 25.43g, and the molar yield is 97.0 percent;
(3) 70.00g of methanol, 11.26g (0.19 mol) of isopropylamine and 20g (0.085 mol) of methyl 3- [4- (2, 3-epoxypropoxy ] phenylpropionate (IV) prepared in the step (2) are added into a reaction bottle, the mixture is stirred and heated to 50 ℃, the reaction is carried out for 4.0 to 5.0 hours at the temperature of 50 ℃, TLC detection reaction is complete, the temperature of 45 to 55 ℃ is controlled, and reduced pressure distillation is carried out, so as to obtain 24.61g of light yellow oily matter with the purity of 93.4 percent and the molar yield of 91.9 percent of converted esmolol (V) of 22.99 g;
(4) Adding 15.00g of methanol, 70.00g of ethyl acetate and 20g of esmolol (V) prepared in the step (3) into a reaction bottle, stirring and cooling to 5 ℃, introducing dry hydrogen chloride gas at the temperature of 5 ℃ until the pH value of the system is less than or equal to 2, stopping introducing the hydrogen chloride gas after the pH value reaches the requirement, stirring and reacting for 1.5h, carrying out suction filtration, leaching a filter cake by using 20.00g of ethyl acetate, and drying the filter cake to obtain 21.68g of esmolol hydrochloride crude product with the molar yield of 96.5% and the purity of 99.3%;
(5) Adding 15.00g of methanol, 70.00g of ethyl acetate and 20g of esmolol hydrochloride crude product into a reaction bottle, stirring and heating to 55-65 ℃ for dissolution, cooling to 0-10 ℃ for crystallization after solution clearing, stirring and crystallization at 0-10 ℃ for 1.0-2.0h, carrying out suction filtration, leaching a filter cake by using 20.00g of ethyl acetate, and drying the filter cake to obtain 19.02g of esmolol hydrochloride, wherein the molar yield is 95.1%, the purity is 99.7%, and a high-phase liquid chromatogram of a final product is shown in figure 2; the total yield of esmolol hydrochloride is 81.5%.
Comparative example 1
The preparation method of esmolol hydrochloride is as described in example 1, except that tetrabutylammonium bromide is not added in the etherification reaction process of the step (2), and the step (2) is specifically as follows:
step (2): 70.00g tetrahydrofuran, 35.00g (0.25 mol) potassium carbonate, 35.00g (0.38 mol) epichlorohydrin and 20.00g (0.11 mol) methyl p-hydroxyphenylpropionate (III) prepared in the step (1) are added into a reaction bottle, the temperature is raised to 60 ℃, the reaction is carried out for 8.0 to 10.0 hours under the condition of temperature control of 60 ℃, TLC detection is complete, the temperature is controlled to 60 ℃ and reduced pressure concentration is carried out, 50.00g toluene is added into the concentrate and stirred uniformly, then 100ml water is used for washing three times each time, after washing, anhydrous sodium sulfate is added for drying, suction filtration and reduced pressure distillation are carried out on the filtrate, thus obtaining 23.82g of light yellow oily matter, the purity of which is 95.2 percent, and the molar yield of 3- [4- (2, 3-epoxypropoxy) methyl phenylpropionate (IV) 22.68 percent is 86.5 percent.
Other steps and conditions were consistent with example 1.
As can be seen from the comparison of the comparative examples, the addition of tetrabutylammonium bromide as the phase transfer catalyst is beneficial to the improvement of the yield and purity of the target product.
Comparative example 2
A process for preparing esmolol hydrochloride as described in example 1, except that the process for preparing methyl (III) p-hydroxyphenylpropionate in step (1) is different, specifically as follows:
Step (1): 70.00g of methanol, 0.11g of concentrated sulfuric acid and 20.00g (0.120 mol) of p-hydroxy benzene propionic acid (II) are added into a reaction bottle, the temperature is raised to 55 ℃, the temperature is controlled to 55 ℃ for reaction for 5-6 hours, TLC detection reaction is complete, 0.20g of potassium carbonate is added, the temperature is controlled to 55 ℃ for reduced pressure distillation, 22.03g of light yellow oily matter is obtained, the purity is 93.3%, and the molar yield of p-hydroxy benzene propionic acid methyl ester (III) is converted into 20.55g, and the molar yield is 94.8%.
Other steps and conditions were consistent with example 1.
As can be seen from the comparison of the comparative examples, the preparation method of methyl parahydroxybenzoate (III) of the present invention is advantageous for obtaining the target product with high yield and high purity.
Claims (4)
1. A method for preparing esmolol hydrochloride, comprising the steps of:
(1) The thionyl chloride reacts with methanol to prepare methyl sulfite chloride; the compound of the formula II and methyl sulfite chloride undergo substitution reaction to prepare a compound of the formula III;
The mass ratio of the methanol to the compound of the formula II is 3-4:1, and the molar ratio of the thionyl chloride to the compound of the formula II is 1.0-1.1:1; the reaction temperature of the methanol and the thionyl chloride is 0-10 ℃; the sulfoxide chloride is added into the methanol in a dropwise manner; the substitution reaction temperature of the methyl sulfite chloride and the compound of the formula II is 30-40 ℃; the reaction liquid obtained by the reaction of the thionyl chloride and the methanol is directly subjected to the next reaction without treatment;
(2) In a solvent A, under the action of potassium carbonate and tetrabutylammonium bromide, carrying out etherification reaction on a compound of a formula III and epoxy chloropropane to obtain a compound of a formula IV;
The solvent A is tetrahydrofuran or acetonitrile; the mass ratio of the solvent A to the compound of the formula III is 3-4:1; the molar ratio of potassium carbonate to the compound of the formula III is 1.5-3.0:1, the molar ratio of epichlorohydrin to the compound of the formula III is 1.5-4.0:1, and the mass ratio of tetrabutylammonium bromide to the compound of the formula III is 0.8-1.2:1; the etherification reaction temperature is 60-65 ℃; the post-treatment steps of the reaction liquid obtained by the etherification reaction are as follows: concentrating the obtained reaction liquid under reduced pressure, adding toluene into the concentrate, stirring uniformly, washing with water, drying with anhydrous sodium sulfate, and distilling under reduced pressure to obtain a compound of formula IV;
(3) In a solvent B, subjecting a compound of the formula IV and isopropylamine to amination reaction to prepare a compound of the formula V;
The solvent B is methanol;
(4) In a solvent C, salifying a compound of the formula V with hydrogen chloride to prepare esmolol hydrochloride;
The solvent C is a mixed solvent of methanol and ethyl acetate, and the mass ratio of the methanol to the ethyl acetate is 1:4-5; the mass ratio of the solvent C to the compound of the formula V is 3.5-4.5:1; the salt forming reaction temperature is 0-10 ℃, and the pH value of a salt forming system is less than or equal to 2; hydrogen chloride is introduced into a mixed solution of a compound of formula V and a solvent C in the form of gas; the post-treatment steps of the reaction liquid obtained by the salification reaction of the compound of the formula V and hydrogen chloride are as follows: filtering the obtained reaction liquid, washing with ethyl acetate, and drying to obtain an esmolol hydrochloride crude product; the obtained esmolol hydrochloride crude product is dissolved in a mixed solvent of methanol and ethyl acetate, and then the esmolol hydrochloride is obtained through recrystallization, filtration, washing with ethyl acetate and drying.
2. The process for preparing esmolol hydrochloride according to claim 1, wherein in step (3) one or more of the following conditions are included:
i. The mass ratio of the solvent B to the compound of the formula IV is 3-4:1;
ii. The molar ratio of isopropylamine to the compound of formula IV is 2.0-2.5:1;
iii, the amination reaction temperature is 45-55 ℃; the reaction time is 4.0-5.0h.
3. The method for preparing esmolol hydrochloride according to claim 1, wherein in the step (4), the reaction time is 1.0-2.0h.
4. The preparation method of esmolol hydrochloride according to claim 1, wherein the mass ratio of methanol to esmolol hydrochloride crude product is 0.5-1.0:1, and the mass ratio of ethyl acetate to esmolol hydrochloride crude product is 3.0-4.0:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110815504.9A CN113480438B (en) | 2021-07-19 | 2021-07-19 | Preparation method of esmolol hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110815504.9A CN113480438B (en) | 2021-07-19 | 2021-07-19 | Preparation method of esmolol hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113480438A CN113480438A (en) | 2021-10-08 |
| CN113480438B true CN113480438B (en) | 2024-05-14 |
Family
ID=77941440
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110815504.9A Active CN113480438B (en) | 2021-07-19 | 2021-07-19 | Preparation method of esmolol hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113480438B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115260045A (en) * | 2022-07-11 | 2022-11-01 | 山东科源制药股份有限公司 | Preparation process of high-purity esmolol hydrochloride |
| CN117209387B (en) * | 2023-09-15 | 2024-04-26 | 中国海洋大学 | Salifying and purifying process of esmolol hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106608863A (en) * | 2015-10-23 | 2017-05-03 | 北京创立科创医药技术开发有限公司 | Preparation method of landiolol hydrochloride |
-
2021
- 2021-07-19 CN CN202110815504.9A patent/CN113480438B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106608863A (en) * | 2015-10-23 | 2017-05-03 | 北京创立科创医药技术开发有限公司 | Preparation method of landiolol hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| Paul W. Erhardt等.Ultra-Short-Acting @-Adrenergic Receptor Blocking Agents. 2. (Ary1oxy)propanolamines Containing Esters on the Aryl Function .J. Med. Chem..1982,1408-1412. * |
| 贺正国等.艾司洛尔盐酸盐的新合成方法.云南大学学报（自然科学版）.2021,第43卷(第43期),985~989. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113480438A (en) | 2021-10-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113480438B (en) | Preparation method of esmolol hydrochloride | |
| CN112079742B (en) | Method for preparing lidocaine through continuous reaction | |
| CN111253273A (en) | Method for preparing lidocaine intermediate α -chloroacetyl-2, 6-dimethylaniline and lidocaine without adding extra alkali | |
| MXPA02005321A (en) | New process. | |
| CN112409201B (en) | Preparation method of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid | |
| CN113651706A (en) | Preparation process of high-purity esmolol hydrochloride | |
| JPS6233223B2 (en) | ||
| CN117019069A (en) | Pipeline reactor and continuous production method of 4-amino-3, 5, 6-trichloropyridine carboxylic acid | |
| CN115260045A (en) | Preparation process of high-purity esmolol hydrochloride | |
| CN111635325A (en) | Method for preparing metoprolol succinate | |
| CN112724033A (en) | Synthesis method and application of deet | |
| CN112521315B (en) | Preparation method of lidocaine degradation impurities | |
| CN115504894B (en) | Synthesis method of ai-vitamin hormone precursor | |
| JPH01102072A (en) | Production of epoxide derivative | |
| CN112521347B (en) | Method for preparing pramoxine hydrochloride by one-pot method | |
| CN115073313B (en) | Method for synthesizing terbutaline sulfate impurity C | |
| CN114085209B (en) | Method for purifying loratadine key intermediate | |
| CN112028842B (en) | Synthesis method of quizalofop-p-ethyl | |
| CN114380729B (en) | Preparation method of high-purity vildagliptin | |
| CN116178190A (en) | Preparation method of procaine hydrochloride | |
| CN115700242A (en) | Method for separating sodium acetate from waste liquid generated in isoborneol synthesis reaction | |
| CN117327021A (en) | Method for removing sticky impurities in hexahydropyridazine synthesis | |
| CN116554083A (en) | Preparation method of indobufen | |
| CN116283488A (en) | Preparation method of propargyl alcohol | |
| CN114315577A (en) | Synthesis method of 2-ethoxymethylene-4, 4-difluoroacetoacetic acid ethyl ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |