CN115109026A - Preparation method of levalbuterol intermediate and hydrochloride with high ee value - Google Patents
Preparation method of levalbuterol intermediate and hydrochloride with high ee value Download PDFInfo
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- 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 title claims abstract description 40
- 229950008204 levosalbutamol Drugs 0.000 title claims abstract description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 72
- 238000003756 stirring Methods 0.000 claims abstract description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- 239000012065 filter cake Substances 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 239000012043 crude product Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 238000007664 blowing Methods 0.000 claims abstract description 13
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000008213 purified water Substances 0.000 claims abstract description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000001704 evaporation Methods 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000007605 air drying Methods 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 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 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 229940087642 levalbuterol hydrochloride Drugs 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 4
- 229960002052 salbutamol Drugs 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims 1
- -1 compound salt Chemical class 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 1
- 208000024716 acute asthma Diseases 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940057282 albuterol sulfate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000014974 beta2-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006828 beta2-adrenergic receptor activity proteins Proteins 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
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- 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
- 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
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
-
- 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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of medicine preparation, in particular to a preparation method of a levalbuterol intermediate and hydrochloride with a high ee value. The method comprises the following specific steps: adding acetone and salbutamol sulfate into a reaction kettle I, cooling, dropwise adding concentrated sulfuric acid, adding toluene after the reaction is finished, adjusting the temperature, adding a sodium hydroxide aqueous solution, continuously stirring, separating liquid, washing with purified water, heating, decompressing and evaporating a toluene layer, adding methanol and D- (+) -dibenzoyl tartrate, stirring at room temperature, filtering to obtain a filter cake, and drying by blowing to obtain an intermediate complex salt crude product; and adding the solvent A and the intermediate compound salt crude product into a reaction kettle II, stirring and dissolving at room temperature, adding the solvent B after the solvent A is dissolved clearly, continuing stirring, filtering to obtain a filter cake, and performing forced air drying to obtain the levosalbutamol intermediate. The method is simple to operate, can obtain the levalbuterol intermediate with the ee value of more than or equal to 99.6% by one-step purification, has good recrystallization effect, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method of a levalbuterol intermediate with a high ee value and hydrochloride.
Background
Chemical name of levosalbutamol hydrochloride: (R) -alpha 1- [ (tert-butylamino) methyl group]-4-hydroxy-1, 3-benzenedimethanol hydrochloride of the formula: c 13 H 22 ClNO 3， Molecular weight: 275.77, structural formula:
levalbuterol is a beta 2-adrenoceptor agonist, and the only quick-acting qi-nutrient expansion drug currently on the market for prevention and treatment has fewer side effects of bone organ machine fare, which is particularly important for the elderly. The absorption rate in vivo is higher than that of dextro salbutamol, and compared with racemic salbutamol, levo salbutamol has the advantages of better curative effect, less side effect, less dosage and the like. The levo-salbutamol can replace salbutamol to become the first choice medicine for relieving acute asthma attack.
The levalbuterol intermediate reacts with hydrochloric acid to perform deprotection and salification, thus obtaining levalbuterol hydrochloride, and the ee value of the levalbuterol intermediate in the process from the reaction of the levalbuterol intermediate to the reaction of the levalbuterol hydrochloride is unchanged, so that the levalbuterol hydrochloride with high ee value can be conveniently obtained from the levalbuterol intermediate with high ee value.
Chinese patent publication No. CN104557572A, entitled "synthetic method of levalbuterol intermediate and levalbuterol hydrochloride," discloses a method for preparing a complex salt of levalbuterol intermediate, in which a solvent used in the method for preparing the complex salt of levalbuterol intermediate is a mixed solvent of ethanol and methanol, and then the complex salt of levalbuterol intermediate is recrystallized by using methanol. In the method, the compound salt of the levalbuterol intermediate is crystallized by using a mixed solvent, and the solvent is difficult to recover. And because the solubility of the levalbuterol intermediate compound salt in methanol is very low, the recrystallization effect is poor, the ee value of the obtained sample is not high, and the ee value of the obtained levalbuterol hydrochloride is not high, the operation is complex, and the method is not suitable for industrial production.
Disclosure of Invention
The present invention is directed to at least solve one of the technical problems of the prior art, and therefore, an aspect of the present invention is to provide a method for preparing a levalbuterol intermediate with a high ee value, comprising the following specific steps:
s1, adding acetone into a reaction kettle I, adding salbutamol sulfate under a stirring state, cooling, dropwise adding concentrated sulfuric acid under a stirring state, adding toluene after the reaction is finished, adjusting the temperature, adding a sodium hydroxide aqueous solution, continuing stirring, separating liquid, washing with purified water, heating and decompressing to evaporate a toluene layer, adding methanol and D- (+) -dibenzoyl tartrate under a stirring state, stirring at room temperature, filtering to obtain a filter cake, and drying the filter cake by blowing air to obtain an intermediate complex salt crude product;
s2, adding the solvent A into the reaction kettle II, adding the intermediate double salt crude product prepared in the step S1 under the stirring state, stirring and dissolving at room temperature, adding the solvent B after the intermediate double salt crude product is dissolved clearly, continuing stirring, filtering to obtain a filter cake, and drying the filter cake by blowing air to obtain the levalbuterol intermediate.
Preferably, the reaction equation of the preparation method is as follows:
preferably, the volume ratio of acetone, albuterol sulfate and concentrated sulfuric acid in S1 is 50-60: 10-20: 1; the volume ratio of acetone to toluene is 2-3: 1; the volume ratio of toluene to aqueous sodium hydroxide solution was 1: 2-3; the volume ratio of toluene to methanol is 2-3: 1; the volume ratio of the methanol to the D- (+) -dibenzoyl tartrate is 10-15: 1; the concentration of the sodium hydroxide aqueous solution is 5-6%.
Preferably, the salbutamol sulfate is added into the S1, the temperature is reduced to 0-5 ℃, concentrated sulfuric acid is dropwise added, and toluene is added after the reaction is finished for 1-3 hours; adjusting the temperature to below 25 ℃, adding a sodium hydroxide aqueous solution, and continuously stirring for 5 min; heating to 50 deg.C, evaporating toluene layer under reduced pressure, adding methanol and D- (+) -dibenzoyl tartrate under stirring, and stirring at room temperature for 2 hr.
Preferably, the solvent A in the S2 is dimethyl sulfoxide or N, N-dimethylformamide, and the solvent A has a purifying function.
Preferably, the solvent B in S2 is methanol, absolute ethyl alcohol or isopropanol, and the solvent B plays a role in crystallization.
Preferably, the volume ratio of the solvent to the crude intermediate double salt in the S2 is 1: 2-8; the volume ratio of the solvent B to the intermediate double salt crude product is 1: 5-30; solvent B was added and stirring continued for 2 h.
Preferably, the temperature of the air blowing drying in the S1 and S2 is 50 ℃, and the time is 4-8 h.
Another aspect of the present invention is to provide a method for preparing levalbuterol hydrochloride with high ee value, wherein the method comprises the following specific steps:
and adding absolute ethyl alcohol into the reaction kettle III, adding the levalbuterol intermediate and hydrochloric acid prepared in the step S2 under a stirring state, after the reaction is finished, adding ethyl acetate into the reaction liquid, continuously stirring, filtering to obtain a filter cake, and drying the filter cake to obtain a finished levalbuterol hydrochloride product.
Preferably, the volume ratio of the absolute ethyl alcohol to the levalbuterol intermediate to the hydrochloric acid to the ethyl acetate is 10-15: 4-5: 1: 25-30; adding the intermediate of the salbutamol and hydrochloric acid into absolute ethyl alcohol, and reacting for 10-12 h; adding ethyl acetate, and continuing stirring for 2 h; the temperature of forced air drying is 50 ℃, and the time is 4-8 h.
The invention has the following beneficial effects:
the method is simple to operate, can obtain the levalbuterol intermediate with the ee value of more than or equal to 99.6% by one-step purification, has good recrystallization effect, does not use heavy metal catalysts, does not cause drug safety risk due to excessive heavy metals of finished products, does not have high-temperature high-pressure reaction, has mild reaction conditions, is easy to recover solvents, safe and environment-friendly, has high product yield, cheap and easily available required raw materials, few three wastes and simple required equipment, and is suitable for large-scale industrial production.
Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, the present invention will be described in further detail with reference to specific embodiments. It should be noted that the embodiments and features of the embodiments of the present application may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced otherwise than as specifically described and, therefore, the scope of the present invention is not limited by the specific embodiments disclosed below.
Example one
Adding 900ml of acetone into a 1.3000ml three-necked bottle, adding 60.0g of salbutamol sulfate while stirring, cooling to 0 ℃, dropwise adding 16.2ml of concentrated sulfuric acid while stirring, reacting for 3h, adding 600ml of toluene after the reaction is finished, adjusting the temperature to be below 25 ℃, adding a sodium hydroxide aqueous solution (36.6g of sodium hydroxide is dissolved in 600ml of purified water), continuing stirring for 5min, separating, washing an organic phase with 400ml of purified water, heating the organic phase to 50 ℃, evaporating a toluene layer under reduced pressure, adding 420ml of methanol and 36.6g of D- (+) -dibenzoyl tartrate while stirring, stirring for 2h at room temperature, filtering to obtain a filter cake, and drying the filter cake by blowing at 50 ℃ for 8h to obtain 38.2g of an intermediate double-salt crude product, wherein the molar yield is as follows: 80.1%, and an ee value of 92.8%.
S2.500ml three-necked bottle is added with 120ml of N, N-dimethylformamide, 30.0g of intermediate compound salt crude product prepared in S1 is added under the stirring state, the mixture is stirred and dissolved at room temperature, 300ml of methanol is added after the mixture is dissolved clearly, the mixture is continuously stirred for 2 hours, a filter cake is obtained by filtration, the filter cake is dried by blowing at 50 ℃ for 7 hours, 24.6g of levosalbutamol intermediate is obtained, and the yield is as follows: 82.0%, ee value 99.88%, purity 99.8%.
Example two
Adding 900ml of acetone into a 1.3000ml three-necked bottle, adding 60.0g of salbutamol sulfate while stirring, cooling to 0 ℃, dropwise adding 16.2ml of concentrated sulfuric acid while stirring, reacting for 3h, adding 600ml of toluene after the reaction is finished, adjusting the temperature to be below 25 ℃, adding a sodium hydroxide aqueous solution (36.6g of sodium hydroxide is dissolved in 600ml of purified water), continuing stirring for 5min, separating, washing an organic phase with 400ml of purified water, heating the organic phase to 50 ℃, evaporating a toluene layer under reduced pressure, adding 420ml of methanol and 36.6g of D- (+) -dibenzoyl tartrate while stirring, stirring for 2h at room temperature, filtering to obtain a filter cake, and drying the filter cake by blowing at 50 ℃ for 6h to obtain 38.2g of an intermediate double-salt crude product, wherein the molar yield is as follows: 80.1%, and an ee value of 92.8%.
S2.500ml three-necked flask is added with 90ml of dimethyl sulfoxide, 30.0g of intermediate compound salt crude product prepared in S1 is added under the stirring state, the mixture is stirred and dissolved at room temperature, 300ml of methanol is added after the mixture is dissolved clearly, the mixture is continuously stirred for 2 hours, a filter cake is obtained by filtration, the filter cake is dried by air blast at 50 ℃ for 8 hours, and the levosalbutamol intermediate 26.0g is obtained, wherein the yield is as follows: 86.7%, ee value 99.84%, purity 99.7%.
EXAMPLE III
Adding 900ml of acetone into a 1.3000ml three-necked bottle, adding 60.0g of salbutamol sulfate while stirring, cooling to 0 ℃, dropwise adding 16.2ml of concentrated sulfuric acid while stirring, reacting for 3h, adding 600ml of toluene after the reaction is finished, adjusting the temperature to be below 25 ℃, adding a sodium hydroxide aqueous solution (36.6g of sodium hydroxide is dissolved in 600ml of purified water), continuing stirring for 5min, separating, washing an organic phase with 400ml of purified water, heating the organic phase to 50 ℃, evaporating a toluene layer under reduced pressure, adding 420ml of methanol and 36.6g of D- (+) -dibenzoyl tartrate while stirring, stirring for 2h at room temperature, filtering to obtain a filter cake, and drying the filter cake by blowing at 50 ℃ for 8h to obtain 38.2g of an intermediate double-salt crude product, wherein the molar yield is as follows: 80.1%, and an ee value of 92.8%.
S2.500ml three-necked flask is added with 90ml of dimethyl sulfoxide, 30.0g of intermediate compound salt crude product prepared in S1 is added under the stirring state, the mixture is stirred and dissolved at room temperature, 600ml of absolute ethyl alcohol is added after the mixture is dissolved clearly, the mixture is continuously stirred for 2 hours, a filter cake is obtained by filtration, the filter cake is dried by blowing at 50 ℃ for 7 hours, 27.0g of levalbuterol intermediate is obtained, and the yield is as follows: 90.0%, ee value 99.80%, purity 99.7%.
Example four
Adding 900ml of acetone into a three-necked bottle S1.3000ml, adding 60.0g of salbutamol sulfate under stirring, cooling to 0 ℃, dropwise adding 16.2ml of concentrated sulfuric acid under stirring, reacting for 3h, adding 600ml of toluene after the reaction is finished, adjusting the temperature to be below 25 ℃, adding an aqueous sodium hydroxide solution (36.6g of sodium hydroxide is dissolved in 600ml of purified water), continuing stirring for 5min, separating, washing an organic phase with 400ml of purified water, heating the organic phase to 50 ℃, evaporating a toluene layer under reduced pressure, adding 420ml of methanol and 36.6g of D- (+) -dibenzoyl tartrate under stirring, stirring for 2h at room temperature, filtering to obtain a filter cake, and drying the filter cake by blowing at 50 ℃ for 8h to obtain 38.2g of an intermediate double-salt crude product, wherein the molar yield is as follows: 80.1%, and an ee value of 92.8%.
Adding 120ml of dimethyl sulfoxide into a S2.500ml three-necked bottle, adding 30.0g of the intermediate compound salt crude product prepared in the S1 under the stirring state, stirring and dissolving at room temperature, adding 300ml of isopropanol after the solution is clear, continuing stirring for 2 hours, filtering to obtain a filter cake, and carrying out forced air drying on the filter cake at 50 ℃ for 4 hours to obtain 26.8g of a levalbuterol intermediate with the yield: 89.3%, ee value 99.80%, purity 99.7%.
EXAMPLE five
Adding 60ml of absolute ethyl alcohol into a 250ml three-neck flask, adding 20.0g of levalbuterol intermediate under the stirring state, adding 4.4ml of hydrochloric acid at room temperature, reacting for 12 hours, adding 120ml of ethyl acetate into the reaction solution, continuously stirring for 2 hours, filtering to obtain a filter cake, and drying the filter cake by blowing at 50 ℃ for 6 hours to obtain 10.8g of levalbuterol hydrochloride, wherein the yield is as follows: 90.0 percent. The ee value was 99.80%.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and it is obvious to those skilled in the art that various modifications and variations can be made in the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of a levo-salbutamol intermediate with a high ee value is characterized by comprising the following steps: the preparation method comprises the following specific steps:
s1, adding acetone into a reaction kettle I, adding salbutamol sulfate under a stirring state, cooling, dropwise adding concentrated sulfuric acid under a stirring state, adding toluene after the reaction is finished, adjusting the temperature, adding a sodium hydroxide aqueous solution, continuing stirring, separating liquid, washing with purified water, heating and decompressing to evaporate a toluene layer, adding methanol and D- (+) -dibenzoyl tartrate under a stirring state, stirring at room temperature, filtering to obtain a filter cake, and drying the filter cake by blowing air to obtain an intermediate complex salt crude product;
s2, adding the solvent A into the reaction kettle II, adding the intermediate double salt crude product prepared in the step S1 under the stirring state, stirring and dissolving at room temperature, adding the solvent B after the intermediate double salt crude product is dissolved clearly, continuing stirring, filtering to obtain a filter cake, and drying the filter cake by blowing air to obtain the levalbuterol intermediate.
2. The method for preparing the levalbuterol intermediate with high ee value according to claim 1, wherein: the reaction equation of the preparation method is as follows:
3. the method for preparing the levalbuterol intermediate with high ee value according to claim 1, wherein: in the S1, the volume ratio of acetone to salbutamol sulfate to concentrated sulfuric acid is 50-60: 10-20: 1; the volume ratio of acetone to toluene is 2-3: 1; the volume ratio of toluene to aqueous sodium hydroxide solution was 1: 2-3; the volume ratio of toluene to methanol is 2-3: 1; the volume ratio of the methanol to the D- (+) -dibenzoyl tartrate is 10-15: 1; the concentration of the sodium hydroxide aqueous solution is 5-6%.
4. The method for preparing the levalbuterol intermediate with high ee value according to claim 1, wherein: adding salbutamol sulfate into S1, cooling to 0-5 ℃, dropwise adding concentrated sulfuric acid, reacting for 1-3 h, and then adding toluene; adjusting the temperature to below 25 ℃, adding a sodium hydroxide aqueous solution, and continuously stirring for 5 min; heating to 50 deg.C, evaporating toluene layer under reduced pressure, adding methanol and D- (+) -dibenzoyl tartrate under stirring, and stirring at room temperature for 2 hr.
5. The preparation method of the levosalbutamol intermediate with high ee value according to claim 1, characterized in that: the solvent A in the S2 is dimethyl sulfoxide or N, N-dimethylformamide.
6. The method for preparing the levalbuterol intermediate with high ee value according to claim 1, wherein: and the solvent B in the S2 is methanol, absolute ethyl alcohol or isopropanol.
7. The method for preparing the levalbuterol intermediate with high ee value according to claim 1, wherein: the volume ratio of the solvent to the crude intermediate double salt in the S2 is 1: 2-8; the volume ratio of the solvent B to the intermediate double salt crude product is 1: 5-30; solvent B was added and stirring continued for 2 h.
8. The preparation method of the levosalbutamol intermediate with high ee value according to claim 1, characterized in that: and the temperature of the air blast drying in the S1 and S2 is 50 ℃, and the time is 4-8 h.
9. The process according to any one of claims 1 to 8, wherein the reaction mixture comprises the following components: the preparation method comprises the following specific steps:
and adding absolute ethyl alcohol into the reaction kettle III, adding the levalbuterol intermediate prepared in the step S2 and hydrochloric acid under a stirring state, after the reaction is finished, adding ethyl acetate into the reaction liquid, continuously stirring, filtering to obtain a filter cake, and drying the filter cake to obtain a finished product of levalbuterol hydrochloride.
10. The process according to claim 9, wherein the preparation of levalbuterol hydrochloride having a high ee value comprises: the volume ratio of the absolute ethyl alcohol to the levalbuterol intermediate to the hydrochloric acid to the ethyl acetate is (10-15): 4-5: 1: 25-30; adding the intermediate of the salbutamol and hydrochloric acid into absolute ethyl alcohol, and reacting for 10-12 h; adding ethyl acetate, and continuing stirring for 2 h; the temperature of forced air drying is 50 ℃, and the time is 4-8 h.
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|---|---|
| CN (1) | CN115109026A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999042460A1 (en) * | 1998-02-20 | 1999-08-26 | Fine Chemicals Corporation (Proprietary) Limited | Process for the production of optically enriched (r)- or (s)-albuterol |
| CN1927813A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of levorotatory albuterol hydrochloride |
| CN1934067A (en) * | 2004-05-20 | 2007-03-21 | 特瓦药物精化学品股份有限公司 | Preparation of levalbuterol hydrochloride |
| CN102260179A (en) * | 2010-05-24 | 2011-11-30 | 苏州睿克气雾医药有限公司 | Novel technology for resolving salbutamol sulfate |
| CN104356009A (en) * | 2014-10-22 | 2015-02-18 | 扬州市三药制药有限公司 | Production technology for synthetizing salbutamol sulphate |
| 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 |
-
2022
- 2022-06-28 CN CN202210777965.6A patent/CN115109026A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999042460A1 (en) * | 1998-02-20 | 1999-08-26 | Fine Chemicals Corporation (Proprietary) Limited | Process for the production of optically enriched (r)- or (s)-albuterol |
| CN1934067A (en) * | 2004-05-20 | 2007-03-21 | 特瓦药物精化学品股份有限公司 | Preparation of levalbuterol hydrochloride |
| CN1927813A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of levorotatory albuterol hydrochloride |
| CN102260179A (en) * | 2010-05-24 | 2011-11-30 | 苏州睿克气雾医药有限公司 | Novel technology for resolving salbutamol sulfate |
| CN104356009A (en) * | 2014-10-22 | 2015-02-18 | 扬州市三药制药有限公司 | Production technology for synthetizing salbutamol sulphate |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| MINO R. CAIRA等: "Resolution of albuterol acetonide" * |
| 陈扬 等: "盐酸左旋沙丁胺醇的制备" * |
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