CN104356009A - Production technology for synthetizing salbutamol sulphate - Google Patents
Production technology for synthetizing salbutamol sulphate Download PDFInfo
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- CN104356009A CN104356009A CN201410562992.7A CN201410562992A CN104356009A CN 104356009 A CN104356009 A CN 104356009A CN 201410562992 A CN201410562992 A CN 201410562992A CN 104356009 A CN104356009 A CN 104356009A
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- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 238000005516 engineering process Methods 0.000 title abstract description 6
- 230000003407 synthetizing effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 229940126214 compound 3 Drugs 0.000 claims abstract description 15
- 229960002052 salbutamol Drugs 0.000 claims abstract description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims abstract description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 6
- 239000011591 potassium Substances 0.000 claims abstract description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 6
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 6
- 238000000605 extraction Methods 0.000 claims abstract description 5
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 230000009467 reduction Effects 0.000 claims abstract description 4
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract description 3
- 239000001117 sulphuric acid Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 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 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 229940125898 compound 5 Drugs 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 238000013019 agitation Methods 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 5
- 238000006722 reduction reaction Methods 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 4
- 229940055858 aluminum chloride anhydrous Drugs 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000010612 desalination reaction Methods 0.000 claims description 4
- 239000000284 extract Substances 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 claims description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 208000012826 adjustment disease Diseases 0.000 claims description 2
- 238000005261 decarburization Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 230000007246 mechanism Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000011033 desalting Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- -1 acetoxyl group Chemical group 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 206010006451 bronchitis Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 208000023504 respiratory system disease Diseases 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- 206010014561 Emphysema Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- CTAOJWMNHTVFDO-UHFFFAOYSA-N CC(C)(C)NCC(c(cc1C=O)ccc1O)=O Chemical compound CC(C)(C)NCC(c(cc1C=O)ccc1O)=O CTAOJWMNHTVFDO-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000009798 acute exacerbation Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000000926 atmospheric chemistry Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
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- 238000013461 design Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ROAYSRAUMPWBQX-UHFFFAOYSA-N ethanol;sulfuric acid Chemical compound CCO.OS(O)(=O)=O ROAYSRAUMPWBQX-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
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- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
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- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a production technology for synthetizing salbutamol sulphate, and relates to the field of chemical synthesis. The production technology comprises the following steps: firstly, performing an Friedel-crafts acylation reaction on salicylal to obtain a chemical compound 3, performing a substitution reaction of tert-butylamine, protecting dihydroxy by propylidene under the catalysis of concentrated sulfuric acid through the reduction of potassium borohydride or sodium borohydride, then performing extraction for desalting, and generating a hydrolysis reaction under acid conditions to obtain sulphuric acid salbutamol. The production technology disclosed by the invention is easy to control and operate, raw materials are simple and easy to obtain, the total mol yield is as high as 40%, the product purity is as high as 99.5%, and the product cost is low.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to a kind of novel method of synthesizing salbutamol sulphate.
Background technology
Salbutamol sulfate 1-(4-hydroxyl-3-hydroxymethyl phenyl)-2-(TERTIARY BUTYL AMINE base) ethanol sulfuric acid salt, it is a kind of potent quick-acting selectivity b-receptor stimulant, for asthmatic bronchitis, the respiratory tract diseases such as the bronchospasm of bronchial asthma and emphysema patient all have good therapeutic action.Salbutamol was found in 1962 by British scholar, was developed, Initial Public Offering in 1968 by Ge Lansu company of Britain, within 1988, registered in China, domestic in production in 1975.Although this is an old kind medicine, still plays irreplaceable effect so far, all ranked before 20 in the sales volume of world's drug market in recent years.Its formulation of salbutamol has tablet, capsule, aerosol and injection etc.
Due to the pollution of environment, the haze weather of China more and more becomes a problem that can not be ignored, and the respiratory system disease that haze weather causes is everybody problem of always paying close attention in the past few days.The moiety of haze comprises hundreds of atmospheric chemistry particulate matter.The aerosol particles that the mainly diameter be wherein harmful to health is less than 10 microns, as fuel and automobile exhaust gas etc., it directly can enter and stick in human respiratory tract and alveolar.Especially submicron particle can be deposited in upper and lower respiratory tract and alveolar respectively, causes the illness such as acute rhinitis and acute bronchitis.For chronic respiratory system diseases patients such as bronchial asthma, chronic bronchitis, obstructive emphysema and chronic obstructive pulmonary diseases, haze weather can make state of an illness acute attack or acute exacerbation.
Salbutamol sulfate is that a kind of application is comparatively of a specified duration, acts on by the β extensively confirmed
2receptor stimulant, adrenergic receptor is mainly distributed in small airway around, and along with air flue caliber diminishes, distribution density is more and more higher, β
2
Receptor stimulant can make bronchial smooth muscle diastole, has very strong selectivity to bronchial smooth muscle Zhong Shi acceptor
。Occurred frequently along with respiratory system disease, the use of salbutamol also can remain high.Although the synthetic route of salbutamol is a lot of at present, it is outmoded that a lot of route all also exists technique, and yield is low, difficult purifying, or there is severe toxicity, the high-risk reaction such as hydrogenation.
Therefore the salbutamol synthesis technique made new advances is developed, all can be significant to enterprise and society.
Chinese patent CN1059905 discloses following a kind of synthetic route:
This route Problems existing is that (1) borine one thioether reagent is listed in severe poisonous chemicals for 2002 and is suitable for carrying out experimental implementation use.(2). the first step reaction (namely hydrolyzable bromide obtains glycol) is not easy to control.(3). reactions steps is more, and route is complicated.
Domestic early stage production synthetic technology route is as follows:
Bromine bromination technique is employed in said synthesis route; toxicity ratio is larger; labour protection requires high; in amination reaction, acetoxyl group is easily by aminolysis; by product is more, and the more yield of side reaction is lower, in addition final step reaction in employing precious metal palladium; not only production cost is high, and product has the risk of heavy metals exceeding standard.
U.S. Patent application US5283359 discloses following a kind of synthetic route:
The main drawback of this synthetic route is that in reaction, greatly excessive DMSO cannot recycle and equally also produces a large amount of waste water, and the oxidizing reaction that DMSO participates in simultaneously can produce a large amount of dimethyl sulphide, polluted air.Reduce to poplar acid esters with borane dimethylsulf iotade water, safety and toxicity are also need strict control on producing.
The people such as Zheng Yumei (chemical intermediate 2005(12) pp8-9) use salicylic aldehyde as the following synthetic method of starting raw material:
The method the first step is reacted, and because the aldehyde radical on aromatic ring exists, it is not high that this step pays gram acidylate yield.Final step reaction borohydride reduction obtains product, because all have the control indexes of boron-containing quantity to this medicine of salbutamol in domestic and international pharmacopeia.This compound is easy to be formed containing boron complex, and Boron contents process will be reached simple not like in bibliographical information of the drug standard by this route.
Shen Kaisheng etc. (organic chemistry 2003 23(6) pp542-545) to report for work, p-Hydroxybenzaldehyde is the following method of starting raw material synthesis salbutamol:
This highway route design is relatively more reasonable, and cost is also lower, but does not specifically describe experimental procedure and reaction conditions in document.And to when finding the phenyl aldehyde that dibasic acid esters is protected and sulfur ylide reagent react in this route research process, because there being highly basic to exist in reactive system, ester is also unstable, more side reaction can be produced.
Summary of the invention
Namely object of the present invention is the novel process of the synthesis salbutamol providing a kind of improvement, the technological deficiency such as yield low, aftertreatment trouble many with the side reaction solving existing synthesis technique.
The present invention includes following steps
1) friedel-crafts acylation: salicylic aldehyde is carried out Fu Ke acyl reacting generating compound 3;
2) 5-{ [(1,1-dimethyl ethyl) amido] ethanoyl } synthesis of-Benzaldehyde,2-hydroxy hydrochloride: compound 3 is carried out the substitution reaction of TERTIARY BUTYL AMINE is raw obtains compound 4;
3) synthesis of 1-(4-hydroxyl-3-hydroxymethyl phenyl)-2-(tertiary fourth is amino) ethanol: compound 4 is obtained compound 5 by POTASSIUM BOROHYDRIDE or sodium borohydride reduction;
4) propylidene protection, desalination: compound 5 two hydroxyl under sulphuric acid catalysis is obtained compound 6 by propylidene protection, then extracts desalination;
5) deprotection salify is hydrolyzed: compound 6 is occurred hydrolysis reaction in acid condition and obtains the husky fourth salbutamol of sulfuric acid.
Reaction mechanism is as follows:
Reactions steps of the present invention is short, the aftertreatment of the gentle particularly Friedel-Crafts reaction of whole technological process reaction conditions is easy to control and operation, raw material is simple and easy to get, total molar yield is up to 40%, product purity is up to more than 99.5%, product cost reduces greatly, is the new preparation process of the salbutamol sulphate that a kind of desirable replicability is high.
Further, in step 1) of the present invention, with methylene dichloride and 1.2-ethylene dichloride for reaction solvent, take Aluminum chloride anhydrous as catalyzer, with chloroacetyl chloride or bromoacetyl chloride for acylating agent, be under the condition of 40 ~ 80 DEG C in temperature of reaction, salicylic aldehyde is first carried out acylation reaction; After completion of the reaction, reaction solution is joined in the mixed solution of methylene dichloride and water by the mode dripped, add concentrated hydrochloric acid again, separate organic phase, aqueous phase dichloromethane extraction, obtains yellow solid and a small amount of oily matter through 40-45 DEG C of concentrating under reduced pressure, and the lower stirring and crystallizing of ice-water bath cooling is filtered, obtain faint yellow solid, after drying, obtain compound 3.Reaction yield can reach more than 80%.
Wherein, reaction solution is joined in the mixed solution of methylene dichloride and water by the mode dripped, the problem that Friedel-Crafts reaction aftertreatment reacts violent can be solved well.
Described step 2) in, take Virahol as solvent, under the temperature of reaction condition of 0-80 DEG C, TERTIARY BUTYL AMINE and compound 3 are carried out substitution reaction; After reaction terminates, drip concentrated hydrochloric acid and react; After reaction terminates, be down to room temperature, after filtration, dry compound 4.Reaction yield can reach more than 80%.
In described step 3), with Virahol, ethanol or methyl alcohol for reaction solvent, with POTASSIUM BOROHYDRIDE or sodium borohydride for reductive agent, under the temperature of reaction condition of 0-60 DEG C, carry out reduction reaction; Reaction terminates rear filtration, then after adding anhydrous sodium sulfate drying, carries out crystallization with acetone, tetrahydrofuran (THF) or ethyl acetate, obtains compound 5.Reaction yield can reach more than 85%.
In described step 4), take acetone as reaction solvent, under the temperature of reaction condition of 0-60 DEG C, compound 5 and the vitriol oil are reacted, after reaction terminates, the pH to 9-10 of adjustment reaction solution, after filtering, gets filtered liquid, add extraction into ethyl acetate, obtain organic phase, reconcentration, drying, obtain compound 6.Reaction yield can reach more than 85%.
In described step 5), by soluble in water for compound 6, after sulphur acid for adjusting pH to 2-3, molten clear after drip acetone, agitation and filtration obtains salbutamol sulfate crude product.
In addition, also salbutamol sulfate crude product can be dissolved in purified water, after decarburization, filter with ethanol, Virahol, acetone or tetrahydrofuran (THF) crystallization, dry salbutamol sulfate fine work, purity can reach more than 99.5%.
Embodiment
Embodiment 1
(1) compound 3(5-acetyl bromide-Benzaldehyde,2-hydroxy) preparation:
Aluminum chloride anhydrous 55 grams is added in reaction flask, stirring adds anhydrous methylene chloride 50 milliliters, anhydrous ethylene dichloride 20 milliliters, is warming up to 50 DEG C, starts to drip chloroacetyl chloride 23.3 grams, dropwise, start to drip salicylic aldehyde 11 grams, dropwise, be incubated 50 DEG C of reactions 20 hours, reaction solution is down to room temperature, is slowly added drop-wise in the methylene dichloride mixed solution of 150 grams of water and 50 milliliters.Add 20 milliliters of concentrated hydrochloric acids; stir; separate organic phase; aqueous phase methylene dichloride 300 milliliters × 2 extracts; 40-45 DEG C of concentrating under reduced pressure obtains yellow solid and a small amount of oily matter; the lower stirring and crystallizing of ice-water bath cooling is filtered, and obtains faint yellow solid, is dried to constant weight and obtains 17.7 g of compound 3(5-acetyl bromide-Benzaldehyde,2-hydroxies).
(2) compound 4(5-{ [(1,1-dimethyl ethyl) amido] ethanoyl }-Benzaldehyde,2-hydroxy hydrochloride) preparation:
In reaction flask, add Virahol 80 milliliters, add 17.7 g of compound 3 and drip 20 grams (TERTIARY BUTYL AMINE, dropwises, lower reaction clarification in 3 hours is stirred in interior temperature rise to 50 DEG C, slowly drip 25ml concentrated hydrochloric acid, dropwise exothermic heat of reaction, be slowly down to stirring at room temperature 12 hours.Filter, dry 15.8 g of compound 4(5-{ [(1,1-dimethyl ethyl) amido] ethanoyl-Benzaldehyde,2-hydroxy hydrochloride), faint yellow solid.
(3) compound 5(1-(4-hydroxyl-3-hydroxymethyl phenyl)-2-(tertiary fourth amino) ethanol) preparation:
15.8 g of compound 4 are added to reaction flask, add Virahol or ethanol or methyl alcohol 150 milliliters, drip POTASSIUM BOROHYDRIDE 8 grams, drip in batches, 20-25 DEG C of reaction is filtered for 3 hours, adds anhydrous sodium sulfate drying, filters and drip ethyl acetate 150 milliliters, agitation and filtration, dry 11.8 g of compound 5(1-(4-hydroxyl-3-hydroxymethyl phenyl)-2-(tertiary fourth is amino) ethanol).
(4) preparation of compound 6:
In reaction flask, add 40 milliliters, acetone, add 15.8 g of compound 5, drip the 1N vitriol oil 8 grams, be incubated 8-10 DEG C of reaction 5 hours, adjust PH=9-10 with sodium methoxide solution, filter, concentrated, add ethyl acetate 60 milliliters, 25 milliliters, water, stirs and separates organic phase, is concentrated into dry 11.8g compound 6.
(5) preparation of compound 7 salbutamol sulfate:
In reaction flask, add 60 milliliters, water, add 11.8 g of compound 6, adjust ph=3-4 with sulfuric acid, molten clear rear dropping 300 milliliters, acetone, 20-25 DEG C of agitation and filtration obtains salbutamol sulfate 10.5 grams.
Above 5 step total recovery 40.4%, HPLC purity 98.9%.
Add purified water 60 milliliters by 10.5 grams again, add gac 1 gram, stir, filter, filtrate added drop-wise tetrahydrofuran (THF) 300 milliliters, the salbutamol sulfate that crystallization filters refining 10.1 grams, Hplc purity 99.6%.
Embodiment 2
(1) preparation of compound 3:
Aluminum chloride anhydrous 110 grams is added in reaction flask, stirring adds anhydrous methylene chloride 100 milliliters, anhydrous ethylene dichloride 50 milliliters, is warming up to 50 DEG C, starts to drip bromoacetyl chloride 23.3 grams, dropwise, start to drip salicylic aldehyde 22 grams, dropwise, be incubated 50 DEG C of reactions 20 hours, reaction solution is down to room temperature, is slowly added drop-wise in the methylene dichloride mixed solution of 300 grams of water and 100 milliliters.Add 50 milliliters of concentrated hydrochloric acids, stir, separate organic phase, aqueous phase methylene dichloride 500 milliliters × 2 extracts, and 40-45 DEG C of concentrating under reduced pressure obtains yellow solid and a small amount of oily matter, and the lower stirring and crystallizing of ice-water bath cooling is filtered, obtain faint yellow solid, be dried to constant weight and obtain 35.5 g of compound 3.
(2) preparation of compound 4:
In reaction flask, add Virahol 160 milliliters, add 35.5 g of compound 3 and drip 40 grams of TERTIARY BUTYL AMINE, dropwise, lower reaction clarification in 3 hours is stirred in interior temperature rise to 50 DEG C, slowly drip 50ml concentrated hydrochloric acid, dropwise exothermic heat of reaction, be slowly down to stirring at room temperature 12 hours.Filter, dry 32.1 g of compound 4, faint yellow solid.
(3) preparation of compound 5:
Add 32.1 g of compound 4 to reaction flask, add Virahol 300 milliliters, drip sodium borohydride 16 grams, drip, 20-25 DEG C of reaction is filtered for 3 hours, adds anhydrous sodium sulfate drying in batches, filter and drip ethyl acetate 150 milliliters, agitation and filtration, dry 23.5 g of compound 5.
(4) preparation of compound 6:
150 milliliters, acetone is added in reaction flask, add 23.5 g of compound 5, drip the 1N vitriol oil 16.1 grams, be incubated 8-10 DEG C of reaction 5 hours, adjust PH=9-10 with sodium methoxide solution, filter, concentrated, add ethyl acetate 150 milliliters, 75 milliliters, water, stirring separates organic phase, is concentrated into dry 23.0g compound 6.
(5) preparation of compound 7 salbutamol sulfate:
In reaction flask, add 130 milliliters, water, add 23.0 g of compound 6, adjust ph=3-4 with sulfuric acid, molten clear rear dropping 350 milliliters, acetone, 20-25 DEG C of agitation and filtration obtains salbutamol sulfate 19.6 grams.
Above 5 step total recoverys 37.7%,
Again 19.6 grams of salbutamol sulfates are added purified water 80 milliliters, add gac 2 grams, stir, filter, filtrate added drop-wise tetrahydrofuran (THF) 350 milliliters, the salbutamol sulfate that crystallization filters refining 19.1 grams, Hplc purity 98.9%.
Although above with general explanation, embodiment and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (7)
1. synthesize a production technique for salbutamol sulphate, it is characterized in that comprising the steps
1) friedel-crafts acylation: salicylic aldehyde is carried out Fu Ke acyl reacting generating compound 3;
2) 5-{ [(1,1-dimethyl ethyl) amido] ethanoyl } synthesis of-Benzaldehyde,2-hydroxy hydrochloride: compound 3 is carried out the substitution reaction of TERTIARY BUTYL AMINE is raw obtains compound 4;
3) synthesis of 1-(4-hydroxyl-3-hydroxymethyl phenyl)-2-(tertiary fourth is amino) ethanol: compound 4 is obtained compound 5 by POTASSIUM BOROHYDRIDE or sodium borohydride reduction;
4) propylidene protection, desalination: compound 5 two hydroxyl under sulphuric acid catalysis is obtained compound 6 by propylidene protection, then extracts desalination;
5) deprotection salify is hydrolyzed: compound 6 is occurred hydrolysis reaction in acid condition and obtains the husky fourth salbutamol of sulfuric acid;
Reaction mechanism is as follows:
。
2. according to the production technique described in claim 1, it is characterized in that: in described step 1), with methylene dichloride and 1.2-ethylene dichloride for reaction solvent, take Aluminum chloride anhydrous as catalyzer, with chloroacetyl chloride or bromoacetyl chloride for acylating agent, be under the condition of 40 ~ 80 DEG C in temperature of reaction, salicylic aldehyde is first carried out acylation reaction; After completion of the reaction, reaction solution is joined in the mixed solution of methylene dichloride and water by the mode dripped, add concentrated hydrochloric acid again, separate organic phase, aqueous phase dichloromethane extraction, obtains yellow solid and a small amount of oily matter through 40-45 DEG C of concentrating under reduced pressure, and the lower stirring and crystallizing of ice-water bath cooling is filtered, obtain faint yellow solid, after drying, obtain compound 3.
3. according to the production technique described in claim 1, it is characterized in that: described step 2) in, take Virahol as solvent, under the temperature of reaction condition of 0-80 DEG C, TERTIARY BUTYL AMINE and compound 3 are carried out substitution reaction; After reaction terminates, drip concentrated hydrochloric acid and react; After reaction terminates, be down to room temperature, after filtration, dry compound 4.
4. according to the production technique described in claim 1, it is characterized in that: in described step 3), with Virahol, ethanol or methyl alcohol for reaction solvent, with POTASSIUM BOROHYDRIDE or sodium borohydride for reductive agent, under the temperature of reaction condition of 0-60 DEG C, carry out reduction reaction; Reaction terminates rear filtration, then after adding anhydrous sodium sulfate drying, carries out crystallization with acetone, tetrahydrofuran (THF) or ethyl acetate, obtains compound 5.
5. according to the production technique described in claim 1, it is characterized in that: in described step 4), take acetone as reaction solvent, under the temperature of reaction condition of 0-60 DEG C, compound 5 and the vitriol oil are reacted, after reaction terminates, the pH to 9-10 of adjustment reaction solution, after filtering, get filtered liquid, add extraction into ethyl acetate, obtain organic phase, reconcentration, drying, obtain compound 6.
6. according to the production technique described in claim 1, it is characterized in that: in described step 5), by soluble in water for compound 6, after sulphur acid for adjusting pH to 2-3, molten clear after drip acetone, agitation and filtration obtains salbutamol sulfate crude product.
7. production technique according to claim 6, is characterized in that: salbutamol sulfate crude product is dissolved in purified water, after decarburization, filters with ethanol, Virahol, acetone or tetrahydrofuran (THF) crystallization, dry salbutamol sulfate fine work.
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| CN105001100A (en) * | 2015-06-11 | 2015-10-28 | 山西云鹏制药有限公司 | Method for refining salbutamol sulfate |
| CN106748819A (en) * | 2016-11-21 | 2017-05-31 | 河南工业大学 | The preparation method and its crystal structure of salbutamol benzoate |
| CN106748824A (en) * | 2016-11-21 | 2017-05-31 | 河南工业大学 | A kind of new salbutamol drug salts salbutamol fumarate and preparation method thereof |
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