CN105439875A - Synthesis method for compound tulobuterol - Google Patents
Synthesis method for compound tulobuterol Download PDFInfo
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- CN105439875A CN105439875A CN201610061248.8A CN201610061248A CN105439875A CN 105439875 A CN105439875 A CN 105439875A CN 201610061248 A CN201610061248 A CN 201610061248A CN 105439875 A CN105439875 A CN 105439875A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
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- C07—ORGANIC CHEMISTRY
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- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
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Abstract
The invention relates to a synthesis method for compound tulobuterol. The technical problems that potential safety hazards exist in an existing method, and cost is high are solved. The method includes the following steps of a, an olefination reaction, wherein 1-(2-chlorphenyl)-1-ethyl alcohol serves as an initial raw material, and in the presence of a catalyst and acid, a heating reaction is conducted to generate 2-chloro-styrene; b, a cyclization reaction, wherein 2-chloro-styrene serves as a raw material, and in the presence of alkali and an oxidizing agent, an epoxidation reaction is conducted to obtain 2-(2-chlorphenyl) ethylene oxide; c, a ring-opening reaction, wherein 2-(2-chlorphenyl) ethylene oxide serves as a raw material and reacts with tert-butylamine to obtain compound 1-(2-chlorphenyl)-2-tert-butylamino ethanol. The synthesis method can be used for preparing tulobuterol.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of synthetic method of compound tulobuterol
Background technology
Tulobuterol (Tulobuterol), the chemistry tertiary fourth monoethanolamine of 1-(2-chloro-phenyl-)-2-by name, its chemical structure is as follows:
Tulobuterol can selective excitement β
2-acceptor, has powerful and lasting dilating effect to bronchial smooth muscle.For alleviating the symptoms such as expiratory dyspnea that the respiratory tract obstruction diseases such as bronchial asthma, chronic bronchitis, asthmatic bronchitis, pulmonary emphysema, sand lung, pneumoconiosis cause.
This medicine is developed by Tanade Seiyaku Co., Ltd (Japan) at first in the form of the hydrochloride salt and was first gone on the market in Japan in 1981, its former synthetic method of grinding is as follows: after bromine bromination, obtain alpha-brominated methyl phenyl ketone (3) by o-chloroacetophenone (2), then 1-Chloro-O-Phenyl-2-bromoethanol (4) is obtained with potassium borohydride reduction, products therefrom and TERTIARY BUTYL AMINE are carried out condensation reaction and are obtained the tertiary fourth monoethanolamine (1) of target compound 1-(2-chloro-phenyl-)-2-, and its reaction formula is as follows:
Prepared by compound 2 in this synthetic method in the reaction of compound 3 and used bromine, bromine is a kind of fuming liquid of reddish-brown, irritant and severe corrosive, even if evaporate also very fast at normal temperatures.Even if mucous membrane also can be burnt when bromine vapor concentration is very low, the symptoms such as appearance cough, Mucosal secretions increase, nasal bleeding, dizziness.Liquid bromine has strong corrodibility to skin, can form the scar being difficult to heal.Therefore, industrial a large amount of use bromine is very inconvenient and easily cause security incident.
Prepared by compound 3 in the reaction of compound 4 and used POTASSIUM BOROHYDRIDE, POTASSIUM BOROHYDRIDE is easily make quick-fried compound, and these product by public security department's control, make it be greatly limited in industrial use in enormous quantities according to " safety management of dangerous chemical products regulations ".And POTASSIUM BOROHYDRIDE when participating in reaction reacting phenomenon violent, can generate heat in a large number, easily make that reaction conditions is uncontrollable even blasts.In a word, there is larger hidden danger in the method in security, makes this technique to a certain extent and be not suitable for industrial amplification production.
In order to effectively address this problem, descendant has carried out a large amount of optimization, mainly to the selection of bromizating agent to this route.People in succession study and employ cupric bromide and various perbromide, and these bromizating agents respectively have relative merits by comparison but are all not suitable for industrial a large amount of use.Such as, cupric bromide can avoid the severe corrosive of bromine and easy and simple to handle, but can produce a large amount of by product cuprous bromides, makes subsequent disposal loaded down with trivial details and add to produce burden; And perbromide is not only expensive, also needing of having is prepared by bromine, and result not only could not be avoided using bromine, needs on the contrary to increase the operation preparing bromizating agent together.The people such as Koshinaka and Eiichi are on the basis of summing up forefathers' research, disclose a kind of novel method of synthesizing tulobuterol, o-chloroacetophenone (2) is obtained 2-(2-chloro-phenyl-)-2-oxoacetaldehyde (5) by tin anhydride oxidation by the method, then be that TERTIARY BUTYL AMINE is carried out reduction amination and obtained the tertiary fourth monoethanolamine (1) of target compound 1-(2-chloro-phenyl-)-2-under POTASSIUM BOROHYDRIDE exists, its synthetic route is as follows:
Compound 2 is obtained compound 5 by tin anhydride oxidation and then carries out next step reaction by the method, avoids and uses strongly corrosion liquid bromine.But the mixed solvent into Isosorbide-5-Nitrae-dioxane and water selected by its solvent, and wherein Isosorbide-5-Nitrae-dioxane is expensive, not the production in enormous quantities of suitability for industrialized; And final step is prepared in the process of target compound 1 by compound 5 and employed the easily quick-fried compound POTASSIUM BOROHYDRIDE of system equally, therefore same exist larger hidden danger in security.
Summary of the invention
There is potential safety hazard, technical problem that cost is higher to solve existing method in the present invention, provides that a kind of technique is simple, materials safety is easy to get, operational safety, yield are high, is applicable to the synthetic method of the tulobuterol of suitability for industrialized production.
For this reason, in the present invention, with 1-(2-chloro-phenyl-)-1-ethanol (6) for starting raw material, reacting by heating generates 2-chloro-styrene (7) in the presence of a catalyst; Then do alkali with sodium bicarbonate, make oxygenant with metachloroperbenzoic acid and carry out epoxidation reaction and obtain 2-(2-chloro-phenyl-) oxyethane (8); Last and TERTIARY BUTYL AMINE is obtained by reacting the tertiary fourth monoethanolamine (1) of target compound 1-(2-chloro-phenyl-)-2-, and the total recovery of three-step reaction is 68%.
Synthetic route of the present invention is as follows:
Note: hydroquinone is Resorcinol
M-CPBA is metachloroperbenzoic acid
Concrete synthesis technique step of the present invention is as follows: (a) olefination: with 1-(2-chloro-phenyl-)-1-ethanol (6) for starting raw material, with compound (6): sal enixum: catalyst molar ratio is for 1:(0.6 ~ 0.8): (0.1 ~ 0.2) feeds intake, react 3 ~ 4 hours at 180 ~ 210 DEG C, aftertreatment obtains 2-chloro-styrene (7); (b) annulation: with 2-chloro-styrene (7) for raw material, with compound (7): sodium bicarbonate: oxygenant mol ratio is for 1:(1.0 ~ 1.2): (0.4 ~ 0.5) feeds intake, react 6 ~ 7 hours under reflux, aftertreatment obtains 2-(2-chloro-phenyl-) oxyethane (8); (c) ring-opening reaction: with 2-(2-chloro-phenyl-) oxyethane (8) for raw material, with compound (8): TERTIARY BUTYL AMINE mol ratio is for 1:(1.2 ~ 1.4) feed intake, react 8 ~ 10 hours at 40 ~ 50 DEG C, aftertreatment also obtains the tertiary fourth monoethanolamine of target compound 1-(2-chloro-phenyl-)-2-after recrystallization.
Preferably, in step (a), catalyzer is to biphenol.
Preferably, in step (a), when temperature of reaction is 200 ~ 205 DEG C, when compound (6) and catalyst molar ratio are 1:0.16, react 3.5 hours, the yield of compound (7) is the highest.
Preferably, in step (b), solvent is the one in methylene dichloride, trichloromethane, toluene, preferred methylene dichloride.
Preferably, in step (b), described oxygenant is metachloroperbenzoic acid.
Preferably, in step (b), alkali used is the one in sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, preferred sodium bicarbonate.
Preferably, in step (c), preferred compound (8) and TERTIARY BUTYL AMINE mol ratio are 1:1.3, and temperature of reaction is 40 ~ 50 DEG C, and the reaction times is 9 hours.
Synthesis technique in the present invention, avoids severe corrosive reagent bromine and easily makes the use of quick-fried compound POTASSIUM BOROHYDRIDE, simplify operational process of craft, improve production security largely, improve production efficiency.
Synthesis technique particular embodiment of the present invention is in the following areas:
(1) develop the variation route of a brand-new synthesis tulobuterol, avoid the use of severe corrosive reagent bromine in previous patent route and the easy quick-fried compound POTASSIUM BOROHYDRIDE of system, thus greatly improve production security.
(2) starting raw material 1-(2-chloro-phenyl-)-1-ethanol (6) is cheap and easy to get.
(3) it is all common common agents that used in building-up process reagent comprises acid, alkali, oxygenant and catalyzer, easy to use, to reaction conditions without particular requirement.
(4) ring-opening reaction reaction conditions is gentle, and side reaction is few, simple to operate, is easy to aftertreatment.
(5) product purity is high, and whole technological process yield is high, reaches 65%.
Accompanying drawing explanation
The 1-of Fig. 1 synthesized by this law (2-chloro-phenyl-)-2-tertiary fourth monoethanolamine (tulobuterol) H-NMR spectrogram.
1) measuring unit: Shandong Forecasting and Analysis Center;
2) INSTRUMENT MODEL: BrukerINOVA-600 nuclear magnetic resonance spectrometer;
3) test condition: solvent DMSO-d
6, δ
tMSmark in 0;
4) test result and parsing: tulobuterol sample
1h spectrum is shown in accompanying drawing 1, and data are in table 1;
Table 1 tulobuterol
1h data and analysis
| Sequence number | Chemical shift | Proton number |
| 1 | 7.56 | 1 |
| 2，3 | 7.36 | 2 |
| 4 | 7.27 | 1 |
| 5 | 4.89 | 1 |
| 6 | 2.68，2.45 | 2 |
| 7，8，9 | 1.02 | 3 |
5) conclusion: sample
1h-NMR spectrum data conforms to the structure of tulobuterol.
The 1-of accompanying drawing 2 synthesized by this law (2-chloro-phenyl-)-2-tertiary fourth monoethanolamine (tulobuterol) mass spectrum.
1) measuring unit: Shandong Forecasting and Analysis Center;
2) INSTRUMENT MODEL: Bruker1200RRLC-6520Accurate-MassQ-Tof;
3) test condition: ESI (+);
4) test result and analysis: the ESI mass spectrum of tulobuterol sample is shown in accompanying drawing 2, and sample molecule quasi-molecular ions and ownership are in table 2;
Table 2 tulobuterol sample molecule quasi-molecular ions and ownership
| Kind | Sample | Ownership |
| Molecular ion peak | 228.1 | [M+H] + |
5) conclusion: mass spectrum records the molecular ion peak [M+H] of this product
+, its mass-to-charge ratio m/z is 228.1, consistent with the molecular ion peak (molecular weight is 227.1) of tulobuterol.
Embodiment
Embodiment is used for describing the present invention further below, but does not impose any restrictions.
The preparation of embodiment 12-chloro-styrene
1-(2-chloro-phenyl-)-1-ethanol 78.3g (0.5mol), 40.8g sal enixum (0.3mol) and 5.5g Resorcinol (0.05mol) are joined in 500ml single port bottle, then 190 ~ 195 DEG C of reactions 3 hours.Reaction system is slowly poured in 300ml ether under whipped state after being down to room temperature, ether is spin-dried for, add 200ml methylene dichloride and 100ml water, abundant stirring, branch vibration layer, organic layer saturated common salt is washed 3 times (50ml × 3), obtains colorless oil 2-chloro-styrene 61.2g, yield 88% after anhydrous sodium sulfate drying filtering and concentrating.
The preparation of embodiment 22-chloro-styrene
1-(2-chloro-phenyl-)-1-ethanol 78.3g (0.5mol), 54.5g sal enixum (0.4mol) and 11.0g Resorcinol (0.1mol) are joined in 500ml single port bottle, then 200 ~ 205 DEG C of reactions 3 hours.Post-treating method, with embodiment 1, obtains product 62.6g, yield 90%.
The preparation of embodiment 32-chloro-styrene
1-(2-chloro-phenyl-)-1-ethanol 78.3g (0.5mol), 47.7g sal enixum (0.35mol) and 8.3g Resorcinol (0.075mol) are joined in 500ml single port bottle, then 210 ~ 215 DEG C of reactions 3 hours.Post-treating method, with embodiment 1, obtains product 58.4g, yield 84%.
The preparation of embodiment 42-(2-chloro-phenyl-) oxyethane
2-chloro-styrene 39g (0.5mol) and 42g sodium bicarbonate (0.5mol) are joined in 500ml single port bottle, add 300ml methylene dichloride again and make solvent, under whipped state, 34.5g (0.2mol) metachloroperbenzoic acid is joined in above-mentioned reaction system, then reflux 6 hours.After being down to room temperature, suction filtration removes insolubles, 100ml water is added in filtrate, water layer is removed after abundant washing, organic layer saturated common salt is washed 3 times (50ml × 3), colorless oil 2-(2-chloro-phenyl-) oxyethane 62.0g is obtained, yield 80% after anhydrous sodium sulfate drying filtering and concentrating.
The preparation of embodiment 52-(2-chloro-phenyl-) oxyethane
2-chloro-styrene 39g (0.5mol) and 50.4g sodium bicarbonate (0.6mol) are joined in 500ml single port bottle, add 300ml trichloromethane again and make solvent, under whipped state, 43.2g (0.25mol) metachloroperbenzoic acid is joined in above-mentioned reaction system, then reflux 6 hours.After being down to room temperature, suction filtration removes insolubles, 100ml water is added in filtrate, water layer is removed after abundant washing, organic layer saturated common salt is washed 3 times (50ml × 3), colorless oil 2-(2-chloro-phenyl-) oxyethane 58.1g is obtained, yield 75% after anhydrous sodium sulfate drying filtering and concentrating.
The preparation of embodiment 62-(2-chloro-phenyl-) oxyethane
2-chloro-styrene 39g (0.5mol) and 46.2g sodium bicarbonate (0.55mol) are joined in 500ml single port bottle, add 300ml toluene again and make solvent, under whipped state, 38.8g (0.23mol) metachloroperbenzoic acid is joined in above-mentioned reaction system, then reflux 6 hours.After being down to room temperature, suction filtration removes insolubles, 100ml water is added in filtrate, water layer is removed after abundant washing, organic layer saturated common salt is washed 3 times (50ml × 3), colorless oil 2-(2-chloro-phenyl-) oxyethane 52.7g is obtained, yield 68% after anhydrous sodium sulfate drying filtering and concentrating.
The preparation of embodiment 72-(2-chloro-phenyl-) oxyethane
2-chloro-styrene 39g (0.5mol) and 55.1g saleratus (0.55mol) are joined in 500ml single port bottle, add 300ml toluene again and make solvent, under whipped state, 38.8g (0.23mol) metachloroperbenzoic acid is joined in above-mentioned reaction system, then reflux 6 hours.After being down to room temperature, suction filtration removes insolubles, 100ml water is added in filtrate, water layer is removed after abundant washing, organic layer saturated common salt is washed 3 times (50ml × 3), colorless oil 2-(2-chloro-phenyl-) oxyethane 49.6g is obtained, yield 64% after anhydrous sodium sulfate drying filtering and concentrating.
The tertiary fourth monoethanolamine of embodiment 81-(2-chloro-phenyl-)-2-preparation
2-(2-chloro-phenyl-) oxyethane 77.5g (0.5mol) is joined in 500ml single port bottle, adds 200ml methyl alcohol as solvent, stir and make it to dissolve.Then 43.8g TERTIARY BUTYL AMINE (0.6mol) is slowly added drop-wise to (rate of addition: 2ml/min) in above-mentioned system, after dropwising, is warming up to 40 ~ 50 DEG C of reactions 8 hours.After being down to room temperature, methyl alcohol in system is spin-dried for, in residuum, add 300ml methylene dichloride make it to dissolve, wash 3 times (100ml × 3) with saturated common salt, point water-yielding stratum, add in organic phase anhydrous magnesium sulfate drying, filtration, concentrated after obtain yellow oil.Gained oily matter 50ml normal hexane is warming up to 50 DEG C of dissolvings, is then down to stirring at room temperature 2 hours, be finally cooled to 5 DEG C of crystallizations, obtain white crystal 1-(2-chloro-phenyl-)-2-tertiary fourth monoethanolamine 96.5g after solid filtering drying, yield 85%.
The tertiary fourth monoethanolamine of embodiment 91-(2-chloro-phenyl-)-2-preparation
2-(2-chloro-phenyl-) oxyethane 77.5g (0.5mol) is joined in 500ml single port bottle, adds 200ml methyl alcohol as solvent, stir and make it to dissolve.Then 47.5g TERTIARY BUTYL AMINE (0.65mol) is slowly added drop-wise to (rate of addition: 2ml/min) in above-mentioned system, after dropwising, is warming up to 40 ~ 50 DEG C of reactions 8 hours.Post-treating method, with embodiment 8, obtains product 103.3g, yield 91%.
The tertiary fourth monoethanolamine of embodiment 101-(2-chloro-phenyl-)-2-preparation
2-(2-chloro-phenyl-) oxyethane 77.5g (0.5mol) is joined in 500ml single port bottle, adds 200ml methyl alcohol as solvent, stir and make it to dissolve.Then 51.1g TERTIARY BUTYL AMINE (0.7mol) is slowly added drop-wise to (rate of addition: 2ml/min) in above-mentioned system, after dropwising, is warming up to 40 ~ 50 DEG C of reactions 8 hours.Post-treating method, with embodiment 8, obtains product 93.1g, yield 82%.
The tertiary fourth monoethanolamine of embodiment 111-(2-chloro-phenyl-)-2-preparation
2-(2-chloro-phenyl-) oxyethane 77.5g (0.5mol) is joined in 500ml single port bottle, adds 200ml methyl alcohol as solvent, stir and make it to dissolve.Then 47.5g TERTIARY BUTYL AMINE (0.65mol) is slowly added drop-wise to (rate of addition: 2ml/min) in above-mentioned system, after dropwising, is warming up to 40 ~ 50 DEG C of reactions 9 hours.Post-treating method, with embodiment 8, obtains product 105.6g, yield 93%.
The tertiary fourth monoethanolamine of embodiment 121-(2-chloro-phenyl-)-2-preparation
2-(2-chloro-phenyl-) oxyethane 77.5g (0.5mol) is joined in 500ml single port bottle, adds 200ml methyl alcohol as solvent, stir and make it to dissolve.Then 47.5g TERTIARY BUTYL AMINE (0.65mol) is slowly added drop-wise to (rate of addition: 2ml/min) in above-mentioned system, after dropwising, is warming up to 40 ~ 50 DEG C of reactions 10 hours.Post-treating method, with embodiment 8, obtains product 97.6g, yield 86%.
Claims (10)
1. a synthetic method for compound tulobuterol, is characterized in that the method comprises the steps:
(a) olefination: with 1-(2-chloro-phenyl-)-1-ethanol for starting raw material, under catalyzer and acid exist, reacting by heating generates 2-chloro-styrene;
B () annulation: with 2-chloro-styrene for raw material, under alkali and oxygenant existent condition, carries out epoxidation reaction and obtains 2-(2-chloro-phenyl-) oxyethane;
C () ring-opening reaction: with 2-(2-chloro-phenyl-) oxyethane for raw material, is obtained by reacting the tertiary fourth monoethanolamine of compound 1-(2-chloro-phenyl-)-2-with TERTIARY BUTYL AMINE.
2. the synthetic method of compound tulobuterol according to claim 1, is characterized in that: in reactions steps (a), and described catalyzer is to biphenol.
3. the synthetic method of compound tulobuterol according to claim 1, is characterized in that: in described step (a), described acid is sal enixum.
4. the synthetic method of compound tulobuterol according to claim 1, is characterized in that: in described step (b), and described alkali is the one in sodium bicarbonate or saleratus.
5. the synthetic method of compound tulobuterol according to claim 1, is characterized in that: in described step (b), described oxygenant is metachloroperbenzoic acid.
6. the synthetic method of compound tulobuterol according to claim 1, is characterized in that: in described step (b), also use solvent, described solvent is the one in methylene dichloride, trichloromethane or toluene.
7. the synthetic method of compound tulobuterol according to claim 1, is characterized in that: in described reactions steps (c), also use solvent, described solvent is methyl alcohol.
8. the synthetic method of compound tulobuterol according to claim 3, it is characterized in that: in described step (a), 1-(2-chloro-phenyl-)-1-ethanol: sal enixum: catalyst molar ratio is 1:(0.6 ~ 0.8): (0.1 ~ 0.2).
9. the synthetic method of compound tulobuterol according to claim 4, it is characterized in that: in described step (b), 2-chloro-styrene: sodium bicarbonate: oxygenant mol ratio is 1:(1.0 ~ 1.2): (0.4 ~ 0.5).
10. the synthetic method of compound tulobuterol according to claim 1, is characterized in that: in described step (c), 2-(2-chloro-phenyl-) oxyethane: TERTIARY BUTYL AMINE mol ratio is 1:(1.2 ~ 1.4); Reaction times was at 8 ~ 10 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205194A (en) * | 2019-12-12 | 2020-05-29 | 山东达因海洋生物制药股份有限公司 | Preparation method of tulobuterol |
| CN116082133A (en) * | 2021-11-08 | 2023-05-09 | 上海医药工业研究院 | Synthetic method of tulobuterol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205194A (en) * | 2019-12-12 | 2020-05-29 | 山东达因海洋生物制药股份有限公司 | Preparation method of tulobuterol |
| CN116082133A (en) * | 2021-11-08 | 2023-05-09 | 上海医药工业研究院 | Synthetic method of tulobuterol |
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