CN109206328A - A kind of preparation method of 2- (2- methoxyphenoxy) ethamine - Google Patents
A kind of preparation method of 2- (2- methoxyphenoxy) ethamine Download PDFInfo
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- CN109206328A CN109206328A CN201811127979.3A CN201811127979A CN109206328A CN 109206328 A CN109206328 A CN 109206328A CN 201811127979 A CN201811127979 A CN 201811127979A CN 109206328 A CN109206328 A CN 109206328A
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- methoxyphenoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/06—Preparation of esters of carbonic or haloformic acids from organic carbonates
- C07C68/065—Preparation of esters of carbonic or haloformic acids from organic carbonates from alkylene carbonates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention proposes a kind of preparation methods of 2- (2- methoxyphenoxy) ethamine, the following steps are included: synthesizing 2- (2- methoxyphenoxy) ethyl alcohol by starting material of guaiacol, 2- (2- methoxyphenoxy) chloroethanes is synthesized through chloro, then it reacts to obtain N- (O-methoxy benzene oxygen ethyl)-phthalimide with potassium phthalimide, most obtains 2- (2- methoxyphenoxy) ethamine through basic hydrolysis afterwards.Four-step reaction yield is respectively 2- (2- methoxyphenoxy) ethanol yield 98.9%, the chloro- ethane recovery 93.7% of 2- (2- methoxyphenoxy) -1-, N- (O-methoxy benzene oxygen ethyl)-phthalimide yield 86.4%, 2- (2- methoxyphenoxy) ethamine yield 91.2%, four step total recoverys are 73.04%, higher than current production technology yield 43% now, reduce the production cost of 2- (2- methoxyphenoxy) ethamine, safety in production process.
Description
Technical field
The present invention relates to Carvedilol material prepared technology field, specially a kind of 2- (2- methoxyphenoxy) ethamine
Preparation method.
Background technique
2- (2- methoxyphenoxy) ethamine is an important intermediate for synthesizing receptor blocking agent Carvedilol, card dimension
Ground Lip river is a kind of medicine for treating essential hypertension, can be used alone or with other antihypertensives especially thiazide diuretic
It is used in combination, Carvedilol, which can also be used for treating Symptomatic congestive heart failure, can reduce the death rate and Xin Xue Guan Shi part
Admission rate improves patient's ordinary circumstance and slows down progression of disease.In the prior art, guaiacol and 1, the reaction of 2- dichloroethanes
There are cappings, so that the yield of 2- (2- methoxyphenoxy) chloroethanes is lower than 60%, final 2- (2- methoxyphenoxy)
The total recovery of ethamine only 43%, causes 2- (2- methoxyphenoxy) production cost higher.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the existing defects, provides a kind of 2- (2- methoxyphenoxy) ethamine
Preparation method, through four-step reaction, respectively obtain 2- (2- methoxyphenoxy) ethanol yield using guaiacol as starting material
98.9%, the chloro- ethane recovery 93.7% of 2- (2- methoxyphenoxy) -1-, N- (O-methoxy benzene oxygen ethyl)-phthalyl are sub-
Amine yield 86.4%, 2- (2- methoxyphenoxy) ethamine yield 91.2%, four step total recoverys are 73.04%, are higher than now raw at present
Production. art yield 43% reduces the production cost of 2- (2- methoxyphenoxy) ethamine, and safety in production process can be effective
Solve the problems in background technique.
To achieve the above object, the present invention proposes: a kind of preparation method of 2- (2- methoxyphenoxy) ethamine, including with
Lower step:
S1) the synthesis of 2- (2- methoxyphenoxy) ethyl alcohol: taking guaiacol 42.5g to be added in 500ml round-bottomed flask, and to
After the DMF of the NaOH and 200ml of round-bottomed flask addition 14.3g, normal-temperature reaction 30min, decompression steams DMF about 100ml；Round bottom is burnt
Appropriate ethylene carbonate is added in bottle, solution is heated to 110 DEG C in round-bottomed flask, and reaches terminal by TLC monitoring reaction；Circle
Solution is cooled to 60 DEG C in the flask of bottom, and 100ml water is added and then hydrolyzes 1h, uses methylene chloride 200ml, 100ml, 100ml respectively
Three times, saturated sodium chloride solution is washed once for extraction, and then anhydrous sodium sulfate is dry, is concentrated to get intermediate 58.1g, and GC analysis contains
Amount is not less than 98%, and yield 98.9%, intermediate directly carries out the next step without further purification.
S2 S1 the) synthesis of the chloro- ethane of 2- (2- methoxyphenoxy) -1-: is added into reaction flask) made from intermediate
54.5g, dry methylene chloride 300g, solution is cooled to 0 DEG C in round-bottomed flask, and thionyl chloride is added dropwise with constant pressure funnel
Add within 80g(1 hours), then solution is warming up to 30 DEG C the reaction was continued 2 hours in round-bottomed flask, and TLC is detected without raw material；Decompression is steamed
Solvent and excessive thionyl chloride out obtain intermediate 58.0g, and GC analysis content is not less than 95%, yield 93.7%, intermediate
Lower part reaction is directly carried out without further purification.
S3) the synthesis of N- (O-methoxy benzene oxygen ethyl)-phthalimide: by 31g intermediate made from S2) and
27.6g potassium phthalimide is added in the DMF of 100g, after 170 DEG C of back flow reaction 3h, TLC analyses are without raw material, decompression
The DMF of 50ml is steamed, the dispersion of 100g methanol is added, cooling filtering, washing is primary, obtains intermediate with 95% ethyl alcohol recrystallization
41.2g, HPLC content are not less than 97%, yield 86.4%.
S4) the synthesis of 2- (2- methoxyphenoxy) ethamine: S3 is taken) obtained 30% hydrogen of intermediate 26.7g and 300ml
Aqueous solution of sodium oxide back flow reaction 7h at 110 DEG C, after fully reacting three times with the toluene extraction of 400ml, and by anhydrous
Na2SO4 is dry, and concentrated post separation obtains product 15.2g, and HPLC content is not less than 99%, 2- (2- methoxyphenoxy) ethamine
Yield is 91.2%.
Compared with prior art, the beneficial effects of the present invention are: using guaiacol as starting material, through four-step reaction, divide
Do not obtain 2- (2- methoxyphenoxy) ethanol yield 98.9%, the chloro- ethane recovery 93.7% of 2- (2- methoxyphenoxy) -1-,
N- (O-methoxy benzene oxygen ethyl)-phthalimide yield 86.4%, 2- (2- methoxyphenoxy) ethamine yield 91.2%,
Four step total recoverys are 73.04%, are higher than at present production technology yield 43% now, reduce 2- (2- methoxyphenoxy) ethamine
Production cost, safety in production process.
Detailed description of the invention
Fig. 1 is the flow chart of 2- of the present invention (2- methoxyphenoxy) ethamine preparation method；
Fig. 2 is the flow chart of prior art 2- (2- methoxyphenoxy) ethamine preparation method.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
Please refer to Fig. 1:
Since the halogen element at the both ends of 2- dichloroethanes does not have in the route that guaiacol and 2- dichloroethanes react in route [I]
The selectivity of height is easy the problem of generating by-product, low yield is caused largely to pollute, and there is NaN3 certain toxicity to meet
Water capacity Yi Fangsheng explosion is not suitable for being applied to Chemical Manufacture
The ammonification of halogenated hydrocarbons is easy to generate secondary amine and tertiary amine in route [II], and the impurity that poor selectivity generates is more.Route.
Route [III] causes total recovery since first step yield is low and there was only 33% or so, and route [III] is that production is often adopted
Technique.
The hydrolysis of amide in route [IV] needs to use LiAlH4 reducing agent, and LiAlH4 meets water and is easy to happen explosion, and
And price is relatively high, is not suitable for industrialized production.
Referring to Fig. 2, the present invention is the following technical schemes are provided: a kind of preparation side of 2- (2- methoxyphenoxy) ethamine
Method, comprising the following steps:
S1) the synthesis of 2- (2- methoxyphenoxy) ethyl alcohol: taking guaiacol 42.5g to be added in 500ml round-bottomed flask, and to
After the DMF of the NaOH and 200ml of round-bottomed flask addition 14.3g, normal-temperature reaction 30min, decompression steams DMF about 100ml；Round bottom is burnt
Appropriate ethylene carbonate is added in bottle, solution is heated to 110 DEG C in round-bottomed flask, and reaches terminal by TLC monitoring reaction；Circle
Solution is cooled to 60 DEG C in the flask of bottom, and 100ml water is added and then hydrolyzes 1h, uses methylene chloride 200ml, 100ml, 100ml respectively
Three times, saturated sodium chloride solution is washed once for extraction, and then anhydrous sodium sulfate is dry, is concentrated to get intermediate 58.1g, and GC analysis contains
Amount is not less than 98%, and yield 98.9%, intermediate directly carries out the next step without further purification.
S2 S1 the) synthesis of the chloro- ethane of 2- (2- methoxyphenoxy) -1-: is added into reaction flask) made from intermediate
54.5g, dry methylene chloride 300g, solution is cooled to 0 DEG C in round-bottomed flask, and thionyl chloride is added dropwise with constant pressure funnel
Add within 80g(1 hours), then solution is warming up to 30 DEG C the reaction was continued 2 hours in round-bottomed flask, and TLC is detected without raw material；Decompression is steamed
Solvent and excessive thionyl chloride out obtain intermediate 58.0g, and GC analysis content is not less than 95%, yield 93.7%, intermediate
Lower part reaction is directly carried out without further purification.
S3) the synthesis of N- (O-methoxy benzene oxygen ethyl)-phthalimide: by 31g intermediate made from S2) and
27.6g potassium phthalimide is added in the DMF of 100g, after 170 DEG C of back flow reaction 3h, TLC analyses are without raw material, decompression
The DMF of 50ml is steamed, the dispersion of 100g methanol is added, cooling filtering, washing is primary, obtains intermediate with 95% ethyl alcohol recrystallization
41.2g, HPLC content are not less than 97%, yield 86.4%.
S4) the synthesis of 2- (2- methoxyphenoxy) ethamine: S3 is taken) obtained 30% hydrogen of intermediate 26.7g and 300ml
Aqueous solution of sodium oxide back flow reaction 7h at 110 DEG C, after fully reacting three times with the toluene extraction of 400ml, and by anhydrous
Na2SO4 is dry, and concentrated post separation obtains product 15.2g, and HPLC content is not less than 99%, 2- (2- methoxyphenoxy) ethamine
Yield is 91.2%.
Benefit of the present invention: using guaiacol as starting material, through four-step reaction, 2- (2- methoxyphenoxy) is respectively obtained
The adjacent benzene of ethanol yield 98.9%, the chloro- ethane recovery 93.7% of 2- (2- methoxyphenoxy) -1-, N- (O-methoxy benzene oxygen ethyl) -
Dicarboximide yield 86.4%, 2- (2- methoxyphenoxy) ethamine yield 91.2%, four step total recoverys are 73.04%, are higher than mesh
Preceding present production technology yield 43% reduces the production cost of 2- (2- methoxyphenoxy) ethamine, safety in production process.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (1)
1. a kind of preparation method of 2- (2- methoxyphenoxy) ethamine, it is characterised in that: the following steps are included:
S1) the synthesis of 2- (2- methoxyphenoxy) ethyl alcohol: taking guaiacol 42.5g to be added in 500ml round-bottomed flask, and to
After the DMF of the NaOH and 200ml of round-bottomed flask addition 14.3g, normal-temperature reaction 30min, decompression steams DMF about 100ml；Round bottom is burnt
Appropriate ethylene carbonate is added in bottle, solution is heated to 110 DEG C in round-bottomed flask, and reaches terminal by TLC monitoring reaction；Circle
Solution is cooled to 60 DEG C in the flask of bottom, and 100ml water is added and then hydrolyzes 1h, uses methylene chloride 200ml, 100ml, 100ml respectively
Three times, saturated sodium chloride solution is washed once for extraction, and then anhydrous sodium sulfate is dry, is concentrated to get intermediate 58.1g, and GC analysis contains
Amount is not less than 98%, and yield 98.9%, intermediate directly carries out the next step without further purification；
S2 S1 the) synthesis of the chloro- ethane of 2- (2- methoxyphenoxy) -1-: is added into reaction flask) made from intermediate 54.5g,
Dry methylene chloride 300g, solution is cooled to 0 DEG C in round-bottomed flask, and it is small that thionyl chloride 80g(1 is added dropwise with constant pressure funnel
When add), then solution is warming up to 30 DEG C the reaction was continued 2 hours in round-bottomed flask, and TLC is detected without raw material；Decompression steams solvent
With excessive thionyl chloride, intermediate 58.0g is obtained, GC analyzes content and is not less than 95%, and yield 93.7%, intermediate is without pure
Change and directly carries out lower part reaction；
S3) the synthesis of N- (O-methoxy benzene oxygen ethyl)-phthalimide: by 31g intermediate and 27.6g made from S2)
Potassium phthalimide is added in the DMF of 100g, and after 170 DEG C of back flow reaction 3h, TLC analyses are without raw material, decompression is steamed
The dispersion of 100g methanol is added in the DMF of 50ml, and cooling filtering, washing is primary, obtains intermediate 41.2g with 95% ethyl alcohol recrystallization,
HPLC content is not less than 97%, yield 86.4%；
S4) the synthesis of 2- (2- methoxyphenoxy) ethamine: S3 is taken) obtained 30% hydroxide of intermediate 26.7g and 300ml
Sodium water solution back flow reaction 7h at 110 DEG C after fully reacting three times with the toluene extraction of 400ml, and passes through anhydrous Na 2SO4
Dry, concentrated post separation obtains product 15.2g, and HPLC content is not less than 99%, 2- (2- methoxyphenoxy) ethamine yield
91.2%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113861047A (en) * | 2021-09-18 | 2021-12-31 | 杭州国瑞生物科技有限公司 | Synthetic method of 2- (2-methoxyphenoxy) ethylamine |
| CN114276220A (en) * | 2020-09-27 | 2022-04-05 | 上海抚佳精细化工有限公司 | Preparation method of o-phenylphenoxyethanol |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009128088A2 (en) * | 2008-04-15 | 2009-10-22 | Shodhana Laboratories Limited | Preparation of 2-(2-alkoxy phenoxy) ethylamine, an intermediate of carvedilol and tamsulosin |
-
2018
- 2018-09-27 CN CN201811127979.3A patent/CN109206328A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009128088A2 (en) * | 2008-04-15 | 2009-10-22 | Shodhana Laboratories Limited | Preparation of 2-(2-alkoxy phenoxy) ethylamine, an intermediate of carvedilol and tamsulosin |
Non-Patent Citations (2)
| Title |
|---|
| 李修刚，等: "2-(2-甲氧基苯氧基)-1-氯-乙烷的合成", 《铜仁学院学报》 * |
| 李修刚，等: "β-芳氧基乙醇的合成方法改进研究", 《化学研究与应用》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276220A (en) * | 2020-09-27 | 2022-04-05 | 上海抚佳精细化工有限公司 | Preparation method of o-phenylphenoxyethanol |
| CN113861047A (en) * | 2021-09-18 | 2021-12-31 | 杭州国瑞生物科技有限公司 | Synthetic method of 2- (2-methoxyphenoxy) ethylamine |
| CN113861047B (en) * | 2021-09-18 | 2024-05-14 | 杭州国瑞生物科技有限公司 | Synthesis method of 2- (2-methoxyphenoxy) ethylamine |
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