CN102267917B - Method for synthesizing methoxyphenamine hydrochloride - Google Patents
Method for synthesizing methoxyphenamine hydrochloride Download PDFInfo
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Abstract
The invention provides a method for synthesizing methoxyphenamine hydrochloride. The method comprises the following steps of: (1) mixing o-methoxyphenylacetic acid with organic alkali, dissolving in acetic anhydride for undergoing a heating reaction, and performing post-treatment to obtain o-methoxybenzyl methyl ketone; (2) putting the o-methoxybenzyl methyl ketone and a methylamine alcohol solution into a high-pressure kettle for performing catalytic hydrogenation to obtain o-methoxy phenpromethamine; and (3) introducing dried HCl gas into a solution containing o-methoxy phenpromethamine for salifying, and recrystallizing the obtained crude product to obtain methoxyphenamine hydrochloride. The method has the advantages of easiness and convenience for operation, mild reaction condition, high reaction yield, small quantity of three wastes, lower raw material cost, easiness for industrialization, and the like.
Description
(1) technical field
The present invention relates to a kind of synthetic method of methoxyphenamine hydrochloride.
(2) background technology
Methoxyphenamine hydrochloride claims Methoxyphenaminium Chloride again, it is a class receptor, agonist, main exciting beta receptor, to the α receptor acting extremely a little less than, antiasthmatic effect is strong than ephedrine, the cardiovascular systems side effect is less, is mainly used in the bronchial asthma person that particularly can not tolerate the ephedrine clinically.Its structural formula is as follows:
The price of methoxyphenamine hydrochloride bulk drug on Chinese market is relatively more expensive at present, the traditional method of preparation methoxyphenamine hydrochloride is J.Am.Chem.Soc., 1953,75 (4), what 921-915 reported is starting raw material with the O-methoxy phenyl aldehyde, under alkaline condition,, through iron/iron trichloride/hydrochloric acid system reduction, make the O-methoxy Propiophenone then with the nitroethane condensation, add methylamine hydrochloride at last, with the amination of platinum dioxide hydrogenating reduction, logical hydrogenchloride salify makes methoxyphenamine hydrochloride.
Nitroethane that relates in this method and platinum dioxide catalyzer price are more expensive, can strengthen production cost; Use iron trichloride and iron can produce a large amount of waste water, waste residue, bigger to environmental hazard.
About the synthetic method of intermediate O-methoxy Propiophenone, Chemistry Letters, 2003,32 (8), it is raw material that 730-731 has reported with the methyl-phenoxide, makes catalyzer with manganese acetate, generates the O-methoxy Propiophenone with the acetone reaction.There is competitive reaction in this method, o-, m-, p-, ratio be 84: 2: 13, the difficulty of separate purifying, and manganese acetate large usage quantity can produce a large amount of waste residues after the reaction, are difficult for handling.
Preparation method about intermediate O-methoxy Vonedrine, Journal of Chromatographic Science, 1989,27 (10), 602-6 has reported that with the O-methoxy Propiophenone methylamine is a raw material, obtains the O-methoxy Vonedrine with the sodium cyanoborohydride reduction, it is more expensive to use sodium cyanoborohydride reductive agent price in the reaction, is unfavorable for suitability for industrialized production.
(3) summary of the invention
The objective of the invention is to overcome the shortcoming of existing methoxyphenamine hydrochloride synthesis technique, develop one easy and simple to handle, reaction conditions is gentle, production safety is easy to control, reaction yield is higher, material consumption is few, the three wastes are few, be easy to handle, can realize advantage such as industrialization.
The technical solution used in the present invention is:
A kind of synthetic method suc as formula the methoxyphenamine hydrochloride shown in (I), described method comprises:
(1) structure is miscible in diacetyl oxide suc as formula O-methoxy toluylic acid shown in (III) and organic bases, in 40～160 ℃ of reactions 1～10 hour, reaction finished the separation and purification of afterreaction liquid and obtains suc as formula the O-methoxy Propiophenone shown in (II) under nitrogen protection; Described organic bases is one of following: triethylamine, pyridine, N-Methylimidazole, 1-phenylimidazole, quinoline, piperidines, Tri-n-Propylamine, tri-isopropyl amine, diethyl propylamine, tri-n-butylamine, 1,2 dimethylimidazole; Be preferably one of following: quinoline, pyridine, N-Methylimidazole; Described O-methoxy toluylic acid: diacetyl oxide: the ratio of the quality of organic bases is 1: 0.5～3: 0.1～0.8;
(2) O-methoxy Propiophenone, 33% (w/w) methylamine alcohol solution, Pt/C catalyzer and the organic solvent B with step (1) gained joins in the autoclave, keep hydrogen pressure at 0.5～5.0MPa, 20～80 ℃ were reacted 2～20 hours down, and reaction finishes the separation and purification of afterreaction liquid and obtains suc as formula the O-methoxy Vonedrine shown in (IV); Described O-methoxy Propiophenone: 33% methylamine alcohol solution: the ratio of the quality of Pt/C catalyzer is 1: 0.5～3.0: 0.005～0.05; Described catalyzer can be the Pt/C catalyzer of the conventional Pt charge capacity 1～10% in this area, and is preferred, among the present invention in the used Pt/C catalyzer charge capacity of Pt be 1% (w/w), water content is 61% (w/w);
(3) the O-methoxy Vonedrine with step (2) gained is dissolved among the organic solvent C, feeds exsiccant HCl gas, and until system pH≤1, the reaction solution separation and purification obtains methoxyphenamine hydrochloride (I);
Described organic solvent A, organic solvent B, organic solvent C independently are one of following or wherein two or more mixtures: C separately
1～C
6Halogenated alkane, C
1～C
6Alcohol, C
2～C
6Ester, C
3～C
6Ketone, C
6～C
9Aromatic hydrocarbons;
Described organic solvent A～C consumption can be selected routinely, and is preferred, and the quality consumption of described organic solvent A is 1～10 times of quality of O-methoxy toluylic acid; The quality consumption of described organic solvent B is 1～10 times of quality of O-methoxy Propiophenone; The quality consumption of described organic solvent C is 1～10 times of quality of O-methoxy Vonedrine.
Preferably, described organic solvent A is one of following: methylene dichloride, chloroform, ethyl acetate; Described organic solvent B is one of following: ethyl acetate, ethanol, methylene dichloride, chloroform; Described organic solvent C is one of following: toluene, ethyl acetate, ethanol, acetone.
Separation and purification can be carried out routinely in described step (1)～(3), preferably, step (1) separation purification method is as follows: excessive acid anhydrides is reclaimed in the reaction solution underpressure distillation, add proper amount of sodium hydroxide solution, regulation system pH value 〉=12 add the organic solvent A extraction then, the organic layer of telling is removed organic bases with dilute hydrochloric acid, pure water washing successively, the reclaim under reduced pressure organic solvent A, the residue underpressure distillation obtains suc as formula the O-methoxy Propiophenone shown in (II);
Step (2) separation purification method is as follows: the reaction solution suction filtration reclaims catalyzer, the reclaim under reduced pressure organic solvent B, and the residue underpressure distillation obtains suc as formula the O-methoxy Vonedrine shown in (IV);
Step (3) separation purification method is as follows: the reaction solution suction filtration, and the filter cake washing with acetone gets the methoxyphenamine hydrochloride crude product, uses organic solvent D recrystallization again, obtains methoxyphenamine hydrochloride (I); Described organic solvent D is following one or more mixture: methyl alcohol, ethanol, n-propyl alcohol, Virahol, benzene, toluene, ethyl acetate; Be preferably one of following: ethanol, toluene; The consumption of described recrystallization organic solvent D is 1～10 times of methoxyphenamine hydrochloride crude product quality.
O-methoxy toluylic acid in the described step (1): diacetyl oxide: the ratio of the quality of organic bases is preferably 1: 1～and 2: 0.3～0.6.
Preferably, temperature of reaction is 90～120 ℃ in the described step (1), 1～5 hour reaction times; Temperature of reaction is 20～50 ℃ in the step (2), hydrogen pressure 1.0～2.0Mpa, 2～10 hours reaction times.
Concrete, described method is as follows:
(1) O-methoxy toluylic acid, N-Methylimidazole is miscible in diacetyl oxide, reacted 1～5 hour in 90～120 ℃ under the nitrogen protection, excessive acid anhydrides is reclaimed in underpressure distillation, add organic bases, regulation system pH value 〉=12 add the organic solvent A extraction then, the organic layer of telling is removed organic bases with dilute hydrochloric acid, pure water washing successively, the reclaim under reduced pressure organic solvent A, the residue underpressure distillation obtains the O-methoxy Propiophenone; Described O-methoxy toluylic acid: diacetyl oxide: the ratio of the quality of organic bases is preferably 1: 1～and 2: 0.3～0.6; Described organic solvent A is one of following: methylene dichloride, chloroform, ethyl acetate;
(2) O-methoxy Propiophenone, 33% methylamine alcohol solution, Pt/C catalyzer and the organic solvent B with step (1) gained joins in the autoclave, fill hydrogen to 1.0～2.0MPa, 20～50 ℃ were reacted 2～10 hours down, suction filtration reclaims catalyzer, the reclaim under reduced pressure organic solvent A, the residue underpressure distillation obtains the O-methoxy Vonedrine; Described O-methoxy Propiophenone: 33% methylamine alcohol solution: the ratio of the quality of Pt/C catalyzer is 1: 0.5～3.0: 0.005～0.05; Described organic solvent B is one of following: ethyl acetate, ethanol, methylene dichloride, chloroform;
(3) the O-methoxy Vonedrine with step (2) gained is dissolved among the organic solvent C, feeds exsiccant HCl gas, until system pH≤1, suction filtration, the filter cake washing with acetone gets the methoxyphenamine hydrochloride crude product, use organic solvent D recrystallization again, obtain described methoxyphenamine hydrochloride; Described organic solvent C is one of following: toluene, ethyl acetate, ethanol, acetone; Described organic solvent D is one of following: ethanol, toluene.
Beneficial effect of the present invention is mainly reflected in:
A) the invention provides a kind of novel method for preparing methoxyphenamine hydrochloride and key intermediate O-methoxy Propiophenone, have environmental protection, be easy to characteristics such as industrialization;
B) avoided from the source because of using iron powder, iron trichloride, reductive agent sodium cyanoborohydride to produce a large amount of waste water, waste residue.That novel process has is easy and simple to handle, reaction conditions is gentle, reaction yield is higher, quantity of three wastes is less, raw materials cost is lower, be easy to advantages such as industrialization.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1: the preparation of O-methoxy Propiophenone (III)
In the 1L there-necked flask; add the 367g diacetyl oxide successively; O-methoxy toluylic acid 300g; pyridine 100g; reacted 6 hours in 40 ℃ under the nitrogen protection; excessive acid anhydrides is removed in decompression, adds 20%NaOH 400mL, stirs; add methylene dichloride 400mL extraction then; the organic layer of telling is removed pyridine, reclaim under reduced pressure methylene dichloride, residue underpressure distillation with dilute hydrochloric acid 150mL, pure water 200mL washing successively; collect the cut of 90～100 ℃/5mmHg; get 197.3g O-methoxy Propiophenone, yield 75%, GC purity 99.3%.
Embodiment 2: the preparation of O-methoxy Propiophenone (III)
The mass ratio that feeds intake is the O-methoxy toluylic acid: diacetyl oxide: N-Methylimidazole=1: 0.5: 0.4, temperature of reaction is 80 ℃, and the reaction times is 5h, and organic solvent A is an ethyl acetate, the quality consumption is 2 times of O-methoxy toluylic acid quality, and other are operated with embodiment 1; Obtain product O-methoxy Propiophenone, yield 79.5%, GC purity 99.2%.
Embodiment 3: the preparation of O-methoxy Propiophenone (III)
The mass ratio that feeds intake is the O-methoxy toluylic acid: diacetyl oxide: quinoline=1: 1: 0.6, temperature of reaction are 160 ℃, and the reaction times is 1h, and organic solvent A is a chloroform, and the quality consumption is 3 times of O-methoxy toluylic acid quality, and other are operated with embodiment 1; Obtain product O-methoxy Propiophenone, yield 72.5%, GC purity 98.9%.
Embodiment 4: the preparation of O-methoxy Propiophenone (III)
The plasmid that feeds intake ratio is the O-methoxy toluylic acid: diacetyl oxide: piperidines=1: 2: 0.8, temperature of reaction are 100 ℃, and the reaction times is 10h, and organic solvent A is a methylene dichloride, and the quality consumption is 10 times of O-methoxy toluylic acid quality, and other are operated with embodiment 1; Obtain product O-methoxy Propiophenone, yield 70%, GC purity 99.1%.
Embodiment 5: the preparation of O-methoxy Propiophenone (III)
The mass ratio that feeds intake is the O-methoxy toluylic acid: diacetyl oxide: tri-n-butylamine=1: 3: 0.7, temperature of reaction are 110 ℃, and the reaction times is 4h, and organic solvent A is a chloroform, and the quality consumption is 5 times of O-methoxy toluylic acid quality, and other are operated with embodiment 1; Obtain product O-methoxy Propiophenone, yield 71.1%, GC purity 99.1%.
Embodiment 6: the preparation of O-methoxy Propiophenone (III)
The mass ratio that feeds intake is the O-methoxy toluylic acid: diacetyl oxide: 1,2 dimethylimidazole=1: 2: 0.4, temperature of reaction are 90 ℃, reaction times is 3h, organic solvent A is an ethyl acetate, and the quality consumption is 6 times of O-methoxy toluylic acid quality, and other are operated with embodiment 1; Obtain product O-methoxy Propiophenone, yield 79.5%, GC purity 99.1%.
Embodiment 7: the preparation of O-methoxy Propiophenone (III)
The mass ratio that feeds intake is the O-methoxy toluylic acid: diacetyl oxide: pyridine=1: 3: 0.1, temperature of reaction is 130 ℃, reaction times is 6h, organic solvent A is a methylene dichloride, the quality consumption is 7 times of O-methoxy toluylic acid quality, and other are operated with embodiment 1, obtain product O-methoxy Propiophenone, yield 70.5%, GC purity 99.1%.
Embodiment 8: the preparation of methoxyphenamine hydrochloride (IV)
In autoclave, add O-methoxy Propiophenone 100g, 33% methylamine alcohol solution 116g, the 1%Pt/C catalyzer (is purchased the triumphant bright catalyzer company limited in Hangzhou, charge capacity 1%, water content 61%) 1.0g, ethyl acetate 100g fills hydrogen to 0.5MPa, and 20 ℃ were reacted 20 hours down, suction filtration reclaims catalyzer, the reclaim under reduced pressure ethyl acetate, the residue underpressure distillation obtains product O-methoxy Vonedrine.
The O-methoxy Vonedrine (IV) of gained is dissolved among the ethanol 100g, feed exsiccant HCl gas, until system pH≤1, the adularescent crystal is separated out, suction filtration, the filter cake washing with acetone gets the methoxyphenamine hydrochloride crude product, uses ethanol 100g recrystallization again, obtain product methoxyphenamine hydrochloride 80.9g, yield 62.5%, fusing point: 130.5～131.7 ℃, HPLC is 99.5%
Embodiment 9: the preparation of methoxyphenamine hydrochloride (IV)
O-methoxy Propiophenone: 33% methylamine alcohol solution: the mass ratio of 1%Pt/C catalyzer is 1: 0.5: 0.05; Organic solvent B is an ethanol, and consumption is 2 times of O-methoxy Propiophenone quality; Organic solvent C is a toluene, and consumption is 2 times of O-methoxy Vonedrine quality; Organic solvent D is a toluene, and consumption is 10 times of methoxyphenamine hydrochloride crude product quality; Temperature of reaction is 30 ℃, and the reaction times is 18h, and hydrogen pressure is 1.0MPa; Other operations obtain the product methoxyphenamine hydrochloride with embodiment 8, yield 62.5%, and fusing point: 129.8-131.4 ℃, HPLC is 99.5%.
Embodiment 10: the preparation of methoxyphenamine hydrochloride (IV)
O-methoxy Propiophenone: 33% methylamine alcohol solution: the mass ratio of 1%Pt/C catalyzer is 1: 3: 0.005, and organic solvent B is a methylene dichloride, and consumption is 3 times of O-methoxy Propiophenone quality; Organic solvent C is an ethyl acetate, and consumption is 5 times of O-methoxy Vonedrine quality; Organic solvent D is ethanol and toluene=1: 4, and consumption is 5 times of methoxyphenamine hydrochloride crude product quality; Temperature of reaction is 40 ℃, and the reaction times is 16h, and hydrogen pressure is 5.0MPa; Other operations obtain the finished product methoxyphenamine hydrochloride with embodiment 8, yield 76.8%, and fusing point: 129.6-131.6 ℃, HPLC is 99.6%.
Embodiment 11: the preparation of methoxyphenamine hydrochloride (IV)
O-methoxy Propiophenone: 33% methylamine alcohol solution: the mass ratio of 1%Pt/C catalyzer is 1: 3: 0.01; Organic solvent B is a chloroform, and consumption is 3 times of O-methoxy Propiophenone quality, is acetone with organic solvent C, and consumption is 1 times of O-methoxy Vonedrine quality; Organic solvent D is an ethyl acetate, and consumption is 4 times of methoxyphenamine hydrochloride crude product quality; Temperature of reaction is 50 ℃, and the reaction times is 6h, and hydrogen pressure is 3.0MPa; Other operations obtain the finished product methoxyphenamine hydrochloride with embodiment 8, yield 66.4%, and fusing point: 129.3-130.6 ℃, HPLC is 99.7%.
Embodiment 12: the preparation of methoxyphenamine hydrochloride (IV)
O-methoxy Propiophenone: 33% methylamine alcohol solution: the mass ratio of 1%Pt/C catalyzer is 1: 2: 0.02; Organic solvent B is a methyl alcohol, and consumption is 3 times of O-methoxy Propiophenone quality; Organic solvent C is an ethanol, and consumption is 2 times of O-methoxy Vonedrine quality; Organic solvent D is an ethyl acetate: toluene=1: 1, consumption are 3 times of methoxyphenamine hydrochloride crude product quality; Temperature of reaction is 60 ℃; Reaction times is 8h, and hydrogen pressure is 2.5MPa; Other operations obtain the finished product methoxyphenamine hydrochloride with embodiment 8, yield 68.5%, and fusing point: 129.7-131.2 ℃, HPLC is 99.5%.
Embodiment 13: the preparation of methoxyphenamine hydrochloride (IV)
O-methoxy Propiophenone: 33% methylamine alcohol solution: the mass ratio of 1%Pt/C catalyzer is 1: 2.5: 0.03; Organic solvent B is an ethyl acetate, and consumption is 7 times of O-methoxy Propiophenone quality; Organic solvent C is a methyl alcohol, and consumption is 5 times of O-methoxy Vonedrine quality; Organic solvent D is an ethanol, and consumption is 6 times of methoxyphenamine hydrochloride crude product quality; Temperature of reaction is 80 ℃, and the reaction times is 2h, and hydrogen pressure is 2.0MPa; Other operations obtain the finished product methoxyphenamine hydrochloride with embodiment 8, yield 58.5%, and fusing point: 128.6-131.8 ℃, HPLC is 99.6%.
Embodiment 14: the preparation of methoxyphenamine hydrochloride (IV)
O-methoxy Propiophenone: 33% methylamine alcohol solution: the mass ratio of 1%Pt/C catalyzer is 1: 3: 0.04; Organic solvent B is an ethanol, and consumption is 9 times of O-methoxy Propiophenone quality; Organic solvent C is an acetone, and consumption is 8 times of O-methoxy Vonedrine quality; Organic solvent D is an ethanol, and consumption is 10 times of methoxyphenamine hydrochloride crude product quality; Temperature of reaction is 40 ℃, and the reaction times is 12h, and hydrogen pressure is 3.5MPa; Other operations obtain the finished product methoxyphenamine hydrochloride with embodiment 8, yield 67.6%, and fusing point: 129.8-131.6 ℃, HPLC is 99.5%.
Claims (9)
1. synthetic method suc as formula the methoxyphenamine hydrochloride shown in (I), described method comprises:
(1) structure is miscible in diacetyl oxide suc as formula O-methoxy toluylic acid shown in (III) and organic bases, in 40～160 ℃ of reactions 1～10 hour, reaction finished the separation and purification of afterreaction liquid and obtains suc as formula the O-methoxy Propiophenone shown in (II) under nitrogen protection; Described organic bases is one of following: triethylamine, pyridine, N-Methylimidazole, 1-phenylimidazole, quinoline, piperidines, Tri-n-Propylamine, tri-isopropyl amine, diethyl propylamine, tri-n-butylamine, 1,2 dimethylimidazole; Described O-methoxy toluylic acid: diacetyl oxide: the ratio of the quality of organic bases is 1:0.5～3:0.1～0.8;
(2) O-methoxy Propiophenone, 33% methylamine alcohol solution, Pt/C catalyzer and the organic solvent B with step (1) gained joins in the autoclave, keep hydrogen pressure at 0.5～5.0MPa, 20～80 ℃ were reacted 2～20 hours down, and reaction finishes the separation and purification of afterreaction liquid and obtains suc as formula the O-methoxy Vonedrine shown in (IV); Described O-methoxy Propiophenone: 33% methylamine alcohol solution: the ratio of the quality of Pt/C catalyzer is 1:0.5～3.0:0.005～0.05;
(3) the O-methoxy Vonedrine with step (2) gained is dissolved among the organic solvent C, feeds exsiccant HCl gas, and until system pH≤1, the reaction solution separation and purification obtains methoxyphenamine hydrochloride (I);
Described organic solvent B, organic solvent C independently are one of following or wherein two or more mixtures: C separately
1～C
6Halogenated alkane, C
1～C
6Alcohol, C
2～C
6Ester, C
3～C
6Ketone, C
6～C
9Aromatic hydrocarbons;
2. the method for claim 1 is characterized in that: the quality consumption of described organic solvent B is 1～10 times of quality of O-methoxy Propiophenone; The quality consumption of described organic solvent C is 1～10 times of quality of O-methoxy Vonedrine.
3. method as claimed in claim 1 or 2 is characterized in that: described organic solvent B is one of following: ethyl acetate, ethanol, methylene dichloride, chloroform; Described organic solvent C is one of following: toluene, ethyl acetate, ethanol, acetone.
4. the method for claim 1, it is characterized in that step (1) separation purification method is as follows: excessive acid anhydrides is reclaimed in the reaction solution underpressure distillation, add sodium hydroxide solution regulation system pH value 〉=12, add the organic solvent A extraction then, the organic layer of telling is removed organic bases with dilute hydrochloric acid, pure water washing successively, the reclaim under reduced pressure organic solvent A, the residue underpressure distillation obtains suc as formula the O-methoxy Propiophenone shown in (II); Described organic solvent A is one of following: methylene dichloride, chloroform, ethyl acetate.
5. the method for claim 1 is characterized in that step (2) separation purification method is as follows: the reaction solution suction filtration reclaims catalyzer, the reclaim under reduced pressure organic solvent B, and the residue underpressure distillation obtains suc as formula the O-methoxy Vonedrine shown in (IV).
6. the method for claim 1 is characterized in that step (3) separation purification method is as follows: the reaction solution suction filtration, the filter cake washing with acetone, the methoxyphenamine hydrochloride crude product, use organic solvent D recrystallization again, obtain methoxyphenamine hydrochloride (I); Described organic solvent D is following one or more mixture: methyl alcohol, ethanol, n-propyl alcohol, Virahol, benzene, toluene, ethyl acetate; The consumption of described recrystallization organic solvent D is 1～10 times of methoxyphenamine hydrochloride crude product quality.
7. the method for claim 1, it is characterized in that O-methoxy toluylic acid in the described step (1): diacetyl oxide: the ratio of the quality of organic bases is 1:1～2:0.3～0.6.
8. the described method of claim 1 is characterized in that temperature of reaction is 90～120 ℃ in the described step (1), 1～5 hour reaction times; Temperature of reaction is 20～50 ℃ in the step (2), hydrogen pressure 1.0～2.0Mpa, 2～10 hours reaction times.
9. the method for claim 1 is characterized in that described method is as follows:
(1) O-methoxy toluylic acid, N-Methylimidazole is miscible in diacetyl oxide, reacted 1～5 hour in 90～120 ℃ under the nitrogen protection, excessive acid anhydrides is reclaimed in underpressure distillation, add organic bases, regulation system pH value 〉=12 add the organic solvent A extraction then, the organic layer of telling is removed organic bases with dilute hydrochloric acid, pure water washing successively, the reclaim under reduced pressure organic solvent A, the residue underpressure distillation obtains the O-methoxy Propiophenone; Described O-methoxy toluylic acid: diacetyl oxide: the ratio of the quality of organic bases is 1:1～2:0.3～0.6; Described organic solvent A is one of following: methylene dichloride, chloroform, ethyl acetate;
(2) O-methoxy Propiophenone, 33% methylamine alcohol solution, Pt/C catalyzer and the organic solvent B with step (1) gained joins in the autoclave, fill hydrogen to 1.0～2.0MPa, 20～50 ℃ were reacted 2～10 hours down, suction filtration reclaims catalyzer, the reclaim under reduced pressure organic solvent B, the residue underpressure distillation obtains the O-methoxy Vonedrine; Described O-methoxy Propiophenone: 33% methylamine alcohol solution: the ratio of the quality of Pt/C catalyzer is 1:0.5～3.0:0.005～0.05; Described organic solvent B is one of following: ethyl acetate, ethanol, methylene dichloride, chloroform;
(3) the O-methoxy Vonedrine with step (2) gained is dissolved among the organic solvent C, feeds exsiccant HCl gas, until system pH≤1, suction filtration, the filter cake washing with acetone gets the methoxyphenamine hydrochloride crude product, use organic solvent D recrystallization again, obtain described methoxyphenamine hydrochloride; Described organic solvent C is one of following: toluene, ethyl acetate, ethanol, acetone; Described organic solvent D is one of following: ethanol, toluene.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101203214A (en) * | 2005-04-13 | 2008-06-18 | 艾升制药公司 | Beta-2 adrenoceptor agonists for treating connective tissue diseases of the skin |
-
2011
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Patent Citations (1)
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Non-Patent Citations (4)
| Title |
|---|
| Christopher Fotsch et al..Synthesis and Structure-Activity Relationships of Trisubstituted Phenyl Urea Derivatives as Neuropeptide Y5 Receptor Antagonists.《J. Med. Chem.》.2001,第44卷(第14期),2344-2356. |
| Physiologically Active Secondary Amines. β-(o-Methoxypheny1)-isopropyl-N-methylamine and Related Compounds;R.V.HEINZELMAN;《J. Am. Chem. Soc.》;19530220;第75卷(第4期);921-925 * |
| R.V.HEINZELMAN.Physiologically Active Secondary Amines. β-(o-Methoxypheny1)-isopropyl-N-methylamine and Related Compounds.《J. Am. Chem. Soc.》.1953,第75卷(第4期),921-925. |
| Synthesis and Structure-Activity Relationships of Trisubstituted Phenyl Urea Derivatives as Neuropeptide Y5 Receptor Antagonists;Christopher Fotsch et al.;《J. Med. Chem.》;20010605;第44卷(第14期);2344-2356 * |
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