CN106083600A - A kind of synthetic method of amphetamine pharmaceutical intermediate 1 phenyl 2 aminopropane - Google Patents

A kind of synthetic method of amphetamine pharmaceutical intermediate 1 phenyl 2 aminopropane Download PDF

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Publication number
CN106083600A
CN106083600A CN201610392910.8A CN201610392910A CN106083600A CN 106083600 A CN106083600 A CN 106083600A CN 201610392910 A CN201610392910 A CN 201610392910A CN 106083600 A CN106083600 A CN 106083600A
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China
Prior art keywords
synthetic method
benzedrine
mass fraction
pharmaceutical intermediate
feature exists
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彭飞
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Chengdu Qiesite Technology Co Ltd
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Chengdu Qiesite Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/86—Separation

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses the synthetic method of a kind of amphetamine pharmaceutical intermediate 1 phenyl 2 aminopropane.By 2,5 dimethyl benzylamines and in ethylo benzene acetone mixed solution, add propiophenone and molybdenum chloride powder, carry out heating up, booster reaction, then lower the temperature, get rid of air, then through filtering, decompression distill, wash, be dehydrated, recrystallization, obtain 1 phenyl 2 aminopropane.This synthetic method was greatly shortened compared to the synthetic method in background technology, response time, and yield significantly improves；The invention provides a kind of new synthetic route simultaneously, lay a good foundation for promoting reaction yield further.

Description

A kind of synthetic method of amphetamine pharmaceutical intermediate benzedrine
Technical field
The present invention relates to the preparation method of a kind of medicine intermediate, belong to organic synthesis field, particularly relate to a kind of peace non- The synthetic method of his bright pharmaceutical intermediate benzedrine.
Background technology
Amphetamine medicine is mainly used in narcolepsy, anesthetics and other central depressant poisoning, spirit depressing Disease etc..Amphetamine medicine has two kinds of optical isomers, and curban is the most active higher one.Other members Also have dexoxyn and Tylagel.These medicines can partly reverse anesthetics, narcotic, hypnotic and ethanol Inhibitory action.Can cause profound mental effect, lower including Vigilance, feeling of fatigue, language increases, and the energy focused on Power strengthens.Eat in ante cibum and can reduce appetite, so being widely used for auxiliary limit food to lose weight.Pilot, trucker Require to keep the task of waking state often to use this medicine for a long time in execution with soldier.In terms for the treatment of hyperkinetic syndrome, also play Main Function, because this medicine just can make infant calm after taking one day, makes them to focus on.It is additionally operable to treatment outbreak Property sleep disease.Benzedrine is as amphetamine pharmaceutical intermediate, and its synthetic method is good and bad for improving medicine conjunction Become product quality, reduce by-products content and there is Important Economic meaning.
Chinese invention patent CN105461576A discloses and a kind of uses O-methoxy propiophenone urging at platinum/C catalyst Under change effect, hydrogenation, temperature rising reflux is synthesized the method for O-methoxy phenpromethamine, but this synthetic method, reaction Overlong time, more than 18 hours, yield was on the low side, less than 80%.Therefore, it is necessary to propose a kind of new 1-phenyl-2-aminopropan Alkane synthetic method.
Summary of the invention
The technical problem existed based on background technology, the present invention propose a kind of amphetamine pharmaceutical intermediate 1-phenyl- The synthetic method of 2-aminopropane.
The synthetic method of a kind of amphetamine pharmaceutical intermediate benzedrine, comprises the steps:
A, in high-pressure reaction vessel add propiophenone (chemical formula 2) 8.3mol, molybdenum chloride powder 10.2mol, 2,5-bis- Methylbenzylamine solution 2L, to ethylo benzene acetone soln 1.5-1.9L, sealed reaction vessel, gets rid of air, raises solution temperature extremely 60-68 DEG C, increase container pressure to 2.1-2.8MPa, reacts 110-150min；
B, reduction solution temperature, to 10-16 DEG C, are got rid of air, are filtered, and filtrate decompression is distilled, and collects the fraction of 70-76 DEG C, Nitromethane solution washs, and pyridine solution washs, and dehydrant is dehydrated, and recrystallization in ethylenediamine solution obtains crystal 1-phenyl-2- Aminopropane (chemical formula 1)；
Preferably, described 2,5-dimethyl benzylamine liquid quality fraction is 35-46%.
Preferably, described is 40-53% to ethylo benzene acetone soln mass fraction.
Preferably, the described residing pressure of decompression distillation is 0.8-0.9kPa.
Preferably, described nitromethane solution mass fraction is 70-83%.
Preferably, described pyridine solution mass fraction is 80-89%.
Preferably, described dehydrant is any one in dead plaster, Anhydrous potassium carbonate.
Preferably, described ethylenediamine solution mass fraction is 85-92%.
Whole course of reaction can represent with following reaction equation:
Compared to synthetic method disclosed in background technology, the amphetamine pharmaceutical intermediate 1-phenyl-2-that the present invention provides The synthetic method of aminopropane, the response time is greatly shortened, and reaction yield significantly improves, and the invention provides a kind of new simultaneously Synthetic route, lays a good foundation for promoting reaction yield further.
Accompanying drawing explanation
Fig. 1 is the mass fraction of the 2,5-dimethylbenzyl amine aqueous solution normal distribution on the impact of reaction yield.Wherein, horizontal Coordinate is the mass fraction of 2,5-dimethylbenzyl amine aqueous solution；Vertical coordinate is reaction yield.
Fig. 2 is the normal distribution on the impact of reaction yield of the mass fraction on ethylo benzene acetone soln.Wherein, horizontal seat It is designated as the mass fraction to ethylo benzene acetone soln；Vertical coordinate is reaction yield.
Detailed description of the invention
Embodiment 1:
The synthetic method of a kind of amphetamine pharmaceutical intermediate benzedrine, comprises the steps:
A, in high-pressure reaction vessel add propiophenone 8.3mol, molybdenum chloride powder 10.2mol, mass fraction is 40% 2,5-dimethylbenzyl amine aqueous solution 2L, mass fraction is 47% couple of ethylo benzene acetone soln 1.9L, sealed reaction vessel, gets rid of sky Gas, raise solution temperature to 68 DEG C, increase container pressure to 2.8MPa, react 150min；
B, reducing solution temperature to 16 DEG C, get rid of air, filter, filtrate 0.9kPa reduces pressure distillation, collects 70-76 DEG C Fraction, mass fraction is 83% nitromethane solution washing, and mass fraction is 85% pyridine solution washing, and dead plaster is dehydrated Agent is dehydrated, and recrystallization in mass fraction is 89% ethylenediamine solution obtains crystal benzedrine 1030.86g, receives Rate 92%.
Embodiment 2:
The synthetic method of a kind of amphetamine pharmaceutical intermediate benzedrine, comprises the steps:
A, in high-pressure reaction vessel add propiophenone 8.3mol, molybdenum chloride powder 10.2mol, mass fraction is 35% 2,5-dimethylbenzyl amine aqueous solution 2L, mass fraction be 40% to ethylo benzene acetone soln 1.5L, sealed reaction vessel, get rid of sky Gas, raise solution temperature to 60 DEG C, increase container pressure to 2.1MPa, react 110min；
B, reducing solution temperature to 10 DEG C, get rid of air, filter, filtrate 0.8kPa reduces pressure distillation, collects 70-76 DEG C evaporate Point, mass fraction is the nitromethane solution washing of 70%, and mass fraction is the pyridine solution washing of 80%, and dead plaster takes off Water preparation is dehydrated, and recrystallization in the ethylenediamine solution that mass fraction is 85% obtains crystal benzedrine 997.86g, Yield 89%.
Embodiment 3:
The synthetic method of a kind of amphetamine pharmaceutical intermediate benzedrine, comprises the steps:
A, in high-pressure reaction vessel add propiophenone 8.3mol, molybdenum chloride powder 10.2mol, mass fraction is 35% 2,5-dimethylbenzyl amine aqueous solution 2L, mass fraction be 40% to ethylo benzene acetone soln 1.7L, sealed reaction vessel, get rid of sky Gas, raise solution temperature to 65 DEG C, increase container pressure to 2.3MPa, react 130min；
B, reducing solution temperature to 12 DEG C, get rid of air, filter, filtrate 0.85kPa reduces pressure distillation, collects 73 DEG C evaporate Point, mass fraction is 78% nitromethane solution washing, and mass fraction is 85% pyridine solution washing, Anhydrous potassium carbonate dehydrant Dehydration, recrystallization in the ethylenediamine solution that mass fraction is 87%, obtain crystal benzedrine 974.84g, yield 87%.
By the response time of embodiment 1-3 with yield compared with background technology, obtain following data:
Response time h Reaction yield %
Embodiment 1 4 92
Embodiment 2 3 89
Embodiment 3 3.5 87
Background technology ＞ 18 ＜ 80
The described method in background technology be Chinese invention patent CN102267917A record utilize O-methoxy benzene The method of acetone synthesis O-methoxy phenpromethamine.
From embodiment 1-3, the synthetic method of the benzedrine that the present invention provides, the response time is permissible Controlling within 5h, the most under the preferred conditions, reaction yield can control more than 85%, provides compared to background technology Synthetic method, the yield of the method significantly improves, and the response time is greatly shortened.
Below embodiment 4-8 is contrasted with embodiment 1, the percent mass comparison yield of each solution in research reaction Impact.
Embodiment 4:
By 2 in embodiment 1, the mass fraction of 5-dimethylbenzyl amine aqueous solution is adjusted, remaining preparation condition and raw material Proportioning is same as in Example 1, obtains reaction yield as follows:
The impact on reaction yield of the mass fraction of table one: 2,5-dimethylbenzyl amine aqueous solution
2,5-dimethyl benzylamine liquid quality fraction % 20 26 31 35 40 46 49 54 59
Reaction yield % 72 81 87 90 92 90 87 80 70
From embodiment 4, the mass fraction of 2,5-dimethylbenzyl amine aqueous solutions is too high or too low all can affect reaction yield, It becomes normal distribution (Fig. 1) with reaction yield, and it is 35-46% that peak value occurs in mass fraction.
Embodiment 5:
Being adjusted by the mass fraction to ethylo benzene acetone soln in embodiment 1, remaining preparation condition is joined with raw material Ratio is same as in Example 1, obtains reaction yield as follows:
Table two: on the impact on reaction yield of the mass fraction of ethylo benzene acetone soln
To ethylo benzene acetone soln mass fraction % 27 32 37 40 47 53 55 60 65
Reaction yield % 53 67 82 88 91 86 82 72 60
From embodiment 5, reaction yield all can be affected on the mass fraction of ethylo benzene acetone soln is too high or too low, its Become normal distribution (Fig. 2) with reaction yield, it is 15-28% that peak value occurs in mass fraction.
Embodiment 6:
The mass fraction of the nitromethane solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials with Embodiment 1 is identical, obtains reaction yield as follows:
Table three: the mass fraction of nitromethane solution is on reaction yield and the impact of wash time
Nitromethane solution mass fraction % 59 63 68 70 77 83 81 85 89
Reaction yield % 70 80 85 91 92 92 92 92 93
Wash time min 35 32 27 20 19 19 18 18 17
From embodiment 8, the too small impact on reaction yield of mass fraction of nitromethane solution is very big, during to washing Between affect the biggest, it is considered to cost, the mass fraction of nitromethane solution is preferably 70-83%.
Embodiment 7:
The mass fraction of the pyridine solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials and enforcement Example 1 is identical, obtains reaction yield as follows:
Table four: the mass fraction of pyridine solution is on reaction yield and the impact of wash time
Pyridine solution mass fraction % 69 73 78 80 85 89 91 93 95
Reaction yield % 90 90 91 91 92 92 92 92 93
Wash time min 35 28 25 18 17 17 17 17 17
From embodiment 8, the mass fraction of pyridine solution is the least on the impact of reaction yield, but affects wash time Bigger, it is considered to cost, the mass fraction of pyridine solution is preferably 70-83%.
Embodiment 8:
The mass fraction of the ethylenediamine solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials and reality Execute example 1 identical, obtain reaction yield as follows:
Table five: the mass fraction of ethylenediamine solution is on reaction yield and the impact of recrystallization time
Ethylenediamine solution mass fraction % 78 81 83 85 89 92 94 96 98
Reaction yield % 92 92 92 92 92 92 92 92 92
Recrystallization time min 25 22 20 15 15 15 15 14 14
From embodiment 8, reaction yield is not affected by the mass fraction of ethylenediamine solution, but the time to recrystallization Affect bigger, it is considered to cost, the mass fraction of ethylenediamine solution is preferably 85-92%.
Embodiment 9:
The residing pressure of decompression distillation in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials and embodiment 1 phase With, obtain reaction yield as follows:
Table six: the residing pressure impact on reaction yield of decompression distillation
The residing pressure kPa of decompression distillation 0.65 0.7 0.75 0.8 0.85 0.9 0.95 1.0 1.2
Reaction yield % 92 92 92 92 92 92 92 92 92
The time min of decompression distillation 8 8 8 9 9 9 13 15 18
From embodiment 9, reaction yield is not affected by the residing pressure of decompression distillation, but the residing pressure of decompression distillation is relatively Time big, the time needed for decompression distillation is longer, it is considered to cost, and the pressure residing for decompression distillation is preferably 0.8-0.9kPa.
Described in above example, the only present invention preferably detailed description of the invention, but protection scope of the present invention not office Being limited to this, any those familiar with the art is in the technical scope that the invention discloses, according to the technology of the present invention Scheme and inventive concept equivalent or change in addition thereof, all should contain within protection scope of the present invention.

Claims (8)

1. the synthetic method of an amphetamine pharmaceutical intermediate benzedrine, it is characterised in that include walking as follows Rapid:
A, in high-pressure reaction vessel add propiophenone 8.3mol, molybdenum chloride powder 10.2mol, 2,5-dimethylbenzyl amine aqueous solutions 2L, to ethylo benzene acetone soln 1.5-1.9L, sealed reaction vessel, gets rid of air, and rising solution temperature, to 60-68 DEG C, raises Container pressure, to 2.1-2.8MPa, reacts 110-150min；
B, reduction solution temperature, to 10-16 DEG C, are got rid of air, are filtered, and filtrate decompression is distilled, and collects the fraction of 70-76 DEG C, nitro Dichloromethane washs, and pyridine solution washs, and dehydrant is dehydrated, and recrystallization in ethylenediamine solution obtains crystal 1-phenyl-2-amino Propane.
2. the synthetic method of amphetamine pharmaceutical intermediate benzedrine as claimed in claim 1, its feature exists In, described 2,5-dimethyl benzylamine liquid quality fraction is 35-46%.
3. the synthetic method of amphetamine pharmaceutical intermediate benzedrine as claimed in claim 1, its feature exists In, described is 40-53% to ethylo benzene acetone soln mass fraction.
4. the synthetic method of amphetamine pharmaceutical intermediate benzedrine as claimed in claim 1, its feature exists In, the described residing pressure of decompression distillation is 0.8-0.9kPa.
5. the synthetic method of amphetamine pharmaceutical intermediate benzedrine as claimed in claim 1, its feature exists In, described nitromethane solution mass fraction is 70-83%.
6. the synthetic method of amphetamine pharmaceutical intermediate benzedrine as claimed in claim 1, its feature exists In, described pyridine solution mass fraction is 80-89%.
7. the synthetic method of amphetamine pharmaceutical intermediate benzedrine as claimed in claim 1, its feature exists In, described dehydrant is any one in dead plaster, Anhydrous potassium carbonate.
8. the synthetic method of amphetamine pharmaceutical intermediate benzedrine as claimed in claim 1, its feature exists In, described ethylenediamine solution mass fraction is 85-92%.
CN201610392910.8A 2016-06-02 2016-06-02 A kind of synthetic method of amphetamine pharmaceutical intermediate 1 phenyl 2 aminopropane Pending CN106083600A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102267917A (en) * 2011-06-15 2011-12-07 浙江工业大学 Method for synthesizing methoxyphenamine hydrochloride

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102267917A (en) * 2011-06-15 2011-12-07 浙江工业大学 Method for synthesizing methoxyphenamine hydrochloride

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IVAN V. MICOVIC ET AL: "Preparation of secondary amines by reductive amination with metallic magnesium", 《J. CHEM. SOC. PERKIN TRANS. 1》 *

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Application publication date: 20161109