CN108047224A - A kind of method for preparing enamine perchlorate - Google Patents
A kind of method for preparing enamine perchlorate Download PDFInfo
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- CN108047224A CN108047224A CN201711193302.5A CN201711193302A CN108047224A CN 108047224 A CN108047224 A CN 108047224A CN 201711193302 A CN201711193302 A CN 201711193302A CN 108047224 A CN108047224 A CN 108047224A
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- indoles
- perchlorate
- ethamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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Abstract
The invention belongs to the field of chemical synthesis, are related to a kind of method for preparing enamine perchlorate, comprise the following steps：(1) 3 ethamine of 1H indoles and γ hydroxypropyl ethyl malonic acid, pyroreaction are added in the first organic solvent；(2) reacted again after adding in phosphorus oxychloride；(3) it is removed under reduced pressure the first organic solvent and excessive phosphorus oxychloride, after water on the rocks, buck, is extracted with dichloromethane, concentrate dichloromethane layer after extraction, obtain grease；(4) in a second organic solvent, the grease is reacted with perchloric acid, crystallization.The preparation method step is few, and post processing is simple, and product quality is good, high income, and environmental pollution is small.
Description
Technical field
1- ethyl -2,3,4,6,7,12- hexahydro -1H- indoles [2,3- is prepared the present invention relates to a kind of in the field of chemical synthesis
A] quinolizine -5- perchlorate method.
Background technology
1- ethyls -2,3,4,6,7,12- hexahydro -1H- indoles [2,3-a] quinolizine -5- perchlorate, the high chlorine of abbreviation enamine
Hydrochlorate, for the important intermediate in chemical and medicine industry synthesis.
The enamine synthetic method of document report at present：Using γ-hydroxypropyl-ethyl malonic acid as starting material, with 1H- Yin
Diindyl -3- ethamine reacts, and decarboxylation temperature is higher, easily generates impurity.Further add in phosphorus oxychloride after, it is necessary to 140 DEG C react 2~
3 it is small when, generate a large amount of black tars substances at this time, it is difficult to post-process, product colour is brown, and yield is relatively low, mole receive
Rate only has 40%.This method needs high temperature, and yield and purity are relatively low, are unfavorable for industrialized production.In addition, ring-closure reaction
When phosphorus oxychloride dosage it is big, post processing trouble, environmental protection pressure is very big.Therefore, develop it is a kind of prepare 1- ethyls -2,3,4,
The method of 6,7,12- hexahydro -1H- indoles [2,3-a] quinolizine -5- perchlorate is always new problem urgently to be resolved hurrily.
The content of the invention
1- ethyls -2,3,4,6,7,12- hexahydro -1H- indoles [2,3-a] quinoline is prepared the object of the present invention is to provide a kind of
The method of piperazine -5- perchlorate, the preparation method route is shorter, and step is few, and post processing is simple, and high income, product quality is good,
And the processing of the three wastes is relatively reasonable.
The object of the present invention is achieved like this：A kind of method for preparing enamine perchlorate, the preparation method are included such as
Lower step：
(1) 1H- indoles -3- ethamine and γ-hydroxypropyl-ethyl malonic acid, pyroreaction are added in the first organic solvent；
(2) reacted again after adding in phosphorus oxychloride；
(3) it is removed under reduced pressure the first organic solvent and excessive phosphorus oxychloride, after water on the rocks, buck, is extracted with dichloromethane,
Dichloromethane layer is concentrated after extraction, obtains grease；
(4) in a second organic solvent, the grease is reacted with perchloric acid, crystallization.
In step (1), the molar ratio of 1H- indoles -3- ethamine and γ-hydroxypropyl-ethyl malonic acid is 1:1~1.5；
In step (1), the quality of 1H- indoles -3- ethamine and the volume ratio of the first organic solvent are 1：5~7, the unit of the quality is
Gram, the unit of the volume is milliliter；In step (1), the temperature of the reaction is 122~142 DEG C, the time of the reaction
For 2~3 it is small when；In step (1), first organic solvent in toluene, dimethylbenzene, n,N-Dimethylformamide one
Kind is several；In step (2), the temperature of the reaction is 95~115 DEG C, when the time of the reaction is 4~6 small；It is described
The volume ratio of phosphorus oxychloride is 1 in the quality of 1H- indoles -3- ethamine and step (2):2~3, the unit of the quality for gram, institute
The unit for stating volume is milliliter；In step (3), the alkali is selected from alkali metal hydroxide, the alkali metal hydroxide choosing
From one or more of potassium hydroxide, sodium hydroxide, the buck is the alkali metal hydroxide of mass content 35%~45%
Object aqueous solution；After the water on the rocks, buck, pH 8~13 is adjusted to；In step (4), second organic solvent be selected from methanol,
One or more of ethyl alcohol；In step (4), the quality of 1H- indoles -3- ethamine is 1 with the volume ratio of the second organic solvent:4
~5；In step (4), the quality of the 1H- indoles -3- ethamine and the volume ratio of perchloric acid are 1:0.4~0.5, the quality
Unit for gram, the unit of the volume is milliliter；In step (4), the temperature of the crystallization is -15~5 DEG C, preferably -10
~0 DEG C, when the crystallization time is 2~4 small；In step (1), the temperature of the reaction is 134~138 DEG C；In step (2),
The temperature of the reaction is 105~110 DEG C；In step (3), after the water on the rocks, buck, pH 12~13 is adjusted to.
The present invention is characterized by its preparation synthetic method.Its principle is：Using γ-hydroxypropyl-ethyl malonic acid as rise
Beginning raw material carries out decarboxylic reaction with 1H- indoles -3- ethamine, and reaction temperature is preferably 134~138 DEG C, and the reaction time is small for 2~3
When, without post processing, it is directly added into 2~3 times of phosphorus oxychloride and carries out ring-closure reaction, reaction temperature is preferably 105~110 DEG C,
When reaction time is 4~6 small, being generated at this time without black tars substance, easy post-processing, product quality is good, and color is glassy yellow,
Mass content 99% (HPLC), and yield improves, molar yield 70% or so.
A kind of side for preparing 1- ethyls -2,3,4,6,7,12- hexahydro -1H- indoles [2,3-a] quinolizine -5- perchlorate
Method compared with prior art, has the advantages that step is few, and post processing is simple, and product quality is good, high income, environmental pollution is small,
It will be widely used in chemical industry synthesis field.
Description of the drawings
The following describes the present invention in detail with reference to the accompanying drawings and embodiments.
Fig. 1 is the structural formula figure of enamine perchlorate.
Fig. 2 is the structural formula figure of γ-hydroxypropyl-ethyl malonic acid.
Fig. 3 is the structural formula figure of 1H- indoles -3- ethamine.
Fig. 4 present invention prepares 1- ethyls -2,3,4,6,7,12- hexahydro -1H- indoles [2,3-a] quinolizine -5- perchlorate
Synthetic route chart.
Specific embodiment
With reference to embodiment, the present invention is described further, and embodiment helps to more fully understand the present invention, but
The present invention is not limited only to following embodiments.
Embodiment one
Added in 1000mL dries four-hole bottle 1H- indoles -3- ethamine 25g, γ-hydroxypropyl-ethyl malonic acid 30g and
125mL dimethylbenzene.It is warming up to 130 DEG C, when mechanical agitation 2 is small.Then phosphorus oxychloride 62.5mL is added dropwise.Under the conditions of 105 DEG C, machine
When tool stirring 4 is small.Decompression boils off dimethylbenzene and excessive phosphorus oxychloride, under water-bath cooling, is added in into remaining liquid
Then 35% sodium hydrate aqueous solution is added dropwise in 250mL ice water, be adjusted to pH 12~13.Add in dichloromethane 300mL, liquid separation, water
Layer adds in 250mL water, adds in dichloromethane 200mL, and liquid separation is collected dichloromethane layer, washed with saturated salt solution 250mL, depressurizes
Concentration and recovery dichloromethane obtains red oil.100mL methanol is added in into red oil, is dripped under the conditions of bathing -5 DEG C outside
Increase chloric acid 10mL, be precipitated yellow solid, when stirring 2 is small under the conditions of 0 DEG C, filter, methanol is washed, and obtains product enamine perchlorate
38.5g, glassy yellow, LC-MS (Waters ' ACQUITY UPLC-Xevo TQ)：M=253, fusing point (SGW X-4 micro melting points
Instrument)：175.5-176.8 DEG C, mass content 92.5% (HPLC), molar yield 69.9%.
Embodiment two
Added in 1000mL dries four-hole bottle 1H- indoles -3- ethamine 25g, γ-hydroxypropyl-ethyl malonic acid 37g and
150mL dimethylbenzene.It is warming up to 134 DEG C, when mechanical agitation 2.5 is small.Then phosphorus oxychloride 50mL is added dropwise.Under the conditions of 105 DEG C, machine
When tool stirring 5 is small.Decompression boils off dimethylbenzene and excessive phosphorus oxychloride, under water-bath cooling, is added in into remaining liquid
Then 40% sodium hydrate aqueous solution is added dropwise in 250mL ice water, be adjusted to pH 12~13.Add in dichloromethane 300mL, liquid separation, water
Layer adds in 250mL water, adds in dichloromethane 200mL, and liquid separation is collected dichloromethane layer, washed with saturated salt solution 250mL, depressurizes
Concentration and recovery dichloromethane obtains red oil.110mL methanol is added in into red oil, is dripped under the conditions of bathing -5 DEG C outside
Increase chloric acid 11mL, be precipitated yellow solid, when stirring 3 is small under the conditions of -5 DEG C, filter, methanol is washed, and obtains product enamine perchlorate
40g, glassy yellow, LC-MS (Waters ' ACQUITY UPLC-Xevo TQ)：M=253, fusing point (SGW X-4 micro-meldometers)：
176.0-177.2 DEG C, mass content 99.3% (HPLC), molar yield 72.9%.
Embodiment three
The influence of decarboxylation temperature
Added in 1000mL dries four-hole bottle 1H- indoles -3- ethamine 25g, γ-hydroxypropyl-ethyl malonic acid 37g and
150mL dimethylbenzene.The temperature reached that heats up is shown in Table 1, when mechanical agitation 2.5 is small.Then phosphorus oxychloride 50mL is added dropwise.At 105 DEG C
Under the conditions of, when mechanical agitation 5 is small.Decompression boils off dimethylbenzene and excessive phosphorus oxychloride, under water-bath cooling, to remaining liquid
Middle addition 250mL ice water, is then added dropwise 40% sodium hydrate aqueous solution, is adjusted to pH 12~13.Dichloromethane 300mL is added in, point
Liquid, water layer add in 250mL water, add in dichloromethane 200mL, and liquid separation is collected dichloromethane layer, washed with saturated salt solution 250mL,
The recycling dichloromethane that is concentrated under reduced pressure obtains red oil.110mL methanol is added in into red oil, bathes -5 DEG C of conditions outside
Yellow solid is precipitated in lower dropwise addition perchloric acid 11mL, when stirring 3 is small under the conditions of -5 DEG C, filters, methanol is washed, and obtains the high chlorine of product enamine
Hydrochlorate, mass content and molar yield are shown in Table 1：
As shown in Table 1, with the rise of decarboxylation temperature, the yield and content of enamine perchlorate gradually rise, then with
The further rise of temperature, yield raises and content reduces, this is because excessively high temperature so that portion of product is carbonized, preferably
Reaction temperature be 134~138 DEG C.
Influence of 1 decarboxylation temperature of table to reaction yield and finished product content
| Decarboxylation temperature (DEG C) | 122 | 126 | 130 | 134 | 138 | 142 |
| Molar yield (%) | 52.2 | 54.3 | 69.3 | 72.9 | 75.3 | 76.2 |
| Mass content (%) | 86.2 | 86.5 | 90.5 | 99.3 | 82.2 | 75.6 |
Example IV
The influence of phosphorus oxychloride dosage
Added in 1000mL dries four-hole bottle 1H- indoles -3- ethamine 25g, γ-hydroxypropyl-ethyl malonic acid 37g and
150mL dimethylbenzene.It is warming up to 134 DEG C, when mechanical agitation 2.5 is small.Then phosphorus oxychloride is added dropwise, the dosage of phosphorus oxychloride is shown in Table 2.
Under the conditions of 105 DEG C, when mechanical agitation 5 is small.Decompression boils off dimethylbenzene and excessive phosphorus oxychloride, under water-bath cooling, to residual
250mL ice water is added in remaining liquid, 40% sodium hydrate aqueous solution is then added dropwise, is adjusted to pH 12~13.Add in dichloromethane
300mL, liquid separation, water layer add in 250mL water, add in dichloromethane 200mL, and liquid separation collects dichloromethane layer, uses saturated salt solution
250mL is washed, and the recycling dichloromethane that is concentrated under reduced pressure obtains red oil.110mL methanol is added in into red oil, outside
Perchloric acid 11mL is added dropwise under the conditions of -5 DEG C of bath, yellow solid is precipitated, when stirring 3 is small under the conditions of -5 DEG C, filters, methanol is washed, must produced
Product enamine perchlorate, mass content and molar yield are shown in Table 2.
As shown in Table 2, increasing with phosphorus oxychloride dosage, the yield and content of enamine perchlorate gradually rise, and
Afterwards with the further rise of phosphorus oxychloride dosage, yield and content rise unobvious, it is contemplated that the post processing of phosphorus oxychloride is asked
Topic, the volume of preferred phosphorus oxychloride are 2-3 times of 1H- indoles -3- ethamine quality.
Influence of the dosage of 2 phosphorus oxychloride of table to reaction yield and finished product content
Embodiment five
The influence of cyclization temperature
Added in 1000mL dries four-hole bottle 1H- indoles -3- ethamine 25g, γ-hydroxypropyl-ethyl malonic acid 37g and
150mL dimethylbenzene.It is warming up to 134 DEG C, when mechanical agitation 2.5 is small.Then phosphorus oxychloride 50mL is added dropwise.Reaction temperature is shown in Table 3, machine
When tool stirring 5 is small.Decompression boils off dimethylbenzene and excessive phosphorus oxychloride, under water-bath cooling, is added in into remaining liquid
Then 40% sodium hydrate aqueous solution is added dropwise in 250mL ice water, be adjusted to pH 12~13.Add in dichloromethane 300mL, liquid separation, water
Layer adds in 250mL water, adds in dichloromethane 200mL, and liquid separation is collected dichloromethane layer, washed with saturated salt solution 250mL, depressurizes
Concentration and recovery dichloromethane obtains red oil.110mL methanol is added in into red oil, is dripped under the conditions of bathing -5 DEG C outside
To increase chloric acid 11mL, be precipitated yellow solid, when stirring 3 is small under the conditions of -5 DEG C, filter, methanol is washed, and obtains product enamine perchlorate,
Mass content and molar yield are shown in Table 3.
As shown in Table 3, with the rise of cyclization temperature, the yield and content of enamine perchlorate gradually rise, then with
The further rise of temperature, yield and content reduce, this is because by-product is generated under hot conditions, preferred reaction temperature
It spends for 105~110 DEG C.
Influence of the 3 cyclization temperature of table to reaction yield and finished product content
| Cyclization temperature (DEG C) | 90 | 95 | 100 | 105 | 110 | 115 |
| Molar yield (%) | 54.3 | 59.3 | 65.2 | 72.9 | 70.1 | 65.8 |
| Mass content (%) | 84.2 | 86.5 | 88.3 | 99.3 | 89.2 | 85.5 |
Embodiment six
Added in 1000mL dries four-hole bottle 1H- indoles -3- ethamine 25g, γ-hydroxypropyl-ethyl malonic acid 44g and
175mL dimethylbenzene.It is warming up to 138 DEG C, when mechanical agitation 3 is small.Then phosphorus oxychloride 75mL is added dropwise.Under the conditions of 110 DEG C, machinery
Stir 6 it is small when.Decompression boils off dimethylbenzene and excessive phosphorus oxychloride, and under water-bath cooling, 250mL is added in into remaining liquid
Then 45% sodium hydrate aqueous solution is added dropwise in ice water, be adjusted to pH 12~13.Dichloromethane 300mL, liquid separation are added in, water layer adds in
250mL water, adds in dichloromethane 200mL, and liquid separation collects dichloromethane layer, washed, be concentrated under reduced pressure back with saturated salt solution 250mL
It receives dichloromethane and obtains red oil.125mL methanol is added in into red oil, high chlorine is added dropwise under the conditions of bathing -5 DEG C outside
Yellow solid is precipitated in sour 12.5mL, when stirring 4 is small under the conditions of -10 DEG C, filters, methanol is washed, and obtains product 37.7g, glassy yellow, LC-
MS(Waters′ACQUITY UPLC-Xevo TQ)：M=253, fusing point (SGW X-4 micro-meldometers)：175.0~176.7
DEG C, mass content 82.5% (HPLC), molar yield 74.6%.
It should be appreciated that for those of ordinary skills, can be improved or converted according to the above description,
And all these modifications and variations should all belong to the protection domain of appended claims of the present invention.
Claims (10)
- A kind of 1. method for preparing enamine perchlorate, it is characterised in that：The preparation method includes the following steps：(1) 1H- indoles -3- ethamine and γ-hydroxypropyl-ethyl malonic acid, pyroreaction are added in the first organic solvent；(2) reacted again after adding in phosphorus oxychloride；(3) it is removed under reduced pressure the first organic solvent and excessive phosphorus oxychloride, after water on the rocks, buck, is extracted, extracted with dichloromethane Dichloromethane layer is concentrated afterwards, obtains grease；(4) in a second organic solvent, the grease is reacted with perchloric acid, crystallization.
- 2. a kind of method for preparing enamine perchlorate according to claim 1, it is characterised in that：In step (1), The molar ratio of 1H- indoles -3- ethamine and γ-hydroxypropyl-ethyl malonic acid is 1:1~1.5；In step (1), 1H- indoles -3- The quality of ethamine and the volume ratio of the first organic solvent are 1：5~7, the unit of the quality for gram, the unit of the volume is Milliliter.
- 3. a kind of method for preparing enamine perchlorate according to claim 1, it is characterised in that：In step (1), institute The temperature of reaction is stated as 122~142 DEG C, when the time of the reaction is 2~3 small；In step (1), described first is organic molten Agent is selected from one or more of toluene, dimethylbenzene, N,N-dimethylformamide.
- 4. a kind of method for preparing enamine perchlorate according to claim 1, it is characterised in that：In step (2), institute The temperature of reaction is stated as 95~115 DEG C, when the time of the reaction is 4~6 small.
- 5. a kind of method for preparing enamine perchlorate according to claim 1, it is characterised in that：1H- indoles-the 3- The volume ratio of phosphorus oxychloride is 1 in the quality and step (2) of ethamine:2~3, the unit of the quality for gram, the list of the volume Position is milliliter.
- 6. a kind of method for preparing enamine perchlorate according to claim 1, it is characterised in that：In step (3), institute It states alkali and is selected from alkali metal hydroxide, the alkali metal hydroxide is selected from one or more of potassium hydroxide, sodium hydroxide, The buck is the alkali metal hydroxide aqueous solution of mass content 35%~45%；After the water on the rocks, buck, pH 8 is adjusted to ~13.
- 7. a kind of method for preparing enamine perchlorate according to claim 1, it is characterised in that：In step (4), institute It states the second organic solvent and is selected from one or more of methanol, ethyl alcohol；In step (4), the quality of 1H- indoles -3- ethamine and the The volume ratio of two organic solvents is 1:4~5；In step (4), the quality of the 1H- indoles -3- ethamine and the volume of perchloric acid Than for 1:0.4~0.5, the unit of the quality for gram, the unit of the volume is milliliter；In step (4), the crystallization Temperature be -15~5 DEG C, preferably -10~0 DEG C, the crystallization time for 2~4 it is small when.
- 8. a kind of method for preparing enamine perchlorate according to claim 3, it is characterised in that：In step (1), institute The temperature for stating reaction is 134~138 DEG C.
- 9. a kind of method for preparing enamine perchlorate according to claim 4, it is characterised in that：In step (2), institute The temperature for stating reaction is 105~110 DEG C.
- 10. a kind of method for preparing enamine perchlorate according to claim 6, it is characterised in that：In step (3), After the water on the rocks, buck, pH 12~13 is adjusted to.
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| CN201711193302.5A CN108047224A (en) | 2017-11-24 | 2017-11-24 | A kind of method for preparing enamine perchlorate |
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| CN201711193302.5A CN108047224A (en) | 2017-11-24 | 2017-11-24 | A kind of method for preparing enamine perchlorate |
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| CN201711193302.5A Pending CN108047224A (en) | 2017-11-24 | 2017-11-24 | A kind of method for preparing enamine perchlorate |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1401579A (en) * | 1972-09-06 | 1975-07-16 | Richter Gedeon Vegyeszet | Indolo-quinolizines |
-
2017
- 2017-11-24 CN CN201711193302.5A patent/CN108047224A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1401579A (en) * | 1972-09-06 | 1975-07-16 | Richter Gedeon Vegyeszet | Indolo-quinolizines |
Non-Patent Citations (2)
| Title |
|---|
| ANDRÁS NEMES ET AL: "Synthesis of metabolites of cis and trans apovincamine derivatives", 《ARKIVOC》 * |
| C. SZANTAY ET AL: "Synthesis of Vinca alkaloids and related compounds. II. Stereoselective and enantioselective synthesis of (+)-vincamine", 《TETRAHEDRON》 * |
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