CN109705046A - A kind of preparation method of high-purity 1- methyl-luminal - Google Patents
A kind of preparation method of high-purity 1- methyl-luminal Download PDFInfo
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- CN109705046A CN109705046A CN201910047981.8A CN201910047981A CN109705046A CN 109705046 A CN109705046 A CN 109705046A CN 201910047981 A CN201910047981 A CN 201910047981A CN 109705046 A CN109705046 A CN 109705046A
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Abstract
The object of the present invention is to provide a kind of preparation methods for preparing high-purity 1- methyl-luminal (lower abbreviation chemical compounds I), including two steps: A, α-ethyl-α-phenyl ethyl malonate (lower abbreviation compound III) acts on methylurea and 1- methyl-luminal sodium (lower abbreviation compound ii) is made in the presence of the methanol solution of sodium methoxide；Compound ii is acidified the crude product that chemical compounds I is made through hydrochloric acid again；B, by the above-mentioned crude product for obtaining chemical compounds I with ethanol water recrystallize chemical compounds I fine work；The process stabilizing, reaction condition is easily controllable, stable product quality, 99.0% or more gained crude product HPLC content, and through once product HPLC purity > 99.9% after purification, high income, production cost is low, is more suitable for industrialized production.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of 1- methyl -5- ethyl -5- phenyl barbital of high-purity
The preparation method of acid.
Background technique
The present invention relates to the by-product impurities that a kind of luminal production process generates, pharmacology is made
It with, structurally similar compounds almost the same with luminal, while being also 5- ethyl -5- phenyl barbital
The main related substance 1- methyl-luminal of one kind generated in sour production process, and in refining pure
Change process is difficult to remove.In order to preferably carry out product quality research and production requirement.Hair of the present invention referring to inventor oneself
Bright patent ZL 2,010 1 0211476.1, a kind of preparation method of luminal carry out experimental study, mention
It has supplied one kind by α-ethyl-α-phenyl ethyl malonate, in the presence of the methanol solution of sodium methoxide, has been acted on methylurea, system
Preparation method of the standby 1- methyl -5- ethyl -5- phenyl bar than compound.The process stabilizing, easy to operate, the period is short, product is received
Rate is high, and at low cost, stable product quality, low energy consumption, and the three wastes are few, is suitble to industrialized production.
Relevant document report；Its synthetic method mainly using ethyl benzoic acid and methylurea as raw material,
It is condensed and obtains under sodium ethoxide catalysis, but since a large amount of by-products generate, cause yield lower, and hardly result in high-purity
Product.Reference structure similar compound pertinent literature Anhui chemical industry, volume 33, the paper 5- ethyl -5- phenyl bar of the 2nd phase report
Than the study on the synthesis of appropriate acid, carry out the research of 1- methyl-luminal lab scale, find its material dosage and
Used catalyst activity etc. all there is a problem of a large amount of.Since what is firstly generated during the reaction is the sodium salt of product, and it is somebody's turn to do
Catalyst sodium ethoxide used in paper is completely converted into the sodium salt of luminal, at most also there was only 42%
Product sodium salt generate, and the reaction is just can be carried out under the catalysis of sodium ethoxide, activity and methanol used in this application
Sodium is compared to relatively poor, therefore the shortcomings that this method technique is that product yield is low, and products obtained therefrom is of poor quality, and by-product is more, and
Xylene extraction need to be used, energy consumption is high, and also higher to the content requirement of sodium ethoxide in ethanol, and the three wastes are more, at high cost.
Summary of the invention
High-purity 1- methyl-luminal compound is prepared the object of the present invention is to provide a kind of
The new process of (lower abbreviation chemical compounds I), the process stabilizing, reaction condition is easily controllable, and entire reaction is complete during steaming alcohol
At easy to operate, reaction condition is mild, and easily controllable, the three wastes are few, stable product quality, gained crude product HPLC content 99.0%
More than, through once product HPLC purity > 99.9% after purification, high income, production cost is low, is more suitable for industrialized production.
The object of the present invention is achieved like this:
A kind of preparation method of high-purity 1- methyl-luminal (lower abbreviation chemical compounds I), including
Two steps:
A, α-ethyl-α-phenyl ethyl malonate (lower abbreviation compound III) is in the presence of the methanol solution of sodium methoxide,
It is acted on methylurea and 1- methyl-luminal sodium (lower abbreviation compound ii) is made；Compound ii is again through salt
Acid is acidified the crude product that chemical compounds I is made；
B, by the above-mentioned crude product for obtaining chemical compounds I with ethanol water recrystallize chemical compounds I fine work.
A kind of preparation method of high-purity compound I is reacted as follows:
A kind of preparation method of high-purity compound I is firstly added suitable in the methanol solution of sodium methoxide
Ethyl acetate is warming up to reflux and eliminates free alkali therein；Methanol sodium content is 30 ± 1% (w/w).
A kind of preparation method of the chemical compounds I of high-purity, the molar ratio of step A reactant are as follows: compound III: first
Sodium alkoxide: methylurea=1:2.0~2.5:2.0~2.5；Reaction is completed during steaming alcohol, steams the control of alcohol temperature end point 115
~120 DEG C.
A kind of preparation method of high-purity compound I after step A steams alcohol, is cooled to 30 DEG C hereinafter, being added
0~5 DEG C of cold-water solution；Purification recovered carbon is added, is filtered, filtrate hydrochloric acid is acidified crystallization, the chemical compounds I crude product of filtering；
Dosage cold water: compound III=4~5:1 (w/w)；Acid out terminal pH value=3~4.
Subtractive process is the crude product of compound (I): ethanol water=1:2~3；Ethanol water content be 75%~
95%.
The present invention and existing the relevant technologies have the advantages that the process stabilizing, and reaction condition is mild, easily controllable, produce
Quality is stablized, and 99% or more gained compound (I) crude product HPLC content, Jing Yici purified compound (I) fine work HPLC is pure
Degree > 99.9%, high income, post-processing is easy, and the three wastes are few, and production cost is low, is suitble to industrialized production.
The present invention is further elaborated with reference to embodiments:
Embodiment 1:
Step A: 372.4g sodium methoxide (content 29%) methanol solution is added in reaction flask, 4.0g acetic acid second is added
Ester is warming up to micro- back flow reaction 30min and eliminates free alkali.Then methylurea 149.6g and 264.3g α-ethyl-α-phenyl is added
Diethyl malonate, heating are distilled to recover solvent to 120 DEG C of interior temperature.30 DEG C are cooled to hereinafter, 5 DEG C of cold water 985.0g stirrings are added
Dissolution, is added purification recovered carbon after dissolution, filtering, and filtrate is acidified crystallization to PH=3 with hydrochloric acid, filtering, washing, dry
Crude product 234.8g, the HPLC content 99.32% of compound (I).
Step B: by step A be made compound (I) crude product be added in reaction flask, add 95% ethyl alcohol 459.6g and
Active carbon, temperature rising reflux decolourize 0.5 hour, filtering, filtrate crystallisation, filtration washing, dry 210.3g compound (I) fine work,
HPLC content 99.95%.
Embodiment 2:
Step A: 435.5g sodium methoxide (content 31%) methanol solution is added in reaction flask, 5.0g acetic acid second is added
Ester is warming up to micro- back flow reaction 25min and eliminates free alkali.Then methylurea 185.2g and 264.3g α-ethyl-α-phenyl is added
Diethyl malonate, heating are distilled to recover solvent to 115 DEG C of interior temperature.30 DEG C are cooled to stir hereinafter, 0 DEG C of cold water 1321.2g is added
Dissolution is mixed, is added after dissolution and refines recovered carbon, filtering, filtrate is acidified crystallization to PH=4, filtering, washing, drying with hydrochloric acid
Obtain crude product 236.5g, the HPLC content 99.51% of compound (I).
Rapid B: the step A crude product that compound (I) is made is added in reaction flask, 85% ethyl alcohol 586.5g and work are added
Property charcoal, temperature rising reflux decolourizes 0.5 hour, filtering, filtrate crystallisation, filtration washing, dry 212.9g compound (I) fine work,
HPLC content 99.97%.
Embodiment 3:
Step A: 348.4g sodium methoxide (content 31%) methanol solution is added in reaction flask, 4.0g acetic acid second is added
Ester is warming up to micro- back flow reaction 20min and eliminates free alkali.Then methylurea 185.2g and 264.3g α-ethyl-α-phenyl is added
Diethyl malonate, heating are distilled to recover solvent to 115 DEG C of interior temperature.30 DEG C are cooled to stir hereinafter, 3 DEG C of cold water 1321.2g are added
Dissolution is mixed, is added after dissolution and refines recovered carbon, filtering, filtrate is acidified crystallization to PH=3.5 with hydrochloric acid, and filtering, is done washing
Dry crude product 234.9g, the HPLC content 99.27% for obtaining compound (I).
Rapid B: the step A crude product that compound (I) is made is added in reaction flask, 75% ethyl alcohol 701.4g and work are added
Property charcoal, temperature rising reflux decolourizes 0.5 hour, filtering, filtrate crystallisation, filtration washing, dry 233.9g compound (I) fine work,
HPLC content 99.92%.
Embodiment 4:
450.0g sodium methoxide (content 30%) methanol solution is added in reaction flask, 4.5g ethyl acetate is added, is risen
Wen Zhiwei back flow reaction 25min eliminates free alkali.Then methylurea 148.2g and 264.3g α-ethyl-α-phenylmalonic acid is added
Diethylester, heating are distilled to recover solvent to 120 DEG C of interior temperature.Be cooled to 30 DEG C hereinafter, be added 2 DEG C of cold water 1189.4g stirring and dissolvings,
Addition purification recovered carbon after dissolution, filtering, filtrate are acidified crystallization to PH=3.5 with hydrochloric acid, and filtering washes, is so dry that change
Close crude product 232.5g, the HPLC content 99.13% of object (I).
Rapid B: the step A crude product that compound (I) is made is added in reaction flask, 95% ethyl alcohol 463.0g and work are added
Property charcoal, temperature rising reflux decolourizes 0.5 hour, filtering, filtrate crystallisation, filtration washing, dry 214.7g compound (I) fine work,
HPLC content 99.94%.
Claims (5)
1. a kind of preparation method of high-purity 1- methyl-luminal (lower abbreviation chemical compounds I), feature
It is that this method includes two steps:
A, α-ethyl-α-phenyl ethyl malonate (lower abbreviation compound III) is in the presence of the methanol solution of sodium methoxide, with first
Base urea, which acts on, is made 1- methyl-luminal sodium (lower abbreviation compound ii)；Compound ii is again through hydrochloric acid acid
Change the crude product that chemical compounds I is made；
B, by the above-mentioned crude product for obtaining chemical compounds I with ethanol water recrystallize chemical compounds I fine work.
2. the preparation method of a kind of high-purity compound I described in accordance with the claim 1, it is characterized in that: in the methanol of sodium methoxide
In solution, it is firstly added suitable ethyl acetate and is warming up to reflux elimination free alkali therein；Methanol sodium content is 30 ± 1%
(w/w)。
3. a kind of preparation method of the chemical compounds I of high-purity described in accordance with the claim 1, it is characterized in that: step A reactant
Molar ratio are as follows: compound III: sodium methoxide: methylurea=1:2.0~2.5:2.0~2.5；Reaction is completed during steaming alcohol,
The control of alcohol temperature end point is steamed at 115~120 DEG C.
4. according to claim 1 or a kind of preparation method of high-purity compound I as claimed in claim 3, it is characterized in that: A is walked
After flash evaporation alcohol, 30 DEG C are cooled to hereinafter, 0~5 DEG C of cold-water solution is added；Purification recovered carbon is added, is filtered, filtrate
Hydrochloric acid is acidified crystallization, the chemical compounds I crude product of filtering；Dosage cold water: compound III=4~5:1 (w/w)；Acid out terminal pH value=3
~4.
5. the preparation method of a kind of high-purity compound I described in accordance with the claim 1, it is characterized in that: chemical compounds I in step B
Crude product: ethanol water=1:2~3 (w/w)；Ethanol water content is 75%~95% (w/w).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115583918A (en) * | 2022-09-29 | 2023-01-10 | 精华制药集团南通有限公司 | Preparation method of methyl phenobarbital |
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2019
- 2019-01-18 CN CN201910047981.8A patent/CN109705046A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115583918A (en) * | 2022-09-29 | 2023-01-10 | 精华制药集团南通有限公司 | Preparation method of methyl phenobarbital |
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