CN108440413A - The preparation method of high quality analgin - Google Patents
The preparation method of high quality analgin Download PDFInfo
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- CN108440413A CN108440413A CN201810386018.8A CN201810386018A CN108440413A CN 108440413 A CN108440413 A CN 108440413A CN 201810386018 A CN201810386018 A CN 201810386018A CN 108440413 A CN108440413 A CN 108440413A
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- analgin
- maa
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- solvent
- reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
- C07D231/48—Oxygen atom in position 3 or 5 and nitrogen atom in position 4 with hydrocarbon radicals attached to said nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to pharmaceutical preparation fields, more particularly to a kind of preparation method of high quality analgin, it is refined by 4 novalgin of intermediate (abbreviation MAA oil) produced to analgin, improve its purity, remove dark colours impurity and the inorganic salts such as colloid, condensation is carried out again and prepares analgin, and the analgin quality of preparation is higher than the standard of analgin.It the raw materials used in the present invention and normally produces raw materials used consistent, does not apply new solvent, the problem of there is no finished product novel solvent residuals, rational technology, the product quality of preparation is higher than the standard of analgin.
Description
Technical field
The invention belongs to pharmaceutical preparation fields, and in particular to a kind of preparation method of high quality analgin.
Background technology
Currently, the market demand of analgin is very powerful, main there are three quality standards, are CP standards, EP marks respectively
Accurate, injection standard.Since the production technology of analgin is longer, intermediate is more, and the impurity of generation is more, especially FAA (4- formyls
Base antipyrine), the quality of MAA directly affect the quality of analgin, prior art is difficult to produce the analgin of injection.It is logical
The quality for improving MAA is crossed, the quality for the analgin prepared is higher than the standard of injection.
Invention content
Solvent, rising temperature for dissolving, cooling analysis is added in intermediate MAA (4- novalgins) oil of analgin production
Crystalline substance is refined, and is improved purity, dark colours impurity and the inorganic salts such as removal colloid, then carry out condensation and prepare analgin, is prepared
Analgin quality be higher than analgin standard.
The present invention provides a kind of preparation methods of high quality analgin, it is characterised in that：
A is refined：It is molten that solvent heating is added in the intermediate 4- novalgins (lower abbreviation MAA oil) of analgin production
Solution, then the crystallization that cools down obtain refined MAA oil；
B condensations prepare analgin：Solvent dissolving is added in refined MAA, adds sodium hydrogensulfite, activated carbon, stirring rises
Temperature, formaldehyde (36%w/v) is added, then heat up, back flow reaction, reaction solution pH value is maintained at 7.0~7.5, and reaction is finished, press filtration；Filter
Liquid cools, and filters, and washs, dry, obtains analgin.
The preparation method of the high quality analgin, it is characterised in that：It is dissolved in step A molten used in MAA oil
A concentration of 80-100% (volume/volume) of agent；The proportioning (weight/volume) of MAA oil and solvent is 1:0.3-1；Solution temperature
It is 60-80 DEG C；Recrystallization temperature is 30-10 DEG C.
The preparation method of the high quality analgin, it is characterised in that：It is according to claim 1 high-quality
Measure the preparation method of analgin, it is characterised in that：In step B：
Refined MAA：Formaldehyde (36%w/v)：Sodium hydrogensulfite：Activated carbon：Solvent burden ratio=1:0.4:0.5:0.03:2.0
(w/w)；60 DEG C are warming up to hereinafter, formaldehyde (36%w/v) is added, is warming up to 78~80 DEG C, back flow reaction 1.5 hours,
Reaction solution pH value is maintained at 7.0~7.5, and reaction is finished, press filtration；Filtrate is cooled to 15~20 DEG C；60-100 DEG C of drying of reduced vacuum,
60-100 DEG C of constant pressure and dry.
The preparation method of the high quality analgin, it is characterised in that：A and step B solvent for use are second
Alcohol, isopropanol.
Compared with prior art, the present invention has the following advantages：
(1) present invention provides a kind of preparation method of high quality analgin, and the analgin of preparation complies fully with note
Penetrate the quality standard with analgin.The quality standard of analgin：First, 25% solution is colourless or is not deeper than yellow green I
Number comparison liquid.The analgin of prior art preparation is extremely difficult to；25% solution of analgin prepared by the present invention is colourless.Its
Two, methanol solution clarity should be clarified.Analgin methanol solution prepared by the present invention is clear with pure methanol ratio, is not had to right
According to liquor ratio；The analgin of prior art preparation is extremely difficult to.Third, sulfate detects, sample liquid must not be more newborn than titer.This
The sample liquid for inventing the analgin prepared is clear；The analgin of prior art preparation is extremely difficult to.
(2) MAA oil solvent for use of the present invention is ethyl alcohol, isopropanol, and removal of impurities mass-energy power is strong, is easily recycled and applies mechanically.
(3) MAA oil solvent for use ethyl alcohol of the present invention, isopropanol concentration be 80-100% (volume/volume), reacted
There is water in journey, concentration can change when alcohol, isopropanol recovering, and 80% to 100% can use.
(4) proportioning (weight/volume) of MAA oil and ethyl alcohol, isopropanol is 1 in the present invention:0.3-1, in matching for this range
Than the quality of MAA is almost the same.
(5) MAA oil solution temperatures are 60-80 DEG C in the present invention, solution temperature wider range, as long as it can be completely dissolved
Row.
(6) MAA oil recrystallization temperatures are 30-10 DEG C in the present invention, and room temperature crystallization is energy saving.
Description of the drawings
Fig. 1 is MAA prepared by the present invention；
Fig. 2 is the MAA of prior art preparation.
Specific implementation mode
With reference to embodiment, the present invention will be further described.
Embodiment 1
In reaction bulb, the MAA oil 200g of Workshop Production are added, 70ml90% ethyl alcohol is added, is warming up to 75 DEG C, MAA is molten
Clearly.Slow cooling is down to 10 DEG C, stirring and crystallizing 2 hours.It filters, appropriate 90% ethyl alcohol washing.99% or more purity, obtains 160g,
Yield 80%.Directly carry out condensation reaction.
MAA50g, 90% ethyl alcohol 100ml, sodium hydrogensulfite 25g, activated carbon 1.5g are added in reaction bulb, stirring heats up,
60 DEG C are warming up to hereinafter, formaldehyde (36%w/v) 20g is added, is warming up to 78~80 DEG C, back flow reaction 1.5 hours, back flow reaction 15
After minute, surveying reaction solution pH value should be 7.0~7.5, if less than being adjusted with sodium carbonate.Reaction is finished, press filtration.Filtrate is cooled to
It 15~20 DEG C, filters, the washing of 90% ethyl alcohol is dry, obtains analgin 70g, yield 86.6%.Product quality complies fully with injection
Standard.
Embodiment 2
In reaction bulb, the MAA oil 200g of Workshop Production are added, 70ml90% isopropanols are added, are warming up to 75 DEG C, MAA
Dissolved clarification.Slow cooling is down to 10 DEG C, stirring and crystallizing 2 hours.It filters, appropriate 90% isopropanol washing.Purity 99.2%, obtains
165g, yield 82.5%.Directly carry out condensation reaction.
MAA50g, 90% ethyl alcohol 100ml, sodium hydrogensulfite 25g, activated carbon 1.5g are added in reaction bulb, stirring heats up,
60 DEG C are warming up to hereinafter, formaldehyde (36%w/v) 20g is added, is warming up to 78~80 DEG C, back flow reaction 1.5 hours, back flow reaction 15
After minute, surveying reaction solution pH value should be 7.0~7.5, if less than being adjusted with sodium carbonate.Reaction is finished, press filtration.Filtrate is cooled to
It 15~20 DEG C, filters, the washing of 90% ethyl alcohol is dry, obtains analgin 71g, yield 87.9%.Product quality complies fully with injection
Standard.
Embodiment 3
In reaction bulb, the MAA oil 200g of Workshop Production are added, 100ml straight alcohols are added, are warming up to 80 DEG C, MAA is molten
Clearly.Slow cooling is down to 20 DEG C, stirring and crystallizing 2 hours.It filters, suitable alcohols washing.Purity 99.3% obtains 156g, yield
78%.Directly carry out condensation reaction.
MAA50g, 90% isopropanol 100ml, sodium hydrogensulfite 25g, activated carbon 1.5g are added in reaction bulb, stirring rises
Temperature is warming up to 60 DEG C hereinafter, addition formaldehyde (36%w/v) 20g, is warming up to 78~80 DEG C, back flow reaction 1.5 hours, reflux is instead
After answering 15 minutes, surveying reaction solution pH value should be 7.0~7.5, if less than being adjusted with sodium carbonate.Reaction is finished, press filtration.Filtrate is cold
But it to 15~20 DEG C, filters, the washing of 90% ethyl alcohol is dry, obtains analgin 70g, yield 86.6%.Product quality complies fully with note
It penetrates and uses standard.
Comparative example 1
MAA oil (content 93%) 53.8g, 90% ethyl alcohol 100ml, sodium hydrogensulfite 25g, activated carbon are added in reaction bulb
1.5g, stirring heating are warming up to 60 DEG C hereinafter, addition formaldehyde (36%w/v) 20g, is warming up to 78~80 DEG C, back flow reaction 1.5
Hour, for back flow reaction after 15 minutes, surveying reaction solution pH value should be 7.0~7.5, if less than being adjusted with sodium carbonate.Reaction is finished,
Press filtration.Filtrate is cooled to 15~20 DEG C, filters, the washing of 90% ethyl alcohol, dry, obtains analgin 65g, yield 80.4%.Product matter
Injection standard is not achieved in amount.
Claims (4)
1. a kind of preparation method of high quality analgin, it is characterised in that：
A is refined：Solvent rising temperature for dissolving is added in the intermediate 4- novalgins (lower abbreviation MAA oil) of analgin production,
Cool down crystallization again, obtains refined MAA oil；
B condensations prepare analgin：Solvent dissolving is added in refined MAA, adds sodium hydrogensulfite, activated carbon, stirring heating adds
Enter formaldehyde (36%w/v), then heat up, back flow reaction, reaction solution pH value is maintained at 7.0~7.5, and reaction is finished, press filtration；Filtrate cools down
Cooling filters, and washs, dry, obtains analgin.
2. the preparation method of high quality analgin according to claim 1, it is characterised in that：It is dissolved in step A
A concentration of 80-100% (volume/volume) of MAA oil solvent for use；The proportioning (weight/volume) of MAA oil and solvent is 1:0.3-
1；Solution temperature is 60-80 DEG C；Recrystallization temperature is 30-10 DEG C.
3. the preparation method of high quality analgin according to claim 1, it is characterised in that：In step B：
Refined MAA：Formaldehyde (36%w/v)：Sodium hydrogensulfite：Activated carbon：Solvent burden ratio=1:0.4:0.5:0.03:2.0 (weights
Amount/weight)；60 DEG C are warming up to hereinafter, addition formaldehyde (36%w/v), is warming up to 78~80 DEG C, back flow reaction 1.5 hours is reacted
Liquid pH value is maintained at 7.0~7.5, and reaction is finished, press filtration；Filtrate is cooled to 15~20 DEG C；60-100 DEG C of drying of reduced vacuum, 60-
100 DEG C of constant pressure and dries.
4. the preparation method of high quality analgin according to claim 1, it is characterised in that：Used in A and step B
Solvent is ethyl alcohol, isopropanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810386018.8A CN108440413A (en) | 2018-04-26 | 2018-04-26 | The preparation method of high quality analgin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810386018.8A CN108440413A (en) | 2018-04-26 | 2018-04-26 | The preparation method of high quality analgin |
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| CN201810386018.8A Pending CN108440413A (en) | 2018-04-26 | 2018-04-26 | The preparation method of high quality analgin |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU823384A1 (en) * | 1978-12-27 | 1981-04-23 | Филиал Всесоюзного Научно-Исследо-Вательского Химико-Фармацевтическогоинститута Им.Серго Орджоникидзе | Method of analgin purification |
| SU1325862A1 (en) * | 1985-05-16 | 1994-08-30 | Усолье-Сибирский химико-фармацевтический комбинат | Process for recovery of benzenesulfoacid antipyrine |
| CN102399191A (en) * | 2011-12-21 | 2012-04-04 | 武汉武药制药有限公司 | Method for synthesizing analgin |
| CN106279030A (en) * | 2016-08-08 | 2017-01-04 | 河北冀衡（集团）药业有限公司 | The method that the MAA crystallization using the molten method of wine to obtain produces COS dipyrone |
-
2018
- 2018-04-26 CN CN201810386018.8A patent/CN108440413A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU823384A1 (en) * | 1978-12-27 | 1981-04-23 | Филиал Всесоюзного Научно-Исследо-Вательского Химико-Фармацевтическогоинститута Им.Серго Орджоникидзе | Method of analgin purification |
| SU1325862A1 (en) * | 1985-05-16 | 1994-08-30 | Усолье-Сибирский химико-фармацевтический комбинат | Process for recovery of benzenesulfoacid antipyrine |
| CN102399191A (en) * | 2011-12-21 | 2012-04-04 | 武汉武药制药有限公司 | Method for synthesizing analgin |
| CN106279030A (en) * | 2016-08-08 | 2017-01-04 | 河北冀衡（集团）药业有限公司 | The method that the MAA crystallization using the molten method of wine to obtain produces COS dipyrone |
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