CN111592556A - Bromoacetyl-7-ACA production process - Google Patents
Bromoacetyl-7-ACA production process Download PDFInfo
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- CN111592556A CN111592556A CN202010279828.0A CN202010279828A CN111592556A CN 111592556 A CN111592556 A CN 111592556A CN 202010279828 A CN202010279828 A CN 202010279828A CN 111592556 A CN111592556 A CN 111592556A
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- aca
- bromoacetyl
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- triethylamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/28—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by an aliphatic carboxylic acid, which is substituted by hetero atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a bromoacetyl-7-ACA production process, which comprises the following steps: s1, adding purified water and 7-ACA into a reaction bottle, and uniformly stirring; s2, adjusting and keeping the temperature of the material at 0-5 ℃, dropwise adding triethylamine within 25-30 minutes, and stirring until the triethylamine is dissolved clearly; s3, adding activated carbon, and stirring and decoloring for 15-20 minutes; s4, filtering, and taking filtrate; s5, adding toluene and calcium salt, controlling the temperature of the material to be 13-20 ℃, accelerating the stirring speed, and dropwise adding bromoacetyl bromide within 30-60 minutes; s6, after dropwise adding bromoacetyl bromide, controlling the temperature to be 18-20 ℃, and stirring for reaction for 1-1.5 hours; s7, filtering to remove excessive calcium salt; standing the filtrate for 1-2 hours, layering, taking the liquid material at the lower layer, and recycling the upper layer for reuse; s9, adding 95% ethanol into the lower-layer liquid material, keeping the temperature at 10-15 ℃, and dropwise adding a hydrochloric acid solution until the pH value is 1.0; s10, reducing the stirring speed, preserving heat and growing the crystals for 30 minutes; s11, filtering, and taking a filter cake; s12, washing a filter cake with purified water; s13, washing a filter cake by using ethanol; s14, discharging, and drying the filter cake to obtain a finished product.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a bromoacetyl-7-ACA production process.
Background
The bromoacetyl-7-ACA is an intermediate of cefathiamidine, and sodium bicarbonate alkali solution is used as an acid-binding agent in the current synthesis process, so that an acidic by-product is neutralized in the reaction process, and the reaction liquid is kept neutral. The neutralization process is partially alkaline, which destroys the reaction raw materials and causes incomplete reaction.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a bromoacetyl-7-ACA production process.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a bromoacetyl-7-ACA production process is characterized by comprising the following steps:
s1, adding purified water and 7-ACA into a reaction bottle, and uniformly stirring;
s2, adjusting and keeping the temperature of the material at 0-5 ℃, dropwise adding triethylamine within 25-30 minutes, and stirring until the triethylamine is dissolved clearly;
s3, adding activated carbon, and stirring and decoloring for 15-20 minutes;
s4, filtering, and taking filtrate;
s5, adding toluene and calcium salt, controlling the temperature of the material to be 13-20 ℃, accelerating the stirring speed, and dropwise adding bromoacetyl bromide within 30-60 minutes;
s6, after the bromoacetyl bromide is dripped, controlling the temperature at 18-20 ℃, and stirring for reaction for 1-1.5 hours;
s7, filtering to remove excessive calcium salt;
standing the filtrate for 1-2 hours, layering, taking the liquid material at the lower layer, and recycling the upper layer for reuse;
s9, adding 95% ethanol into the lower-layer liquid material, keeping the temperature at 10-15 ℃, and dropwise adding a hydrochloric acid solution until the pH value is 1.0;
s10, reducing the stirring speed, preserving heat and growing the crystals for 30 minutes;
s11, filtering, and taking a filter cake;
s12, washing a filter cake with purified water;
s13, washing the filter cake by using ethanol;
s14, discharging, and drying the filter cake to obtain a finished product.
Preferably, in the step S1, the ratio of the mass of the 7-ACA to the volume of the purified water is 0.045-0.05 kg/L.
Preferably, in the step S2, the mass ratio of triethylamine to 7-ACA is 7: 20-19: 50.
Preferably, in the step S3, the mass ratio of the sum of the mass of 7-ACA and triethylamine to the mass of the activated carbon is 10: 1-11: 1.
preferably, in the step S5, the mass sum of the 7-ACA and the triethylamine is 0.129-0.13 kg/L of toluene and the mass ratio of the mass sum of the 7-ACA and the triethylamine to the calcium salt is 12: 5-13: 5; the mass ratio of the sum of the 7-ACA and the triethylamine to the bromoacetyl bromide is 13: 10-7: 5.
Preferably, in the step S10, the volume ratio of the sum of the mass of the 7-ACA and the triethylamine and the mass of the calcium salt and the bromoacetyl bromide to the ethanol is 0.22-0.79 kg/L.
Preferably, in the step S13, the volume ratio of the sum of the mass of the 7-ACA and the triethylamine and the mass of the calcium salt and the bromoacetyl bromide to the purified water is 0.25-0.3 kg/L.
Preferably, in the step S14, the volume ratio of the sum of the mass of the 7-ACA and the triethylamine and the mass of the calcium salt and the bromoacetyl bromide to the ethanol is 2-2.36 kg/L.
The invention has the beneficial effects that: the novel synthesis process adopts the calcium salt to replace sodium bicarbonate solution, utilizes the characteristic that the calcium salt is alkalescent or neutral and is insoluble in water and can be neutralized and reacted with acidic byproducts, keeps the reaction solution neutral, has simple and easily controlled operation process, has no harm to reaction raw materials, promotes the reaction to be completely finished, and improves the product quality and the product yield.
Detailed Description
The claimed solution will now be described in further detail with reference to specific embodiments.
The acetyl-7-ACA production process in the embodiment is characterized by comprising the following steps:
s1, adding 1400ml of purified water and 70g of 7-ACA into a reaction bottle, and uniformly stirring;
s2, adjusting and keeping the temperature of the material at 0-5 ℃, dropwise adding 25g of triethylamine within 25-30 minutes, and stirring for 5-15 minutes after dropwise adding is finished to completely dissolve the material;
s3, adding 9.5g of activated carbon, and stirring and decoloring for 15-20 minutes;
s4, filtering, and taking filtrate;
s5, adding 736ml of toluene and 38g of calcium salt, adjusting and maintaining the temperature of the material at 13-20 ℃, and dropwise adding 68g of bromoacetyl bromide within 30-60 minutes under rapid stirring;
s6, after the dropwise addition is finished, controlling the temperature of the material to be 18-20 ℃, and stirring for reaction for 1-1.5 hours;
s7, after the reaction is finished, filtering to remove excessive calcium salt;
s8, standing the filtrate for 1-2 hours, and layering;
s9, taking the lower-layer filtrate, and recycling the upper-layer methylbenzene for reuse;
s10, adding 886ml of 95% ethanol into the lower-layer filtrate, adjusting and keeping the temperature of the materials at 10-15 ℃, and dropwise adding a 1:1 hydrochloric acid solution until the pH value is 1.0;
s11, reducing the rotating speed, and carrying out heat preservation and crystal growth for 50-70 minutes;
s12, filtering and draining the mother liquor;
s13, washing a filter cake by using 800ml of purified water;
s14, washing a filter cake by using 100ml of 95% ethanol;
s15, discharging, and drying the filter cake until the water content is less than or equal to 0.5%;
collecting powder to obtain acetyl bromide-7-ACA 87.5g, with the product purity of 99.4% and the yield of 0.866.
Example two
The acetyl-7-ACA production process in the embodiment is characterized by comprising the following steps:
s1, adding 1600ml of purified water and 80g of 7-ACA into a reaction bottle, and uniformly stirring;
s2, adjusting and keeping the temperature of the material at 0-5 ℃, dropwise adding 29g of triethylamine within 25-30 minutes, and stirring for 5-15 minutes after dropwise adding is finished to completely dissolve the material;
s3, adding 10g of activated carbon, and stirring and decoloring for 15-20 minutes;
s4, filtering, and taking filtrate;
s5, adding 845ml of toluene and 44g of calcium salt, adjusting and maintaining the temperature of the material at 13-20 ℃, and dropwise adding 83g of bromoacetyl bromide within 30-60 minutes under rapid stirring;
s6, after the dropwise addition is finished, controlling the temperature of the material to be 18-20 ℃, and stirring for reaction for 1-1.5 hours;
s7, after the reaction is finished, filtering to remove excessive calcium salt;
s8, standing the filtrate for 1-2 hours, and layering;
s9, taking the lower-layer filtrate, and recycling the upper-layer methylbenzene for reuse;
s10, adding 1375ml of 95% ethanol into the lower-layer filtrate, adjusting and keeping the temperature of the materials at 10-15 ℃, and dropwise adding a 1:1 hydrochloric acid solution until the pH value is 1.0;
s11, reducing the rotating speed, and carrying out heat preservation and crystal growth for 50-70 minutes;
s12, filtering and draining the mother liquor;
s13, washing a filter cake by using 800ml of purified water;
s14, washing a filter cake by using 100ml of 95% ethanol;
s15, discharging, and drying the filter cake until the water content is less than or equal to 0.5%;
collecting powder to obtain 99.8g of bromoacetyl-7-ACA, wherein the purity of the product is 99.4 percent, and the yield is 0.864.
EXAMPLE III
The acetyl-7-ACA production process in the embodiment is characterized by comprising the following steps:
s1, adding 1650ml of purified water and 75g of 7-ACA into a reaction bottle, and uniformly stirring;
s2, adjusting and keeping the temperature of the material at 0-5 ℃, dropwise adding 28.5g of triethylamine within 25-30 minutes, and stirring for 5-15 minutes after dropwise adding is finished to completely dissolve the material;
s3, adding 10g of activated carbon, and stirring and decoloring for 15-20 minutes;
s4, filtering to obtain filtrate;
s5, adding 800ml of toluene and 40g of calcium salt, adjusting and keeping the temperature of the material at 13-20 ℃, and dropwise adding 78g of bromoacetyl bromide within 30-60 minutes under rapid stirring;
s6, after the dropwise addition is finished, controlling the temperature of the material to be 18-20 ℃, and stirring for reaction for 1-1.5 hours;
s7, after the reaction is finished, filtering to remove excessive calcium salt;
s8, standing the filtrate for 1-2 hours, and layering;
s9, taking the lower-layer filtrate, and recycling the upper-layer methylbenzene for reuse;
s10, adding 1300ml of 95% ethanol into the lower-layer filtrate, adjusting and keeping the temperature of the materials at 10-15 ℃, and dropwise adding a 1:1 hydrochloric acid solution until the pH value is 1.0;
s11, reducing the rotating speed, and carrying out heat preservation and crystal growth for 50-70 minutes;
s12, filtering and draining the mother liquor;
s13, washing a filter cake by using 800ml of purified water;
s14, washing a filter cake by using 100ml of 95% ethanol;
s15, discharging, and drying the filter cake until the water content is less than or equal to 0.5%;
collecting powder to obtain 94.6g of bromoacetyl-7-ACA, wherein the purity of the product is 99.5 percent, and the yield is 0.873.
The above-described embodiments are merely preferred embodiments of the present invention, which is not intended to limit the present invention in any way. Those skilled in the art can make many changes and modifications to the disclosed embodiments, or modify equivalent embodiments to practice the disclosed embodiments, without departing from the scope of the disclosed embodiments. Therefore, equivalent variations made according to the idea of the present invention should be covered within the protection scope of the present invention without departing from the contents of the technical solution of the present invention.
Claims (8)
1. A bromoacetyl-7-ACA production process is characterized by comprising the following steps:
s1, adding purified water and 7-ACA into a reaction bottle, and uniformly stirring;
s2, adjusting and keeping the temperature of the material at 0-5 ℃, dropwise adding triethylamine within 25-30 minutes, and stirring until the triethylamine is dissolved clearly;
s3, adding activated carbon, and stirring and decoloring for 15-20 minutes;
s4, filtering, and taking filtrate;
s5, adding toluene and calcium salt, controlling the temperature of the material to be 13-20 ℃, accelerating the stirring speed, and dropwise adding bromoacetyl bromide within 30-60 minutes;
s6, after the bromoacetyl bromide is dripped, controlling the temperature at 18-20 ℃, and stirring for reaction for 1-1.5 hours;
s7, filtering to remove excessive calcium salt;
standing the filtrate for 1-2 hours, layering, taking the liquid material at the lower layer, and recycling the upper layer for reuse;
s9, adding 95% ethanol into the lower-layer liquid material, keeping the temperature at 10-15 ℃, and dropwise adding a hydrochloric acid solution until the pH value is 1.0;
s10, reducing the stirring speed, preserving heat and growing the crystals for 30 minutes;
s11, filtering, and taking a filter cake;
s12, washing a filter cake with purified water;
s13, washing the filter cake by using ethanol;
s14, discharging, and drying the filter cake to obtain a finished product.
2. The bromoacetyl-7-ACA production process according to claim 1, wherein: in the step S1, the ratio of the mass of the 7-ACA to the volume of the purified water is 0.045-0.05 kg/L.
3. The bromoacetyl-7-ACA production process according to claim 1, wherein: in the step S2, the mass ratio of triethylamine to 7-ACA is 7: 20-19: 50.
4. The bromoacetyl-7-ACA production process according to claim 1, wherein: in the step S3, the mass ratio of the sum of the mass of the 7-ACA and the triethylamine to the mass of the activated carbon is 10: 1-11: 1.
5. the bromoacetyl-7-ACA production process according to claim 1, wherein: in the step S5, the mass sum of the 7-ACA and the triethylamine is 0.129-0.13 kg/L of toluene and the mass ratio of the mass sum of the 7-ACA and the triethylamine to the calcium salt is 12: 5-13: 5; the mass ratio of the sum of the 7-ACA and the triethylamine to the bromoacetyl bromide is 13: 10-7: 5.
6. The bromoacetyl-7-ACA production process according to claim 1, wherein: in the step S10, the volume ratio of the sum of the mass of the 7-ACA and the triethylamine and the mass of the calcium salt and the bromoacetyl bromide to the ethanol is 0.22-0.79 kg/L.
7. The bromoacetyl-7-ACA production process according to claim 1, wherein: in the step S13, the volume ratio of the total mass of the 7-ACA and the triethylamine, the calcium salt and the bromoacetyl bromide to the purified water is 0.25-0.3 kg/L.
8. The bromoacetyl-7-ACA production process according to claim 1, wherein: in the step S14, the volume ratio of the sum of the mass of the 7-ACA and the triethylamine and the mass of the calcium salt and the bromoacetyl bromide to the ethanol is 2-2.36 kg/L.
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| CN202010279828.0A CN111592556A (en) | 2020-04-10 | 2020-04-10 | Bromoacetyl-7-ACA production process |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114113359A (en) * | 2021-05-07 | 2022-03-01 | 佛山市南海北沙制药有限公司 | Central control detection method of 7-ACA derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103102358A (en) * | 2011-11-10 | 2013-05-15 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Cephalosporin compound, crystal thereof, and preparation method and application thereof |
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2020
- 2020-04-10 CN CN202010279828.0A patent/CN111592556A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103102358A (en) * | 2011-11-10 | 2013-05-15 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Cephalosporin compound, crystal thereof, and preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114113359A (en) * | 2021-05-07 | 2022-03-01 | 佛山市南海北沙制药有限公司 | Central control detection method of 7-ACA derivative |
| CN114113359B (en) * | 2021-05-07 | 2024-02-20 | 佛山市南海北沙制药有限公司 | Central control detection method of 7-ACA derivative |
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