CN104610407B - The process for purification of hydrocortisone acetate - Google Patents
The process for purification of hydrocortisone acetate Download PDFInfo
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- CN104610407B CN104610407B CN201510040693.1A CN201510040693A CN104610407B CN 104610407 B CN104610407 B CN 104610407B CN 201510040693 A CN201510040693 A CN 201510040693A CN 104610407 B CN104610407 B CN 104610407B
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- hypochlorite
- purification
- hydrocortisone acetate
- dichloromethane
- methanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the process for purification of a kind of hydrocortisone acetate, this process for purification includes utilizing chlorine or utilizing hypochlorite, glacial acetic acid and sodium chloride Dichlorodiphenyl Acetate hydrocortisone crude product to be purified, and obtains hydrocortisone acetate fine work.The process for purification of the present invention is simple and convenient, low production cost, yield height, product purity height, process stabilizing, be suitable for a large amount of producing hydrocortisone acetate fine work.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to the process for purification of a kind of hydrocortisone acetate.
Background technology
Refining out the hydrocortisone acetate meeting EP8.0 standard, current domestic technique is essentially by dichloromethane, chloroform warp
Cross repeatedly making beating (generally 4～8 times) to obtain.This technological operation operation is loaded down with trivial details, and repeatedly making beating causes production cost high, produces
The three wastes many, environmental pollution is big, and yield low (about 60%).Therefore, the refined side of new hydrocortisone acetate is developed
Method becomes the task of top priority.
Summary of the invention
The technical problem to be solved in the present invention is to overcome the deficiencies in the prior art, it is provided that a kind of simple and convenient, low production cost,
Yield height, products therefrom purity height, process stabilizing, the process for purification of applicable mass-produced hydrocortisone acetate.
For solve above-mentioned technical problem, the present invention by the following technical solutions:
The process for purification of a kind of hydrocortisone acetate, described process for purification includes utilizing chlorine or utilizing hypochlorite, ice second
Acid and sodium chloride Dichlorodiphenyl Acetate hydrocortisone crude product are purified, and obtain hydrocortisone acetate fine work.
In above-mentioned process for purification, it is preferred that described process for purification comprises the following steps: adding acetic acid hydrogenation in reactor can
Loose crude product, dichloromethane and methanol, then temperature rising reflux filters clearly to the most molten, and filtration system keeps 30 DEG C～40 DEG C, to mistake
Filter system is passed through chlorine, stirring after being passed through, concentrate and remove dichloromethane, after concentration, be cooled to 0 DEG C～5 DEG C, centrifugal,
To hydrocortisone acetate fine work.
In above-mentioned process for purification, it is preferred that in described process for purification, the weight portion of each raw material is: hydrocortisone acetate crude product
1 part, dichloromethane 6～10 parts, methanol 4～6 parts, 0.1 part of chlorine；During concentrating removal dichloromethane, work as first
Stop when alcohol residual volume is 1 weight portion concentrating.
In above-mentioned process for purification, it is preferred that described process for purification comprises the following steps: adding acetic acid hydrogenation in reactor can
Loose crude product, dichloromethane and methanol, then temperature rising reflux filters clearly to the most molten, and filtration system keeps 20 DEG C～45 DEG C, to mistake
Filter system adds hypochlorite and sodium chloride, then drips glacial acetic acid, stir after finishing, concentrate and remove dichloromethane, after concentration
It is cooled to 0 DEG C～10 DEG C, centrifugal, obtain hydrocortisone acetate fine work.
In above-mentioned process for purification, it is preferred that in described process for purification, the weight portion of each raw material is: hydrocortisone acetate crude product
1 part, dichloromethane 6～10 parts, methanol 4～6 parts, hypochlorite 0.5～0.65 part, 0.1 part of sodium chloride, total glacial acetic acid
0.25～0.35 part；Remove during dichloromethane concentrating, when methanol residual volume is 1～stops concentrating during 1.5 weight portion.
In above-mentioned process for purification, it is preferred that described hypochlorite includes in sodium hypochlorite, calcium hypochlorite and lithium hypochlorite
Plant or multiple.
In above-mentioned process for purification, it is preferred that when described hypochlorite is sodium hypochlorite, the weight portion of each raw material is acetic acid hydrogenation
Cortisone crude product 1 part, dichloromethane 6～10 parts, methanol 4～6 parts, sodium hypochlorite 0.5 part, 0.1 part of sodium chloride, total ice
Acetic acid 0.35 part, filtration system keeps 35 DEG C～45 DEG C, is cooled to 0 DEG C～5 DEG C, when methanol residual volume is 1 weight after concentration
Stop during part concentrating.
In above-mentioned process for purification, it is preferred that when described hypochlorite is calcium hypochlorite, the weight portion of each raw material is acetic acid hydrogenation
Cortisone crude product 1 part, dichloromethane 6～10 parts, methanol 4～6 parts, calcium hypochlorite 0.5～0.65 part, 0.1 part of sodium chloride,
Total glacial acetic acid 0.25 part, filtration system keeps 20 DEG C～35 DEG C, is cooled to 0 DEG C～10 DEG C, when methanol residual volume is 1.5 after concentration
Stop during weight portion concentrating.
In the present invention, the major impurity of hydrocortisone acetate crude product is that NSC 24345 (i.e. prepares hydrocortisone acetate mistake
Unreacted raw material completely in journey), utilize chlorine or utilize hypochlorite, glacial acetic acid and sodium chloride to be turned by NSC 24345
Turning to double chlorine thing, obtain hydrocortisone acetate fine work, reaction principle is as follows:
Compared with prior art, it is an advantage of the current invention that:
The process for purification of the present invention utilizes chlorine or indirectly uses hypochlorite, glacial acetic acid and sodium chloride to prepare chlorine, refines
Hydrocortisone acetate.This process for purification can realize primary purification can draw qualified products, and qualification rate, up to 99%, refines and receives
Rate can reach more than 80%, and production cost is only about the half of existing process for refining, and reaction is simple, easy and simple to handle, work
Skill is stable, it is easy to accomplish mass industrialized production, has higher industrial value and Prospects of Sustainable Development, is the purest
Change the process of hydrocortisone acetate.
The process for purification of the present invention is compared to existing technique, it is to avoid loaded down with trivial details chloroform making beating operation, greatly reduces production operation
Operation, is greatly improved control cost, alleviates three-protection design pressure, decreases the pollution to environment, is sustainable metaplasia
The important leverage produced.
Detailed description of the invention
Below in conjunction with concrete preferred embodiment, the invention will be further described, but protection model not thereby limiting the invention
Enclose.
Material and instrument employed in following example are commercially available.
Embodiment 1:
The process for purification of the hydrocortisone acetate of a kind of present invention, comprises the following steps: add 1 weight portion in reactor
Hydrocortisone acetate crude product, 6 weight parts Methylene chloride, 5 parts by weight Methanol, temperature rising reflux is the most molten clearly, filters, filtration system
Keep 30 DEG C, be passed through 0.1 weight portion chlorine.Finishing, stir half an hour, concentrate and remove dichloromethane, methanol residual volume is 1
Stop during weight portion concentrating, be cooled to 0 DEG C, centrifugal, obtain hydrocortisone acetate fine work.Refined yield: 80.5%,
HPLC=99.20%, external standard content: 97.10%, meet EP 8.0.HPLC retention time is consistent with standard control.
Embodiment 2:
The process for purification of the hydrocortisone acetate of a kind of present invention, comprises the following steps: add 1 weight portion in reactor
Hydrocortisone acetate crude product, 8 weight parts Methylene chloride, 6 parts by weight Methanol, temperature rising reflux is the most molten clearly, filters, filtration system
Keep 40 DEG C, be subsequently adding 0.5 weight portion sodium hypochlorite, 0.1 parts by wt NaCl, then drip glacial acetic acid, total glacial acetic acid amount
It is 0.35 weight portion, finishes, stir half an hour, concentrate and remove dichloromethane, stop when methanol residual volume is 1 weight concentrating,
It is cooled to 5 DEG C, centrifugal, obtain hydrocortisone acetate fine work.Refined yield: 81.5%, HPLC=99.10%, external standard content:
98.10%, meet EP 8.0.HPLC retention time is consistent with standard control.
Embodiment 3:
The process for purification of the hydrocortisone acetate of a kind of present invention, comprises the following steps: add 1 weight portion in reactor
Hydrocortisone acetate crude product, 10 weight parts Methylene chloride, 4 parts by weight Methanol, temperature rising reflux is the most molten clearly, filters, filtering bodies
System keeps 35 DEG C, adds 0.5 weight portion calcium hypochlorite, 0.1 parts by wt NaCl, then drips glacial acetic acid, and total glacial acetic acid amount is
0.25 weight portion, finishes, and stirs half an hour, concentrates and removes dichloromethane, stops concentrating when methanol residual volume is 1.5 weight portion,
It is cooled to 10 DEG C, centrifugal, obtain hydrocortisone acetate fine work.Refined yield: 80.3%, HPLC=99.12%, external standard contains
Amount: 97.30%, meets EP 8.0.HPLC retention time is consistent with standard control.
The above is only the preferred embodiment of the present invention, and protection scope of the present invention is not limited merely to above-described embodiment.All
The technical scheme belonged under thinking of the present invention belongs to protection scope of the present invention.It is noted that for the art is common
For technical staff, improvements and modifications under the premise without departing from the principles of the invention, these improvements and modifications also should be regarded as this
Bright protection domain.
Claims (4)
1. the process for purification of a hydrocortisone acetate, it is characterised in that described process for purification includes utilizing chlorine or utilizing hypochlorite, glacial acetic acid and sodium chloride Dichlorodiphenyl Acetate hydrocortisone crude product to be purified, and obtains hydrocortisone acetate fine work；
When utilizing chlorine to be purified, described process for purification comprises the following steps: add hydrocortisone acetate crude product, dichloromethane and methanol in reactor, then temperature rising reflux filters clearly to molten, and filtration system keeps 30 DEG C～40 DEG C, chlorine it is passed through in filtration system, stirring after being passed through, concentrates and removes dichloromethane, be cooled to 0 DEG C～5 DEG C after concentration, centrifugal, obtain hydrocortisone acetate fine work；In described process for purification, the weight portion of each raw material is: hydrocortisone acetate crude product 1 part, dichloromethane 6～10 parts, methanol 4～6 parts, 0.1 part of chlorine；During concentrating removal dichloromethane, stop when methanol residual volume is 1 weight portion concentrating；
When utilizing hypochlorite, glacial acetic acid and sodium chloride to be purified, described process for purification comprises the following steps: add hydrocortisone acetate crude product, dichloromethane and methanol in reactor, and temperature rising reflux is the most molten clearly, then filters, filtration system keeps 20 DEG C～45 DEG C, in filtration system, add hypochlorite and sodium chloride, then drip glacial acetic acid, stir after finishing, concentrate and remove dichloromethane, 0 DEG C～10 DEG C it is cooled to after concentration, centrifugal, obtain hydrocortisone acetate fine work；In described process for purification, the weight portion of each raw material is: hydrocortisone acetate crude product 1 part, dichloromethane 6～10 parts, methanol 4～6 parts, hypochlorite 0.5～0.65 part, 0.1 part of sodium chloride, total glacial acetic acid 0.25～0.35 part；Remove during dichloromethane concentrating, when methanol residual volume is 1～stops concentrating during 1.5 weight portion.
Process for purification the most according to claim 1, it is characterised in that described hypochlorite includes one or more in sodium hypochlorite, calcium hypochlorite and lithium hypochlorite.
Process for purification the most according to claim 2, it is characterized in that, when described hypochlorite is sodium hypochlorite, the weight portion of each raw material is hydrocortisone acetate crude product 1 part, dichloromethane 6～10 parts, methanol 4～6 parts, sodium hypochlorite 0.5 part, 0.1 part of sodium chloride, total glacial acetic acid 0.35 part, filtration system keeps 35 DEG C～45 DEG C, is cooled to 0 DEG C～5 DEG C after concentration, stops when methanol residual volume is 1 weight portion concentrating.
Process for purification the most according to claim 2, it is characterized in that, when described hypochlorite is calcium hypochlorite, the weight portion of each raw material is hydrocortisone acetate crude product 1 part, dichloromethane 6～10 parts, methanol 4～6 parts, calcium hypochlorite 0.5～0.65 part, 0.1 part of sodium chloride, total glacial acetic acid 0.25 part, filtration system keeps 20 DEG C～35 DEG C, is cooled to 0 DEG C～10 DEG C after concentration, stops when methanol residual volume is 1.5 weight portion concentrating.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510040693.1A CN104610407B (en) | 2015-01-27 | 2015-01-27 | The process for purification of hydrocortisone acetate |
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| CN201510040693.1A CN104610407B (en) | 2015-01-27 | 2015-01-27 | The process for purification of hydrocortisone acetate |
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| CN104610407B true CN104610407B (en) | 2016-08-17 |
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| CN107400153B (en) * | 2017-04-23 | 2019-08-27 | 浙江仙琚制药股份有限公司 | A kind of preparation method of hydrocortisone acetate |
| CN114075258B (en) * | 2020-08-11 | 2023-03-28 | 浙江神洲药业有限公司 | Preparation method of hydrocortisone |
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| AU2315488A (en) * | 1987-08-14 | 1989-03-09 | Upjohn Company, The | Improved 9alpha-dehalogenation process |
| CN102603842B (en) * | 2012-02-20 | 2013-10-23 | 湖南新合新生物医药有限公司 | Preparation method of hydrocortisone acetate or analogue thereof |
| CN103724386A (en) * | 2013-11-19 | 2014-04-16 | 华中药业股份有限公司 | Preparation method of cortisone acetate |
| CN103641876B (en) * | 2013-11-22 | 2016-01-06 | 湖南新合新生物医药有限公司 | The preparation method of cortisone acetic ester |
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Denomination of invention: Refining method of hydrocortisone acetate Effective date of registration: 20230613 Granted publication date: 20160817 Pledgee: Hunan Bank Co.,Ltd. Jinshi Branch Pledgor: HUNAN XINHEXIN BIOLOGICAL MEDICINE Co.,Ltd. Registration number: Y2023980043801 |
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Date of cancellation: 20230905 Granted publication date: 20160817 Pledgee: Hunan Bank Co.,Ltd. Jinshi Branch Pledgor: HUNAN XINHEXIN BIOLOGICAL MEDICINE Co.,Ltd. Registration number: Y2023980043801 |