CN113583071A - Preparation method of hydrocortisone crude product - Google Patents
Preparation method of hydrocortisone crude product Download PDFInfo
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- CN113583071A CN113583071A CN202110923858.5A CN202110923858A CN113583071A CN 113583071 A CN113583071 A CN 113583071A CN 202110923858 A CN202110923858 A CN 202110923858A CN 113583071 A CN113583071 A CN 113583071A
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- hydrocortisone
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- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 title claims abstract description 124
- 229960000890 hydrocortisone Drugs 0.000 title claims abstract description 62
- 239000012043 crude product Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 83
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- 229960001067 hydrocortisone acetate Drugs 0.000 claims abstract description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 43
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 claims abstract description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 32
- 238000001035 drying Methods 0.000 claims abstract description 30
- 239000000413 hydrolysate Substances 0.000 claims abstract description 25
- 239000000047 product Substances 0.000 claims abstract description 23
- 229960000583 acetic acid Drugs 0.000 claims abstract description 21
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 108010009736 Protein Hydrolysates Proteins 0.000 claims abstract description 12
- UBANCVOKRLKBGJ-KGWLDMEJSA-N [2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] 4-(nitrooxymethyl)benzoate Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(CCC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)C1=CC=C(CO[N+]([O-])=O)C=C1 UBANCVOKRLKBGJ-KGWLDMEJSA-N 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 229910001868 water Inorganic materials 0.000 claims description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 17
- 238000005070 sampling Methods 0.000 claims description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000004809 thin layer chromatography Methods 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000011049 filling Methods 0.000 claims description 8
- 238000004321 preservation Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 5
- 238000005086 pumping Methods 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 claims description 3
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 claims description 3
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- 229960004544 cortisone Drugs 0.000 claims description 3
- 238000007599 discharging Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 139
- 230000007062 hydrolysis Effects 0.000 abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 10
- 238000007086 side reaction Methods 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 14
- 230000001276 controlling effect Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000010924 continuous production Methods 0.000 description 2
- 210000003298 dental enamel Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 206010004053 Bacterial toxaemia Diseases 0.000 description 1
- 208000013222 Toxemia Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 208000017515 adrenocortical insufficiency Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000703 anti-shock Effects 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- -1 electricity Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a hydrocortisone crude product, which comprises the following steps: feeding materials into a reaction kettle to obtain a solution A; preparing a hydrolysate, and dripping the hydrolysate into the reaction kettle to obtain a solution B; detecting whether the solution B contains hydrocortisone acetate; after confirming that no hydrocortisone acetate exists in the solution B, adding glacial acetic acid into the solution B to terminate the reaction to obtain a solution C; concentrating the solution C to obtain a solution D; carrying out water-out treatment on the solution D to obtain a solution E; and carrying out centrifugal treatment and drying treatment on the solution E to obtain a crude hydrocortisone product. Dichloromethane and methanol are used as solvents to accelerate the dissolution rate of hydrocortisone acetate under the low-temperature condition, and sodium hydroxide and potassium carbonate aqueous solution are used as hydrolysis liquid to accelerate the hydrolysis rate of hydrocortisone acetate, monitor the reaction degree, avoid side reaction and improve the purity and yield of products.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of a hydrocortisone crude product.
Background
Hydrocortisone, also known as cortisol, is an adrenocortical hormone, has obvious influence on carbohydrate metabolism, has anti-inflammatory, immunosuppressive, antitoxic and antishock effects, and is mainly used for treating acute and chronic adrenocortical insufficiency, toxemia, allergic diseases, shock and other diseases complicated with serious infection.
Chinese patent CN201110201729.1 discloses a preparation method of hydrocortisone, which comprises the steps of adding hydrocortisone acetate into methanol, adding a methanol solution of 2% sodium hydroxide, stirring and reacting for more than 4 hours at 0-8 ℃, adding acetic acid for neutralization after the reaction is finished, carrying out reduced pressure concentration to recover a solvent, crystallizing the methanol, filtering, washing with methanol, and drying to obtain the hydrocortisone. However, it has problems of long reaction time, low yield, inability to recycle the solvent, inability to monitor the reaction degree, and the like. Therefore, it is necessary to develop a new preparation method to solve the above existing problems.
Disclosure of Invention
Aiming at the problems, the invention discloses a preparation method of a hydrocortisone crude product, which comprises the following steps:
feeding materials into a reaction kettle to obtain a solution A;
preparing a hydrolysate, and dripping the hydrolysate into the reaction kettle to obtain a solution B;
detecting whether the solution B contains hydrocortisone acetate;
after confirming that no hydrocortisone acetate exists in the solution B, adding glacial acetic acid into the solution B to terminate the reaction to obtain a solution C;
concentrating the solution C to obtain a solution D;
carrying out water-out treatment on the solution D to obtain a solution E;
and carrying out centrifugal treatment and drying treatment on the solution E to obtain a crude hydrocortisone product.
Furthermore, it is characterized in that the first and second electrodes,
feeding materials into a reaction kettle to obtain a solution A, wherein the method comprises the following specific steps: adding methanol, dichloromethane and hydrocortisone acetate into a reaction kettle, stirring for 10min, cooling the solution in the reaction kettle to-3 to-1 ℃, keeping the temperature, stirring for 30min, and replacing with nitrogen to obtain a solution A;
preparing a hydrolysate, and dripping the hydrolysate into the reaction kettle to obtain a solution B, wherein the method comprises the following specific steps: adding water, sodium hydroxide and potassium carbonate into a preparation tank, stirring until the water, the sodium hydroxide and the potassium carbonate are completely dissolved to obtain a hydrolysate, and pumping the hydrolysate into a dropwise adding tank for later use;
controlling the temperature of the solution A to be-5 to-1 ℃, dripping the hydrolysate into the solution A in the reaction kettle, and stirring for 1.5 hours at the temperature of-5 to-1 ℃ to obtain a solution B;
detecting whether the solution B contains hydrocortisone acetate or not, and the specific steps comprise: after the hydrolysate is dropwise added for 1h, 1mL of the solution B is taken out of a sampling tube, and whether a sample of the solution B contains hydrocortisone acetate is detected by adopting thin-layer chromatography;
after confirming that no hydrocortisone acetate exists in the solution B, adding glacial acetic acid into the solution B to terminate the reaction to obtain a solution C, and the specific steps comprise: when no hydrocortisone acetate is detected in the solution B, adding glacial acetic acid into the solution B, adjusting the pH value of the solution to 6-7, and stopping the reaction to obtain a solution C;
concentrating the solution C to obtain a solution D, and specifically comprising the following steps: controlling the temperature of the solution C at 40-45 ℃, concentrating dichloromethane in a water bath at normal pressure, concentrating methanol under reduced pressure until the solution C is nearly dry, adding water into the solution C, and continuously concentrating until no methanol residue exists in the solution C to obtain a solution D;
carrying out water-out treatment on the solution D to obtain a solution E, and specifically comprising the following steps: adding water into the solution D, cooling to 0-5 ℃, and stirring for 2 hours under the condition of heat preservation to obtain a solution E;
and carrying out centrifugal treatment and drying treatment on the solution E to obtain a crude hydrocortisone product, and specifically comprising the following steps: and centrifuging the solution E, and then drying to obtain a crude hydrocortisone product.
Further, the weight percentages of the methanol, the dichloromethane and the hydrocortisone acetate are 5.544: 9.282: 1.
still further, the nitrogen substitution comprises the substeps of:
vacuumizing the reaction kettle to-0.04 MPa, filling nitrogen for replacement to 0MPa, and repeating the operation for 3 times.
Further, the weight percentage of the water, the sodium hydroxide and the potassium carbonate is 200: 2: 3.
furthermore, the dropping time of the hydrolysate is 30-50 min.
Further, the developing solvent used for the thin layer chromatography is 4 weight percent: 1 benzene: and mixing the solution with acetone.
Further, the centrifugal treatment is water washing for 5-10 min, rinsing with purified water once, and centrifuging for 1 h.
Further, the taking of 1mL of the solution B in a sampling tube comprises the following substeps:
adding 2-3 drops of glacial acetic acid into a dry and clean sampling tube;
the stirrer in the reaction vessel was closed, and 1mL of solution B was sampled by discharging the solution under pressure in the reaction vessel.
Furthermore, the drying treatment comprises the following specific operation steps:
uniformly loading the wet cortisone crude product into a tray, and putting the tray into a dryer;
baking for 40-48 h at the temperature of 85-90 ℃;
turning over the wet hydrocortisone crude product every 6-8 h, and recording the drying temperature every hour;
drying and bagging to obtain a crude product of hydrocortisone.
Compared with the prior art, the invention has the beneficial effects that: the method has the advantages that dichloromethane and methanol are used as solvents, the dichloromethane is more than the methanol, the dissolving rate of the hydrocortisone acetate under the low-temperature condition can be accelerated, sodium hydroxide and potassium carbonate aqueous solution are used as hydrolysis liquid, the hydrolysis rate of the hydrocortisone acetate can be accelerated, the production period for preparing the hydrocortisone is greatly reduced, the reaction degree is monitored by adopting thin-layer chromatography, side reactions are avoided, and the product purity and yield are improved. After the reaction is terminated, dichloromethane and methanol are concentrated and recovered for subsequent production, so that the dosage of the solvent is reduced, and the production cost is reduced.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and those skilled in the art can also obtain other drawings according to the drawings without creative efforts.
FIG. 1 shows a flow chart for the preparation of crude hydrocortisone according to an embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
FIG. 1 shows a flow chart for the preparation of crude hydrocortisone according to an embodiment of the present invention. As shown in figure 1, the preparation method of the crude hydrocortisone provided by the invention comprises the following steps:
(1) feeding materials into a reaction kettle to obtain a solution A, wherein the method comprises the following specific steps: adding methanol, dichloromethane and hydrocortisone acetate into a reaction kettle, stirring for 10min, cooling the solution in the reaction kettle to-3 to-1 ℃, keeping the temperature, stirring for 30min, and replacing with nitrogen to obtain a solution A; in order to improve the purity and yield of the hydrocortisone, the weight percentages of methanol, dichloromethane and hydrocortisone acetate are regulated through mass continuous production, preferably 5.544: 9.282: 1; the preparation process is an anaerobic reaction, so that nitrogen replacement is thorough;
(2) preparing a hydrolysate, and dripping the hydrolysate into the reaction kettle to obtain a solution B, wherein the method comprises the following specific steps: adding water, sodium hydroxide and potassium carbonate into a preparation tank, stirring until the water, the sodium hydroxide and the potassium carbonate are completely dissolved to obtain a hydrolysate, and pumping the hydrolysate into a dropwise adding tank for later use;
controlling the temperature of the solution A to be-5 to-1 ℃, dripping the hydrolysate into the solution A in the reaction kettle within 30 to 50min, and stirring for 1.5 hours at the temperature of-5 to-1 ℃ to obtain a solution B;
wherein, in order to improve the hydrolysis rate and reduce the production period, the weight percentages of water, sodium hydroxide and potassium carbonate are regulated through mass continuous production, preferably 200: 2: 3; in the dropping process of the hydrolysate, the temperature of the solution needs to be strictly controlled not to exceed-1 ℃ at most; the hydrolysis is carried out at the specified time and temperature, so that side reactions can be avoided, and the purity and yield of the product are improved;
(3) detecting whether the solution B contains hydrocortisone acetate or not, and the specific steps comprise: after the hydrolysate is dripped for 1 hour, the reaction degree is tracked, 1mL of the solution B is taken out and placed in a sampling tube, 2-3 drops of glacial acetic acid are filled in the sampling tube, and whether a sample of the solution B contains hydrocortisone acetate or not is detected by adopting thin layer chromatography;
specifically, the developing solvent used for the thin layer chromatography is 4 weight percent: 1 benzene: acetone mixed solution; if hydrocortisone acetate is detected in the solution B, and the reaction is not finished, re-sampling and testing are carried out after 20-30 min until the hydrocortisone acetate in the solution B is completely reacted; when hydrocortisone acetate is detected in the solution B, preferably performing a sampling test after 20 min;
(4) after confirming that no hydrocortisone acetate exists in the solution B, adding glacial acetic acid into the solution B to terminate the reaction to obtain a solution C, and the specific steps comprise: when no hydrocortisone acetate is detected in the sample of the solution B, adding glacial acetic acid into the solution B, adjusting the pH value of the solution to 6-7, stopping the reaction, and stirring for 20min to obtain a solution C; when no hydrocortisone acetate exists in the detection solution B, glacial acetic acid is immediately added into the solution B for quenching reaction, and delay cannot be delayed, otherwise, the purity of the finally obtained product does not reach the standard;
(5) concentrating the solution C to obtain a solution D, and specifically comprising the following steps: controlling the temperature of the solution C at 40-45 ℃, concentrating dichloromethane in a water bath at normal pressure, concentrating methanol under reduced pressure until the solution C is nearly dry, adding water into the solution C, and continuously concentrating until no methanol residue exists in the solution C to obtain a solution D;
(6) carrying out water-out treatment on the solution D to obtain a solution E, and specifically comprising the following steps: adding water into the solution D, cooling to 0-5 ℃, and stirring for 2 hours under the condition of heat preservation to obtain a solution E;
(7) and carrying out centrifugal treatment and drying treatment on the solution E to obtain a crude hydrocortisone product, and specifically comprising the following steps: and washing the solution E with water for 5-10 min, rinsing with purified water once, centrifuging for 1h, and drying at the temperature of 85-90 ℃ for 40-48 h to obtain a crude hydrocortisone product.
The nitrogen replacement comprises the following substeps:
vacuumizing the reaction kettle to-0.04 MPa, filling nitrogen to replace to 0MPa, and repeating the operation for 3 times.
The sampling method comprises the following steps: the labor protection article is worn well, a dry and clean sampling tube is prepared, 2-3 drops of glacial acetic acid are added into the sampling tube, a stirrer in a reaction kettle is closed, 1mL of solution B is sampled by discharging materials in the reaction kettle in a pressure mode, and then whether the solution sample contains hydrocortisone acetate or not is detected by using a thin layer chromatography.
The drying treatment comprises the following specific operation steps:
uniformly loading the wet cortisone crude product into a tray, and putting the tray into a dryer;
baking for 40-48 h at the temperature of 85-90 ℃;
turning over the wet hydrocortisone crude product every 6-8 h, and recording the drying temperature every hour;
drying and bagging to obtain a crude product of hydrocortisone.
Some of the product names, uses and specifications used in the following examples are described in table 1 below.
Table 1 product name and specification
The above are only optional product specifications for the feed components to which the present invention relates, and the feed components of the present invention can be purchased commercially.
Example 1
1. Pre-production status inspection
1.1, checking that the production equipment is intact and the cleaning is finished; the meter is verified to be qualified and within the valid period; the reaction kettle, the preparation tank, the dropping tank and other containers are cleaned;
1.2, the production environment meets the requirements, and no material or sundries irrelevant to the batch production exist in the production area;
1.3, supplying common media such as water, electricity, gas, frozen brine and the like normally; all valves are in the correct state;
2. preparation before production
2.1, cleaning a 2000L enamel reaction kettle, and confirming that the 2000L enamel reaction kettle runs normally, is clean and dry, and the temperature in the kettle is room temperature;
2.2, cleaning the centrifuge, and confirming that no other products remain inside and outside the centrifuge;
2.3, confirming the weight of the raw materials such as hydrocortisone acetate, dichloromethane, methanol, sodium hydroxide, potassium carbonate, glacial acetic acid and the like;
2.4, confirming the quality of raw materials such as hydrocortisone acetate, dichloromethane, methanol, sodium hydroxide, potassium carbonate, glacial acetic acid and the like;
3. feeding reaction process
3.1, feeding: 277.2kg of methanol, 464.1kg of dichloromethane and 50kg of hydrocortisone acetate are added into the reaction kettle and stirred for 10 min; cooling the system in the reaction kettle to-3 ℃, keeping the temperature and stirring for 30min to obtain a solution A, replacing the solution A with nitrogen for 3 times, vacuumizing to-0.04 MPa each time, filling nitrogen for replacing to 0MPa, and repeating the steps for three times;
3.2, preparing hydrolysate: adding 100kg of water, 1kg of sodium hydroxide and 1.5kg of potassium carbonate into a preparation tank, stirring until the mixture is completely dissolved to obtain a hydrolysate, and pumping the hydrolysate into a dropwise adding tank for later use;
3.3, hydrolysis: controlling the temperature of the solution A at-5 ℃, dripping the hydrolysate into the solution A in the reaction kettle within 30min, and after finishing dripping, keeping the temperature at-5 ℃ and stirring for 1.5h to obtain a solution B;
3.4, detection: after the hydrolysate is dripped for 1 hour, the reaction degree is tracked, 1mL of the solution B is taken out and put in a sampling tube, 2 drops of glacial acetic acid are filled in the sampling tube in advance, and whether the solution B contains hydrocortisone acetate or not is detected by adopting thin-layer chromatography; the developing agent is prepared from the following components in percentage by weight: 1 benzene: acetone mixed solution;
3.5, terminating the reaction: when no hydrocortisone acetate is detected in the solution B, adding glacial acetic acid into the solution B, adjusting the pH value of the solution to 6, stopping the reaction, and stirring for 20min to obtain a solution C;
3.6, concentration: heating the solution C, controlling the temperature at 40 ℃, concentrating in a water bath at normal pressure to obtain about 450kg of dichloromethane, filling the dichloromethane into a barrel, concentrating under reduced pressure to obtain about 260kg of methanol until the solution C is nearly dry, adding 150kg of water into the solution C, and continuously concentrating until the solution C has no methanol residue to obtain a solution D;
3.7, water separation: adding 500L of water into the solution D, cooling the solution D to 0 ℃, and stirring for 2 hours under the condition of heat preservation to obtain a solution E;
3.8, centrifugation: centrifuging the solution E, filling a filter bag and filter paper in a centrifuge, washing each centrifuge for 5min, rinsing with 20kg of purified water once, spin-drying for 1h, and weighing to obtain a batch of wet hydrocortisone crude products;
3.9, drying: uniformly loading wet hydrocortisone crude products into a tray, putting the tray into a dryer, baking for 48 hours at the temperature of 85 ℃, turning over the hydrocortisone crude products every 6 hours, recording the drying temperature once every hour, drying, and bagging to obtain the hydrocortisone crude products;
3.10, weighing 43.25kg of the weight of the crude hydrocortisone, and calculating the yield of the product;
4. product detection
4.1, taking a hydrocortisone crude product, and detecting by QC according to a quality standard; the test results of the crude hydrocortisone are shown in table 2, the crude hydrocortisone is light yellow powdery solid, the drying weight loss is 0.09%, the purity is 97.8%, and the crude hydrocortisone meets the quality standard.
TABLE 2 quality standards and test results for crude hydrocortisone
| Item | Standard of merit | Sample (I) |
| Traits | White-like or pale yellow powdery solid | Pale yellow powdery solid |
| Loss on drying | ≤1％ | 0.09％ |
| Purity of | The total impurities are less than or equal to 3.0 percent | 97.8％ |
| Yield of | 91％ | 96.2％ |
Example 2
The steps of pre-production state inspection, pre-production preparation and product detection in this example are the same as the specific steps in example 1, except that the steps of the feeding reaction process are as follows:
3. feeding reaction process
3.1, feeding: 277.2kg of recovered methanol, 464.1kg of dichloromethane solvent (the total amount of the recovered solvent is 741.3kg, and the specific gravity is 1.06-1.07 g/ml) and 50kg of hydrocortisone acetate are put into a reaction kettle and stirred for 10 min; cooling the system in the reaction kettle to-1 deg.C, stirring for 30min under heat preservation to obtain solution A, displacing with nitrogen for 3 times, vacuumizing to-0.04 MPa each time, and then displacing with nitrogen to 0MPa, repeating for three times;
3.2, preparing hydrolysate: adding 100kg of water, 1kg of sodium hydroxide and 1.5kg of potassium carbonate into a preparation tank, stirring until the mixture is completely dissolved to obtain a hydrolysate, and pumping the hydrolysate into a dropwise adding tank for later use;
3.3, hydrolysis: controlling the temperature of the solution A at-1 ℃, dripping the hydrolysate into the solution A in the reaction kettle within 50min, and after finishing dripping, keeping the temperature at-1 ℃ and stirring for 1.5h to obtain a solution B;
3.4, detection: after the hydrolysate is dripped for 1 hour, the reaction degree is tracked, 1mL of the solution B is taken out and put in a sampling tube, 3 drops of glacial acetic acid are filled in the sampling tube in advance, and whether the solution B contains hydrocortisone acetate or not is detected by adopting thin-layer chromatography; the developing solvent is benzene with the weight percentage of 4: 1: acetone mixed solution;
3.5, terminating the reaction: when no hydrocortisone acetate is detected in the solution B, adding glacial acetic acid into the solution B, adjusting the pH value of the solution to 7, stopping the reaction, and stirring for 20min to obtain a solution C;
3.6, concentration: heating the solution C, controlling the temperature at 45 ℃, concentrating in a water bath at normal pressure to obtain about 450kg of dichloromethane, filling the dichloromethane into a barrel, concentrating under reduced pressure to obtain about 260kg of methanol until the solution C is nearly dry, adding 150kg of water into the solution C, and continuously concentrating until the solution C has no methanol residue to obtain a solution D;
3.7, water separation: adding 500L of water into the solution D, cooling the solution D to 5 ℃, and stirring for 2 hours under the condition of heat preservation to obtain a solution E;
3.8, centrifugation: centrifuging the solution E, filling a filter bag and filter paper in a centrifuge, washing each centrifuge for 10min, rinsing with purified water once, spin-drying for 1h, and weighing to obtain a batch of wet hydrocortisone crude products;
3.9, drying: uniformly loading wet hydrocortisone crude products into a tray, putting the tray into a dryer, baking for 40h at the temperature of 90 ℃, turning over the hydrocortisone crude products every 8h, recording the drying temperature every hour, and bagging after drying treatment to obtain the hydrocortisone crude products;
3.10, weighing 41.75kg of the crude hydrocortisone, and calculating the yield of the product;
4. product detection
4.1, taking a hydrocortisone crude product, and detecting by QC according to a quality standard; the test results of the crude hydrocortisone are shown in table 3, and the crude hydrocortisone is light yellow powdery solid, has a drying weight loss of 0.8% and a purity of 97.2%, and all meets the quality standard.
TABLE 3 quality standards and test results for crude hydrocortisone
According to the preparation method of the crude hydrocortisone, dichloromethane and methanol are used as solvents, the dichloromethane is more than the methanol, the dissolving rate of the hydrocortisone acetate under the low-temperature condition can be increased, the sodium hydroxide and potassium carbonate aqueous solution are used as hydrolysis liquid, the hydrolysis rate of the hydrocortisone acetate can be increased, the production period for preparing the hydrocortisone is greatly reduced, the reaction degree is monitored by adopting a thin-layer chromatography, side reactions are avoided, and the purity and the yield of the product are improved. After the reaction is terminated, dichloromethane and methanol are concentrated and recovered for subsequent production, so that the dosage of the solvent is reduced, and the production cost is reduced.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A preparation method of a hydrocortisone crude product is characterized by comprising the following steps:
feeding materials into a reaction kettle to obtain a solution A;
preparing a hydrolysate, and dripping the hydrolysate into the reaction kettle to obtain a solution B;
detecting whether the solution B contains hydrocortisone acetate;
after confirming that no hydrocortisone acetate exists in the solution B, adding glacial acetic acid into the solution B to terminate the reaction to obtain a solution C;
concentrating the solution C to obtain a solution D;
carrying out water-out treatment on the solution D to obtain a solution E;
and carrying out centrifugal treatment and drying treatment on the solution E to obtain a crude hydrocortisone product.
2. The method for preparing crude hydrocortisone as claimed in claim 1, wherein the crude hydrocortisone is further processed into a crude hydrocortisone extract,
feeding materials into a reaction kettle to obtain a solution A, wherein the method comprises the following specific steps: adding methanol, dichloromethane and hydrocortisone acetate into a reaction kettle, stirring for 10min, cooling the solution in the reaction kettle to-3 to-1 ℃, keeping the temperature, stirring for 30min, and replacing with nitrogen to obtain a solution A;
preparing a hydrolysate, and dripping the hydrolysate into the reaction kettle to obtain a solution B, wherein the method comprises the following specific steps: adding water, sodium hydroxide and potassium carbonate into a preparation tank, stirring until the water, the sodium hydroxide and the potassium carbonate are completely dissolved to obtain a hydrolysate, and pumping the hydrolysate into a dropwise adding tank for later use;
controlling the temperature of the solution A to be-5 to-1 ℃, dripping the hydrolysate into the solution A in the reaction kettle, and stirring for 1.5 hours at the temperature of-5 to-1 ℃ to obtain a solution B;
detecting whether the solution B contains hydrocortisone acetate or not, and the specific steps comprise: after the hydrolysate is dropwise added for 1h, 1mL of the solution B is taken out of a sampling tube, and whether a sample of the solution B contains hydrocortisone acetate is detected by adopting thin-layer chromatography;
after confirming that no hydrocortisone acetate exists in the solution B, adding glacial acetic acid into the solution B to terminate the reaction to obtain a solution C, and the specific steps comprise: when no hydrocortisone acetate is detected in the solution B, adding glacial acetic acid into the solution B, adjusting the pH value of the solution to 6-7, and stopping the reaction to obtain a solution C;
concentrating the solution C to obtain a solution D, and specifically comprising the following steps: controlling the temperature of the solution C at 40-45 ℃, concentrating dichloromethane in a water bath at normal pressure, concentrating methanol under reduced pressure until the solution C is nearly dry, adding water into the solution C, and continuously concentrating until no methanol residue exists in the solution C to obtain a solution D;
carrying out water-out treatment on the solution D to obtain a solution E, and specifically comprising the following steps: adding water into the solution D, cooling to 0-5 ℃, and stirring for 2 hours under the condition of heat preservation to obtain a solution E;
and carrying out centrifugal treatment and drying treatment on the solution E to obtain a crude hydrocortisone product, and specifically comprising the following steps: and centrifuging the solution E, and then drying to obtain a crude hydrocortisone product.
3. The method for preparing the crude hydrocortisone as claimed in claim 2, wherein the weight percentages of the methanol, the dichloromethane and the hydrocortisone acetate are 5.544: 9.282: 1.
4. a crude hydrocortisone preparation method as claimed in claim 2, wherein the nitrogen replacement comprises the following substeps:
vacuumizing the reaction kettle to-0.04 MPa, filling nitrogen for replacement to 0MPa, and repeating the operation for 3 times.
5. The method for preparing the crude hydrocortisone as claimed in claim 2, wherein the weight percentages of the water, sodium hydroxide and potassium carbonate are 200: 2: 3.
6. the method for preparing the crude hydrocortisone as claimed in claim 2, wherein the dropping time of the hydrolysate is 30-50 min.
7. The method for preparing the crude hydrocortisone as claimed in claim 2, wherein the developing solvent used in the thin layer chromatography is a mixture of 4 wt.%: 1 benzene: and mixing the solution with acetone.
8. The method for preparing the crude hydrocortisone as claimed in claim 1 or 2, wherein the centrifugation treatment comprises washing with water for 5-10 min, rinsing with purified water once, and centrifuging for 1 h.
9. The method for preparing crude hydrocortisone as claimed in claim 1, wherein the step of taking 1mL of the solution B in a sampling tube comprises the following substeps:
adding 2-3 drops of glacial acetic acid into a dry and clean sampling tube;
the stirrer in the reaction vessel was closed, and 1mL of solution B was sampled by discharging the solution under pressure in the reaction vessel.
10. The method for preparing the crude hydrocortisone as claimed in claim 1 or 2, wherein the drying treatment comprises the following steps:
uniformly loading the wet cortisone crude product into a tray, and putting the tray into a dryer;
baking for 40-48 h at the temperature of 85-90 ℃;
turning over the wet hydrocortisone crude product every 6-8 h, and recording the drying temperature every hour;
drying and bagging to obtain a crude product of hydrocortisone.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101125876A (en) * | 2007-09-24 | 2008-02-20 | 丽江映华生物药业有限公司 | Preparation technique for high-purity hydrocortisone |
| CN101397323A (en) * | 2007-09-29 | 2009-04-01 | 天津药业研究院有限公司 | Preparation of hydrocortisone |
| CN105367618A (en) * | 2015-11-17 | 2016-03-02 | 华中药业股份有限公司 | Method for preparing hydrocortisone |
| CN107619423A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of hydrocortisone |
| CN110642911A (en) * | 2019-10-18 | 2020-01-03 | 海南顿斯医药科技有限公司 | 1/10 water hydrocortisone compound |
| CN111518151A (en) * | 2020-04-27 | 2020-08-11 | 浙江神洲药业有限公司 | Preparation method of high-purity hydrocortisone |
-
2021
- 2021-08-12 CN CN202110923858.5A patent/CN113583071A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101125876A (en) * | 2007-09-24 | 2008-02-20 | 丽江映华生物药业有限公司 | Preparation technique for high-purity hydrocortisone |
| CN101397323A (en) * | 2007-09-29 | 2009-04-01 | 天津药业研究院有限公司 | Preparation of hydrocortisone |
| CN105367618A (en) * | 2015-11-17 | 2016-03-02 | 华中药业股份有限公司 | Method for preparing hydrocortisone |
| CN107619423A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of hydrocortisone |
| CN110642911A (en) * | 2019-10-18 | 2020-01-03 | 海南顿斯医药科技有限公司 | 1/10 water hydrocortisone compound |
| CN111518151A (en) * | 2020-04-27 | 2020-08-11 | 浙江神洲药业有限公司 | Preparation method of high-purity hydrocortisone |
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