CN108059647B - Synthesis method of alclometasone dipropionate intermediate 11-beta hydroxy pregna - Google Patents
Synthesis method of alclometasone dipropionate intermediate 11-beta hydroxy pregna Download PDFInfo
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- 229960004229 alclometasone dipropionate Drugs 0.000 title abstract description 10
- DJHCCTTVDRAMEH-DUUJBDRPSA-N alclometasone dipropionate Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O DJHCCTTVDRAMEH-DUUJBDRPSA-N 0.000 title abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title description 7
- 238000001308 synthesis method Methods 0.000 title description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 21
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 238000007348 radical reaction Methods 0.000 claims abstract description 12
- 150000003254 radicals Chemical class 0.000 claims abstract description 9
- LJAOOBNHPFKCDR-UHFFFAOYSA-K chromium(3+) trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Cr+3] LJAOOBNHPFKCDR-UHFFFAOYSA-K 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 10
- 229910021556 Chromium(III) chloride Inorganic materials 0.000 claims description 9
- 229960000359 chromic chloride Drugs 0.000 claims description 9
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 239000005457 ice water Substances 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 238000007670 refining Methods 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
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- 239000011259 mixed solution Substances 0.000 description 3
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- 238000002360 preparation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
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- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 102000000412 Annexin Human genes 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
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- 230000007803 itching Effects 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
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- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
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- 150000003431 steroids Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a synthetic method of an alclometasone dipropionate intermediate 11-beta hydroxypregna. The compound of formula II is used as a raw material, and the compound is subjected to free radical reaction under the action of zinc powder, chromium trichloride hexahydrate and thioglycolic acid to obtain the 11-beta-hydroxypregna. The method provided by the invention is simple to operate, high in yield and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a synthetic method of an alclometasone dipropionate intermediate 11-beta hydroxypregna.
Background
The alclometasone dipropionate is a low-and-medium-effect corticosteroid hormone medicament, and pharmacological test researches show that the alclometasone dipropionate has the effects of resisting inflammation, allergy and hyperplasia. Clinical use shows that the alclometasone dipropionate has the effects of resisting inflammation, relieving itching and contracting blood vessels. It is generally believed that corticosteroids inhibit the hydrolysis of membrane phospholipids by phospholipase a2 to release arachidonic acid by inducing lipocortins, thereby controlling the biosynthesis of inflammatory mediators such as prostaglandins and leukotrienes, and playing an anti-inflammatory role, and 11-beta-hydroxypregna is a very key intermediate of alclometasone dipropionate, and the structural formula of the corticosteroid is as follows:
the method for synthesizing 11-beta-hydroxypregna in the prior art comprises the following steps:
in the US patent No. 5426198, zinc powder, thioglycolic acid, chromium trichloride are reacted in a mixed solvent of N, N dimethyl formamide and tetrahydrofuran, and the reaction is carried out under reflux at a temperature which is found out, wherein the reaction is completed within 2.5 days at the room temperature, the reflux reaction is carried out within 1.1 h, the purity of the method is 80-95%, the reaction time is long, the energy consumption is high, the production cost is high, and the method is not suitable for industrial production.
The method for introducing 11-alpha hydroxyl by a microbial conversion method and converting 11-alpha hydroxyl into 11-beta hydroxyl by a chemical synthesis method is the most common method for introducing 11-beta hydroxyl in steroid synthesis at home and abroad at present, and the method is immature in technology, long in synthesis route, long in production period, high in production cost and not suitable for industrial industrialization.
Therefore, the inventor of the invention develops a preparation method of 11-beta-hydroxypregna with mild reaction conditions, simple operation, short time consumption and high product purity.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing 11- β hydroxypregna, which has the advantages of mild reaction conditions, short reaction time and simple operation.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the 11-beta-hydroxypregna is generated by a free radical reaction of a compound shown as a formula II under the action of zinc powder, chromium trichloride hexahydrate and thioglycolic acid, wherein the reaction solvent is one or more of N, N-dimethylformamide, acetone and N, N-dimethylacetamide, and the reaction formula is as follows:
preferably, the reaction temperature of the radical reaction is-50 to 50 ℃.
Further preferably, the reaction temperature of the free radical reaction is-10 to 10 ℃.
Preferably, the molar ratio of the compound of formula II to the solvent is 1:1.0 to 20.0, preferably 1.0:1.0 to 10.0, and more preferably 1.0:5.0 to 10.0.
Preferably, the molar ratio of the compound of formula II to the zinc powder is 1: 1.0-10.0.
More preferably, the molar ratio of the compound of formula ii to zinc powder is 1.0:1.0 to 5.0, and still more preferably 1.0:1.0 to 3.0.
Preferably, the molar ratio of the compound of formula II to thioglycolic acid is 1:1.0 to 10.0.
More preferably, the molar ratio of the compound of formula II to mercaptoacetic acid is 1:1.0 to 5.0, still more preferably 1.0:1.0 to 3.0.
Preferably, the molar ratio of the compound shown in the formula II to the chromium trichloride hexahydrate is 1: 0.1-5.0.
More preferably, the molar ratio of the compound of formula II to chromium trichloride hexahydrate is 1:0.1 to 2.0, still more preferably 1.0:0.1 to 1.0.
Preferably, the reaction time of the radical reaction is 0.5 to 5 hours.
The method for preparing the 11-beta-hydroxypregna comprises the following steps:
1) under the anaerobic condition, adding chromium trichloride, zinc powder, thioglycollic acid and a compound shown in a formula II into a solvent to perform free radical reaction to obtain a solution 1;
2) pouring the solution 1 into ice water, centrifuging, dissolving precipitate with tetrahydrofuran, and filtering to obtain filtrate;
3) concentrating the filtrate, adding ethyl acetate and petroleum ether, and refining to obtain the product 11-beta-hydroxypregna.
Preferably, the preparation method comprises the following steps:
1) adding a solvent and chromium trichloride into a reaction kettle under the condition of nitrogen protection and deoxidation, stirring, dissolving and cooling; adding zinc powder, keeping the temperature, dropwise adding thioglycollic acid, and dropwise adding a mixed solution of a compound shown in the formula II and a solvent.
2) After the reaction is finished, pouring the reaction liquid into ice water, filtering, dissolving a filter cake by tetrahydrofuran, and then adding anhydrous sodium sulfate for drying.
3) Concentrating the filtrate, and refining with ethyl acetate and petroleum ether to obtain 11-beta-hydroxypregna.
The second purpose of the invention is to provide the 11-beta-hydroxypregna prepared by the method of the first purpose, which has the advantages of high product purity and short reaction time, and greatly improves the production efficiency.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the 11-beta-hydroxypregna is generated by a free radical reaction of a compound shown as a formula II under the action of zinc powder, chromium trichloride hexahydrate and thioglycolic acid, and the reaction formula is as follows:
preferably, the solvent for the reaction is one or more of N, N-dimethylformamide, acetone and N, N-dimethylacetamide.
The method for preparing the 11-beta-hydroxypregna comprises the following steps:
1) adding chromium trichloride, zinc powder, thioglycollic acid and a compound shown as a formula II into a solvent, and carrying out a free radical reaction at-50 ℃ to obtain a solution 1;
2) pouring the solution 1 into ice water, centrifuging, dissolving precipitate with tetrahydrofuran, and filtering to obtain filtrate;
3) concentrating the filtrate, adding ethyl acetate and petroleum ether, and refining to obtain the product 11-beta-hydroxypregna.
The third purpose of the invention is to provide the application of the 11-beta-hydroxypregna of the second purpose in preparing the alclometasone dipropionate, and the key intermediate 11-beta-hydroxypregna is prepared by the method of the first purpose and has the advantages of high product purity and short reaction time.
The invention has the beneficial effects that: the method for preparing the alclometasone dipropionate intermediate 11-beta hydroxy pregna provided by the invention has the following advantages:
1. the reaction condition is mild, the operation is simple, and solvent extraction is not needed;
2. the preparation time is shortened, the whole process time is 6.0-10 hours, the production cost is reduced, the production efficiency is greatly improved, and the industrial production is facilitated;
3. the process is stable, the impurities in the product are not more than 1%, and the purity of the 11-beta-hydroxypregna reaches more than 99%.
Drawings
FIG. 1 is a chromatogram of the product of example 1
FIG. 2 is a chromatogram of the product of example 2
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail (with reference to the accompanying drawings). The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1
1) Under the condition of vacuumizing and introducing nitrogen for deoxidation, adding 1.2kg of chromium trichloride and 21.5L of dimethylformamide into a dry and clean 50L reaction kettle, stirring and dissolving the chromium trichloride and the 21.5L of dimethylformamide clearly, cooling to-5 ℃, adding 1.2kg of zinc powder, dropwise adding 1.4kg of thioglycolic acid, slowly dropwise adding 3.4kg of a compound of a formula II dissolved by 17.2L of dimethylformamide at the temperature of-10-0 ℃, and vacuumizing and introducing nitrogen for deoxidation to mixed liquid;
2) reacting at constant temperature of-10-0 ℃ for 0.5-1.0 h, and monitoring the disappearance of the raw materials by TLC (thin layer chromatography, chloroform: acetone is 4: 1);
3) pouring the reaction solution into 164L of ice water with the temperature of 0-5 ℃, stirring for 10-20 minutes, centrifuging, stirring and dissolving a filter cake with 40.0L of tetrahydrofuran, adding anhydrous sodium sulfate, drying for 1 hour, and filtering;
4) concentrating the filtrate until the flow is cut off, adding ethyl acetate into the residue to dissolve the residue, adding petroleum ether, stirring and crystallizing for 1-2 hours, centrifuging, putting the filter cake into a vacuum drying oven, drying under reduced pressure at 40-50 ℃ for 1.5-2.5 hours under the vacuum degree of less than or equal to-0.08 MPa, and obtaining 3.24kg of a product, wherein the yield is 90%, and the purity is 99.2%. The chromatogram of the product is shown in FIG. 1, and the chromatographic detection result of the product is shown in Table 1.
TABLE 1 chromatographic test results for the products
| Peak # | Retention time | Area of | Height | Area% | Theoretical plate # | Tailing factor | Degree of separation |
| 1 | 9.529 | 39542 | 2012 | 0.113 | 5121 | 1.035 | 0.000 |
| 2 | 11.466 | 151549 | 6067 | 0.435 | 5363 | 0.869 | 3.342 |
| 3 | 15.658 | 34597379 | 1092036 | 99.238 | 5956 | 1.222 | 5.831 |
| 4 | 21.866 | 74734 | 1613 | 0.214 | 6358 | 0.835 | 6.505 |
| Total of | 34863204 | 1101729 | 100.000 |
Example 2
1) Under the condition of vacuumizing and introducing nitrogen for deoxidation, 161.5g of chromium trichloride and 3.0L of dimethylacetamide are added into a dry and clean 10L reaction kettle and stirred for dissolving, the temperature is reduced to minus 5-5 ℃, 157.5g of zinc powder is added, 161.5g of mercaptoacetic acid is added dropwise, 600g of a compound of a formula II dissolved by 2.4L of dimethylacetamide is slowly added dropwise at the temperature of minus 10-0 ℃, and the mixed solution is vacuumized and introduced with nitrogen for deoxidation;
2) reacting at constant temperature of-10-0 ℃ for 0.5-1.0 h, and monitoring the disappearance of the raw materials by TLC (thin layer chromatography, chloroform: acetone is 4: 1);
3) pouring the reaction solution into 24L of ice water with the temperature of 0-5 ℃, stirring for 10-20 minutes, centrifuging, stirring and dissolving a filter cake with 8.0L of tetrahydrofuran, adding anhydrous sodium sulfate, drying for 1 hour, and filtering;
4) concentrating the filtrate until the flow is cut off, adding ethyl acetate into the residue to dissolve the residue, adding petroleum ether, stirring and crystallizing for 1-2 hours, centrifuging, putting the filter cake into a vacuum drying oven, drying under reduced pressure at 40-50 ℃ for 1.5-2.5 hours under the vacuum degree of less than or equal to-0.08 MPa to obtain 464.6g of a product, wherein the yield is 92.0%, and the purity is 99.1%. The chromatogram of the product is shown in FIG. 2, and the chromatographic detection result of the product is shown in Table 2.
TABLE 2 chromatographic test results for the products
| Peak # | Retention time | Area of | Height | Area% | Theoretical plate # | Tailing factor | Degree of separation |
| 1 | 4.752 | 22332 | 1411 | 0.063 | 2225 | 1.340 | 0.000 |
| 2 | 8.027 | 9161 | 442 | 0.026 | 3241 | 1.022 | 6.776 |
| 3 | 11.391 | 42289 | 1612 | 0.119 | 4078 | 0.989 | 5.266 |
| 4 | 12.179 | 5932 | 265 | 0.017 | 6510 | 1.245 | 1.196 |
| 5 | 13.990 | 170235 | 4581 | 0.478 | 3679 | 0.815 | 2.373 |
| 6 | 19.987 | 35295179 | 774453 | 99.100 | 4649 | 1.191 | 5.724 |
| 7 | 29.422 | 70556 | 1191 | 0.198 | 5411 | 1.074 | 6.806 |
| Total of | 35615683 | 783954 | 100.000 |
Example 3
1) Under the condition of vacuumizing and introducing nitrogen for deoxidation, 113.0g of chromium trichloride, 1.0L of dimethylformamide and 1.1L of acetone are added into a dry and clean 10L reaction kettle and stirred for dissolution, the temperature is reduced to minus 5-5 ℃, 110.2gg of zinc powder is added, 140.6g of thioglycolic acid is dropwise added, 420g of a compound of a formula II dissolved by 1.7L of dimethylacetamide is slowly dropwise added at the temperature of minus 10-0 ℃, and the mixed solution is vacuumized and introduced with nitrogen for deoxidation;
2) reacting at constant temperature of-10-0 ℃ for 0.5-1.0 h, and monitoring the disappearance of the raw materials by TLC (thin layer chromatography, chloroform: acetone is 4: 1);
3) pouring the reaction solution into 20L of ice water with the temperature of 0-5 ℃, stirring for 10-20 minutes, centrifuging, stirring and dissolving a filter cake with 7.0L of tetrahydrofuran, adding anhydrous sodium sulfate, drying for 1 hour, and filtering;
4) concentrating the filtrate until the flow is cut off, adding ethyl acetate into the residue to dissolve the residue, adding petroleum ether, stirring and crystallizing for 1-2 hours, centrifuging, putting the filter cake into a vacuum drying oven, drying under reduced pressure at 40-50 ℃ for 1.5-2.5 hours under the vacuum degree of less than or equal to-0.08 MPa, and obtaining 300.0g of a product, wherein the yield is 85%, and the purity is 99.2%.
The 11-beta-hydroxypregna can be obtained by reacting and purifying within 6-10 hours through the above embodiments, and the purity of the 11-beta-hydroxypregna in the product is as high as more than 99%. The reaction condition for preparing the 11-beta-hydroxypregna provided by the invention is mild, the operation is simple, the production cost is greatly reduced, the production efficiency is improved, and the method is suitable for industrial production.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (3)
1. A method for preparing 11-beta hydroxypregna is characterized in that a compound shown as a formula II is used as a raw material, one or more of N, N-dimethylformamide, acetone and N, N-dimethylacetamide is used as a solvent, a free radical reaction is carried out under the action of zinc powder, chromium trichloride hexahydrate and thioglycolic acid to generate the 11-beta hydroxypregna, the temperature of the free radical reaction is-50 ℃, the reaction time is 0.5-5 hours, the molar ratio of the compound shown as the formula II to the zinc powder is 1: 1.0-10.0, the molar ratio of the compound shown as the formula II to the thioglycolic acid is 1: 1.0-10.0, the molar ratio of the compound shown as the formula II to the chromium trichloride hexahydrate is 1: 0.1-5.0,
the reaction formula is as follows:
2. the method according to claim 1, wherein the temperature of the radical reaction is-10 to 10 ℃.
3. The method according to any one of claims 1 to 2, comprising the steps of:
1) under the anaerobic condition, adding chromium trichloride, zinc powder, thioglycollic acid and a compound shown in a formula II into a solvent to perform free radical reaction to obtain a solution 1;
2) pouring the solution 1 into ice water, centrifuging, dissolving precipitate with tetrahydrofuran, and filtering to obtain filtrate;
3) concentrating the filtrate, adding ethyl acetate and petroleum ether, and refining to obtain the product 11-beta-hydroxypregna.
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| CN109796515B (en) * | 2019-02-21 | 2020-08-11 | 湖南科瑞生物制药股份有限公司 | Method for preparing reduced intermediate for alclometasone dipropionate |
| CN109651476B (en) * | 2019-02-21 | 2020-08-11 | 湖南科瑞生物制药股份有限公司 | Method for preparing reduced intermediate product for alclometasone dipropionate |
| CN109796514B (en) * | 2019-02-21 | 2020-08-11 | 湖南科瑞生物制药股份有限公司 | Method for preparing alclometasone dipropionate from etherified intermediate |
| CN109678920B (en) * | 2019-02-21 | 2020-08-11 | 湖南科瑞生物制药股份有限公司 | Method for preparing alclometasone dipropionate |
| CN109651478B (en) * | 2019-02-21 | 2020-08-11 | 湖南科瑞生物制药股份有限公司 | Method for preparing dehydrogenated intermediate for alclometasone dipropionate |
| CN109666054B (en) * | 2019-02-21 | 2020-08-11 | 湖南科瑞生物制药股份有限公司 | Method for preparing alclometasone dipropionate product |
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| CN112375114A (en) * | 2020-11-12 | 2021-02-19 | 湖南新合新生物医药有限公司 | Preparation method of prednisolone acetate |
| CN116217646A (en) * | 2023-03-07 | 2023-06-06 | 重庆华邦胜凯制药有限公司 | Preparation method and production system of 16 alpha-hydroxy prednisone intermediate |
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