CN113045400A - Preparation method of oxandrolone intermediate - Google Patents
Preparation method of oxandrolone intermediate Download PDFInfo
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- CN113045400A CN113045400A CN202110309415.7A CN202110309415A CN113045400A CN 113045400 A CN113045400 A CN 113045400A CN 202110309415 A CN202110309415 A CN 202110309415A CN 113045400 A CN113045400 A CN 113045400A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
- C07J1/0037—Androstane derivatives substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being a saturated hydrocarbon group
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of organic synthesis. The invention provides a preparation method of 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A carbon loss-5 alpha-androstane-2-oxygen-containing carboxylic acid, which comprises the following steps: 1) mixing the meiandrosaponol, 2-iodoxybenzoic acid, a catalyst and a solvent, and then carrying out an oxidation reaction to obtain a compound 1; 2) the compound 1, an oxidant aqueous solution, bicarbonate and acetone are mixed and then subjected to oxidation reaction to obtain 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid. The purity of the product obtained by the preparation method is more than or equal to 98 percent, and the yield is 95-97 percent; the preparation method disclosed by the invention has the advantages of low reaction temperature, short production period of the product, simplicity in operation, low production cost and environmental friendliness, and the reaction time is obviously shortened.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of an oxandrolone intermediate.
Background
The chemical name of the oxandrolone is 17 beta-hydroxy-17 alpha-methyl-2-oxa-5 alpha-androstane-3-ketone, which is a lipid and protein metabolism improver and can promote the assimilation of in vivo protein with negligible side effect. The oxandrolone is used as an auxiliary medicament, is clinically used for treating catabolic diseases such as muscular atrophy caused by HIV (human immunodeficiency Virus), weight loss caused by major operation or serious burn, neuromuscular disease, alcoholic liver and the like, and has good development value and industrialization prospect.
At present, the raw materials commonly adopted for synthesizing the oxandrolone are methylepiandrostanol, epiandrosterone, meiandrolone and the like. Wherein, a key intermediate in the process for preparing the oxandrolone from the methylepiandrostanol and the meiandrosadrol is 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid. The preparation of 17 β -hydroxy-17 α -methyl-1-oxo-1, 2-ring-opened-a nor-5 α -androst-2-oxocarboxylic acid often employs the following two schemes: (1) osmium tetroxide and lead tetraacetate are used as oxidation, and (2) ozone oxidation is carried out. The disadvantages of the first solution are: osmium tetroxide is extremely toxic and expensive; lead tetraacetate is easy to pollute the environment. The disadvantages of the second solution are: the ozone oxidation needs special ozone-making equipment; the reaction temperature is below-30 ℃, the production is not easy to realize, and the energy consumption is high; the yield of the product is low and is not more than 70 percent.
Therefore, the research and development of the preparation method of the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid, which improves the reaction efficiency and yield, reduces the cost and has simple process, has very important significance.
Disclosure of Invention
The invention aims to provide a preparation method of 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid aiming at the defects of the prior art. The purity and yield of the product obtained by the preparation method are obviously improved, wherein the purity is more than or equal to 98 percent, and the yield is 95-97 percent; the preparation method disclosed by the invention has the advantages of low reaction temperature, short production period of the product, simplicity in operation, low production cost and environmental friendliness, and the reaction time is obviously shortened.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A decarbonization-5 alpha-androstane-2-oxycarboxylic acid, which takes meiandrosterone as a raw material to prepare the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A decarbonization-5 alpha-androstane-2-oxycarboxylic acid through the following route:
17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opened-A nor-5 alpha-androst-2-oxycarboxylic acid
The preparation method of the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid comprises the following steps:
1) mixing the meiandrosaponol, 2-iodoxybenzoic acid, a catalyst and a solvent, and then carrying out an oxidation reaction to obtain a compound 1;
2) the compound 1, an oxidant aqueous solution, bicarbonate and acetone are mixed and then subjected to oxidation reaction to obtain 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid.
Preferably, the catalyst in the step 1) is p-toluenesulfonic acid or methanesulfonic acid; the solvent comprises one or more of N, N-dimethylformamide, N-dimethylacetamide, benzene, toluene and dimethyl sulfoxide.
Preferably, the mass-volume ratio of the meiandrosaur, the 2-iodoxybenzoic acid, the catalyst and the solvent in the step 1) is 7.5-8.5 g: 22-25 g: 1-1.3 g: 230-240 mL.
Preferably, the temperature of the oxidation reaction in the step 1) is 47-62 ℃, and the time is 10-15 h.
Preferably, the mass-volume ratio of the oxidant aqueous solution, the bicarbonate and the acetone in the step 2) is 60-80 mL: 3-5 g: 350-450 mL.
Preferably, the mass-volume ratio of the oxidant aqueous solution in the step 2) to the melanolone in the step 1) is 60-80 mL: 7.5-8.5 g.
Preferably, the oxidizer in the aqueous oxidizer solution in the step 2) is perchlorate, dichromate or periodate; the bicarbonate is potassium bicarbonate or sodium bicarbonate.
Preferably, in the oxidant aqueous solution in the step 2), the mass fraction of the oxidant is 10-20%; the bicarbonate is an aqueous bicarbonate solution; the volume of the bicarbonate water solution is 20-30 mL.
Preferably, the temperature of the oxidation reaction in the step 2) is 50-65 ℃, and the time is 3-5 h.
The beneficial effects of the invention include the following:
1) the preparation method disclosed by the invention is low in required reaction temperature, short in production period of products, simple to operate, green and environment-friendly, and the reaction time is obviously shortened.
2) The purity and yield of the product obtained by the preparation method are obviously improved, and the production cost is obviously reduced.
Detailed Description
The invention provides a preparation method of 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A decarbonization-5 alpha-androstane-2-oxycarboxylic acid, which takes meiandrosterone as a raw material to prepare the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A decarbonization-5 alpha-androstane-2-oxycarboxylic acid through the following route:
17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opened-A nor-5 alpha-androst-2-oxycarboxylic acid
The preparation method of the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid comprises the following steps:
1) mixing the meiandrosaponol, 2-iodoxybenzoic acid, a catalyst and a solvent, and then carrying out an oxidation reaction to obtain a compound 1;
2) the compound 1, an oxidant aqueous solution, bicarbonate and acetone are mixed and then subjected to oxidation reaction to obtain 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid.
The catalyst in step 1) of the present invention is preferably p-toluenesulfonic acid or methanesulfonic acid; the solvent preferably comprises one or more of N, N-dimethylformamide, N-dimethylacetamide, benzene, toluene and dimethyl sulfoxide, and when the solvent simultaneously comprises a plurality of components, the components are preferably mixed in equal mass ratio; the solvent is further preferably one or two of N, N-dimethylformamide, N-dimethylacetamide and benzene.
The mass-volume ratio of the meiandrosaur, the 2-iodoxybenzoic acid, the catalyst and the solvent in the step 1) is preferably 7.5-8.5 g: 22-25 g: 1-1.3 g: 230 to 240mL, more preferably 8 g: 23-24 g: 1.2 g: 235 mL.
The temperature of the oxidation reaction in the step 1) is preferably 47-62 ℃, more preferably 50-60 ℃, and more preferably 53-57 ℃; the time of the oxidation reaction is preferably 10-15 hours, and more preferably 12-14 hours.
The mass-volume ratio of the oxidant aqueous solution, the bicarbonate and the acetone in the step 2) of the invention is preferably 60-80 mL: 3-5 g: 350-450 mL, more preferably 65-75 mL: 4 g: 370-420 mL, more preferably 68-72 mL: 4 g: 390-400 mL.
The mass-volume ratio of the oxidant aqueous solution in the step 2) and the meroandrol in the step 1) is preferably 60-80 mL: 7.5-8.5 g, more preferably 65-75 mL: 7.8-8.2 g.
The oxidizing agent in the aqueous oxidizing agent solution in step 2) of the present invention is preferably perchlorate, dichromate or periodate; the bicarbonate is preferably potassium bicarbonate or sodium bicarbonate.
In the oxidant aqueous solution in the step 2), the mass fraction of the oxidant is preferably 10-20%, more preferably 12-17%, and even more preferably 14-16%; the bicarbonate is preferably an aqueous bicarbonate solution; the volume of the bicarbonate aqueous solution is preferably 20-30 mL, more preferably 23-28 mL, and even more preferably 25-27 mL.
The temperature of the oxidation reaction in the step 2) is preferably 50-65 ℃, more preferably 53-62 ℃, and more preferably 56-60 ℃; the time of the oxidation reaction is preferably 3-5 hours, and more preferably 4 hours.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Adding 8g of meiandrosaponol into a reaction kettle filled with 167mLN, N-dimethylformamide and 167mL of N, N-dimethylacetamide mixed solvent, adding 23g of 2-iodoxybenzoic acid and 1.2g of methanesulfonic acid, heating to 55 ℃, reacting for 13h, and tracking the reaction end point by a TLC point plate. After the reaction is finished, the reaction liquid is cooled to room temperature, the reaction liquid is filtered, a filter cake is washed three times by 100mL of ethyl acetate, and the reduction state of the 2-iodoxybenzoic acid in the filter cake can be recycled. The organic phase filtrate was diluted with 100mL of ethyl acetate, washed once with 100mL of a saturated aqueous solution of sodium hydrogencarbonate and once with 100mL of saturated brine, dried over anhydrous sodium sulfate, and the filtered filtrate was concentrated under reduced pressure to remove the solvent, and then dried under vacuum at 60 ℃ for 2 hours to give Compound 1.
Adding 400mL of acetone into a reaction kettle, adding the compound 1, dropwise adding 25mL of potassium bicarbonate aqueous solution (containing 4g of potassium bicarbonate) and 70mL of potassium periodate aqueous solution (the mass fraction of the potassium periodate is 15%), wherein the dropwise adding time is 30min, reacting for 3.5h at 60 ℃, and tracking the reaction endpoint by a TLC point plate. Cooling the reaction liquid to room temperature, filtering, rinsing a filter cake with 100mL of acetone, decompressing and concentrating the filtrate to recover the acetone, then cooling the filtrate to 3 ℃, adjusting the pH value to 4.0 by using 30mL of concentrated hydrochloric acid with the mass fraction of 30%, stirring for 1h, filtering, washing the filter cake to be neutral by using purified water and n-butane in sequence, and drying the filter cake to constant weight at 80 ℃ to obtain the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon loss-5 alpha-androstane-2-oxycarboxylic acid.
Example 2
Adding 7.5g of meiandrosaponol into a reaction kettle filled with 150mL of toluene and 80mL of dimethyl sulfoxide mixed solvent, adding 22g of 2-iodoxybenzoic acid and 1g of p-toluenesulfonic acid, heating to 50 ℃ for reaction for 15h, and tracking the reaction end point by a TLC point plate. After the reaction is finished, the reaction liquid is cooled to room temperature, the reaction liquid is filtered, a filter cake is washed three times by 90mL of ethyl acetate, and the reduction state of the 2-iodoxybenzoic acid in the filter cake can be recycled. The organic phase filtrate was diluted with 90mL of ethyl acetate, washed with 95mL of a saturated aqueous sodium bicarbonate solution and 95mL of a saturated brine in this order, dried over anhydrous sodium sulfate, and the filtered filtrate was concentrated under reduced pressure to remove the solvent, and then dried under vacuum at 60 ℃ for 2 hours to obtain Compound 1.
370mL of acetone was added to the reaction kettle, Compound 1 was added dropwise, 22mL of an aqueous sodium bicarbonate solution (containing 3g of sodium bicarbonate) and 62mL of an aqueous potassium perchlorate solution (mass fraction of potassium perchlorate: 18%) were added dropwise over 30min, the reaction was carried out at 52 ℃ for 4.5h, and the end point of the reaction was followed by TLC spots. Cooling the reaction liquid to room temperature, filtering, rinsing a filter cake with 95mL of acetone, decompressing and concentrating the filtrate to recover the acetone, then cooling the filtrate to 5 ℃, adjusting the pH value to 4.0 by using 30mL of concentrated hydrochloric acid with the mass fraction of 30%, stirring for 1h, filtering, washing the filter cake to be neutral by using purified water and n-butane in sequence, and drying the filter cake to constant weight at 75 ℃ to obtain the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon loss-5 alpha-androstane-2-oxycarboxylic acid.
Example 3
Adding 8.5g of the meiandrosaponol into a reaction kettle filled with 240mL of toluene, adding 25g of 2-iodoxybenzoic acid and 1.3g of methanesulfonic acid, heating to 60 ℃, reacting for 10h, and tracking the reaction end point by a TLC point plate. After the reaction is finished, the reaction liquid is cooled to room temperature, the reaction liquid is filtered, a filter cake is washed three times by 110mL of ethyl acetate, and the reduction state of the 2-iodoxybenzoic acid in the filter cake can be recycled. The organic phase filtrate was diluted with 110mL of ethyl acetate, washed once with 120mL of a saturated aqueous solution of sodium hydrogencarbonate and once with 100mL of saturated brine, dried over anhydrous sodium sulfate, and the filtered filtrate was concentrated under reduced pressure to remove the solvent, and then dried under vacuum at 60 ℃ for 2 hours to obtain Compound 1.
Adding 420mL of acetone into a reaction kettle, adding the compound 1, dropwise adding 28mL of potassium bicarbonate aqueous solution (containing 4.5g of potassium bicarbonate) and 75mL of potassium periodate aqueous solution (the mass fraction of the potassium periodate is 12%), dropwise adding for 30min, reacting for 3h at 65 ℃, and tracking the reaction endpoint by a TLC point plate. Cooling the reaction liquid to room temperature, filtering, rinsing a filter cake with 110mL of acetone, decompressing and concentrating the filtrate to recover the acetone, then cooling the filtrate to 2 ℃, adjusting the pH value to 4.0 by using 40mL of concentrated hydrochloric acid with the mass fraction of 30%, stirring for 1h, filtering, washing the filter cake to be neutral by using purified water and n-butane in sequence, and drying the filter cake to constant weight at 80 ℃ to obtain the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon loss-5 alpha-androstane-2-oxycarboxylic acid.
Comparative example 1
23g of 2-iodoxybenzoic acid and 0.5g of p-toluenesulfonic acid were added. Other conditions were the same as in example 1.
Comparative example 2
The preparation method comprises the following steps of heating the minolone, N-dimethylformamide, N-dimethylacetamide, 2-iodoxybenzoic acid and methanesulfonic acid to 40 ℃ and reacting for 25 hours. Other conditions were the same as in example 1.
Comparative example 3
The preparation method comprises the following steps of heating the minolone, N-dimethylformamide, N-dimethylacetamide, 2-iodoxybenzoic acid and methanesulfonic acid to 70 ℃ for reacting for 8 hours. Other conditions were the same as in example 1.
Comparative example 4
35mL of an aqueous potassium hydrogencarbonate solution (containing 6g of potassium hydrogencarbonate) and 50mL of an aqueous potassium periodate solution (the mass fraction of potassium periodate was 20%) were added under the same conditions as in example 1.
The product of comparative example 4 was 68% in yield and 70% pure.
The products prepared in examples 1-3 and comparative examples 1-4 were confirmed by infrared spectroscopy, nuclear magnetic resonance hydrogen spectroscopy, mass spectrometry, and elemental analysis.
The yields and purities of the products prepared in examples 1 to 3 and comparative examples 1 to 4 are shown in Table 1.
TABLE 1 yield and purity of the product
| Product(s) | Yield of | Purity of |
| Example 1 | 97％ | 99％ |
| Example 2 | 96％ | 98％ |
| Example 3 | 95％ | 98％ |
| Comparative example 1 | 72％ | 80％ |
| Comparative example 2 | 65％ | 70％ |
| Comparative example 3 | 70％ | 72％ |
| Comparative example 4 | 68％ | 70％ |
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A preparation method of 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A decarbonization-5 alpha-androstane-2-oxycarboxylic acid is characterized in that merestragon is used as a raw material, and the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A decarbonization-5 alpha-androstane-2-oxycarboxylic acid is prepared through the following route:
17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opened-A nor-5 alpha-androst-2-oxycarboxylic acid
The preparation method of the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid comprises the following steps:
1) mixing the meiandrosaponol, 2-iodoxybenzoic acid, a catalyst and a solvent, and then carrying out an oxidation reaction to obtain a compound 1;
2) the compound 1, an oxidant aqueous solution, bicarbonate and acetone are mixed and then subjected to oxidation reaction to obtain 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A decarbonization-5 alpha-androstane-2-oxygen-containing carboxylic acid.
2. The method according to claim 1, wherein the catalyst of step 1) is p-toluenesulfonic acid or methanesulfonic acid; the solvent comprises one or more of N, N-dimethylformamide, N-dimethylacetamide, benzene, toluene and dimethyl sulfoxide.
3. The preparation method according to claim 1 or 2, wherein the mass-volume ratio of the meroandrol in step 1) to the 2-iodoxybenzoic acid to the catalyst to the solvent is 7.5-8.5 g: 22-25 g: 1-1.3 g: 230-240 mL.
4. The preparation method according to claim 3, wherein the temperature of the oxidation reaction in the step 1) is 47-62 ℃ and the time is 10-15 h.
5. The preparation method according to claim 4, wherein the mass-to-volume ratio of the aqueous oxidant solution, the bicarbonate and the acetone in the step 2) is 60-80 mL: 3-5 g: 350-450 mL.
6. The preparation method according to claim 4 or 5, wherein the mass-to-volume ratio of the aqueous oxidant solution in step 2) to the minolone in step 1) is 60-80 mL: 7.5-8.5 g.
7. The method according to claim 6, wherein the oxidizing agent in the aqueous oxidizing agent solution of step 2) is perchlorate, dichromate or periodate; the bicarbonate is potassium bicarbonate or sodium bicarbonate.
8. The preparation method according to claim 7, characterized in that in the aqueous solution of the oxidizing agent in the step 2), the mass fraction of the oxidizing agent is 10-20%; the bicarbonate is an aqueous bicarbonate solution; the volume of the bicarbonate water solution is 20-30 mL.
9. The preparation method of claim 8, wherein the temperature of the oxidation reaction in the step 2) is 50-65 ℃ and the time is 3-5 h.
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