CN113045400B - Preparation method of oxaandrosane intermediate - Google Patents
Preparation method of oxaandrosane intermediate Download PDFInfo
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- CN113045400B CN113045400B CN202110309415.7A CN202110309415A CN113045400B CN 113045400 B CN113045400 B CN 113045400B CN 202110309415 A CN202110309415 A CN 202110309415A CN 113045400 B CN113045400 B CN 113045400B
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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-oxygenated carboxylic acid, which comprises the following steps: 1) Mixing the emasculone, the 2-iodized benzoic acid, a catalyst and a solvent, and then carrying out an oxidation reaction to obtain a compound 1; 2) And (3) mixing the compound 1, an oxidant aqueous solution, bicarbonate and acetone, and performing an oxidation reaction to obtain the 17β -hydroxy-17α -methyl-1-oxo-1, 2-ring-opening-A carbon loss-5α -androstane-2-oxygenated 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 of the invention has the advantages of low reaction temperature, short production period, simple operation, low production cost and environmental protection, and simultaneously obviously shortens the reaction time.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of an oxygen androsaceus intermediate.
Background
The chemical name of the androstane oxide 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 proteins with negligible side effects. The oxygen androsan is taken as an auxiliary drug, is clinically used for treating catabolic diseases such as muscle atrophy caused by HIV, weight reduction caused by large-scale operation or serious burn, neuromuscular diseases, alcoholic liver disease and the like, and has good development value and industrialization prospect.
At present, raw materials commonly adopted for synthesizing the oxygen androstane are methyl epiandrosterol, epiandrosterone, metaandrostane and the like. One key intermediate in the process of preparing the oxygen androsterone from the methyl epiandrosterone and the metaandrosterone is 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon loss-5 alpha-androstane-2-oxygen-containing carboxylic acid. The preparation of 17β -hydroxy-17α -methyl-1-oxo-1, 2-ring-opened-a carbon loss-5α -androstane-2-oxygenated carboxylic acid often employs two schemes: (1) The osmium tetroxide and the lead tetroxide are used as oxidation, and (2) the ozone oxidation is carried out. The first solution has the disadvantage of: osmium tetroxide is extremely toxic and expensive; lead tetraacetate easily pollutes the environment. The second solution has the disadvantage of: special ozone preparing equipment is needed for ozone oxidation; the reaction temperature is below minus 30 ℃, the production is not easy to realize, and the energy consumption is higher; the yield of the product is lower 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 carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid has very important significance, and the reaction efficiency and the yield are improved, the cost is reduced and the process is simple.
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 carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid aiming at the defects of the prior art. The purity and the 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 of the invention has the advantages of low reaction temperature, short production period, simple operation, low production cost and environmental protection, and simultaneously obviously shortens the reaction time.
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-open-loop-A carbon-losing-5 alpha-androstane-2-oxygenated carboxylic acid, which takes mailinolone as a raw material and prepares 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-open-loop-A carbon-losing-5 alpha-androstane-2-oxygenated carboxylic acid through the following route:
17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-open-a carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid
The preparation method of the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid comprises the following steps:
1) Mixing the emasculone, the 2-iodized benzoic acid, a catalyst and a solvent, and then carrying out an oxidation reaction to obtain a compound 1;
2) And (3) mixing the compound 1, an oxidant aqueous solution, bicarbonate and acetone, and performing an oxidation reaction to obtain the 17β -hydroxy-17α -methyl-1-oxo-1, 2-ring-opening-A carbon loss-5α -androstane-2-oxygenated 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 emasculone, the 2-iodized benzoic acid, the catalyst and the solvent in the step 1) is 7.5-8.5 g: 22-25 g:1 to 1.3g: 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, in the step 2), the mass volume ratio of the oxidant aqueous solution, the bicarbonate and the acetone 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 emasculone in the step 1) is 60-80 mL:7.5 g to 8.5g.
Preferably, the oxidant in the aqueous oxidant solution in step 2) is perchlorate, dichromate or periodate; the bicarbonate is potassium bicarbonate or sodium bicarbonate.
Preferably, in the step 2), the mass fraction of the oxidant in the oxidant aqueous solution is 10-20%; the bicarbonate is bicarbonate water 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 points:
1) The preparation method of the invention has the advantages of low reaction temperature, short production period, simple operation and environmental protection, and simultaneously obviously shortens the reaction time.
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-open-loop-A carbon-losing-5 alpha-androstane-2-oxygenated carboxylic acid, which takes mailinolone as a raw material and prepares 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-open-loop-A carbon-losing-5 alpha-androstane-2-oxygenated carboxylic acid through the following route:
17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-open-a carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid
The preparation method of the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid comprises the following steps:
1) Mixing the emasculone, the 2-iodized benzoic acid, a catalyst and a solvent, and then carrying out an oxidation reaction to obtain a compound 1;
2) And (3) mixing the compound 1, an oxidant aqueous solution, bicarbonate and acetone, and performing an oxidation reaction to obtain the 17β -hydroxy-17α -methyl-1-oxo-1, 2-ring-opening-A carbon loss-5α -androstane-2-oxygenated 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 several components, the components are preferably mixed in equal mass ratios; the solvent is further preferably one or two of N, N-dimethylformamide, N-dimethylacetamide and benzene.
The mass volume ratio of the emasculone, the 2-iodized benzoic acid, the catalyst and the solvent in the step 1) is preferably 7.5-8.5 g: 22-25 g:1 to 1.3g:230 to 240mL, more preferably 8g: 23-24 g:1.2g:235mL.
The temperature of the oxidation reaction in step 1) of the present invention is preferably 47 to 62 ℃, more preferably 50 to 60 ℃, and even more preferably 53 to 57 ℃; the time of the oxidation reaction is preferably 10 to 15 hours, more preferably 12 to 14 hours.
The mass volume ratio of the oxidant aqueous solution, the bicarbonate and the acetone in the step 2) is preferably 60-80 mL: 3-5 g:350 to 450mL, more preferably 65 to 75mL:4g:370 to 420mL, more preferably 68 to 72mL:4g: 390-400 mL.
The mass volume ratio of the oxidant aqueous solution in the step 2) to the emasculone in the step 1) is preferably 60-80 mL:7.5 to 8.5g, more preferably 65 to 75mL: 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 aqueous solution of the oxidant 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 aqueous bicarbonate solution is preferably 20 to 30mL, more preferably 23 to 28mL, and even more preferably 25 to 27mL.
The temperature of the oxidation reaction in step 2) of the present invention is preferably 50 to 65 ℃, more preferably 53 to 62 ℃, and even more preferably 56 to 60 ℃; the time of the oxidation reaction is preferably 3 to 5 hours, 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
8g of Mexiranolone was added to a reaction vessel containing a mixed solvent of 167mLN, N-dimethylformamide and 167mL of N, N-dimethylacetamide, 23g of 2-iodoxybenzoic acid and 1.2g of methanesulfonic acid were added, the reaction was heated to 55℃for 13 hours, and the TLC plate was used to track the end of the reaction. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filter cake is washed three times by 100mL of ethyl acetate, and the reduced state of the 2-iodoacyl benzoic acid in the filter cake can be recycled. The organic phase filtrate was diluted with 100mL of ethyl acetate, and washed once with 100mL of a saturated aqueous sodium bicarbonate solution and 100mL of a saturated brine, respectively, and dried over anhydrous sodium sulfate, and the filtrate after filtration was concentrated under reduced pressure to remove the solvent, and then dried in vacuo at 60℃for 2 hours to give Compound 1.
400mL of acetone was added to the reaction vessel, compound 1 was added, 25mL of potassium bicarbonate aqueous solution (containing 4g of potassium bicarbonate) and 70mL of potassium periodate aqueous solution (mass fraction of potassium periodate: 15%) were added dropwise for 30 minutes, then reacted at 60℃for 3.5 hours, and the TLC plate followed the end of the reaction. The reaction solution is cooled to room temperature, filtered, the filter cake is rinsed by 100mL of acetone, the filtrate is decompressed and concentrated to recycle the acetone, then the filtrate is cooled to 3 ℃, 30mL of concentrated hydrochloric acid with the mass fraction of 30% is used for adjusting the pH value to 4.0, the mixture is stirred for 1h and then filtered, the filter cake is washed to be neutral by purified water and n-butane in sequence, and the filter cake is dried to constant weight at 80 ℃ to obtain 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid.
Example 2
7.5g of Mexiranolone was added to a reaction vessel containing a mixed solvent of 150mL of toluene and 80mL of dimethyl sulfoxide, 22g of 2-iodoxybenzoic acid and 1g of p-toluenesulfonic acid were added, the reaction was carried out by heating to 50℃for 15 hours, and the TLC plate followed the end of the reaction. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filter cake is washed three times by 90mL of ethyl acetate, and the reduced state of the 2-iodoacyl benzoic acid in the filter cake can be recycled. The organic phase filtrate was diluted with 90mL of ethyl acetate, and then washed once with 95mL of saturated aqueous sodium bicarbonate and 95mL of saturated brine, respectively, dried over anhydrous sodium sulfate, and the filtrate after filtration was concentrated under reduced pressure to remove the solvent, followed by vacuum drying at 60℃for 2 hours to give compound 1.
370mL of acetone was added to the reaction vessel, compound 1 was added, 22mL of an aqueous sodium hydrogencarbonate solution (containing 3g of sodium hydrogencarbonate) and 62mL of an aqueous potassium perchlorate solution (mass fraction of potassium perchlorate: 18%) were added dropwise for 30min, then reacted at 52℃for 4.5 hours, and the TLC plate was followed by the end point of the reaction. The reaction solution is cooled to room temperature, filtered, the filter cake is rinsed by 95mL of acetone, the filtrate is decompressed and concentrated to recycle the acetone, then the filtrate is cooled to 5 ℃, 30mL of concentrated hydrochloric acid with the mass fraction of 30% is used for adjusting the pH value to 4.0, the mixture is stirred for 1h and then filtered, the filter cake is washed to be neutral by purified water and n-butane in sequence, and the filter cake is dried to constant weight at 75 ℃ to obtain 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid.
Example 3
8.5g of Mexiranolone was added to a reaction vessel containing 240mL of toluene, 25g of 2-iodoxybenzoic acid and 1.3g of methanesulfonic acid were added, the reaction was heated to 60℃for 10 hours, and the TLC plate followed the end of the reaction. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filter cake is washed three times by 110mL of ethyl acetate, and the reduced state of the 2-iodoacyl benzoic acid in the filter cake can be recycled. The organic phase filtrate was diluted with 110mL of ethyl acetate, and washed once with 120mL of a saturated aqueous sodium bicarbonate solution and 100mL of a saturated brine, respectively, and dried over anhydrous sodium sulfate, and the filtrate after filtration was concentrated under reduced pressure to remove the solvent, and then dried in vacuo at 60℃for 2 hours to give Compound 1.
420mL of acetone was added to the reaction vessel, compound 1 was added, 28mL of potassium bicarbonate aqueous solution (containing 4.5g of potassium bicarbonate) and 75mL of potassium periodate aqueous solution (mass fraction of potassium periodate: 12%) were added dropwise for 30 minutes, then reacted at 65℃for 3 hours, and the TLC plate followed the end of the reaction. The reaction solution is cooled to room temperature, filtered, the filter cake is rinsed by 110mL of acetone, the filtrate is decompressed and concentrated to recycle the acetone, then the filtrate is cooled to 2 ℃, the pH value is regulated to 4.0 by 40mL of concentrated hydrochloric acid with the mass fraction of 30 percent, the mixture is stirred for 1h and then filtered, the filter cake is washed to be neutral by purified water and n-butane in sequence, and the filter cake is dried to constant weight at 80 ℃ to obtain 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon loss-5 alpha-androstane-2-oxygenated carboxylic 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 emasculone, N-dimethylformamide, N-dimethylacetamide, 2-iodoxybenzoic acid and methanesulfonic acid are heated to 40 ℃ for reaction for 25 hours. Other conditions were the same as in example 1.
Comparative example 3
The emasculone, N-dimethylformamide, N-dimethylacetamide, 2-iodoxybenzoic acid and methanesulfonic acid are heated to 70 ℃ for reaction for 8 hours. Other conditions were the same as in example 1.
Comparative example 4
35mL of an aqueous potassium hydrogen carbonate solution (containing 6g of potassium hydrogen carbonate) and 50mL of an aqueous potassium periodate solution (the mass fraction of potassium periodate was 20%) were added, and the other conditions were the same as in example 1.
The product yield of comparative example 4 was 68% and purity was 70%.
The products prepared in examples 1 to 3 and comparative examples 1 to 4 were confirmed by infrared spectrum, nuclear magnetic resonance hydrogen spectrum and mass spectrum tests 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 is good | 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 merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (5)
1. The preparation method of the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon-losing-5 alpha-androstane-2-oxygenated carboxylic acid is characterized by taking the mailinolone as a raw material and preparing the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon-losing-5 alpha-androstane-2-oxygenated carboxylic acid through the following route:
17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-open-a carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid
The preparation method of the 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring opening-A carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid comprises the following steps:
1) Mixing the emasculone, the 2-iodized benzoic acid, a catalyst and a solvent, and then carrying out an oxidation reaction to obtain a compound 1;
2) Mixing a compound 1, an oxidant aqueous solution, bicarbonate and acetone, and performing an oxidation reaction to obtain 17 beta-hydroxy-17 alpha-methyl-1-oxo-1, 2-ring-opening-A carbon loss-5 alpha-androstane-2-oxygenated carboxylic acid;
the mass volume ratio of the emasculone, the 2-iodized benzoic acid, the catalyst and the solvent in the step 1) is 7.5-8.5 g: 22-25 g:1 to 1.3g: 230-240 mL;
the temperature of the oxidation reaction in the step 1) is 47-62 ℃ and the time is 10-15 h;
the catalyst in the step 1) is p-toluenesulfonic acid or methylsulfonic acid;
step 2) the oxidant in the oxidant aqueous solution is perchlorate, dichromate or periodate; the bicarbonate is potassium bicarbonate or sodium bicarbonate;
and 2) the oxidation reaction temperature is 50-65 ℃ and the time is 3-5 h.
2. The method according to claim 1, wherein the solvent of step 1) contains one or more of N, N-dimethylformamide, N-dimethylacetamide, benzene, toluene and dimethylsulfoxide.
3. The preparation method according to claim 2, wherein the mass-to-volume ratio of the oxidant aqueous solution, bicarbonate and acetone in the step 2) is 60-80 mL: 3-5 g: 350-450 mL.
4. The preparation method according to claim 2 or 3, wherein the mass-to-volume ratio of the aqueous oxidant solution in step 2) to the emasculone in step 1) is 60-80 mL:7.5 g to 8.5g.
5. The preparation method according to claim 4, wherein 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 bicarbonate water solution; the volume of the bicarbonate water solution is 20-30 mL.
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| EP1387851A1 (en) * | 2001-05-15 | 2004-02-11 | Cedarburg Pharmaceuticals, Llc. | Process for the synthesis of oxandrolone |
| US6787659B2 (en) * | 2001-12-11 | 2004-09-07 | Barr Laboratories, Inc. | Process for the production of oxandrolone |
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| CH695422A5 (en) * | 2002-04-05 | 2006-05-15 | Siegfried Generics Int Ag | A process for introducing a 1,2 double bond at 3-oxo-4-azasteroidverbindungen. |
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