CN102286052A - Method for synthetising pregnenolol compound - Google Patents
Method for synthetising pregnenolol compound Download PDFInfo
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- CN102286052A CN102286052A CN 201110196181 CN201110196181A CN102286052A CN 102286052 A CN102286052 A CN 102286052A CN 201110196181 CN201110196181 CN 201110196181 CN 201110196181 A CN201110196181 A CN 201110196181A CN 102286052 A CN102286052 A CN 102286052A
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Abstract
The invention relates to a method for synthetising a pregnenolol compound. The pregnenolol compound is prepared by using pseudo steroid sapogenin as the raw material through a one-pot method of oxone oxidization and alkali elimination hydrolysis reaction. Compared with the prior art, the method for synthetising the pregnenolol compound has the advantages that the condition is mild; the method is simple and convenient to operate; the problem of environmental protection is solved; the utilization degree of steroid sapogenin is improved; and the method is more suitable for the requirement of the industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of NSC 37741 compound.It is a raw material with pseudo-steroid sapogenines, prepares through oxone oxidation and alkali elimination hydrolysis reaction " one kettle way ".Utilize the method for the synthetic NSC 37741 compound of the present invention, more easy and simple to handle than existing document mild condition, solved environmental pollution problems simultaneously, also improved the availability of steroid sapogenines, be more suitable for industrial needs.
Technical background
The NSC 37741 derivative comprises a series of pregnant steroids-16-alkene-20-ketone compound, and they are hydrolysates of acetic acid NSC 37741.The technology of producing the acetic acid NSC 37741 at present still is adopted as steroid sapogenin degradation method (Marker:J.Am.Chem.Soc.1940,62 3350 of Americanized scholar Marker in the forties invention in last century; 1941,63 774; 1947,69 2167).Promptly in diacetyl oxide and acetate, pressurize, high temperature (more than 200 ℃) cracking steroid sapogenines becomes corresponding false steroid sapogenines, provides corresponding acetic acid NSC 37741 through chromic anhydride oxidation and elimination reaction again.Though this technology is used chromic anhydride as the oxygenant in the oxidative degradation process all the time, thereby problem of environmental pollution and wastage of material problem in the acetic acid NSC 37741 production process is not really solved through through many improvement.At these problems, studied nonmetal chromium oxidising agent (hydrogen peroxide, the oxygen etc.) oxidizing reaction of steroid sapogenines and false steroid sapogenines robot systems such as Tian Weisheng, having applied for corresponding is oxygenant oxidation degradation of steroid sapogenin and false steroid sapogenines with hydrogen peroxide, the technology (Chinese patent 03141641.1) of the important synthetic intermediates of synthesizing steroid medicine such as preparation NSC 37741.On this basis, keep and explore and research, seek new breakthrough.
By experiment, Tian Weisheng group finds that pseudo-steroid sapogenines can obtain a series of 20 alpha-hydroxyl radical steroid sapogenins (referring to CN200710044933.0) by the oxone oxidation under the certain reaction condition.With pseudo-sisalagenin is example, reacts as follows:
This method reaction conditions gentleness, easy and simple to handle, shortcoming is that reaction obtains two compounds, be difficult for separation and purification, and can't synthesize NSC 37741, the problem to be solved in the present invention is exactly on the basis of this reaction, can synthesize the NSC 37741 compound by experiment.
Summary of the invention
The technical scheme that the present invention solves provides a kind of synthetic method of NSC 37741 compound.
The synthetic method of NSC 37741 compound of the present invention is synthetic by following steps;
Wherein, Ac is an ethanoyl, and C5-C6 is singly-bound or two key.
In acetone, compound 1 and sodium bicarbonate (NaHCO
3), water (H
2O), potassium hydrogen persulfate (oxone) reacted 12～24 hours to room temperature at-10 ℃, distillating recovering solvent is used the trimethyl carbinol and water dissolution then, add mineral alkali 50 ℃ to reflux temperature reaction 8～15 hours, obtain compound 2; Compound 1 and NaHCO
3, H
2The mol ratio of O and oxone is 1: 4～10: 200～400: 3～10; Compound 1 is 1: 3～8 with the mol ratio of mineral alkali; Described mineral alkali is potassium hydroxide or sodium hydroxide.
The present invention is on the basis of patent, by changing amount of reagent, temperature of reaction and reaction times, obtained a new single midbody compound, and can synthesize the NSC 37741 compound easily by this compound, midbody compound is met acid and is decomposed easily, does not therefore need separation and purification, has directly realized the synthetic method of two-step reaction " one kettle way ".Entire method is easy and simple to handle, mild condition, and the productive rate height has solved the problem of environmental pollution in the acetic acid NSC 37741 production process, has also solved the problem of the steroidal wasting of resources in the reaction simultaneously.
Specific implementation method
To help to understand the present invention by following specific implementation method, but not limit content of the present invention.
Embodiment 1 compound 2a's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1a 4.26g, add 70mL acetone as solvent, then to wherein adding 3.56g NaHCO
3(4eq.) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 23mL, take by weighing 19.58g Oxone (3eq.) then and join in the reaction solution, cryosel is bathed and was returned to room temperature reaction gradually 18 hours, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness,, add the 70mL trimethyl carbinol as solvent then to wherein adding 2.37g KOH (4.2eq.), 5ml water, reflux 10 hours, TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up is used the EtOAc extracting twice then, anhydrous sodium sulfate drying, and the column chromatography purification product gets compound 2a 1.81g, yield 57.7%.
1H-NMR(400MHz，CDCl
3)δ6.69-6.67(q，1H，J
1＝4Hz，J
2＝1.6Hz，J
3＝4Hz)，3.63-3.55(m，1H)，2.25(s，3H)，0.88(s，3H)，0.84(s，3H).
Embodiment 2 compound 2a's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1a 5g, add 80mL acetone as solvent, then to wherein adding 5.88g NaHCO
3(7eq.) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 60mL, take by weighing 30.74g Oxone (5eq.) then and join in the reaction solution, cryosel is bathed and was returned to room temperature reaction gradually 15 hours, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness,, add the 70mL trimethyl carbinol as solvent then to wherein adding 2.8g KOH (5eq.), 5ml water, reflux 9 hours, TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up, then with the EtOAc extraction, anhydrous sodium sulfate drying, the column chromatography purification product gets compound 2a1.79g, yield 56.9%.
Embodiment 3 compound 2a's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1a 5g, add 80mL acetone as solvent, then to wherein adding 7.56g NaHCO
3(9eq.) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 25mL, take by weighing 43.03g Oxone (7eq.) then and join in the reaction solution, cryosel is bathed and is risen to ice bath reaction 24 hours, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness,, add the 80mL trimethyl carbinol as solvent then to wherein adding 3.36g KOH (6eq.), 6ml water, 60 ℃ were reacted 12 hours down, and TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up, then with the EtOAc extraction, anhydrous sodium sulfate drying, the column chromatography purification product gets compound 2a 1.77g, yield 56.4%.
Embodiment 4 compound 2a's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1a 5g, add 80mL acetone as solvent, then to wherein adding 8.4g NaHCO
3(10eq.) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 25mL, take by weighing 61.47g Oxone (10eq.) then and join in the reaction solution, reaction was 18 hours under cryosel was bathed and risen to 10 ℃, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness,, add the 80mL trimethyl carbinol as solvent then to wherein adding 4.48g KOH (8eq.), 6ml water, 50 ℃ were reacted 9 hours down, and TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up, then with the EtOAc extraction, anhydrous sodium sulfate drying, the column chromatography purification product gets compound 2a 1.76g, yield 56.1%.
Embodiment 5 compound 2a's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1a 5g, add 80mL acetone as solvent, then to wherein adding 5.04g NaHCO
3(6eq.) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 25mL, take by weighing 18.44g Oxone (3eq.) then and join in the reaction solution, cryosel is bathed to rise under the room temperature and was reacted 18 hours, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness,, add the 80mL trimethyl carbinol as solvent then to wherein adding 4.48g KOH (8eq.), 6ml water, 50 ℃ were reacted 9 hours down, and TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up, then with the EtOAc extraction, anhydrous sodium sulfate drying, the column chromatography purification product gets compound 2a 1.85g, yield 58.8%.
Embodiment 6 compound 2b's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1b 4.98g, add 70mL acetone as solvent, then to wherein adding 4.2g NaHCO
3(5eq) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 23mL, take by weighing 30.7g Oxone (5eq) then and join in the reaction solution, ice bath reaction 18 hours, TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness, then to wherein adding 2.8g KOH (5eq.), add the 70mL trimethyl carbinol as solvent, add 5ml water again, reflux and stirred 9 hours, TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up is used the EtOAc extracting twice then, anhydrous sodium sulfate drying, and the column chromatography purification product gets compound 2b 1.82g, yield 57.9%.
1H-NMR(400MHz，CDCl
3)δ6.70(s，1H)，5.37-5.35(d，J＝8Hz，1H)，3.55-3.50(m，1H)，2.26(s，3H)，1.05(s，3H)，0.92(s，3H).
Embodiment 7 compound 2b's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1b 4.98g, add 70mL acetone as solvent, then to wherein adding 5.88g NaHCO
3(7eq) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 24mL, take by weighing 39.95g Oxone (6.5eq) then and join in the reaction solution, cryosel is bathed and is risen to 10 ℃ of reactions 22 hours, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness, then to wherein adding 3.36g KOH (6eq.), add the 70mL trimethyl carbinol as solvent, add 6ml water again, 60 ℃ were stirred 12 hours down, and TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up is used the EtOAc extracting twice then, anhydrous sodium sulfate drying, and the column chromatography purification product gets compound 2b 1.80g, yield 57.4%.
Embodiment 8 compound 2b's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1b 4.98g, add 70mL acetone as solvent, then to wherein adding 8.4g NaHCO
3(10eq) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 25mL, take by weighing 49.17g Oxone (8eq) then and join in the reaction solution, ice bath reacted 18 hours down, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness, then to wherein adding 4.48g KOH (8eq.), add the 70mL trimethyl carbinol as solvent, add 6ml water again, 50 ℃ were stirred 11 hours down, and TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up is used the EtOAc extracting twice then, anhydrous sodium sulfate drying, and the column chromatography purification product gets compound 2b 1.78g, yield 56.8%.
Embodiment 9 compound 2b's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1b 4.98g, add 70mL acetone as solvent, then to wherein adding 4.2g NaHCO
3(5eq) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 23mL, take by weighing 27.66g Oxone (4.5eq) then and join in the reaction solution, ice bath reacted 24 hours down, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness, then to wherein adding 1.68g KOH (3eq.), add the 70mL trimethyl carbinol as solvent, add 6ml water again, reflux and stirred 15 hours, TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up is used the EtOAc extracting twice then, anhydrous sodium sulfate drying, and the column chromatography purification product gets compound 2b 1.80g, yield 57.2%.
Embodiment 10 compound 2b's is synthetic
In the there-necked flask of 250mL, take by weighing compound 1b 4.98g, add 70mL acetone as solvent, then to wherein adding 4.2g NaHCO
3(5eq) solid, and place cryosel bathe to go up to stir cooling the reaction solution.To wherein adding water 23mL, take by weighing 18.44g Oxone (3eq) then and join in the reaction solution, 10 ℃ were reacted 24 hours down, and TLC follows the tracks of reaction until reacting completely.Revolve steaming until evaporate to dryness, then to wherein adding 1.68g KOH (3eq.), add the 70mL trimethyl carbinol as solvent, add 6ml water again, reflux and stirred 15 hours, TLC follows the tracks of reaction, finds to react completely.Revolve to steam and remove most of trimethyl carbinol, thin up is used the EtOAc extracting twice then, anhydrous sodium sulfate drying, and the column chromatography purification product gets compound 2b 1.76, yield 56.2%.
Claims (1)
1. the synthetic method of a NSC 37741 compound is characterized in that by following steps synthetic:
In acetone, compound 1 reacted 12～24 hours to room temperature at-10 ℃ with sodium bicarbonate, water, potassium hydrogen persulfate, and distillating recovering solvent is used the trimethyl carbinol and water dissolution then, add mineral alkali 50 ℃ to reflux temperature reaction 8～15 hours, obtain compound 2; The mol ratio of compound 1, sodium bicarbonate, water and potassium hydrogen persulfate is 1: 4～10: 200～400: 3～10; Compound 1 is 1: 3～8 with the mol ratio of mineral alkali; Described mineral alkali is potassium hydroxide or sodium hydroxide; Wherein, compound 1 and 2 structure are:
Wherein, Ac is an ethanoyl, and C5-C6 is singly-bound or two key.
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|---|---|---|---|
| CN 201110196181 CN102286052B (en) | 2011-07-13 | 2011-07-13 | Method for synthetising pregnenolol compound |
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| CN 201110196181 CN102286052B (en) | 2011-07-13 | 2011-07-13 | Method for synthetising pregnenolol compound |
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| CN102286052B CN102286052B (en) | 2013-03-06 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1341603A (en) * | 2001-06-29 | 2002-03-27 | 中国科学院上海有机化学研究所 | Synthesis method of pregnen ketoalcohol compound |
| CN1475494A (en) * | 2003-07-16 | 2004-02-18 | 中国科学院上海有机化学研究所 | Cleaning production technique of 16-dehydro pregnenetrolone and its same kind compound |
-
2011
- 2011-07-13 CN CN 201110196181 patent/CN102286052B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1341603A (en) * | 2001-06-29 | 2002-03-27 | 中国科学院上海有机化学研究所 | Synthesis method of pregnen ketoalcohol compound |
| CN1475494A (en) * | 2003-07-16 | 2004-02-18 | 中国科学院上海有机化学研究所 | Cleaning production technique of 16-dehydro pregnenetrolone and its same kind compound |
Non-Patent Citations (2)
| Title |
|---|
| 《J.AM.Chem.Soc.》 19401231 RUSSELL E.MARKER Sterols.CXIII.Sapogenins.XLII.The Conversion of the Sapogenins to the Pregnenolones 第3350-3352页 1 第62卷, 第12期 * |
| 《化学学报》 20101231 季菲 等 由孕甾-3S,5R,6R,16S,20S-五醇合成黄体酮 第2331~2337页 1 第68卷, 第22期 * |
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Granted publication date: 20130306 Termination date: 20210713 |