CN108033989A - The preparation method of canrenone - Google Patents
The preparation method of canrenone Download PDFInfo
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- CN108033989A CN108033989A CN201711463417.1A CN201711463417A CN108033989A CN 108033989 A CN108033989 A CN 108033989A CN 201711463417 A CN201711463417 A CN 201711463417A CN 108033989 A CN108033989 A CN 108033989A
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- reaction
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- canrenone
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- toluene
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- 0 CC(CC1)(C(CC2)C3C1C(C)(CCC(*)=C1)C1=CC3)C2=O Chemical compound CC(CC1)(C(CC2)C3C1C(C)(CCC(*)=C1)C1=CC3)C2=O 0.000 description 3
- OYTKOSJTPXLJSN-PXJFBPCZSA-N C[C@@](C(C(C1)C2CC2)C2CC3)(C=CC2[C@@](C)(CC2)C3=CC2=O)C1=O Chemical compound C[C@@](C(C(C1)C2CC2)C2CC3)(C=CC2[C@@](C)(CC2)C3=CC2=O)C1=O OYTKOSJTPXLJSN-PXJFBPCZSA-N 0.000 description 1
- UJVLDDZCTMKXJK-IXHQKZKNSA-N C[C@](CCC1[C@@]2(C)CC3)(C(CC4)C1C=CC2=CC3=O)C4(CC1)OC1=O Chemical compound C[C@](CCC1[C@@]2(C)CC3)(C(CC4)C1C=CC2=CC3=O)C4(CC1)OC1=O UJVLDDZCTMKXJK-IXHQKZKNSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/001—Lactones
- C07J21/003—Lactones at position 17
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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 present invention provides a kind of preparation method of canrenone, the synthesis of canrenone adds catalyst using dehydrogenation product chemical compounds I as substrate, carries out lactonization reaction, optimization reaction circuit.Neutrality is adjusted to after the reaction was complete, is directly concentrated, ethanol is carried secretly with toluene, reaction under high pressure is directly carried out after recycling dry solvent, post processing reactions steps is reduced, avoids E cyclopentanecarboxylic acid ethyl ester group from hydrolyzing, greatly reduce reaction under high pressure difficulty.Greatly improving the operability of reaction reduces production cost so that side reaction greatly reduces, each to walk the relatively easy realization of reaction, and yield is greatly improved, and makes production more economical, safe, is more suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, more particularly to a kind of preparation method of canrenone.
Background technology
Canrenone (canrenone), entitled -17 α of 17 beta-hydroxy-3-oxy-pregnant steroid -4, the 6- diene -21- carboxylic acids of chemistry -
Y- lactones, are common diuretics, and the important intermediate of synthesis aldosterone receptor antagonist spirolactone.Canrenone can be with
It is widely used in cardiovascular disease medicine -- the important preparation for staying body bulk pharmaceutical chemicals such as eplerenone.There are patent US3919198 reports
Synthetic route：Using 4-AD as substrate, canrenone is obtained through following reaction：
In the reaction scheme, dehydrogenation reaction is carried out again after first carrying out the cyclic esterification of E rings, at sodium hydroxide
When managing product, lactone hydrolysis can be made, and Ethyl formate group easily hydrolyzes on lactonic ring, and the product after hydrolyzing last
Step is difficult that the reaction was complete, and producing new impurity causes yield and purity extremely low.
The disclosure of background above technology contents is only used for inventive concept and the technical solution that auxiliary understands the present invention, it is not
The prior art of present patent application is necessarily belonged to, shows the applying date of the above in present patent application in no tangible proof
In the case of disclosed, above-mentioned background technology should not be taken to the novelty and creativeness of evaluation the application.
The content of the invention
It is an object of the invention to propose a kind of preparation method of the high canrenone of high income, purity, concrete technical scheme
It is as follows：
A kind of preparation method of canrenone, synthetic route are as follows：
The preparation method of the canrenone comprises the following steps：
Using chemical compounds I as reaction starting material, organic solvent, sodium ethoxide, diethyl malonate, catalyst I are added successively
Enter in reaction vessel, temperature rising reflux, add chemical compounds I, after the reaction was complete, reaction solution adjusts pH to neutrality, concentrates out ethanol, adds
Enter toluene, water, canrenone is obtained after reaction under high pressure.
Preferably, the preparation method of the canrenone, the preparation method include：Under the protection of inert gas,
Added organic solvent, sodium ethoxide, diethyl malonate, catalyst I into reactor successively, stir 0.3~1h, add chemical combination
Thing I, 4~7h of insulation reaction, after TLC shows that the reaction was complete, is cooled to -5~5 DEG C, and adding acid for adjusting pH, decompression is dense to 7.0~7.2
Contract after most of solvent, add toluene and be concentrated to dryness, add toluene as reaction dissolvent, reaction solution is transferred to autoclave
In, water is added, nitrogen displacement air is used after good seal, is heated up, after the reaction was complete, is concentrated dry toluene, add water to stir, filter,
Drying obtains canrenone.
Preferably, the volume mass ratio of the preparation method of the canrenone, the diethyl malonate and chemical compounds I
For diethyl malonate:Chemical compounds I=(0.6~1.2) V:1W.
Preferably, the volume mass ratio of the preparation method of the canrenone, the sodium ethoxide and chemical compounds I is ethanol
Sodium：Chemical compounds I=(0.3~0.9) W:1W.
Preferably, the volume mass ratio of the preparation method of the canrenone, the toluene and chemical compounds I is toluene：
Chemical compounds I=(5~12) V:1W.
Preferably, the preparation method of the canrenone, the volume mass of water and chemical compounds I ratio in the reaction under high pressure
For water：Chemical compounds I=(0.5~1) V:1W.
Preferably, the preparation method of the canrenone, the organic solvent is methanol, one kind in ethanol or more
Kind.
Preferably, the preparation method of the canrenone, the inert gas is nitrogen, in helium, argon gas, neon
It is a kind of.
Preferably, the preparation method of the canrenone, the catalyst I are potassium dihydrogen phosphate or sodium dihydrogen phosphate.
Preferably, the preparation method of the canrenone, the reaction under high pressure temperature are 100 DEG C~130 DEG C.
Compared with prior art, the present invention advantage have it is following：
By the present invention in that by the use of dehydrogenation product chemical compounds I as substrate, then lactonization reaction is carried out, optimization reaction circuit.
The use of catalyst prevents E from changing the hydrolysis of Ethyl formate group, the difficulty of reaction under high pressure is greatly reduced, in being adjusted to after the reaction was complete
Property, directly concentrate, ethanol is pressed from both sides with toluene, reaction under high pressure is directly carried out after recycling dry solvent, reduce post processing reactions steps, avoid
Esterification is post-processed into oily phenomenon.Improving the operability of reaction reduces production cost so that side reaction subtracts significantly
Less, each to walk the relatively easy realization of reaction, yield is higher, makes production more economical, safe, is more suitable for industrial production.
Brief description of the drawings
Fig. 1 is the chromatograms of the canrenone prepared by the embodiment of the present invention 1；
Fig. 2 is the chromatograms of canrenone prepared in comparative example 1 of the present invention.
Embodiment
A kind of preparation method of canrenone, specific experiment operation are as follows：
Under the protection of inert gas, added into reactor successively by organic solvent, sodium ethoxide, diethyl malonate,
Catalyst I, stirs 0.3~1h, adds chemical compounds I, 4~7h of insulation reaction, after TLC shows that the reaction was complete, is cooled to -5~5
DEG C, add acid for adjusting pH to be concentrated under reduced pressure out after most of solvent to 7.0~7.2, add toluene and be concentrated to dryness, add toluene work
For reaction dissolvent, reaction solution is transferred in autoclave, water is added, nitrogen displacement air is used after good seal, heat up, reacted
Quan Hou, concentrates dry toluene, adds water to stir, and filters, drying obtains canrenone.
Wherein：The volume mass of diethyl malonate and chemical compounds I ratio is diethyl malonate:Chemical compounds I=(0.6~
1.2)V:1W；
The volume mass of sodium ethoxide and chemical compounds I ratio is sodium ethoxide：Chemical compounds I=(0.3~0.9) W:1W；
The volume mass of toluene and chemical compounds I ratio is toluene：Chemical compounds I=(5~12) V:1W；
The volume mass of water and chemical compounds I ratio is water in reaction under high pressure：Chemical compounds I=(0.5~1) V:1W；
Organic solvent is methanol, the one or more in ethanol；
Inert gas is nitrogen, one kind in helium, argon gas, neon；
Catalyst I is potassium dihydrogen phosphate or sodium dihydrogen phosphate；
The reaction under high pressure temperature is 100 DEG C~130 DEG C.
Process route is as follows：
Several specific embodiments are set forth below to be explained in detail：
Embodiment 1
A kind of preparation method of canrenone, technological process are as follows：
Specific experiment step is as follows：
Under nitrogen protection, 150ml ethanol is added into there-necked flask, 15g sodium ethoxides are warming up to 78 DEG C, addition 18ml the third two
Diethyl phthalate, 0.15g potassium dihydrogen phosphates, stir 0.3h, add 30g chemical compounds Is, insulation reaction 4h, TLC (PE：EA=4:1) show
After showing that the reaction was complete, cool down -5 DEG C, add appropriate glacial acetic acid tune pH to 7.0, after concentrating out most of solvent, add toluene recovery to do surplus
After remaining solvent, add 150ml toluene, be transferred in autoclave, add 15ml water, nitrogen displacement three times, heats up 100 DEG C, instead after sealing
Answer 24h, pressure 2.5kg, TLC (PE：EA=4:1) display is after the reaction was complete, cooling, is concentrated into sticky, adds water to continue dense dry first
Benzene, adds suitable quantity of water to stir 1h, filters, a small amount of washing, drying.Obtain product 33.1g, yield 110%, purity 98.27%.
Embodiment 2
A kind of preparation method of canrenone, technological process are as follows：
Specific experiment step is as follows：
Under helium protection, 150ml methanol and 150ml ethanol are added into there-necked flask, 15g sodium ethoxides, are warming up to 78 DEG C, add
Enter 60ml diethyl malonates, 0.25g potassium dihydrogen phosphates, stir 0.5h, add 50g chemical compounds Is, insulation reaction 5h, TLC (PE：
EA=4:1) after showing that the reaction was complete, cool down 0 DEG C, add appropriate glacial acetic acid tune pH to 7.1, after concentrating out most of solvent, add first
After benzene recycles dry residual solvent, add 300ml toluene, be transferred in autoclave, add 35ml water, helium replacement three times, rises after sealing
120 DEG C, pressure 3kg of temperature, reacts 20h, TLC (PE：EA=4:1) display is after the reaction was complete, cooling, be concentrated into it is sticky, add water after
Continue dense dry toluene, add suitable quantity of water to stir 1h, filter, a small amount of washing, drying.Obtain product 54g, yield 108%, purity
98.1%.
Embodiment 3
A kind of preparation method of canrenone, technological process are as follows：
Specific experiment step is as follows：
Under argon gas protection, 350ml ethanol is added into there-necked flask, 45g sodium ethoxides are warming up to 78 DEG C, addition 40ml the third two
Diethyl phthalate, 0.1g sodium dihydrogen phosphates, stir 1h, add 50g chemical compounds Is, insulation reaction 7h, TLC (PE：EA=4:1) show
After the reaction was complete, cool down 5 DEG C, add appropriate glacial acetic acid tune pH to 7.2, after concentrating out most of solvent, add toluene recovery to do residue
After solvent, add 600ml toluene, be transferred in autoclave, add 50ml water, argon gas is replaced three times after sealing, is heated up 130 DEG C, pressure
3.5kg, reacts 20h, TLC (PE：EA=4:1) display is after the reaction was complete, cooling, is concentrated into sticky, adds water to continue dense dry toluene,
Add suitable quantity of water to stir 1h, filter, a small amount of washing, drying.Obtain product 54.5g, yield 109%, purity 97.9%.
Comparative example 1
Canrenone is made in preparation method according to embodiment 1, but uses catalyst I, obtains product 20.14g, yield
67.13%, purity 70.76%.
It can be seen that to add during the reaction in embodiment 1 from the yield and purity of embodiment 1 and comparative example 1 and urge
I yield 110% of agent, purity 98.27%, and the yield 67.13% in comparative example 1, purity 70.76%, well below implementation
The level of example 1,21% impurity is because causing high pressure depickling de-ester reaction not after E cyclopentanecarboxylic acid ethyl ester hydrolysis formic acid behind Fig. 2
Completely, Ethyl formate hydrolysis is avoided, reduces height as catalyst present invention uses potassium dihydrogen phosphate or sodium dihydrogen phosphate
Press the difficulty of de-ester reaction.
Above content is to combine specific/preferred embodiment further description made for the present invention, it is impossible to
Assert that the specific implementation of the present invention is confined to these explanations.Come for general technical staff of the technical field of the invention
Say, without departing from the inventive concept of the premise, it can also make some replacements or modification to the embodiment that these have been described,
And these are substituted or variant should all be considered as belonging to protection scope of the present invention.
Claims (10)
1. a kind of preparation method of canrenone, it is characterised in that synthetic route is as follows：
The preparation method of the canrenone comprises the following steps：
Using chemical compounds I as reaction starting material, organic solvent, sodium ethoxide, diethyl malonate, catalyst I are added instead successively
Answer in container, temperature rising reflux, add chemical compounds I, after the reaction was complete, reaction solution adjusts pH to neutrality, concentrates out ethanol, adds first
Benzene, water, obtain canrenone after reaction under high pressure.
2. the preparation method of canrenone as claimed in claim 1, it is characterised in that：The preparation method includes：In inertia
Under the protection of gas, added organic solvent, sodium ethoxide, diethyl malonate, catalyst I, stirring 0.3 into reactor successively
~1h, adds chemical compounds I, 4~7h of insulation reaction, after TLC shows that the reaction was complete, is cooled to -5~5 DEG C, adds acid for adjusting pH extremely
7.0~7.2, it is concentrated under reduced pressure out after most of solvent, adds toluene and be concentrated to dryness, adds toluene as reaction dissolvent, will be anti-
Answer liquid to be transferred in autoclave, add water, nitrogen displacement air is used after good seal, heat up, after the reaction was complete, concentrate dry first
Benzene, adds water to stir, and filters, drying obtains canrenone.
3. such as the preparation method of claim 1-2 any one of them canrenones, it is characterised in that：The diethyl malonate
Volume mass ratio with chemical compounds I is diethyl malonate:Chemical compounds I=(0.6~1.2) V:1W.
4. such as the preparation method of claim 1-2 any one of them canrenones, it is characterised in that：The sodium ethoxide and chemical combination
The volume mass ratio of thing I is sodium ethoxide：Chemical compounds I=(0.3~0.9) W:1W.
5. such as the preparation method of claim 1-2 any one of them canrenones, it is characterised in that：The toluene and compound
I volume mass ratio is toluene：Chemical compounds I=(5~12) V:1W.
6. such as the preparation method of claim 1-2 any one of them canrenones, it is characterised in that：Water in the reaction under high pressure
Volume mass ratio with chemical compounds I is water：Chemical compounds I=(0.5~1) V:1W.
7. such as the preparation method of claim 1-2 any one of them canrenones, it is characterised in that：The organic solvent is first
One or more in alcohol, ethanol.
8. the preparation method of canrenone as claimed in claim 1, it is characterised in that：The inert gas for nitrogen, helium,
One kind in argon gas, neon.
9. such as the preparation method of claim 1-2 any one of them canrenones, it is characterised in that：The catalyst I is phosphorus
Acid dihydride potassium or sodium dihydrogen phosphate.
10. the preparation method of canrenone as claimed in claim 1, it is characterised in that：The reaction under high pressure temperature is 100 DEG C
~130 DEG C.
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| CN201711463417.1A CN108033989A (en) | 2017-12-28 | 2017-12-28 | The preparation method of canrenone |
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| CN201711463417.1A CN108033989A (en) | 2017-12-28 | 2017-12-28 | The preparation method of canrenone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028542A (en) * | 2019-05-17 | 2019-07-19 | 山东宝利甾体生物科技有限公司 | The clean preparation method of canrenone |
| CN113461767A (en) * | 2020-03-31 | 2021-10-01 | 天津药业研究院股份有限公司 | Synthesis method of canrenone |
| CN113512086A (en) * | 2021-08-20 | 2021-10-19 | 天津信谊津津药业有限公司 | Method for preparing spironolactone intermediate canrenone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919198A (en) * | 1973-02-06 | 1975-11-11 | Roussel Uclaf | Dienic derivatives of the androstane series and process |
| CN101845474A (en) * | 2010-05-20 | 2010-09-29 | 台州南峰药业有限公司 | Synthetic method of 11alpha hydroxy-canrenone |
| CN105777843A (en) * | 2016-05-12 | 2016-07-20 | 江苏省海洋资源开发研究院(连云港) | Method for preparing canrenone |
-
2017
- 2017-12-28 CN CN201711463417.1A patent/CN108033989A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919198A (en) * | 1973-02-06 | 1975-11-11 | Roussel Uclaf | Dienic derivatives of the androstane series and process |
| CN101845474A (en) * | 2010-05-20 | 2010-09-29 | 台州南峰药业有限公司 | Synthetic method of 11alpha hydroxy-canrenone |
| CN105777843A (en) * | 2016-05-12 | 2016-07-20 | 江苏省海洋资源开发研究院(连云港) | Method for preparing canrenone |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028542A (en) * | 2019-05-17 | 2019-07-19 | 山东宝利甾体生物科技有限公司 | The clean preparation method of canrenone |
| CN113461767A (en) * | 2020-03-31 | 2021-10-01 | 天津药业研究院股份有限公司 | Synthesis method of canrenone |
| CN113512086A (en) * | 2021-08-20 | 2021-10-19 | 天津信谊津津药业有限公司 | Method for preparing spironolactone intermediate canrenone |
| CN113512086B (en) * | 2021-08-20 | 2022-11-29 | 天津信谊津津药业有限公司 | Method for preparing spironolactone intermediate canrenone |
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Application publication date: 20180515 |