CN106977568A - A kind of preparation method of the diketone of 4 alkene of female steroid 3,17 - Google Patents
A kind of preparation method of the diketone of 4 alkene of female steroid 3,17 Download PDFInfo
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- CN106977568A CN106977568A CN201710258714.6A CN201710258714A CN106977568A CN 106977568 A CN106977568 A CN 106977568A CN 201710258714 A CN201710258714 A CN 201710258714A CN 106977568 A CN106977568 A CN 106977568A
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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
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
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Abstract
The invention provides a kind of preparation method of the diketone of 4 alkene of female steroid 3,17, methods described includes：Hydrogenation reaction：Under nitrogen protection; the first solvent and palladium catalyst are added into reaction vessel; 10 60min are stirred, hydrogen are passed through into the reaction vessel to replace nitrogen, after nitrogen displacement terminates; the raw material with formula I and stirring are added into the reaction vessel; 10 60 DEG C are warming up to, hydrogen is passed through and reacts 2 10h, reaction is press-filtered out palladium catalyst after terminating using nitrogen; the midbody solution with compounds of formula II is obtained, it is standby under nitrogen protection；Ring-closure reaction：Under nitrogen protection, the obtained midbody solution of normal pressure concentration adds the de- reagent of acid into sticky midbody solution and stirred to sticky; reaction temperature is 60 100 DEG C; reaction time is 0.5 5h, and the second solvent is added into reacted solution, stirs 10 30min; reagent water is added dropwise; cooling, is filtered, drying; there must be the diketone of 4 alkene of female steroid 3,17 of general formula III；Reaction scheme is as follows：
Description
Technical field
The invention belongs to medical environment chemical field, it is related to a kind of chemical synthesis process of steroid hormone medicine, particularly
It is related to a kind of preparation method of the alkene of female steroid-4-3,17- diketone.
Background technology
Alkene -3, the 17- diketone of female steroid -4 is a kind of important Steroid medicine intermediates, available for preparing contraceptive alkynes promise
Ketone, anti-early pregnancy drug mifepristone, medicine Tibolone of women's climacteric syndrome etc..In Chinese patent CN
In 104497088A, preparing the technique of alkene -3, the 17- diketone of female steroid -4 needs to carry out grignard reaction, oxidation and ring-closure reaction, reduction
And ring-closure reaction is prepared, have the shortcomings that course of reaction is numerous and diverse, route is long；In Chinese patent CN 104788524A, system
A variety of oxidants are needed to use during standby alkene -3, the 17- diketone of female steroid -4, cost of material is high, be unfavorable for while producing waste liquid
Recycle and reuse, it is big for environment pollution.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of preparation method of the alkene -3,17- of female steroid -4 diketone, with whole
Or part solves above-mentioned technical problem.
In order to solve the above problems, the invention discloses a kind of preparation method of the alkene -3,17- of female steroid -4 diketone, the side
Method includes：
Hydrogenation reaction：Under nitrogen protection, the first solvent and palladium catalyst are added into reaction vessel, 10-60min is stirred,
Hydrogen is passed through into the reaction vessel to replace nitrogen, after nitrogen displacement terminates, adds to have into the reaction vessel and leads to
The raw material of Formulas I and stirring, are warming up to 10-60 DEG C, are passed through hydrogen reaction 2-10h, and reaction is press-filtered out palladium using nitrogen after terminating and urged
Agent, obtains the midbody solution with compounds of formula II, standby under nitrogen protection；
Ring-closure reaction：Under nitrogen protection, the obtained midbody solution of normal pressure concentration is to sticky, to sticky intermediate
The de- reagent of acid is added in solution and is stirred, reaction temperature is 60-100 DEG C, and the reaction time is 0.5-5h, into reacted solution
The second solvent is added, 10-30min is stirred, reagent water is added dropwise, is cooled, is filtered, drying obtains alkene -3 of female steroid -4 with general formula III,
17- diketone；
Reaction scheme is as follows：
Alternatively, in the hydrogenation process, the volume ratio of the quality of the raw material and first solvent is 1:
1-1:10；
The mass ratio of the quality of the raw material and the palladium catalyst is 1:0.1-1:0.5.
Alternatively, in the hydrogenation process, first solvent is methanol, ethanol, acetone, normal propyl alcohol and isopropyl
One or more in alcohol.
Alternatively, in the hydrogenation process, the palladium catalyst is load palladium reagent.
Alternatively, the load palladium reagent is one in palladium carbon, palladium calcium carbonate, palladium barium sulfate, palladium aluminum oxide and palladium sponge
Plant or a variety of.
Alternatively, during the ring-closure reaction, the quality of the raw material and the mass ratio of the de- reagent of the acid are 1:
0.5-1:5。
Alternatively, during the ring-closure reaction, the volume ratio of the quality of the raw material and second solvent is 1:
0.5-1:5。
Alternatively, during the ring-closure reaction, the de- reagent of acid be one kind in sulfuric acid, phosphoric acid and perchloric acid or
It is a variety of；
Alternatively, during the ring-closure reaction, second solvent is methanol, ethanol, acetone, normal propyl alcohol and isopropyl
One or more in alcohol.
Compared with prior art, the present invention includes advantages below：
The embodiments of the invention provide a kind of preparation method of the alkene -3,17- of female steroid -4 diketone, the preparation method be with
Compounds of formula I is raw material, and hydrogenated reaction and ring-closure reaction prepare alkene -3, the 17- diketone of female steroid -4, with raw material it is cheap,
Simple to operate, synthetic route is short and the low feature of production cost.
Brief description of the drawings
Fig. 1 is a kind of flow chart of the preparation method of the alkene of female steroid-4-3,17- diketone described in the embodiment of the present invention.
Embodiment
In order to facilitate the understanding of the purposes, features and advantages of the present invention, it is below in conjunction with the accompanying drawings and specific real
Applying mode, the present invention is further detailed explanation.
The implementation process of the method for the invention is described in detail below by embodiment.
The embodiments of the invention provide a kind of preparation method of the alkene of female steroid-4-3,17- diketone.
Reference picture 1, it illustrates a kind of preparation method of the alkene -3,17- of female steroid -4 diketone described in the embodiment of the present invention
Flow chart, the described method comprises the following steps：
Step 1, hydrogenation reaction：Under nitrogen protection, the first solvent and palladium catalyst are added into reaction vessel, 10- is stirred
60min, hydrogen is passed through into the reaction vessel to replace nitrogen, after nitrogen displacement terminates, and is added into the reaction vessel
Raw material and stirring with formula I, are warming up to 10-60 DEG C, are passed through hydrogen reaction 2-10h, and reaction uses nitrogen press filtration after terminating
Go out palladium catalyst, obtain the midbody solution with compounds of formula II, it is standby under nitrogen protection.
Preferably, in the hydrogenation process, the volume ratio of the quality of the raw material and first solvent is 1:
1-1:10。
Preferably, in the hydrogenation process, the mass ratio of the quality of the raw material and the palladium catalyst is 1:
0.1-1:0.5。
Preferably, in the hydrogenation process, first solvent is methanol, ethanol, acetone, normal propyl alcohol and isopropyl
One or more in alcohol.
Preferably, in the hydrogenation process, the palladium catalyst is load palladium reagent.Further, the load
Palladium reagent is preferably the one or more in palladium carbon, palladium calcium carbonate, palladium barium sulfate, palladium aluminum oxide and palladium sponge.
Step 2, ring-closure reaction：Under nitrogen protection, the obtained midbody solution of normal pressure concentration is to sticky, to sticky
The de- reagent of acid is added in midbody solution and is stirred, reaction temperature is 60-100 DEG C, and the reaction time is 0.5-5h, to reacted
Add the second solvent in solution, stir 10-30min, reagent water is added dropwise, cool, filter, drying, obtain the female steroid with general formula III-
4 alkene -3,17- diketone.
Preferably, during the ring-closure reaction, the quality of the raw material and the mass ratio of the de- reagent of the acid are 1:
0.5-1:5。
Preferably, during the ring-closure reaction, the mass ratio of the raw material and second solvent is 1:0.5-1:
5。
Preferably, during the ring-closure reaction, the de- reagent of acid be one kind in sulfuric acid, phosphoric acid and perchloric acid or
It is a variety of；
Preferably, during the ring-closure reaction, second solvent is methanol, ethanol, acetone, normal propyl alcohol and isopropyl
One or more in alcohol.
The reaction scheme of the alkene -3,17- diketone of female steroid -4 is as follows：
The embodiments of the invention provide a kind of preparation method of the alkene -3,17- of female steroid -4 diketone, the preparation method be with
Compounds of formula I is raw material, and hydrogenated reaction and ring-closure reaction prepare alkene -3, the 17- diketone of female steroid -4, with raw material it is cheap,
Simple to operate, synthetic route is short and the low feature of production cost.
To make those skilled in the art more fully understand the present invention, illustrate this hair below by way of multiple specific embodiments
The preparation method for the alkene -3,17- diketone of female steroid -4 that bright embodiment is provided.
Embodiment 1
(1) hydrogenation reaction.
Room temperature, under nitrogen protection, in the four-hole bottle of 250ml clean drieds, adds 200ml ethanol, stirring adds 5g palladiums
Carbon, stirs 30min.Hydrogen replaces nitrogen, leads to after hydrogen 30min, adds 20g raw materials, heats up 50 DEG C, leads to hydrogen reaction 6h,
HPLC detection reactions terminate.Palladium carbon is press-filtered out using nitrogen, the midbody solution with compounds of formula II is obtained, nitrogen is protected
It is standby under shield.
(2) ring-closure reaction.
Under nitrogen protection, midbody solution of the normal pressure concentration with compounds of formula II is concentrated into thick, addition
30g phosphoric acid, 80 DEG C of reaction 3h, HPLC detections have been reacted.20ml ethanol is added, 20min is stirred, 150ml water, cooling, mistake is added dropwise
Filter, 50 DEG C of drying, obtaining 16.4g has alkene -3, the 17- diketone of female steroid -4 of general formula III, HPLC tests, and product purity is
95.3%.
Embodiment 2
(1) hydrogenation reaction.
Room temperature, under nitrogen protection, in the four-hole bottle of 250ml clean drieds, adds 20ml methanol, stirring adds 2g palladiums
Barium sulfate, stirs 10min.Hydrogen replaces nitrogen, leads to after hydrogen 10min, adds 20g raw materials, heats up 10 DEG C, leads to hydrogen reaction
2h, HPLC detection reaction terminate.Palladium barium sulfate is press-filtered out using nitrogen, the intermediate with compounds of formula II is obtained molten
Liquid, it is standby under nitrogen protection.
(2) ring-closure reaction.
Under nitrogen protection, midbody solution of the normal pressure concentration with compounds of formula II is concentrated into thick, addition
10g perchloric acid, 60 DEG C of reaction 5h, HPLC detections have been reacted.10ml methanol is added, 10min is stirred, 200ml water is added dropwise, is cooled,
Filtering, 50 DEG C of drying, obtaining 15.8g has alkene -3, the 17- diketone of female steroid -4 of general formula III, HPLC tests, and product purity is
96.1%.
Embodiment 3
(1) hydrogenation reaction.
Room temperature, under nitrogen protection, in the four-hole bottle of 250ml clean drieds, adds 150ml acetone, stirring adds 10g
Palladium calcium carbonate, stirs 30min.Hydrogen replaces nitrogen, leads to after hydrogen 60min, adds 20g raw materials, heats up 35 DEG C, leads to hydrogen reaction
4h, HPLC detection reaction terminate.The sour calcium of palladium carbon is press-filtered out using nitrogen, the intermediate with compounds of formula II is obtained molten
Liquid, it is standby under nitrogen protection.
(2) ring-closure reaction.
Under nitrogen protection, midbody solution of the normal pressure concentration with compounds of formula II is concentrated into thick, addition
50g phosphoric acid, 75 DEG C of reaction 1h, HPLC detections have been reacted.60ml acetone is added, 10min is stirred, 300ml water, cooling, mistake is added dropwise
Filter, 50 DEG C of drying, obtaining 17.5g has alkene -3, the 17- diketone of female steroid -4 of general formula III, HPLC tests, and product purity is
95.2%.
Embodiment 4
(1) hydrogenation reaction.
Room temperature, under nitrogen protection, in the four-hole bottle of 1000ml clean drieds, adds 250ml normal propyl alcohol and 250ml isopropyls
Alcohol, stirring adds 25g palladium sponges, stirs 60min.Hydrogen replaces nitrogen, leads to after hydrogen 120min, adds 50g raw materials, heating
60 DEG C, lead to hydrogen reaction 10h, HPLC detection reaction and terminate.Palladium sponge is press-filtered out using nitrogen, the chemical combination with formula II is obtained
The midbody solution of thing, it is standby under nitrogen protection.
(2) ring-closure reaction.
Under nitrogen protection, midbody solution of the normal pressure concentration with compounds of formula II is concentrated into thick, addition
150g phosphoric acid and 100g sulfuric acid, 100 DEG C of reaction 0.5h, HPLC detection reactions terminate.Add 150ml normal propyl alcohols and 100ml isopropyls
Alcohol, stirs 30min, and 400ml water is added dropwise, and cools, filtering, 50 DEG C of drying, and obtaining 41.5g has alkene -3 of female steroid -4 of general formula III,
17- diketone, HPLC tests, product purity is 95.5%.
A kind of preparation method of the alkene -3,17- of female steroid -4 diketone provided by the present invention is described in detail above, this
Apply specific case in text to be set forth the principle and embodiment of the present invention, the explanation of above example is only intended to
Help to understand method and its core concept of the invention；Simultaneously for those of ordinary skill in the art, the think of according to the present invention
Think, will change in specific embodiments and applications, in summary, this specification content should not be construed as pair
The limitation of the present invention.
Claims (9)
1. a kind of preparation method of the alkene -3,17- of female steroid -4 diketone, it is characterised in that methods described includes：
Hydrogenation reaction：Under nitrogen protection, the first solvent and palladium catalyst are added into reaction vessel, 10-60min is stirred, to institute
State and hydrogen is passed through in reaction vessel to replace nitrogen, after nitrogen displacement terminates, added into the reaction vessel with formula I
Raw material is simultaneously stirred, and is warming up to 10-60 DEG C, is passed through hydrogen reaction 2-10h, and reaction is press-filtered out palladium catalyst after terminating using nitrogen,
The midbody solution with compounds of formula II is obtained, it is standby under nitrogen protection；
Ring-closure reaction：Under nitrogen protection, the obtained midbody solution of normal pressure concentration is to sticky, to sticky midbody solution
Middle to add the de- reagent of acid and stir, reaction temperature is 60-100 DEG C, and the reaction time is 0.5-5h, is added into reacted solution
Second solvent, stirs 10-30min, and reagent water is added dropwise, and cools, and filters, and drying obtains the alkene -3,17- of female steroid -4 with general formula III
Diketone；
Reaction scheme is as follows：
2. preparation method according to claim 1, it is characterised in that in the hydrogenation process, the raw material
Quality and the volume ratio of first solvent are 1:1-1:10；
The mass ratio of the quality of the raw material and the palladium catalyst is 1:0.1-1:0.5.
3. preparation method according to claim 1, it is characterised in that in the hydrogenation process, described first is molten
Agent is the one or more in methanol, ethanol, acetone, normal propyl alcohol and isopropanol.
4. preparation method according to claim 1, it is characterised in that in the hydrogenation process, the palladium chtalyst
Agent is load palladium reagent.
5. preparation method according to claim 4, it is characterised in that the load palladium reagent is palladium carbon, palladium calcium carbonate, palladium
One or more in barium sulfate, palladium aluminum oxide and palladium sponge.
6. preparation method according to claim 1, it is characterised in that during the ring-closure reaction, the raw material
The mass ratio that quality takes off reagent with the acid is 1:0.5-1:5.
7. preparation method according to claim 1, it is characterised in that during the ring-closure reaction, the raw material
Quality and the volume ratio of second solvent are 1:0.5-1:5.
8. preparation method according to claim 1, it is characterised in that during the ring-closure reaction, the de- examination of acid
Agent is the one or more in sulfuric acid, phosphoric acid and perchloric acid.
9. preparation method according to claim 1, it is characterised in that during the ring-closure reaction, described second is molten
Agent is the one or more in methanol, ethanol, acetone, normal propyl alcohol and isopropanol.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710258714.6A CN106977568A (en) | 2017-04-19 | 2017-04-19 | A kind of preparation method of the diketone of 4 alkene of female steroid 3,17 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710258714.6A CN106977568A (en) | 2017-04-19 | 2017-04-19 | A kind of preparation method of the diketone of 4 alkene of female steroid 3,17 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114195845A (en) * | 2021-12-31 | 2022-03-18 | 湖南新合新生物医药有限公司 | Preparation method of 19-nor-4-androstenedione |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1058028A (en) * | 1964-12-15 | 1967-02-08 | Roussel Uclaf | Processes for preparing steroid compounds |
| US3691190A (en) * | 1970-05-21 | 1972-09-12 | Gabriel Saucy | Isoxazolyl-substituted benzindenediones |
| CN106496297A (en) * | 2016-10-26 | 2017-03-15 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of stanolone |
-
2017
- 2017-04-19 CN CN201710258714.6A patent/CN106977568A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1058028A (en) * | 1964-12-15 | 1967-02-08 | Roussel Uclaf | Processes for preparing steroid compounds |
| US3691190A (en) * | 1970-05-21 | 1972-09-12 | Gabriel Saucy | Isoxazolyl-substituted benzindenediones |
| CN106496297A (en) * | 2016-10-26 | 2017-03-15 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of stanolone |
Non-Patent Citations (1)
| Title |
|---|
| 赵临襄等主编: "《化学制药工艺学》", 31 August 2015 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114195845A (en) * | 2021-12-31 | 2022-03-18 | 湖南新合新生物医药有限公司 | Preparation method of 19-nor-4-androstenedione |
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