CN106977570A - A kind of method for synthesizing 16 dehydrogenation progesterone - Google Patents
A kind of method for synthesizing 16 dehydrogenation progesterone Download PDFInfo
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- CN106977570A CN106977570A CN201710254647.0A CN201710254647A CN106977570A CN 106977570 A CN106977570 A CN 106977570A CN 201710254647 A CN201710254647 A CN 201710254647A CN 106977570 A CN106977570 A CN 106977570A
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- progesterone
- hydroxy
- alpha
- corpus luteum
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
Abstract
The invention provides a kind of method for synthesizing 16 dehydrogenation progesterone, it the described method comprises the following steps：17 α hydroxyl progesterones esterifications, 17 α hydroxyl progesterones ester hydrolysis reactions, 17 α hydroxy progesterone ketone esters decrease temperature crystallines, 17 α hydroxy progesterone ketone esters analysis of material, 17 α hydroxy progesterone ketone esters separation of solid and liquid, the drying of 17 α hydroxy progesterones ketone esters, the cooling of 17 α hydroxy progesterone ketone esters elimination reactions, 16 dehydrogenation progesterone decrease temperature crystallines, 16 dehydrogenation progesterone analysis of material, 16 dehydrogenation progesterone, 16 dehydrogenation progesterone separation of solid and liquid, 16 dehydrogenation progesterone are dried.16 dehydrogenation progesterone are prepared using method provided in an embodiment of the present invention, product purity is up to more than 99%, and product yield is up to more than 90%, with the features such as product quality is high, product purity is high, product yield is high and is easy to large-scale production.
Description
Technical field
The invention belongs to medical environment chemical field, more particularly to a kind of method of synthesis 16- dehydrogenation progesterone.
Background technology
16- dehydrogenation progesterone is a kind of important Steroid medicine intermediates, available for synthesis progesterone, hydrocortisone,
The steroid drugs such as dexamethasone, betamethasone.16- dehydrogenation progesterone is white or off-white color crystalline powder, and 185 DEG C of fusing point~
195 DEG C, its structural formula is：
17 Alpha-hydroxy progesterone belong to 21- methyl-17-alphas-hydroxy kind steroidal compounds, under the prior art, and 21- methyl-
It is generally acknowledged problem that hydroxyl in 17 Alpha-hydroxy class steroidal compounds, which is eliminated,.At present, using 17 Alpha-hydroxy progesterone as Material synthesis
The technology of 16- dehydrogenation progesterone is mainly using semicarbazide hydrochloride as deshydroxy agent, but the shortcoming of the technology is to react choosing
Selecting property is poor, poor product quality and product yield are low.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of method of synthesis 16- dehydrogenation progesterone, with whole or portion
Decompose above-mentioned technical problem of determining.
In order to solve the above problems, the invention discloses a kind of method of synthesis 16- dehydrogenation progesterone, methods described includes
Following steps：
Step (1), 17 Alpha-hydroxy progesterone esterifications：By 17 Alpha-hydroxy progesterone, the first solvent, esterifying reagent and urge
Agent is added in reactor and is well mixed, and is warming up to 60~80 DEG C, 2.0~6.0h of insulation reaction；
Step (2), 17 Alpha-hydroxy progesterone ester hydrolysis reactions：Water is added into the reaction mass obtained by step (1), is heated up
To 85~105 DEG C, 2.0~6.0h of insulation reaction；
Step (3), 17 Alpha-hydroxy corpus luteum ketone ester decrease temperature crystallines：Reaction mass obtained by step (2) is naturally cooling to 20
~30 DEG C, obtain solid-liquid mixtures；
Step (4), 17 Alpha-hydroxy corpus luteum ketone ester analysis of material：Water is added into the solid-liquid mixtures obtained by step (3), is stirred
1h, separates out 17 Alpha-hydroxy corpus luteum ketone ester solid materials；
Step (5), 17 Alpha-hydroxy corpus luteum ketone ester solid- liquid separations：Solid-liquid point is carried out to the reaction mass obtained by step (4)
From separating obtained mother liquor enters wastewater treatment, and 17 Alpha-hydroxy corpus luteum ketone ester wet feeds of gained enter next step；
Step (6), 17 Alpha-hydroxy corpus luteum ketone esters are dried：By 17 Alpha-hydroxy corpus luteum ketone ester wet feeds obtained by step (5) 60
~80 DEG C of dryings, obtain 17 Alpha-hydroxy corpus luteum ketone ester finished products；
Step (7), 17 Alpha-hydroxy corpus luteum ketone ester elimination reactions：By 17 Alpha-hydroxy corpus luteum ketone ester finished products obtained by step (6)
It is well mixed in the reactor with eliminating reagent, is warming up to 240~300 DEG C, 0.2~3.0h of insulation reaction；
Step (8), 16- dehydrogenation progesterone decrease temperature crystallines：Reaction solution obtained by step (7) is cooled to 60~80 DEG C, institute
Obtain material and enter next step；
Step (9), 16- dehydrogenation progesterone analysis of material：The second solvent is added into the reaction mass obtained by step (8), is separated out
16- dehydrogenation progesterone solid materials, obtain solid-liquid mixtures；
Step (10), the cooling of 16- dehydrogenations progesterone：Solid-liquid mixtures obtained by step (9) are cooled to 5~15 DEG C, stirred
Mixing 1h makes 16- dehydrogenation progesterone solid materials further separate out；
Step (11), 16- dehydrogenation progesterone solid- liquid separations：Separation of solid and liquid is carried out to the reaction mass obtained by step (10),
The concentrated Posterior circle of mother liquor is utilized, and obtains 16- dehydrogenation progesterone wet feeds；
Step (12), 16- dehydrogenations progesterone are dried：By the 16- dehydrogenation progesterone wet feeds obtained by step (11) 50~70
DEG C drying, obtains 16- dehydrogenation progesterone finished products.
Alternatively, in the step (1), first solvent is dichloromethane, DMF, ethanol, four
At least one of hydrogen furans, ethyl acetate and acetic acid；
The esterifying reagent is at least one of chloroacetic chloride, paratoluensulfonyl chloride, acetic anhydride；
The catalyst be the concentrated sulfuric acid, trifluoroacetic acid, trichloroacetic acid, p-methyl benzenesulfonic acid, fluoboric acid and perchloric acid at least
It is a kind of.
Alternatively, in the step (1), the mol ratio of the 17 Alpha-hydroxy progesterone and first solvent is 1:10~
1:30；
The mol ratio of the 17 Alpha-hydroxy progesterone and the esterifying reagent is 1:1~1:5；
The mol ratio of the 17 Alpha-hydroxy progesterone and the catalyst is 1:1~1:3.
Alternatively, the water of addition and the 17 Alpha-hydroxy corpus luteum used in the step (1) in the step (2)
The mass ratio of ketone is 0.5:1~2.0:1.
Alternatively, the water of addition and the 17 Alpha-hydroxy corpus luteum used in the step (1) in the step (4)
The mass ratio of ketone is 5:1~15:1.
Alternatively, in the step (7), the elimination reagent is at least one of detergent alkylate, biphenyl, Biphenyl Ether.
Alternatively, in the step (7), the mol ratio of the 17 Alpha-hydroxy corpus luteum ketone ester finished product and the elimination reagent is
1:2~1:10.
Alternatively, in the step (9), second solvent be petroleum ether, n-hexane, normal heptane, isooctane at least
It is a kind of.
Alternatively, second solvent used in the step (9) and the 17 α-hydroxyl used in the step (7)
The mass ratio of base corpus luteum ketone ester is 3:1~15:1.
Compared with prior art, the present invention includes advantages below：
(1), the embodiment of the present invention makes full use of than 17 acyl protecting groups of 3 acyl protecting groups in 17 Alpha-hydroxy progesterone
The characteristics of facile hydrolysis, 17 hydroxyls are protected using acyl group, the measured 17 Alpha-hydroxy corpus luteum ketone ester of matter can be obtained, closed with technique
The characteristics of reason.
(2), the embodiment of the present invention makes full use of ester group that the characteristics of elimination reaction is selectively high occurs at high temperature, using height
17 Alpha-hydroxy corpus luteum ketone esters are converted into 16- dehydrogenation progesterone by the de- ester technology of temperature, can reach product yield height, product purity
Good purpose.
(3) 16- dehydrogenation progesterone, is prepared using method provided in an embodiment of the present invention, product purity is produced up to more than 99%
Product yield is up to more than 90%, with product quality is high, product purity is high, product yield is high and is easy to the spies such as large-scale production
Point.
Brief description of the drawings
Fig. 1 is a kind of flow chart of the method for synthesis 16- dehydrogenation progesterone 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 method of synthesis 16- dehydrogenation progesterone.Course of reaction is as follows：
Reference picture 1, it illustrates a kind of flow of the method for synthesis 16- dehydrogenation progesterone described in the embodiment of the present invention
Figure, the described method comprises the following steps：
Step (1), 17 Alpha-hydroxy progesterone esterifications：By 17 Alpha-hydroxy progesterone, the first solvent, esterifying reagent and urge
Agent is added in reactor and is well mixed, and is warming up to 60~80 DEG C, 2.0~6.0h of insulation reaction.
In the embodiment of the present invention, 17 Alpha-hydroxy progesterone are dissolved using the first solvent, under catalyst action, esterification are used
Esterification occurs for reagent and 17 Alpha-hydroxy progesterone, and the hydroxyl on 17 of 17 Alpha-hydroxy progesterone is converted into ester group.
The embodiment of the present invention makes full use of than 17 acyl protecting groups Yishui River of 3 acyl protecting groups in 17 Alpha-hydroxy progesterone
The characteristics of solution, 17 hydroxyls are protected using acyl group, the measured 17 Alpha-hydroxy corpus luteum ketone ester of matter can be obtained, with rational technology
Feature.
In the embodiment of the present invention, it is preferable that in the step (1), first solvent is dichloromethane, N, N- dimethyl
At least one of formamide, ethanol, tetrahydrofuran, ethyl acetate and acetic acid.
Preferably, R is acetyl group or p-toluenesulfonyl.Preferably, the esterifying reagent is chloroacetic chloride, tolysulfonyl
At least one of chlorine, acetic anhydride.
Preferably, catalyst be the concentrated sulfuric acid, trifluoroacetic acid, trichloroacetic acid, p-methyl benzenesulfonic acid, fluoboric acid and perchloric acid in extremely
Few one kind.
Preferably, the mol ratio of the 17 Alpha-hydroxy progesterone and first solvent is 1:10~1:30.
Preferably, the mol ratio of the 17 Alpha-hydroxy progesterone and the esterifying reagent is 1:1~1:5.
Preferably, the mol ratio of the 17 Alpha-hydroxy progesterone and the catalyst is 1:1~1:3.
Step (2), 17 Alpha-hydroxy progesterone ester hydrolysis reactions：Water is added into the reaction mass obtained by step (1), is heated up
To 85~105 DEG C, 2.0~6.0h of insulation reaction.
In the esterification process of step (1), while there occurs esterification on 17 of 17 Alpha-hydroxy progesterone, 17
Carbonyl on 3 of Alpha-hydroxy progesterone is also reacted, and carbonyl double bond is opened, effective group of esterifying reagent and former carbonyl
In oxygen atom connection.
Because 3 groups in target product 16- dehydrogenation progesterone are carbonyl, therefore this step is by controlling reaction bar
Part, reaction is hydrolyzed to the reaction mass obtained by step (1), and the group on 3 is reduced to required carbonyl group, obtained
The Alpha-hydroxy corpus luteum ketone ester of product 17.
In the embodiment of the present invention, it is preferable that the quality of the water of addition and the 17 α-hydroxyl used in step (1) in step (2)
The mass ratio of base progesterone is 0.5:1~2.0:1.
Step (3), 17 Alpha-hydroxy corpus luteum ketone ester decrease temperature crystallines：Reaction mass obtained by step (2) is naturally cooling to 20
~30 DEG C, obtain solid-liquid mixtures.
Cooling processing, the Alpha-hydroxy corpus luteum ketone ester of decrease temperature crystalline 17 are carried out to the reaction mass obtained by step (2).
Step (4), 17 Alpha-hydroxy corpus luteum ketone ester analysis of material：Water is added into the solid-liquid mixtures obtained by step (3), is stirred
1h, separates out 17 Alpha-hydroxy corpus luteum ketone ester solid materials.
After 17 Alpha-hydroxy corpus luteum ketone ester solid materials terminate, reagent water is added into obtained solid-liquid mixtures, is analysed
Go out 17 Alpha-hydroxy corpus luteum ketone ester solid materials.
In the embodiment of the present invention, it is preferable that the quality of the water of addition and the original used in step (1) in the step (4)
The mass ratio for expecting 17 Alpha-hydroxy progesterone is 5:1~15:1.
Step (5), 17 Alpha-hydroxy corpus luteum ketone ester solid- liquid separations：Solid-liquid point is carried out to the reaction mass obtained by step (4)
From separating obtained mother liquor enters wastewater treatment, and 17 Alpha-hydroxy corpus luteum ketone ester wet feeds of gained enter next step.
Step (6), 17 Alpha-hydroxy corpus luteum ketone esters are dried：By 17 Alpha-hydroxy corpus luteum ketone ester wet feeds obtained by step (5) 60
~80 DEG C of dryings, obtain 17 Alpha-hydroxy corpus luteum ketone ester finished products.
Step (7), 17 Alpha-hydroxy corpus luteum ketone ester elimination reactions：By 17 Alpha-hydroxy corpus luteum ketone ester finished products obtained by step (6)
It is well mixed in the reactor with eliminating reagent, is warming up to 240~300 DEG C, 0.2~3.0h of insulation reaction.
Structure based on 17 Alpha-hydroxy corpus luteum ketone esters and target product 16- dehydrogenation progesterone, this step is obtaining 16- dehydrogenations
After progesterone, by controlling reaction condition, Processing for removing is carried out to its 17 ester groups, eliminated on the ester group and 16 on 17
Hydrogen, produce carbon-carbon double bond on 16 and 17.
The embodiment of the present invention makes full use of ester group that the characteristics of elimination reaction is selectively high occurs at high temperature, de- using high temperature
17 Alpha-hydroxy corpus luteum ketone esters are converted into 16- dehydrogenation progesterone by ester technology, can reach that product yield is high, good product purity
Purpose.
In the embodiment of the present invention, it is preferable that in the step (7), the elimination reagent is detergent alkylate, biphenyl, connection
At least one of phenylate.
Preferably, the mol ratio of the 17 Alpha-hydroxy corpus luteum ketone ester finished product and the elimination reagent is 1:2~1:10.
Step (8), 16- dehydrogenation progesterone decrease temperature crystallines：Reaction solution obtained by step (7) is cooled to 60~80 DEG C, institute
Obtain material and enter next step.
Step (9), 16- dehydrogenation progesterone analysis of material：The second solvent is added into the reaction mass obtained by step (8), is separated out
16- dehydrogenation progesterone solid materials, obtain solid-liquid mixtures.
In the embodiment of the present invention, it is preferable that in the step (9), second solvent is petroleum ether, n-hexane, positive heptan
At least one of alkane, isooctane.
Preferably, second solvent used in the step (9) and the 17 α-hydroxyl used in the step (7)
The mass ratio of base corpus luteum ketone ester is 3:1~15:1.
Step (10), the cooling of 16- dehydrogenations progesterone：Solid-liquid mixtures obtained by step (9) are cooled to 5~15 DEG C, stirred
Mixing 1h makes 16- dehydrogenation progesterone solid materials further separate out.
Step (11), 16- dehydrogenation progesterone solid- liquid separations：Separation of solid and liquid is carried out to the reaction mass obtained by step (10),
The concentrated Posterior circle of mother liquor is utilized, and obtains 16- dehydrogenation progesterone wet feeds.
Step (12), 16- dehydrogenations progesterone are dried：By the 16- dehydrogenation progesterone wet feeds obtained by step (11) 50~70
DEG C drying, obtains 16- dehydrogenation progesterone finished products.
16- dehydrogenation progesterone is prepared using method provided in an embodiment of the present invention, product purity is up to more than 99%, and product is received
Rate is up to more than 90%, with the features such as product quality is high, product purity is high, product yield is high and is easy to large-scale production.
To make those skilled in the art more fully understand the present invention, illustrate this hair below by way of multiple specific embodiments
The method for the synthesis 16- dehydrogenation progesterone that bright embodiment is provided.
Embodiment 1
(1), 17 Alpha-hydroxy progesterone esterification：By the Alpha-hydroxy progesterone of 60g (0.182mol) 17,73g
(1.000mol) N,N-dimethylformamide, 72g (0.817mol) ethyl acetate, 18.54g (0.182mol) acetic anhydride, 10g
(0.100mol) mass fraction is well mixed in the reactor for 98% concentrated sulfuric acid and 7.2g (0.0820mol) fluoboric acid, is risen
Temperature is to 80 DEG C, and insulation reaction 2.0h, HPLC detect that starting material left is below 0.5%；
(2), 17 Alpha-hydroxy progesterone ester hydrolysis reaction：300g water is added in reaction mass one step up, 85 are warming up to
DEG C, insulation reaction 6.0h, HPLC detection, starting material left is below 0.5%；
(3), 17 Alpha-hydroxy corpus luteum ketone ester decrease temperature crystalline：The reaction mass of previous step is naturally cooling to 20 DEG C,；
(4), 17 Alpha-hydroxy corpus luteum ketone ester analysis of material：300g water is added in material one step up, 1h is stirred；
(5), 17 Alpha-hydroxy corpus luteum ketone ester solid- liquid separation：The solid-liquid mixtures of previous step after filtering, obtain 17 α-hydroxyl
Base corpus luteum ketone ester wet feed, mother liquor enters wastewater treatment；
(6), 17 Alpha-hydroxy corpus luteum ketone esters are dried：By 17 Alpha-hydroxy corpus luteum ketone ester wet feeds in 60 DEG C of dryings, 17 α -ester are obtained
Base progesterone finished product；
(7), 17 Alpha-hydroxy corpus luteum ketone ester elimination reaction：By the Alpha-hydroxy corpus luteum ketone ester finished products of 60g (0.182mol) 17 and 56g
(0.364mol) biphenyl is added in reactor, rising temperature for dissolving, is well mixed, and is warming up to 240 DEG C, insulation reaction 3.0h, HPLC inspection
Survey, starting material left is below 0.5%；
(8), 16- dehydrogenations progesterone decrease temperature crystalline：The reaction mass of previous step is cooled to 60 DEG C；
(9), 16- dehydrogenations progesterone analysis of material：180g petroleum ethers are added in reaction solution one step up, make 16- dehydrogenation corpus luteum
Ketone is separated out；
(10), 16- dehydrogenations progesterone cools：The solid-liquid mixtures of previous step are cooled to 5 DEG C, 1h is stirred, makes solids
Material is further separated out；
(11), 16- dehydrogenations progesterone solid- liquid separation：The solid-liquid mixtures of previous step obtain 16- dehydrogenations yellow after centrifugation
Body ketone wet feed, the concentrated Posterior circle of mother liquor is utilized；
(12), 16- dehydrogenations progesterone is dried：By 16- dehydrogenation progesterone wet feeds in 50 DEG C of dryings, 16- dehydrogenation corpus luteum are obtained
Ketone finished product, product purity 99.2%, product yield 91%.
Embodiment 2
(1), 17 Alpha-hydroxy progesterone esterification：By the Alpha-hydroxy progesterone of 60g (0.182mol) 17,216g
(3.00mol) tetrahydrofuran, 29.5g (0.640mol) ethanol, 35.7g (0.455mol) chloroacetic chloride, 14.3g (0.100mol) matter
Amount fraction is well mixed in the reactor for 70% perchloric acid and 9.3g (0.0820mol) trifluoroacetic acid, is warming up to 70 DEG C, guarantor
Temperature reaction 4.0h, HPLC detection, starting material left is below 0.5%；
(2), 17 Alpha-hydroxy progesterone ester hydrolysis reaction：60g water is added in reaction mass one step up, 95 are warming up to
DEG C, insulation reaction 4.0h, HPLC detection, starting material left is below 0.5%；
(3), 17 Alpha-hydroxy corpus luteum ketone ester decrease temperature crystalline：The reaction mass of previous step is naturally cooling to 25 DEG C,；
(4), 17 Alpha-hydroxy corpus luteum ketone ester analysis of material：600g water is added in material one step up, 1h is stirred；
(5), 17 Alpha-hydroxy corpus luteum ketone ester solid- liquid separation：The solid-liquid mixtures of previous step obtain 17 α-hydroxyl after centrifugation
Base corpus luteum ketone ester wet feed, mother liquor enters wastewater treatment；
(6), 17 Alpha-hydroxy corpus luteum ketone esters are dried：By 17 Alpha-hydroxy corpus luteum ketone ester wet feeds in 70 DEG C of dryings, 17 α -ester are obtained
Base progesterone finished product；
(7), 17 Alpha-hydroxy corpus luteum ketone ester elimination reaction：By the Alpha-hydroxy corpus luteum ketone ester finished products of 60g (0.182mol) 17 with
216g (1.27mol) Biphenyl Ether is added in reactor, rising temperature for dissolving, is well mixed, is warming up to 270 DEG C, insulation reaction 1.0h,
HPLC detects that starting material left is below 0.5%；
(8), 16- dehydrogenations progesterone decrease temperature crystalline：The reaction mass of previous step is cooled to 70 DEG C；
(9), 16- dehydrogenations progesterone analysis of material：300g n-hexanes and 300g normal heptanes are added in reaction solution one step up, is made
16- dehydrogenations progesterone is separated out；
(10), 16- dehydrogenations progesterone cools：The solid-liquid mixtures of previous step are cooled to 10 DEG C, 1h is stirred, makes solid
Material is further separated out；
(11), 16- dehydrogenations progesterone solid- liquid separation：The solid-liquid mixtures of previous step after filtering, obtain 16- dehydrogenations yellow
Body ketone wet feed, the concentrated Posterior circle of mother liquor is utilized；
(12), 16- dehydrogenations progesterone is dried：By 16- dehydrogenation progesterone wet feeds in 60 DEG C of dryings, 16- dehydrogenation corpus luteum are obtained
Ketone finished product, product purity 99%, product yield 90%.
Embodiment 3
(1), 17 Alpha-hydroxy progesterone esterification：By the Alpha-hydroxy progesterone of 60g (0.182mol) 17,327.9g
(5.46mol) acetic acid, 173.5g (0.910mol) paratoluensulfonyl chloride, 86.1g (0.500mol) p-methyl benzenesulfonic acid and 7.5g
(0.0460mol) trichloroacetic acid is well mixed in the reactor, is warming up to 60 DEG C, insulation reaction 6.0h, HPLC detection, raw material is remained
Remaining less than 0.5%；
(2), 17 Alpha-hydroxy progesterone ester hydrolysis reaction：120g water is added in reaction mass one step up, 105 are warming up to
DEG C, insulation reaction 2.0h, HPLC detection, starting material left is below 0.5%；
(3), 17 Alpha-hydroxy corpus luteum ketone ester decrease temperature crystalline：The reaction mass of previous step is naturally cooling to 30 DEG C,；
(4), 17 Alpha-hydroxy corpus luteum ketone ester analysis of material：900g water is added in material one step up, 1h is stirred；
(5), 17 Alpha-hydroxy corpus luteum ketone ester solid- liquid separation：The solid-liquid mixtures of previous step after filtering, obtain 17 α-hydroxyl
Base corpus luteum ketone ester wet feed, mother liquor enters wastewater treatment；
(6), 17 Alpha-hydroxy corpus luteum ketone esters are dried：By 17 Alpha-hydroxy corpus luteum ketone ester wet feeds in 80 DEG C of dryings, 17 α -ester are obtained
Base progesterone finished product；
(7), 17 Alpha-hydroxy corpus luteum ketone ester elimination reaction：By the Alpha-hydroxy corpus luteum ketone ester finished products of 60g (0.182mol) 17 with
448.5g (1.82mol) detergent alkylate is added in reactor, rising temperature for dissolving, is well mixed, is warming up to 300 DEG C, insulation reaction
0.2h, HPLC detect that starting material left is below 0.5%；
(8), 16- dehydrogenations progesterone decrease temperature crystalline：The reaction mass of previous step is cooled to 80 DEG C；
(9), 16- dehydrogenations progesterone analysis of material：450g isooctane is added in reaction solution one step up, makes 16- dehydrogenation corpus luteum
Ketone is separated out；
(10), 16- dehydrogenations progesterone cools：The solid-liquid mixtures of previous step are cooled to 15 DEG C, 1h is stirred, makes solid
Material is further separated out；
(11), 16- dehydrogenations progesterone solid- liquid separation：The solid-liquid mixtures of previous step obtain 16- dehydrogenations yellow after centrifugation
Body ketone wet feed, the concentrated Posterior circle of mother liquor is utilized；
(12), 16- dehydrogenations progesterone is dried：By 16- dehydrogenation progesterone wet feeds in 70 DEG C of dryings, 16- dehydrogenation corpus luteum are obtained
Ketone finished product, product purity 99.3%, product yield 90.5%.
A kind of method of synthesis 16- dehydrogenation progesterone provided by the present invention is described in detail above, herein
Apply specific case to be set forth the principle and embodiment of the present invention, the explanation of above example is only intended to help
Understand the method and its core concept of the present invention；Simultaneously for those of ordinary skill in the art, according to the thought of the present invention,
It will change in specific embodiments and applications, in summary, this specification content should not be construed as to this
The limitation of invention.
Claims (9)
1. a kind of method of synthesis 16- dehydrogenation progesterone, it is characterised in that the described method comprises the following steps：
Step (1), 17 Alpha-hydroxy progesterone esterifications：By 17 Alpha-hydroxy progesterone, the first solvent, esterifying reagent and catalyst
Added in reactor and it is well mixed, is warming up to 60~80 DEG C, 2.0~6.0h of insulation reaction；
Step (2), 17 Alpha-hydroxy progesterone ester hydrolysis reactions：Water is added into the reaction mass obtained by step (1), 85 are warming up to
~105 DEG C, 2.0~6.0h of insulation reaction；
Step (3), 17 Alpha-hydroxy corpus luteum ketone ester decrease temperature crystallines：Reaction mass obtained by step (2) is naturally cooling to 20~30
DEG C, obtain solid-liquid mixtures；
Step (4), 17 Alpha-hydroxy corpus luteum ketone ester analysis of material：Water is added into the solid-liquid mixtures obtained by step (3), 1h, analysis is stirred
Go out 17 Alpha-hydroxy corpus luteum ketone ester solid materials；
Step (5), 17 Alpha-hydroxy corpus luteum ketone ester solid- liquid separations：Separation of solid and liquid is carried out to the reaction mass obtained by step (4), point
Mother liquor from gained enters wastewater treatment, and 17 Alpha-hydroxy corpus luteum ketone ester wet feeds of gained enter next step；
Step (6), 17 Alpha-hydroxy corpus luteum ketone esters are dried：By 17 Alpha-hydroxy corpus luteum ketone ester wet feeds obtained by step (5) 60~80
DEG C drying, obtains 17 Alpha-hydroxy corpus luteum ketone ester finished products；
Step (7), 17 Alpha-hydroxy corpus luteum ketone ester elimination reactions：By 17 Alpha-hydroxy corpus luteum ketone ester finished products obtained by step (6) with disappearing
Except reagent is well mixed in the reactor, 240~300 DEG C, 0.2~3.0h of insulation reaction are warming up to；
Step (8), 16- dehydrogenation progesterone decrease temperature crystallines：Reaction solution obtained by step (7) is cooled to 60~80 DEG C, gains
Material enters next step；
Step (9), 16- dehydrogenation progesterone analysis of material：The second solvent is added into the reaction mass obtained by step (8), 16- is separated out and goes
Hydrogen progesterone solid material, obtains solid-liquid mixtures；
Step (10), the cooling of 16- dehydrogenations progesterone：Solid-liquid mixtures obtained by step (9) are cooled to 5~15 DEG C, 1h is stirred
16- dehydrogenation progesterone solid materials are made further to separate out；
Step (11), 16- dehydrogenation progesterone solid- liquid separations：Separation of solid and liquid, mother liquor are carried out to the reaction mass obtained by step (10)
Concentrated Posterior circle is utilized, and obtains 16- dehydrogenation progesterone wet feeds；
Step (12), 16- dehydrogenations progesterone are dried：16- dehydrogenation progesterone wet feeds obtained by step (11) is dry at 50~70 DEG C
It is dry, obtain 16- dehydrogenation progesterone finished products.
2. according to the method described in claim 1, it is characterised in that in the step (1), first solvent is dichloromethane
At least one of alkane, N,N-dimethylformamide, ethanol, tetrahydrofuran, ethyl acetate and acetic acid；
The esterifying reagent is at least one of chloroacetic chloride, paratoluensulfonyl chloride, acetic anhydride；
The catalyst is at least one of the concentrated sulfuric acid, trifluoroacetic acid, trichloroacetic acid, p-methyl benzenesulfonic acid, fluoboric acid and perchloric acid.
3. according to the method described in claim 1, it is characterised in that in the step (1),
The mol ratio of the 17 Alpha-hydroxy progesterone and first solvent is 1:10~1:30；
The mol ratio of the 17 Alpha-hydroxy progesterone and the esterifying reagent is 1:1~1:5；
The mol ratio of the 17 Alpha-hydroxy progesterone and the catalyst is 1:1~1:3.
4. according to the method described in claim 1, it is characterised in that the water of addition and the step in the step (2)
(1) mass ratio of the 17 Alpha-hydroxy progesterone used in is 0.5:1~2.0:1.
5. according to the method described in claim 1, it is characterised in that the water of addition and the step in the step (4)
(1) mass ratio of the 17 Alpha-hydroxy progesterone used in is 5:1~15:1.
6. according to the method described in claim 1, it is characterised in that in the step (7), the elimination reagent is dodecyl
At least one of benzene, biphenyl, Biphenyl Ether.
7. according to the method described in claim 1, it is characterised in that in the step (7), the 17 Alpha-hydroxy corpus luteum ketone ester into
The mol ratio of product and the elimination reagent is 1:2~1:10.
8. according to the method described in claim 1, it is characterised in that in the step (9), second solvent be petroleum ether,
At least one of n-hexane, normal heptane, isooctane.
9. according to the method described in claim 1, it is characterised in that second solvent used in the step (9) and institute
The mass ratio for stating the 17 Alpha-hydroxy corpus luteum ketone ester used in step (7) is 3:1~15:1.
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| CN201710254647.0A CN106977570A (en) | 2017-04-18 | 2017-04-18 | A kind of method for synthesizing 16 dehydrogenation progesterone |
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| CN110407902A (en) * | 2019-07-15 | 2019-11-05 | 浙江工业大学 | A kind of method of steroidal compounds removing 17- acetoxyl group |
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