CN105777834A - Preparation process of progesterone - Google Patents
Preparation process of progesterone Download PDFInfo
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- CN105777834A CN105777834A CN201610283541.9A CN201610283541A CN105777834A CN 105777834 A CN105777834 A CN 105777834A CN 201610283541 A CN201610283541 A CN 201610283541A CN 105777834 A CN105777834 A CN 105777834A
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- China
- Prior art keywords
- progesterone
- adds
- ethanol
- toluene
- preparation technology
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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 discloses a preparation process of progesterone. In the preparation process, initial pulping is performed by cyclohexane, and colloids contained in crude products after oppenauer oxidation of the crude projects, so that purity of the crude products is increased. Through decolorizing and refining of ethyl alcohol, ethyl alcohol can be used directly for re-crystallization without drying, and mother liquor obtained by centrifuging re-crystallization can be directly applied in decolorization and refining. This process upgrades purity and increases yield although re-crystallization is added, and material loss and great consumption of ethyl alcohol as much ethyl alcohol is used for washing filter cake due to the fact that decolorization and refining are unqualified are reduced.
Description
Technical field
The present invention relates to the synthesis of hormonal medicaments, be specifically related to the preparation technology of a kind of Progesterone.
Background technology
Progesterone, chemical name: DELTA4-pregn-3,20-dione, molecular formula: C21H30O2.Being a kind of natural progestogen secreted by corpus luteum, the endometrium in vivo estrogen excited has notable Morphology Effects, required for maintaining gestation.Progesterone is clinically used for the amenorrhea such as threatened abortion, habitual abortion or the reactive diagnosis etc. of amenorrhea reason.
Chinese invention patent CN201510821638.6 discloses a kind of method preparing Progesterone.The method is with compound 3-(2, 2-dimethyl-1, 3-dioxy propyl group)-5-alkene-17-ketone (II) is initiation material, condensation reaction is there is with sulfonvlmethvl isocyanide compound (III) under the effect of alkali, prepare formamido sulfonyl methylene compound (IV), compound (IV) obtains isocyano group sulfonyl methylene compound (V) through dehydration, compound (V) obtains isocyano group sulfonvlmethvl compound (VI) through reduction reaction, compound (VI) obtains isocyano group sulfonyl ethyl compound (VII) through methylation reaction, final compound (VII) obtains target product Progesterone (I) through hydrolysis.
Chinese invention patent CN201510715996.9 provides the synthetic method of a kind of Progesterone, including step: 1) 3 β-ether-3,5-androstane diene-17-ketone is dissolved with in the solvent of highly basic, it is slowly added to 2-chloropropionate, addition, ring-closure reaction is occurred to obtain 3 β-ether-3,5-androstane diene-17,20-epoxy-20-methyl-20-carboxylic acid, ethyl ester；2) under nitrogen or inert gas shielding, in the solvent containing lithium chloride, 3 β-ether-3,5-androstane diene-17,20-epoxy-20-methyl-20-carboxylic acid, ethyl ester obtains Progesterone through high temperature decarboxylation, hydrolysis.
The preparation technology relative complex of above Progesterone, final products purity is not high, and product recovery rate is relatively low.
Summary of the invention
For reaching object above, the present invention adopts the technical scheme that: a kind of high-purity, high recovery rate the preparation technology of Progesterone, comprise the following steps:
S1, mixes pregnenolone with toluene, and stirring is warming up to 115～120 DEG C, and toluene dehydration is steamed in backflow；
S2, adds Ketohexamethylene, continues to steam toluene dehydration to the greatest extent, adding aluminum isopropylate., carries out steam punching and evaporate, steam toluene and Ketohexamethylene to the greatest extent after reacting 2h in 112～120 DEG C；
S3, adds water and carries out cooling crystallization, and centrifugal rejection filter, filter cake hexamethylene carries out making beating process, and sucking filtration obtains Progesterone crude product.
On the basis of technique scheme, it is preferred that in described step S1, the pregnenolone of each mass fraction adds the toluene of 16～20 mass fractions.
On the basis of technique scheme, it is preferred that in described step S2, the pregnenolone of each mass fraction adds the Ketohexamethylene of 2～3 mass fractions, adds the aluminum isopropylate. of 0.2 mass fraction.
On the basis of technique scheme, it is preferred that in described step S3, the pregnenolone of each mass fraction adds the water of 6～8 mass fractions, add the hexamethylene of 1～2 mass fraction.
On the basis of technique scheme, it is preferred that 17 Alpha-hydroxy Progesterone of each molfraction in described step S2, the corresponding ethanol adding 10 molfractions.
On the basis of technique scheme, preferably, also include step S4, by Progesterone dissolving crude product in ethanol, add activated carbon, decolouring, filter and remove activated carbon, freezing and crystallizing after concentrating filter liquor removing ethanol, dry by centrifugation, add ethanol and carry out recrystallization process, then through being centrifuged, dry, pulverize and to obtain Progesterone fine work.It is further preferred that in described step S4, it is Progesterone crude product 10 times that first time adds ethanol quality, it is Progesterone crude product 1 times that second time adds ethanol quality.
Compared with prior art, it is an advantage of the current invention that:
(1) hexamethylene is adopted to carry out preliminary making beating process, the colloid contained in crude product after removing the oxidation of crude product walsh, improves crude product purity；
(2) after ethanol decolorization is refining, direct ethanol need not be dried and carry out recrystallization process, recrystallization is centrifuged the mother solution obtained and directly applies mechanically decolorizing and refining process, although this process adds recrystallization operation, but improve purity and the yield of fine work, decrease and cause a large amount of consumptions of loss of material and ethanol because the decolorizing and refining a large amount of ethanol of defective use waters filter wash cake.
Accompanying drawing explanation
Fig. 1 is the flow chart of the preparation technology of the Progesterone of the present invention.
Detailed description of the invention
Shown in Figure 1, the preparation technology of the Progesterone of the present invention, comprise the following steps:
First, moisture content is removed.
S1, mixes pregnenolone with toluene, and stirring is warming up to 115～120 DEG C, and toluene dehydration is steamed in backflow；
Secondly, continue to remove moisture content, carry out walsh oxidation reaction, and remove toluene and Ketohexamethylene.
S2, adds Ketohexamethylene, continues to steam toluene dehydration to the greatest extent, adding aluminum isopropylate., carries out steam punching and evaporate, steam toluene and Ketohexamethylene to the greatest extent after reacting 2h in 112～120 DEG C；
Then, add water precipitation, and remove impurity of tentatively pulling an oar with hexamethylene obtains Progesterone crude product.
S3, adds water and carries out cooling crystallization, and centrifugal rejection filter, filter cake hexamethylene carries out making beating process, and sucking filtration obtains Progesterone crude product.
Finally, refining, it is thus achieved that Progesterone fine work.
S5, adds ethanol by 17a-hydroxyl progesterone acetate crude product and carries out making beating process, be cooled to 0～5 DEG C, centrifugal, obtains 17a-hydroxyl progesterone acetate fine work.
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1
S1, adds the toluene of 18 mass fractions in walsh oxidation tank, adds the pregnenolone of 1 mass fraction, and stirring is warming up to 118 DEG C, backflow, steams benzene dehydration to visor without the obvious globule；
S2, adds the Ketohexamethylene of 2.5 mass fractions, continues to steam toluene dehydration to the greatest extent, is rapidly added the aluminum isopropylate. of 0.2 mass fraction, carries out steam punching and evaporates, steam toluene and Ketohexamethylene to the greatest extent after 116 DEG C of oxidation reaction 2h；
S3, the water adding 7 mass fractions carries out cooling crystallization, and centrifugal rejection filter, the filter cake hexamethylene of 1.5 mass fractions carries out making beating process, and sucking filtration obtains Progesterone crude product；
S4, being put into by the Progesterone crude product of 1 mass fraction dissolves in bleacher, dissolve with the ethanol of 10 times of quality, add activated carbon decolorizing, activated carbon, filtrate suction condensing crystallizing tank, freezing and crystallizing after concentrated recovery section ethanol is removed through filtering, recrystallization process is carried out with the ethanol of 1 times of quality again, then through being centrifuged, dry, pulverize and to obtain Progesterone fine work after drying mother solution by centrifugation.
Products obtained therefrom carries out chromatography detection, and gained Progesterone fine work purity is >=99%.
Calculating the refining 17a-hydroxyl progesterone acetate fine work of gained, product recovery rate is 82%.
Embodiment 2
S1, adds the toluene of 16 mass fractions in walsh oxidation tank, adds the pregnenolone of 1 mass fraction, and stirring is warming up to 115 DEG C, backflow, steams benzene dehydration to visor without the obvious globule；
S2, adds the Ketohexamethylene of 2 mass fractions, continues to steam toluene dehydration to the greatest extent, is rapidly added the aluminum isopropylate. of 0.2 mass fraction, carries out steam punching and evaporates, steam toluene and Ketohexamethylene to the greatest extent after 112 DEG C of oxidation reaction 2h；
S3, the water adding 6 mass fractions carries out cooling crystallization, and centrifugal rejection filter, the filter cake hexamethylene of 1 mass fraction carries out making beating process, and sucking filtration obtains Progesterone crude product；
S4, being put into by the Progesterone crude product of 1 mass fraction dissolves in bleacher, dissolve with the ethanol of 10 times of quality, add activated carbon decolorizing, activated carbon, filtrate suction condensing crystallizing tank, freezing and crystallizing after concentrated recovery section ethanol is removed through filtering, recrystallization process is carried out with the ethanol of 1 times of quality again, then through being centrifuged, dry, pulverize and to obtain Progesterone fine work after drying mother solution by centrifugation.
Products obtained therefrom carries out chromatography detection, and gained Progesterone fine work purity is >=99%.
Calculating the refining 17a-hydroxyl progesterone acetate fine work of gained, product recovery rate is 80%.
Embodiment 3
S1, adds the toluene of 20 mass fractions in walsh oxidation tank, adds the pregnenolone of 1 mass fraction, and stirring is warming up to 120 DEG C, backflow, steams benzene dehydration to visor without the obvious globule；
S2, adds the Ketohexamethylene of 3 mass fractions, continues to steam toluene dehydration to the greatest extent, is rapidly added the aluminum isopropylate. of 0.2 mass fraction, carries out steam punching and evaporates, steam toluene and Ketohexamethylene to the greatest extent after 120 DEG C of oxidation reaction 2h；
S3, the water adding 8 mass fractions carries out cooling crystallization, and centrifugal rejection filter, the filter cake hexamethylene of 2 mass fractions carries out making beating process, and sucking filtration obtains Progesterone crude product；
S4, being put into by the Progesterone crude product of 1 mass fraction dissolves in bleacher, dissolve with the ethanol of 10 times of quality, add activated carbon decolorizing, activated carbon, filtrate suction condensing crystallizing tank, freezing and crystallizing after concentrated recovery section ethanol is removed through filtering, recrystallization process is carried out with the ethanol of 1 times of quality again, then through being centrifuged, dry, pulverize and to obtain Progesterone fine work after drying mother solution by centrifugation.
Products obtained therefrom carries out chromatography detection, and gained Progesterone fine work purity is >=99%.
Calculating the refining 17a-hydroxyl progesterone acetate fine work of gained, product recovery rate is 79%.
The present invention is not limited to above-mentioned embodiment, for those skilled in the art, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, and these improvements and modifications are also considered as within protection scope of the present invention.The content not being described in detail in this specification belongs to the known prior art of professional and technical personnel in the field.
Claims (6)
1. the preparation technology of a Progesterone, it is characterised in that comprise the following steps:
S1, mixes pregnenolone with toluene, and stirring is warming up to 115～120 DEG C, and toluene dehydration is steamed in backflow；
S2, adds Ketohexamethylene, continues to steam toluene dehydration to the greatest extent, adding aluminum isopropylate., carries out steam punching and evaporate, steam toluene and Ketohexamethylene to the greatest extent after reacting 2h in 112～120 DEG C；
S3, adds water and carries out cooling crystallization, and centrifugal rejection filter, filter cake hexamethylene carries out making beating process, and sucking filtration obtains Progesterone crude product.
2. the preparation technology of Progesterone as claimed in claim 1, it is characterised in that: in described step S1, the pregnenolone of each mass fraction adds the toluene of 16～20 mass fractions.
3. the preparation technology of Progesterone as claimed in claim 1, it is characterised in that: in described step S2, the pregnenolone of each mass fraction adds the Ketohexamethylene of 2～3 mass fractions, adds the aluminum isopropylate. of 0.2 mass fraction.
4. the preparation technology of Progesterone as claimed in claim 1, it is characterised in that: in described step S3, the pregnenolone of each mass fraction adds the water of 6～8 mass fractions, adds the hexamethylene of 1～2 mass fraction.
5. the preparation technology of Progesterone as claimed in claim 1, it is characterized in that: also include step S4, by Progesterone dissolving crude product in ethanol, add activated carbon, decolouring, filter and remove activated carbon, freezing and crystallizing after concentrating filter liquor removing ethanol, dry by centrifugation, add ethanol and carry out recrystallization process, then through being centrifuged, dry, pulverize and to obtain Progesterone fine work.
6. the preparation technology of Progesterone as claimed in claim 5, it is characterised in that: in described step S4, it is Progesterone crude product 10 times that first time adds ethanol quality, and it is Progesterone crude product 1 times that second time adds ethanol quality.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610283541.9A CN105777834A (en) | 2016-04-29 | 2016-04-29 | Preparation process of progesterone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610283541.9A CN105777834A (en) | 2016-04-29 | 2016-04-29 | Preparation process of progesterone |
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| CN105777834A true CN105777834A (en) | 2016-07-20 |
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| CN201610283541.9A Pending CN105777834A (en) | 2016-04-29 | 2016-04-29 | Preparation process of progesterone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108802373A (en) * | 2018-05-31 | 2018-11-13 | 湖南远璟生物技术有限公司 | A kind of progesterone magnetic microparticle chemiluminescence immune quantitative detection reagent box and preparation method thereof |
| CN108802365A (en) * | 2018-05-31 | 2018-11-13 | 湖南远璟生物技术有限公司 | A kind of preparation method of progesterone enzyme conjugates |
| CN113999275A (en) * | 2021-11-30 | 2022-02-01 | 陕西众和振华生物科技有限公司 | Carbon neutralization process for comprehensive recovery treatment of progesterone mother liquor |
-
2016
- 2016-04-29 CN CN201610283541.9A patent/CN105777834A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108802373A (en) * | 2018-05-31 | 2018-11-13 | 湖南远璟生物技术有限公司 | A kind of progesterone magnetic microparticle chemiluminescence immune quantitative detection reagent box and preparation method thereof |
| CN108802365A (en) * | 2018-05-31 | 2018-11-13 | 湖南远璟生物技术有限公司 | A kind of preparation method of progesterone enzyme conjugates |
| CN113999275A (en) * | 2021-11-30 | 2022-02-01 | 陕西众和振华生物科技有限公司 | Carbon neutralization process for comprehensive recovery treatment of progesterone mother liquor |
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Application publication date: 20160720 |
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