CN104945464B - A kind of synthetic method of betamethasone epoxy hydrolysate - Google Patents
A kind of synthetic method of betamethasone epoxy hydrolysate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
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Abstract
The invention belongs to steroid hormone class pharmaceutical synthesis field, it is specifically related to the synthetic method of a kind of betamethasone epoxy hydrolysate, thing is eliminated as raw material including with betamethasone, obtain betamethasone epoxy hydrolysate finished product through bromine hydroxylation reaction and epoxy hydrolysis, run, from reducing elutriation, the overall yield expecting to improve betamethasone epoxy hydrolysate.The present invention reduces the hydrolysis in the reaction of bromine hydroxyl thing, and by epoxy, hydrolyze two cloth operations and be merged into a step, thus improve the yield of betamethasone epoxy hydrolysate.
Description
Technical field
The invention belongs to steroid hormone class pharmaceutical synthesis field, be specifically related to the synthesis of a kind of betamethasone epoxy hydrolysate
Method.
Background technology
Betamethasone is the isomers of dexamethasone, and effect is same with dexamethasone, but antiinflammatory action relatively fills in rice
Pine, triamcinolone etc. are all strong, are used for treating activeness rheumatism, rheumatoid arthritis, lupus erythematosus, seriously propping up
San bronchial asthma, serious dermatitis, acute leukemia etc., be also used for some Comprehensive Treatment infected.
Betamethasone epoxy hydrolysate, is a kind of important intermediate of synthesis betamethasone, is the master of synthesis betamethasone
Raw material, molecular formula: C22H28O5, commodity another name: DB11；9 β, 11 beta epoxide-16 Beta-methyl pregnant steroid-1,4-diene-
17 α, 21-glycol-3,20-diketone；Betamethasone epoxy.CAS No.:981-34-0, molecular structural formula:
The current synthetic route of betamethasone epoxy hydrolysate is: (the synthetic route reference of CAS No.:981-34-0
Document: Organic Process Research and Development, vol.5, #4p.376 382.) with his rice again
It is raw material that pine eliminates thing, forms through the reaction of bromine hydroxyl, epoxidation esterification and hydrolysis, and process route is as follows:
The problem that this synthesis route exists mainly has: in his esterification post processing of this technique times, hydrolyze during elutriation
Part runs material, thus causes product yield to incur loss, and betamethasone bromine hydroxyl thing can be directly synthesized epoxy hydrolysis
Thing.According to theoretical yield, and from the point of view of the yield (about 65%) of this betamethasone epoxy hydrolysate technique, times he
The space that the yield of rice pine epoxy hydrolysate is still improved.
Summary of the invention
For the problem overcoming above-mentioned prior art to exist, it is desirable to provide the conjunction of a kind of betamethasone epoxy hydrolysate
One-tenth method, on the one hand improves product yield, on the other hand optimizes big commercial production, save the energy, reduce and produce into
This.
For realizing the goal of the invention of the present invention, inventor provides following technical scheme:
The synthetic method of a kind of betamethasone epoxy hydrolysate, comprises the steps:
(1) with betamethasone digest as raw material, betamethasone bromine hydroxyl thing, course of reaction are prepared through bromine hydroxylation reaction
For:
Add 3.6-3.7V dioxane in dry bromine hydroxyl retort, 1W betamethasone eliminates thing, logical nitrogen,
Stirring is the most molten clearly；Control temperature between 10～18 DEG C, be slowly added into perchloric acid 0.128V, control temperature 10～
Between 20 DEG C, add times his 101 (referring to N-bromo-succinimide) of 0.56-0.57W, after finishing in
10～20 DEG C of insulation reaction 20-40 minute, add 3.125-3.25V methanol, stir 5-8 minute；By reactant liquor
Drawing in elutriation in the interior temperature 5-10 DEG C bromine hydroxyl elutriation tank of existing sodium sulfite solution and 40-42V water, elutriation temperature controls
Between 5～20 DEG C, after elutriation, maintain in temperature 5-20 DEG C, stir 60-65 minute, stand 2 hours with
On；Centrifugal, washing, dry, obtain betamethasone bromine hydroxyl thing wet product,
(2) betamethasone bromine hydroxyl thing obtains betamethasone epoxy hydrolysate finished product, course of reaction through epoxy hydrolysis
For:
In bromine hydroxyl washing tank, add 5.6V dichloromethane, 2V water, put under stirring that step (1) obtains times he
Rice pine bromine hydroxyl thing wet product, in controlling, temperature 25-30 DEG C, stirs 25-30 minute, until betamethasone in bromine hydroxyl washing tank
Bromine hydroxyl thing wet product is all dissolved；Stir molten clear after, stand layering in 20-30 minute, organic layer puts into feed liquid basin, and
In in basin, organic layer nitrogen is pressed into epoxy reaction tank, open loop oxygen retort interlayer set frozen cooling；Water layer is used
Dichloromethane extracted several times, after extraction, organic layer is incorporated to feed liquid basin, is pressed into epoxy reaction tank in the lump with nitrogen；Epoxy
Add 5.6-5.7V methanol in retort, wait being cooled to-6～when-2 DEG C, logical nitrogen, control temperature-6～-2 DEG C it
Between, dropping sodium sulfite and sodium hydroxide solution；Drip and finish, control temperature-5～0 DEG C, react 2-2.5 hour；Sampling
HPLC detects, and controls temperature and adds 50% glacial acetic acid solution 1V between-5～5 DEG C, stir 20-25 minute, surveys
Reacting liquid pH value should be 5-6；Closing nitrogen, epoxy reaction liquid is drawn in epoxy concentration tank, normal pressure is concentrated into interior temperature
45-55 DEG C, then when being evaporated to material liquid volume 6.25-6.875V, add 6.25V water and continue to be evaporated to feed liquid body
When amassing as 4.69-5V, add 12.5V water elutriation, feed liquid be cooled to 0-5 DEG C, continue stirring 30-40 minute,
Stand more than 2 hours, centrifugal, washing, dry, discharging, dry to obtain betamethasone epoxy hydrolysate crude product.
Synthesis route of the present invention after improvement is as follows:
Betamethasone epoxy hydrolysate is the main material of synthesis betamethasone.Inventor is according to theoretical yield, and from former times
From the point of view of the yield (about 65%) of Ta meter Song epoxy hydrolysate technique, the yield of this betamethasone epoxy hydrolysate carries
High space, therefore, technique former to betamethasone epoxy hydrolysate is optimized.Locate after his esterification of former technique times
In reason, during elutriation, hydrolyzable moiety occurs running material, causes yield to incur loss, and betamethasone bromine hydroxyl thing can be direct
Synthesis betamethasone epoxy hydrolysate, therefore, during process optimization, it is considered to improve betamethasone from reducing elutriation race material
The overall yield of epoxy hydrolysate.Finding when optimizing technique, the present invention is reducing potassium carbonate and the consumption of acetone and contracting
Under conditions of the short reaction operating time, steady quality can also be obtained while reducing supplementary material and power cost excellent
Betamethasone epoxy hydrolysate product.
The synthesis of former betamethasone epoxy hydrolysate technique is with betamethasone elimination thing as raw material, through bromine hydroxylation reaction, epoxy
Esterification and hydrolysis form.The technique of betamethasone epoxy hydrolysate of the present invention mainly optimizes esterification
Condition, decreases the hydrolysis in the esterification reaction of betamethasone bromine hydroxyl thing, thus improves betamethasone epoxy hydrolysate
Yield (being brought up to 70-75% by former technique 65%).
As preferably, according to the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, wherein: described
Step (1) in: sodium sulfite solution be 0.22-0.23W sodium sulfite is dissolved in the water of 1.25V preparation and
Become.
As preferably, according to the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, wherein: described
Step (1) in: survey elutriation liquid with starch-kalium iodide reagent paper during elutriation, the aobvious blueness of reagent paper.
As preferably, according to the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, wherein: described
Step (1) in: washing, dry refer to washing 2.5-3 hour, dry 2.5-3 hour.
As preferably, according to the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, wherein: described
Step (2) in: water layer dichloromethane extracted several times refer to water layer 1.25V dichloromethane extraction, repeat
Twice.
As preferably, according to the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, wherein: described
Step (2) in: sodium sulfite and sodium hydroxide solution are by the sodium sulfite of 0.02W and 0.225W hydroxide
Sodium is dissolved in 0.94V water and 0.31-0.32V methanol formulated, lowers the temperature 25-30 DEG C after dissolving, standby.
As preferably, according to the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, wherein: described
Step (2) in: measured reaction liquid pH value should be 5-6, measures with two kinds of precision test papers of 3.8-5.4 and 5.4-7.
As preferably, according to the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, wherein: described
Step (2) in: dry refer to washing 2-2.5 hour, dry 30-40 minute.
As preferably, according to the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, wherein: described
Step (2) in: dry betamethasone epoxy hydrolysate crude product refer in 60-70 DEG C dry 10-12 hour times
Ta meter Song epoxy hydrolysate crude product.
Particularly, the synthetic method of a kind of betamethasone epoxy hydrolysate of the present invention, comprise the steps:
(1) with betamethasone elimination thing as raw material, betamethasone bromine hydroxyl thing, course of reaction are prepared through bromine hydroxylation reaction
For:
Add 115-118L dioxane in dry bromine hydroxyl retort, 32kg betamethasone eliminates thing, logical nitrogen
Gas, stirring is the most molten clearly；Control temperature, between 10～18 DEG C, is slowly added into perchloric acid 4.1L, controls temperature and exists
Between 10～20 DEG C, add times his 101 (referring to N-bromo-succinimide) of 18-18.24kg, after finishing in
10～20 DEG C of insulation reaction 20-40 minute, add 100-104L methanol, stir 5-8 minute；Reactant liquor is drawn
Enter existing sodium sulfite solution (being dissolved in the water of 40L by 7-7.36kg sodium sulfite) and 1280-1344L water is interior
Elutriation in 5-10 DEG C of bromine hydroxyl elutriation tank of temperature, elutriation temperature controls between 5～20 DEG C (with starch-iodine during elutriation
Change potassium reagent paper and survey elutriation liquid, the not aobvious blueness of reagent paper), (survey with starch-kalium iodide reagent paper during elutriation after elutriation
Elutriation liquid, the not aobvious blueness of reagent paper), in maintaining, temperature 5-20 DEG C, stirs 60-65 minute, stands more than 2 hours；
Centrifugal, wash 2.5-3 hour, dry 2.5-3 hour, obtain betamethasone bromine hydroxyl thing wet product,
(2) betamethasone bromine hydroxyl thing obtains betamethasone epoxy hydrolysate finished product, course of reaction through epoxy hydrolysis
For:
In bromine hydroxyl washing tank, add 180L dichloromethane, 64L water, put under stirring that step (1) obtains times he
Rice pine bromine hydroxyl thing wet product, in controlling, temperature 25-30 DEG C, stirs 25-30 minute, until betamethasone in bromine hydroxyl washing tank
Bromine hydroxyl thing wet product is all dissolved；Stir molten clear after, stand layering in 20-30 minute, organic layer puts into feed liquid basin, and
In in basin, organic layer nitrogen is pressed into epoxy reaction tank, open loop oxygen retort interlayer set frozen cooling；Water layer is used
Dichloromethane extracted several times (dichloromethane of water layer 40L, 40L is extracted twice), organic layer pan feeding after extraction
Liquid basin, is pressed into epoxy reaction tank in the lump with nitrogen；Add 179-182L methanol in epoxy reaction tank, wait to be cooled to-
6～when-2 DEG C, logical nitrogen, control temperature between-6～-2 DEG C, dropping sodium sulfite and sodium hydroxide solution (will
6.4kg sodium sulfite and 7.2kg sodium hydroxide are dissolved in 30L water and 10-11.2L methanol, and lower the temperature after dissolving 25-
30℃)；Drip and finish, control temperature-5～0 DEG C, react 2-2.5 hour；Sampling HPLC detection, control temperature-
Adding 50% glacial acetic acid solution 32L between 5～5 DEG C, stir 20-25 minute, measured reaction liquid pH value should be 5-6
(measure with two kinds of precision test papers of 3.8-5.4 and 5.4-7.)；Close nitrogen, epoxy reaction liquid is drawn in epoxy concentration tank
In, normal pressure is concentrated into interior temperature 45-55 DEG C, then when being evaporated to material liquid volume 200-220L, adds 200L water and continue
It is evaporated to material liquid volume when being 150-160L, adds 400L water elutriation, feed liquid is cooled to 0-5 DEG C, continue
Stir 30-40 minute, stand more than 2 hours, centrifugal, wash 2-2.5 hour, dry 30-40 minute, go out
Material, dries 10-12 hour to obtain betamethasone epoxy hydrolysate crude product in 60-70 DEG C.
Compared with prior art, advantages of the present invention has:
1, the present invention optimizes existing synthesis technique, improves betamethasone epoxy hydrolysate by reducing elutriation race material
Overall yield, decreases the consumption of potassium carbonate and acetone in course of reaction, shorten the operation time, reduces former
Adjuvant and power cost.
2, the innovative technology of the present invention mainly optimizes epoxy reaction condition, reduces the hydrolysis in the reaction of bromine hydroxyl thing,
And by epoxy, hydrolyze two cloth operations and be merged into a step, thus improve the yield of betamethasone epoxy hydrolysate.
3, properties of product of the present invention are high, and steady quality has the features such as energy-conservation, production cost is low, are more suitable for big
Technical scale metaplasia is produced.
Figure of description
Fig. 1 is the infrared spectrum collection of illustrative plates of betamethasone epoxy hydrolysate sample of the present invention.
Fig. 2 is the ultraviolet spectra collection of illustrative plates (solvent: dehydrated alcohol) of betamethasone epoxy hydrolysate sample of the present invention.
Fig. 3-1 to Fig. 3-5 is the proton nmr spectra collection of illustrative plates of betamethasone epoxy hydrolysate sample of the present invention.
Fig. 4 is the proton nmr spectra collection of illustrative plates (increasing the weight of water coke slurry) of betamethasone epoxy hydrolysate sample of the present invention.
Fig. 5-1 and Fig. 5-2 is the carbon-13 nmr spectra collection of illustrative plates of betamethasone epoxy hydrolysate sample of the present invention.
Fig. 6 is the nuclear magnetic resonance, NMR DEPT spectrogram spectrum of betamethasone epoxy hydrolysate sample of the present invention.
Fig. 7-1 and Fig. 7-2 is the nuclear magnetic resonance, NMR 1H-1HCOSY spectrogram of betamethasone epoxy hydrolysate sample of the present invention
Spectrum.
Fig. 8-1 and Fig. 8-2 is the nuclear magnetic resonance, NMR hsqc spectrum collection of illustrative plates of betamethasone epoxy hydrolysate sample of the present invention.
Fig. 9-1 to Fig. 9-4 is the nuclear magnetic resonance, NMR HMBC spectrogram spectrum of betamethasone epoxy hydrolysate sample of the present invention.
Figure 10 is the mass-spectrogram (ESI spectrum) of betamethasone epoxy hydrolysate sample of the present invention.
Detailed description of the invention
Below in conjunction with embodiment, further illustrate present disclosure.Should be appreciated that the enforcement not office of the present invention
Being limited to the following examples, any pro forma accommodation being made the present invention and/or change fall within the present invention and protect
Protect scope.
In the present invention, if not refering in particular to, all of part, percentage ratio are unit of weight, all of equipment and raw material etc.
All it is commercially available or the industry is conventional.If without specializing, the method that embodiment uses is generally in the art
Technology.
Embodiment 1
The synthetic method of a kind of betamethasone epoxy hydrolysate, comprises the steps:
(1) with betamethasone digest as raw material, betamethasone bromine hydroxyl thing, course of reaction are prepared through bromine hydroxylation reaction
For:
Add 118L dioxane in dry bromine hydroxyl retort, 32kg betamethasone eliminates thing, and logical nitrogen stirs
Mix to molten clearly；Control temperature, between 10～18 DEG C, is slowly added into perchloric acid 4.1L, controls temperature at 10～20 DEG C
Between, add times his 101 (i.e. N-bromo-succinimides) of 18.24kg, in 10 DEG C of insulation reaction after finishing
40 minutes, add 104L methanol, stir 8 minutes；Reactant liquor is drawn in existing sodium sulfite solution (by 7-
7.36kg sodium sulfite is dissolved in the water of 40L) and the interior temperature 5-10 DEG C bromine hydroxyl elutriation tank of 1344L water in elutriation, water
Eutectoid temperature controls (to survey elutriation liquid with starch-kalium iodide reagent paper, the not aobvious blueness of reagent paper) between 5～20 DEG C, and elutriation is complete
(surveying elutriation liquid with starch-kalium iodide reagent paper, the not aobvious blueness of reagent paper) after finishing, in maintaining, temperature 5-20 DEG C, stirs 65 points
Clock, stands more than 2 hours；Centrifugal, wash 3 hours, dry 3 hours, obtain betamethasone bromine hydroxyl thing wet product,
(2) betamethasone bromine hydroxyl thing obtains betamethasone epoxy hydrolysate finished product, course of reaction through epoxy hydrolysis
For:
In bromine hydroxyl washing tank, add 180L dichloromethane, 64L water, put under stirring that step (1) obtains times he
Rice pine bromine hydroxyl thing wet product, in controlling, temperature 25-30 DEG C, stirs 30 minutes, until betamethasone bromine hydroxyl in bromine hydroxyl washing tank
Thing wet product is all dissolved；Stir molten clear after, stand layering in 30 minutes, organic layer puts into feed liquid basin, and by basin
Organic layer nitrogen is pressed in epoxy reaction tank, open loop oxygen retort interlayer set frozen cooling；Water layer 40L,
The dichloromethane of 40L is extracted twice, and after extraction, organic layer is incorporated to feed liquid basin, is pressed into epoxy reaction in the lump with nitrogen
Tank；Add 182L methanol in epoxy reaction tank, wait being cooled to-6～when-2 DEG C, logical nitrogen, control temperature-6～-
Between 2 DEG C, 6.4kg sodium sulfite and 7.2kg sodium hydroxide (are dissolved in 30L by dropping sodium sulfite and sodium hydroxide solution
In water, 11.2L methanol, lower the temperature 25-30 DEG C after dissolving)；Drip and finish, control temperature-5～0 DEG C, react 2.5 hours；Take
Sample HPLC detects, and controls temperature and adds 50% glacial acetic acid solution 32L between-5～5 DEG C, stirs 25 minutes, surveys anti-
Liquid pH value is answered to should be 5-6 (measuring with two kinds of precision test papers of 3.8-5.4 and 5.4-7)；Close nitrogen, epoxy reaction liquid is drawn in
In epoxy concentration tank, normal pressure is concentrated into interior temperature 45-55 DEG C, then when being evaporated to material liquid volume 220L, adds 200L water
Continue to be evaporated to material liquid volume when being 160L, add 400L water elutriation, feed liquid is cooled to 0-5 DEG C, continue to stir
Mix 40 minutes, stand more than 2 hours, centrifugal, to wash 2.5 hours, dry 40 minutes, discharging, in 60-70 DEG C
Dry 12 hours to obtain betamethasone epoxy hydrolysate crude product, HPLC content 96%；Betamethasone epoxy hydrolysate is thick
Product refine, and eliminate in terms of thing by betamethasone, and total recovery is 75%.
The betamethasone epoxy hydrolysate fine work obtained for doing structural confirmation, carried out ultraviolet spectra, infrared spectrum,
Nuclear magnetic resoance spectrum and mass spectral analysis, rationally, chemical constitution confirms as betamethasone epoxy hydrolysate to each collection of illustrative plates ownership.Respectively
Profiling results is as Figure 1-10 shows.
Embodiment 2
The synthetic method of a kind of betamethasone epoxy hydrolysate, comprises the steps:
(1) with betamethasone digest as raw material, betamethasone bromine hydroxyl thing, course of reaction are prepared through bromine hydroxylation reaction
For:
Add 115L dioxane in dry bromine hydroxyl retort, 32kg betamethasone eliminates thing, and logical nitrogen stirs
Mix to molten clearly；Control temperature, between 10～18 DEG C, is slowly added into perchloric acid 4.1L, controls temperature at 10～20 DEG C
Between, add times his 101 (i.e. N-bromo-succinimides) of 18kg, in 20 DEG C of insulation reaction 20 after finishing
Minute, add 100L methanol, stir 5 minutes；Reactant liquor is drawn in existing sodium sulfite solution (by 7-
7.36kg sodium sulfite is dissolved in the water that 40L is) and the interior temperature 5-10 DEG C bromine hydroxyl elutriation tank of 1280L water in elutriation,
Elutriation temperature controls (to survey elutriation liquid with starch-kalium iodide reagent paper, the not aobvious blueness of reagent paper) between 5～20 DEG C, elutriation
After (surveying elutriation liquid with starch-kalium iodide reagent paper, the aobvious blueness of reagent paper), temperature 5-20 DEG C in maintaining, stir 60
Minute, stand more than 2 hours；Centrifugal, wash 2.5 hours, dry 2.5 hours, obtain betamethasone bromine hydroxyl thing
Wet product,
(2) betamethasone bromine hydroxyl thing obtains betamethasone epoxy hydrolysate finished product, course of reaction through epoxy hydrolysis
For:
In bromine hydroxyl washing tank, add 180L dichloromethane, 64L water, put under stirring that step (1) obtains times he
Rice pine bromine hydroxyl thing wet product, in controlling, temperature 25-30 DEG C, stirs 25 minutes, until betamethasone bromine hydroxyl in bromine hydroxyl washing tank
Thing wet product is all dissolved；Stir molten clear after, stand layering in 20 minutes, organic layer puts into feed liquid basin, and by basin
Organic layer nitrogen is pressed in epoxy reaction tank, open loop oxygen retort interlayer set frozen cooling；Water layer 40L,
The dichloromethane of 40L is extracted twice, and after extraction, organic layer is incorporated to feed liquid basin, is pressed into epoxy reaction in the lump with nitrogen
Tank；Add 179L methanol in epoxy reaction tank, wait being cooled to-6～when-2 DEG C, logical nitrogen, control temperature-6～-
Between 2 DEG C, 6.4kg sodium sulfite and 7.2kg sodium hydroxide (are dissolved in 30L by dropping sodium sulfite and sodium hydroxide solution
In water, 10L methanol, lower the temperature 25-30 DEG C after dissolving)；Drip and finish, control temperature-5～0 DEG C, react 2 hours；Sampling
HPLC detects, and controls temperature and adds 50% glacial acetic acid solution 32L between-5～5 DEG C, stirs 20 minutes, measured reaction
Liquid pH value should be 5-6 (measuring with two kinds of precision test papers of 3.8-5.4 and 5.4-7)；Close nitrogen, epoxy reaction liquid is drawn in ring
In oxygen concentration tank, normal pressure is concentrated into interior temperature 45-55 DEG C, then when being evaporated to material liquid volume 200L, adds 200L water and continue
The continuous material liquid volume that is evaporated to when being 150L, adds 400L water elutriation, feed liquid is cooled to 0-5 DEG C, continue stirring
30 minutes, stand more than 2 hours, centrifugal, wash 2 hours, dry 30 minutes, discharging, in 60-70 DEG C of drying
Within 10 hours, obtain betamethasone epoxy hydrolysate crude product, HPLC content 95%；By betamethasone epoxy hydrolysate crude product essence
System, eliminates in terms of thing by betamethasone, and total recovery is 70%.
The betamethasone epoxy hydrolysate fine work obtained for doing structural confirmation, carried out ultraviolet spectra, infrared spectrum,
Nuclear magnetic resoance spectrum and mass spectral analysis, rationally, chemical constitution confirms as betamethasone epoxy hydrolysate to each collection of illustrative plates ownership.Respectively
Profiling results is as Figure 1-10 shows.
Charge ratio explanation in embodiment:
The former technique of comparative example 1
The synthetic method of a kind of betamethasone epoxy hydrolysate, comprises the steps:
57.6-60.8L dimethylformamide, 57.6-60.8L acetone and 32kg is added in dry bromine hydroxyl retort
Betamethasone eliminates thing, logical nitrogen, and stirring is the most molten clearly.Control temperature 10-18 DEG C, be slowly added into 4.1L perchloric acid,
Time is 10-20 minute, finishes, and temperature is adjusted to 10-12 DEG C, add 17.92-18.24kg times he 101, mistake
Journey lucifuge, doubles his 101 process temperatures and controls at 10-20 DEG C, and the time is about 50-60 minute, finishes, in 17-22
DEG C insulation reaction 30-50 minute, sampling HPLC detection.After completion of the reaction bromine hydroxyl reaction material hydraulic pressure is entered esterification
In tank, adding the dilution of 320L acetone, stir 15 minutes, in controlling, temperature 10-18 DEG C, is uniformly added into wet chemical
(96kg potassium carbonate is dissolved in 352-384L water), adds for 15-20 minute, is warming up to 44-48 DEG C, insulation reaction 3-4
Hour, sampling HPLC detection, after reaction terminates, stops stirring, stands overnight.Next day, add glacial acetic acid aqueous solution
(38.4-40L glacial acetic acid is dissolved in 38.4-40L water) is neutralized to pH=6-7, neutralizes complete, stirs 15-30 minute,
Pressurization concentrates, dense go out after major part acetone, rush till the water of 2-2.5V continues to be concentrated into without acetone.It is cooled to 30
Analyse in the 0-10 DEG C of elutriation tank being placed with 40-42V water below DEG C, stir 1 hour, stand more than 2 hours, from
The heart.Put complete, wash by water 1-1.5 hour, dry 30-50 minute, obtain betamethasone epoxy carboxylate wet product.Discharging,
Drying 18-22 hour in 58-62 DEG C, discharging obtains betamethasone epoxy carboxylate.
Open vacuum, hydrolysis tank draw in 4-4.3V methanol, 6-6.5V dichloromethane, put into 1W times he
Meter Song Huan oxygen carboxylate, agitating solution, logical nitrogen, open frozen cooling, configure sodium hydrate methanol solution (0.2W
Sodium hydroxide adds in 3-3.3V methanol, stirring and dissolving), molten clear cooling, treat that sodium hydrate methanol solution temperature is down to
0-10 DEG C, sodium hydrate methanol solution is pulled to alkali liquid high-level groove standby.When hydrolysis liquid temp drops to-13 to-10
DEG C, starting to drip sodium hydrate methanol solution, uniformly drip, the time controls, at 55-60 minute, to drip complete, protects
Temperature reaction 10-15 minute, sampling HPLC detection.React complete after, add 50% acetum (by 1.15-
1.2V glacial acetic acid is in 1.15-1.2V water), stir 15-30 minute, measured reaction liquid pH value should be 5-7.Water
Solving reactant liquor and draw in hydrolysis concentration tank, normal pressure is concentrated into interior temperature 40-55 DEG C, and concentrated solvent amount is about 6V dichloromethane
Alkane.Concentrating under reduced pressure goes out methanol about 4-5V again, and the continuation pressurization that adds water concentrates, and add water 3 times (1.5V/ time), until
Dense to without methanol.Dense complete, add the water elutriation of 26-27V.Open freezing valve, elutriation liquid is cooled to 0-10
DEG C, stop stirring, stand and be centrifuged for more than 2 hours.Put complete, wash by water 1-1.5 hour, dry 1-1.5 hour, obtain again
Ta meter Song epoxy hydrolysate wet product.Drying 14-20 hour in 60-70 DEG C, it is thick that discharging obtains betamethasone epoxy hydrolysate
Product.
In epoxy making beating tank, put into 1W betamethasone epoxy hydrolysate, the acetone of 0.8-1.2V, open stirring, water-bath
Feed liquid is heated to 30-35 DEG C, stirring, it is incubated 2 hours, insulation terminates, and is cooled to 0-5 DEG C, discharging.From
The heart, with the cold acetone drip washing of 0.2-0.3V, then dries discharging in 30 minutes, obtains betamethasone epoxy hydrolysate wet product,
Drying 12-18 hour in 58-68 DEG C, discharging obtains betamethasone epoxy hydrolysate fine work.Yield about 65%.
Charge ratio explanation in comparative example:
(1) bromine hydroxyl, epoxy reaction
| Material name | Specification | Proportioning | Inventory |
| Betamethasone eliminates thing | Intermediate | 1W | 32kg |
| Dimethylformamide | Industry | 1.8-1.9V | 57.6-60.8L |
| Acetone | Industry | 1.8-1.9V | 57.6-60.8L |
| Perchloric acid | Analytical pure | 0.128V | 4.1L |
| Times he 101 | Industry | 0.56-0.57W | 18.0-18.24kg |
| Acetone | Industry | 10V | 320L |
| Potassium carbonate | Industry | 3W | 96kg |
| Water | Drinking water | 11-12V | 352-384L |
| Glacial acetic acid | Industry | 1.2-1.25V | 38.4-40L |
| Water | Drinking water | 1.2-1.25V | 38.4-40L |
| Water | Drinking water | 40-42V | 1280-1344L |
(2) hydrolysis
| Material name | Specification | Proportioning | Inventory | Remarks |
| Times his epoxy-ester compound | Intermediate | 1W | - | |
| Dichloromethane | Industry | 6.0-6.5V | - | |
| Methanol | Industry | 4.0-4.3V | - | |
| Sodium hydroxide | Analytical pure | 0.2W | - | |
| Methanol | Industry | 3.0-3.3V | - | Join sodium hydroxide solution |
| Glacial acetic acid | Industry | 1.15-1.2V | - | |
| Water | Drinking water | 1.15-1.2V | - | Join glacial acetic acid solution |
| Water | Drinking water | 26-27V | - |
(3) refined
| Material name | Specification | Proportioning | Inventory |
| Times his epoxy crude product | - | 1W | - |
| Acetone | Industry | 0.8-1.2V | - |
| Acetone | Industry | 0.2-0.3V | - |
Claims (7)
1. the synthetic method of a betamethasone epoxy hydrolysate, it is characterised in that comprise the steps:
(1) with betamethasone elimination thing as raw material, preparing betamethasone bromine hydroxyl thing through bromine hydroxylation reaction, course of reaction is:
Add 3.6-3.7L dioxane in dry bromine hydroxyl retort, 1kg betamethasone eliminates thing, logical nitrogen, and stirring is the most molten clearly；Control temperature between 10～18 DEG C, be slowly added into perchloric acid 0.128 L, control temperature between 10～20 DEG C, add 0.56-0.57kg times he 101, in 20～30 DEG C of insulation reaction 20-40 minute after finishing；Reactant liquor is drawn in elutriation in the interior temperature 5-10 DEG C bromine hydroxyl elutriation tank of existing sodium sulfite solution and 40-42L water, and elutriation temperature controls between 5～20 DEG C, and after elutriation, in maintaining, temperature 5-20 DEG C, stirs 60-65 minute, stand more than 2 hours；Centrifugal, washing, dry, obtain betamethasone bromine hydroxyl thing wet product,
Described sodium sulfite solution is to be dissolved in the water of 1.25L formulated by 0.22-0.23kg sodium sulfite,
(2) betamethasone bromine hydroxyl thing obtains betamethasone epoxy hydrolysate finished product through epoxy hydrolysis, and course of reaction is:
Adding 5.6L dichloromethane, 2L water in bromine hydroxyl washing tank, put into the betamethasone bromine hydroxyl thing wet product that step (1) obtains under stirring, in controlling, temperature 25-30 DEG C, stirs 25-30 minute, until betamethasone bromine hydroxyl thing wet product is all dissolved in bromine hydroxyl washing tank；Stir molten clear after, stands layering in 20-30 minute, organic layer puts into feed liquid basin, and by during in basin, organic layer nitrogen is pressed into epoxy reaction tank, open loop oxygen retort interlayer overlaps frozen cooling；Water layer dichloromethane extracted several times, after extraction, organic layer is incorporated to feed liquid basin, is pressed into epoxy reaction tank in the lump with nitrogen；Add 5.6-5.7L methanol in epoxy reaction tank, wait being cooled to-6～when-2 DEG C, logical nitrogen, control temperature between-6～-2 DEG C, dropping sodium sulfite and sodium hydroxide solution；Drip and finish, control temperature-5～0 DEG C, react 2-2.5 hour；Sampling HPLC detection, controls temperature and adds 50% glacial acetic acid solution 1L between-5～5 DEG C, stir 20-25 minute, and measured reaction liquid pH value should be 5-6；Closing nitrogen, epoxy reaction liquid is drawn in epoxy concentration tank, normal pressure is concentrated into interior temperature 45-55 DEG C, when being evaporated to material liquid volume 6.25-6.875L again, add 6.25L water and continue to be evaporated to material liquid volume when being 4.69-5L, add 12.5L water elutriation, feed liquid is cooled to 0-5 DEG C, continues stirring 30-40 minute, stand more than 2 hours, centrifugal, washing, dries, discharging, dry to obtain betamethasone epoxy hydrolysate crude product
Described sodium sulfite and sodium hydroxide solution are to be dissolved in 0.94L water and 0.31-0.32L methanol formulated by sodium sulfite and the 0.225kg sodium hydroxide of 0.02kg, lower the temperature 25-30 DEG C after dissolving, standby,
Described times he 101 refer to N-bromo-succinimide,
General chemical structure formula has:
、、。
The synthetic method of a kind of betamethasone epoxy hydrolysate the most according to claim 1, it is characterised in that in described step (1): survey elutriation liquid with starch-kalium iodide reagent paper during elutriation, the not aobvious blueness of reagent paper.
The synthetic method of a kind of betamethasone epoxy hydrolysate the most according to claim 1, it is characterised in that in described step (1): washing, dries and refers to washing 2.5-3 hour, dry 2.5-3 hour.
The synthetic method of a kind of betamethasone epoxy hydrolysate the most according to claim 1, it is characterised in that in described step (2): water layer dichloromethane extracted several times refers to the dichloromethane extraction of water layer 1.25L, is repeated twice.
The synthetic method of a kind of betamethasone epoxy hydrolysate the most according to claim 1, it is characterised in that in described step (2): measured reaction liquid pH value should be 5-6, measures with two kinds of precision test papers of 3.8-5.4 and 5.4-7.
The synthetic method of a kind of betamethasone epoxy hydrolysate the most according to claim 1, it is characterised in that in described step (2): washing, dries and refers to washing 2-2.5 hour, dry 30-40 minute.
The synthetic method of a kind of betamethasone epoxy hydrolysate the most according to claim 1, it is characterised in that in described step (2): dry betamethasone epoxy hydrolysate crude product refer in 60-70 DEG C dry 10-12 hour betamethasone epoxy hydrolysate crude product.
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