CN105777852A - Deflazacort synthetic method - Google Patents
Deflazacort synthetic method Download PDFInfo
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- CN105777852A CN105777852A CN201410799032.2A CN201410799032A CN105777852A CN 105777852 A CN105777852 A CN 105777852A CN 201410799032 A CN201410799032 A CN 201410799032A CN 105777852 A CN105777852 A CN 105777852A
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- deflazacort
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a deflazacort synthetic method, and deflazacort can be synthesized from epoxy progesterone as a starting material by dehydrogenation, oxidation, protection, ammonolysis for ring opening, ring closing, reduction, hydrolysis deprotection, loading of iodine and displacement reaction. A process route is simplified, production control points are optimized, the method is energy-saving and consumption-reducing, production efficiency is greatly improved, and the product overall yield can reach more than 68%. Production cost is saved, product market competition power is strong, and the method has great economic benefits and social benefits.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, more particularly to the synthetic method of a kind of deflazacort.
Background technology
Deflazacort, general medicine name: DEFLAZACORT, another name: Azacort, Lantadin, Deflan, Calcort, Oxazacort, DL-485-IT, L-5458, chemical structural formula: molecular formula: C25H31NO6, molecular weight: 441.52.1985, Italy's Initial Public Offering.Aeroseb-Dex, has the effect such as antiinflammatory, antiallergic increase gluconeogenesis for third generation glucocorticoid.It functions as 10 ~ 20 times of prednisolone, 40 times of hydrocortisone.For treating former and secondary hypocortisolism, rheumatism collagenosis, dermatosis, allergic disease, ophthalmic diseases, fulminant and disseminata phthisis, hemopoietic system illness, ulcerative colitis, idiopathic nephrotic syndrome, the disease such as Hematopoietic Malignancies.
The existing synthesis route of deflazacort is shown in Fig. 1:
This technique walks biofermentation through the first, the second liang, then again through 11 hydroxyl oxidizes, and 21 carbonyl-protections, then epoxy addition again, then closed loop, carbonyl reduction, then through deprotection, obtain target product, total synthetic route totally 10 step finally by upper iodization.Process line is tediously long, and middle separation process is loaded down with trivial details, and the production cycle is longer, and production efficiency is comparatively low, and three waste discharge is also more, and total recovery is only about 40%.
Summary of the invention
It is desirable to provide the deflazacort synthetic method that a kind of synthetic route is simple, production efficiency improves, production cost is saved.
For achieving the above object, one deflazacort synthetic method of the present invention, its specific embodiments is:
The synthetic method of a kind of deflazacort of the present invention; it is characterized in that; with epoxy Progesterone for initiation material, through dehydrogenation, oxidation, upper protection, aminolysis open loop, closed loop, ring is former, be hydrolyzed deprotection, upper iodine, displacement reaction synthesize deflazacort, and synthetic route of the present invention is shown in Fig. 2.
The synthetic method of a kind of deflazacort of the present invention, it is characterised in that in deflazacort preparation process midbody compound ground Na Chakete methyl hydrazinocarboxylate (compound 5) with ground Na Chakete (compound 6) synthesis.
It is characterized in that, the reaction temperature of ground Na Chakete methyl hydrazinocarboxylate aminolysis ring-opening reaction is 32-35 DEG C, and the insulation reaction time is 24 hours.
The synthetic method of a kind of deflazacort of the present invention, it is characterised in that preparation ground Na Chakete methyl hydrazinocarboxylate post processing regulated value PH=6-7.
The synthetic method of a kind of deflazacort of the present invention, it is characterized in that in the process of preparation ground Na Chakete methyl hydrazinocarboxylate, after adding acetic anhydride, temperature control 30-35 DEG C, the insulation reaction time is 4-5 hour, after dropping sodium carbonate liquor, in closed loop procedure, temperature control is to 50-60 DEG C, and the insulation reaction time is 2-3 hour.
The synthetic method of a kind of deflazacort of the present invention, it is characterised in that in ground Na Chakete preparation process, after adding potassium boron hydrogen, reduction reaction controls temperature at 0 ± 1 DEG C, 5 hours insulation reaction time.
The synthetic method of a kind of deflazacort of the present invention, it is characterised in that in ground Na Chakete preparation process, after reduction reaction, reaction system regulates pH=6-7.
The synthetic method of a kind of deflazacort of the present invention, it is characterised in that in ground Na Chakete preparation process, after adding formaldehyde, deprotection reaction control
Temperature 30-40 DEG C, the insulation reaction time is 8-10 hour.
The synthetic method of a kind of deflazacort of the present invention, it is characterised in that the solvent that synthetic route is used is one or more in absolute methanol, magnesium chloride hexahydrate, sodium borohydride, glacial acetic acid, water, hydrochloric acid, formaldehyde, sodium hydroxide, chloroform, methanol, ethyl acetate.
The synthetic method of a kind of deflazacort of the present invention, it is characterised in that absolute methanol moisture content≤0.5%, concentration of hydrochloric acid 20-30%, sodium hydroxide 3W water dissolution.
The synthetic method of a kind of deflazacort of the present invention, deflazacort prepared by this technique is mainly used in treatment former and secondary hypocortisolism, rheumatism collagenosis, dermatosis, allergic disease, ophthalmic diseases, fulminant and disseminata phthisis, hemopoietic system illness, ulcerative colitis, idiopathic nephrotic syndrome, Hematopoietic Malignancies.
The method have the benefit that
Synthetic route of the present invention is on the basis of former conventional processing routes; single step reaction discharging is merged in two step biofermentation adjustment; open loop and closed loop are adjusted to single step reaction discharging; carbonyl reduction and deprotection are adjusted to single step reaction discharging; original 10 step reactions are made to become 7 steps reaction dischargings through optimizing production control point; so that reaction circuit simplifies, shorten the production cycle, thus improve production efficiency.In addition initiation material of the present invention is easy to get, and solvent is conventional solvent, and process energy consumption is low, greatly reduces production cost, improves product market competitive power.Total yield of products can reach more than 68%.Great market development economic benefit and social benefit.
Accompanying drawing illustrates:
Fig. 1: existing synthesis route figure；
Fig. 2: synthesis route figure of the present invention.
Detailed description of the invention
Example below, only for further illustrating the present invention, does not limit the present invention in any form.
Embodiment 1:
Synthetic route of the present invention is shown in Fig. 2.
The present invention, with epoxy Progesterone (compound 1) for initiation material, protects to obtain compound 4 on dehydrogenation, oxidation, carbonyl, and compound 4 is former through aminolysis open loop, closed loop, ring, hydrolysis deprotection, upper iodine, displacement reaction synthesis deflazacort.
Embodiment 2:
The preparation of deflazacort intermediate ground Na Chakete methyl hydrazinocarboxylate (compound 5):
1. DMF200ml puts into clean reaction bulb, and stirring is lower adds 100g compound 4, temperature of charge 30-35 DEG C, the incomplete molten state of material.
2. close other valve, open ammonia valve, insulation reaction 24 hours at temperature control 32-35 DEG C, after feed liquid is dissolved substantially, close ammonia valve, sampling is TLC until reacting completely, and as reaction is incomplete, extends the response time.
3. reaction is finished, and slightly lowers the temperature, and is slowly added into about 150ml glacial acetic acid, temperature control about 30 DEG C, regulates reactant liquor pH=5-6.
4. in feed liquid, add 150ml acetic anhydride, temperature control 30-35 DEG C insulation reaction 4-5 hour, if reaction is not exclusively, then add a small amount of acetic anhydride to reacting completely.
5. reaction is finished, drip 10% sodium carbonate liquor 4000ml, (rate of addition need to be controlled in case slug), dropping is finished, and feed liquid is warming up to 50-60 DEG C, insulated and stirred 2-3 hour, then being cooled to room temperature, sucking filtration, filter cake 500ml washing dries, discharging, in about 80 DEG C drying, obtains ground Na Chakete methyl hydrazinocarboxylate weight 220.3g.HPLC98.8%.
Embodiment 2
The preparation of deflazacort intermediate ground Na Chakete (compound 6):
1. 500ml absolute methanol puts into clean reaction bulb, and stirring is lower adds 100g compound 5 to entirely molten.
2. being slowly uniformly added into potassium boron hydrogen 10g under stirring, control temperature at 0 ± 1 DEG C, insulation reaction 5 hours, TLC detects to reacting completely.
3. reaction is complete, is slowly added into a small amount of acetic acid, temperature control less than 10 DEG C, regulates PH=6-7, and heating in water bath concentration methanol, add water 500ml in reactor, and reactant liquor is dropped to room temperature.
4. slowly dropping 30%100ml hydrochloric acid, material temperature is less than 50 DEG C, after material is entirely molten.Adding formaldehyde 100ml, temperature control 30-40 DEG C insulation reaction 8-10 hour in feed liquid, TLC detection reaction is to reacting completely.
5. cooling, slowly drips about 50ml, liquid caustic soda, adjusts reactant liquor PH=6-7. in dropping process in reactant liquor
6. reaction bulb system adds 500ml dichloromethane extraction, separates organic layer, water layer 200ml × 2 dichloromethane extraction twice, merge organic layer.
7. water-bath negative pressure concentration of organic layers, to dry, adds 100ml ethyl acetate, repeats above operation.The freezing crystallize of stirring, filters, washes cake, and discharging, in about 80 DEG C drying, obtains compound deflazacort weight 82.6g.HPLC98.5%.
Claims (10)
1. the synthetic method of a deflazacort; the method is with epoxy Progesterone for initiation material; protection on dehydrogenation, oxidation, carbonyl, aminolysis open loop, closed loop, ring are former, hydrolysis deprotection, upper iodine, displacement reaction synthesis deflazacort, it is characterised in that the synthesis of ground Na Chakete methyl hydrazinocarboxylate and ground Na Chakete.
2. the synthetic method of a kind of deflazacort according to claim 1, it is characterised in that in ground Na Chakete methyl hydrazinocarboxylate preparation process, the reaction temperature of aminolysis ring-opening reaction is 32-35 DEG C, and the insulation reaction time is 24 hours.
3. the synthetic method of a kind of deflazacort according to claim 1, it is characterised in that in ground Na Chakete methyl hydrazinocarboxylate preparation process, regulates pH=6-7 after aminolysis.
4. the synthetic method of a kind of deflazacort according to claim 1, it is characterized in that, in process prepared by ground Na Chakete methyl hydrazinocarboxylate, temperature control 30-35 DEG C after addition acetic anhydride, the insulation reaction time is 4-5 hour, after dropping sodium carbonate liquor, in closed loop procedure, temperature control is to 50-60 DEG C, and the insulation reaction time is 2-3 hour.
5. the synthetic method of a kind of deflazacort according to claim 1, it is characterised in that in ground Na Chakete preparation process, after adding potassium boron hydrogen, reduction reaction controls temperature at 0 ± 1 DEG C, 5 hours insulation reaction time.
6. the synthetic method of a kind of deflazacort according to claim 1, it is characterised in that in ground Na Chakete preparation process, after reduction reaction, reaction system regulates pH=6-7.
7. the synthetic method of a kind of deflazacort according to claim 1, it is characterised in that in ground Na Chakete preparation process, adds deprotection reaction temperature control 30-40 DEG C after formaldehyde, and the insulation reaction time is 8-10 hour.
8. the synthetic method of a kind of deflazacort according to claim 1, it is characterised in that the solvent that synthetic route is used is one or more in absolute methanol, magnesium chloride hexahydrate, sodium borohydride, glacial acetic acid, water, hydrochloric acid, formaldehyde, sodium hydroxide, chloroform, methanol, ethyl acetate.
9. the synthetic method of a kind of deflazacort according to claim 8, it is characterised in that absolute methanol moisture content≤0.5%, concentration of hydrochloric acid 20-30%, sodium hydroxide 3W water dissolution.
10. the synthetic method of a kind of deflazacort according to claim 1-9, deflazacort prepared by this technique is mainly used in treatment former and secondary hypocortisolism, rheumatism collagenosis, dermatosis, allergic disease, ophthalmic diseases, fulminant and disseminata phthisis, hemopoietic system illness, ulcerative colitis, idiopathic nephrotic syndrome, Hematopoietic Malignancies.
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| CN201410799032.2A CN105777852A (en) | 2014-12-22 | 2014-12-22 | Deflazacort synthetic method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107459549A (en) * | 2017-08-24 | 2017-12-12 | 岳阳环宇药业有限公司 | A kind of deflazacort fast reaction technique and production system |
| CN115850360A (en) * | 2022-12-16 | 2023-03-28 | 湖南新合新生物医药有限公司 | Preparation method of deflazacort intermediate |
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2014
- 2014-12-22 CN CN201410799032.2A patent/CN105777852A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107459549A (en) * | 2017-08-24 | 2017-12-12 | 岳阳环宇药业有限公司 | A kind of deflazacort fast reaction technique and production system |
| CN107459549B (en) * | 2017-08-24 | 2018-08-21 | 岳阳环宇药业有限公司 | A kind of deflazacort fast reaction technique and production system |
| CN115850360A (en) * | 2022-12-16 | 2023-03-28 | 湖南新合新生物医药有限公司 | Preparation method of deflazacort intermediate |
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