CN103183714A - Synthetic method for loteprednol - Google Patents
Synthetic method for loteprednol Download PDFInfo
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- CN103183714A CN103183714A CN2011104504507A CN201110450450A CN103183714A CN 103183714 A CN103183714 A CN 103183714A CN 2011104504507 A CN2011104504507 A CN 2011104504507A CN 201110450450 A CN201110450450 A CN 201110450450A CN 103183714 A CN103183714 A CN 103183714A
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- Prior art keywords
- loteprednol
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- acid
- synthetic method
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- 229960001798 loteprednol Drugs 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title claims abstract description 10
- YPZVAYHNBBHPTO-MXRBDKCISA-N loteprednol Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)OCCl)[C@@H]4[C@@H]3CCC2=C1 YPZVAYHNBBHPTO-MXRBDKCISA-N 0.000 title abstract 3
- PJBIHXWYDMFGCV-UHFFFAOYSA-N chloro(chlorosulfonyloxy)methane Chemical compound ClCOS(Cl)(=O)=O PJBIHXWYDMFGCV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- XQCKXOKBWVXUJH-UHFFFAOYSA-N CCOC([O])=O Chemical compound CCOC([O])=O XQCKXOKBWVXUJH-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- MCKJPJYRCPANCC-XLXYOEISSA-N (8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-17-carboxylic acid Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(O)=O)[C@@H]4[C@@H]3CCC2=C1 MCKJPJYRCPANCC-XLXYOEISSA-N 0.000 claims 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 238000007265 chloromethylation reaction Methods 0.000 abstract description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 abstract 2
- 238000000034 method Methods 0.000 abstract 2
- 229960004424 carbon dioxide Drugs 0.000 abstract 1
- 235000011089 carbon dioxide Nutrition 0.000 abstract 1
- -1 carboxylate carbonic anhydride Chemical class 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- DMKSVUSAATWOCU-HROMYWEYSA-N loteprednol etabonate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)OCCl)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O DMKSVUSAATWOCU-HROMYWEYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 1
- 206010015943 Eye inflammation Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960003744 loteprednol etabonate Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
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- Steroid Compounds (AREA)
Abstract
The invention method discloses a synthetic method for loteprednol. The loteprednol is prepared by esterification through chloromethylation with chloromethyl chlorosulfate under the action of a phase transfer catalyst tetrabutylammonium hydrogen sulfate after hydrolysis of 17[alpha]-(ethoxycarbonyl)oxy-11[beta]-hydroxyl-3-oxo androstene-1,4-diene-17[beta]-ethyl carboxylate carbonic anhydride. The process is convenient for operations and has high yield reaching over 80%.
Description
Technical field
The present invention relates to a kind of synthetic method of loteprednol, belong to technical field of medicine synthesis.
Background technology
Loteprednol according to Bodor principle research and design, has solved the toxicity problem of cortex alcohols medicine as " soft medicine ", and the strong characteristics of anti-inflammatory have obtained further reinforcement simultaneously.Different with prednisolone, loteprednol easily is hydrolyzed to the organic acid of non-activity, and after being used for eyes, metabolism is the product of non-activity rapidly, reduced system toxicity, and anti-inflammatory action is stronger than prednisolone.Loteprednol is the medicine of eye inflammation after first is specially adapted to perform the operation.At first the side effect of the intraocular pressure of this medicine rising is less, safe; Secondly find in clinical application that this product has promoter action to wound healing, the scar that uses this product operation back to form is the lightest.This medicine of market is widely used for the postoperative anti-inflammatory of cataract patient abroad.According to investigation, will be above 17,000,000,000 dollars to global ophthalmic remedy in 2015, visible this product prospect is quite optimistic.
In Chen Aijun " synthesis of loteprednol etabonate improvement ", be with 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1,4-diene-17 β-carboxylic acid ethyl carbonate acid anhydride optional water is freed the ethoxycarbonyl salify, changes into ester with the chloroiodomethane chloromethyl again and gets, and total recovery is 56.4%.
Summary of the invention
The object of the present invention is to provide a kind of simple to operation, yield is high, is suitable for the synthetic method of the loteprednol of large-scale industrial production.
The present invention is with 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1,4-diene-17 β-carboxylic acid ethyl carbonate acid anhydride optional water is freed ethoxycarbonyl and is got 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1,4-diene-17 β-carboxylic acid, make with chlorsulfonic acid chloromethyl ester chloromethylation under the effect of phase-transfer catalyst 4-butyl ammonium hydrogen sulfate more afterwards, total recovery can reach more than 80%.
Technical scheme of the present invention is:
1.(1) with 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1,4-diene-17 β-carboxylic acid ethyl carbonate acid anhydride is added to the water, stirred 30 minutes;
(2) dripping alkali liquid in the above-mentioned solution is until solution clarification, room temperature reaction 2 hours;
(3) drip acid after reaction finishes in solution, adjust pH 2～4 stirred 30 minutes, made the pH value constant;
(4) suction filtration is washed to pH5～7, namely gets 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1 after the drying, 4-diene-17 β-carboxylic acid.
2. (1) with 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1, and 4-diene-17 β-carboxylic acid joins in the IodineSodium Solution that contains 10%～15% saleratus or sodium bicarbonate and 3%～4%, stirring and dissolving;
(2) add methylene dichloride and phase-transfer catalyst 4-butyl ammonium hydrogen sulfate, room temperature drips the dichloromethane solution of chlorsulfonic acid chloromethyl ester, drips off reaction 2～3 hours;
(3) organic phase washing, evaporate to dryness after the siccative drying;
(4) add dehydrated alcohol, after the heating for dissolving, cooling crystallization, suction filtration gets loteprednol after the drying.
Embodiment:
Embodiment 1: add 200ml water in the 1000ml three-necked bottle, whipped state adds 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1,4-diene-17 β-carboxylic acid ethyl carbonate acid anhydride 49.1g, stirred 30 minutes, room temperature drips triethylamine and clarifies until solution, room temperature reaction is dripping hydrochloric acid adjust pH to 3 after 2 hours, it is constant to stir 30 minutes repetition measurement pH values, suction filtration, be washed to pH value 6, namely get 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1 after the drying, 4-diene-17 β-carboxylic acid 37.8g.Yield is 90.2%.
Embodiment 2: add the solution 300ml that contains 12% saleratus and 3% sodium iodide in the 1000ml three-necked bottle, add 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1 under the whipped state, 4-diene-17 β-carboxylic acid 30.0g, add methylene dichloride 200ml and 4-butyl ammonium hydrogen sulfate 1.5g after the stirring and dissolving again, room temperature drips the dichloromethane solution that 70ml contains chlorsulfonic acid chloromethyl ester 14.3g, drip off reaction 3 hours, dichloromethane layer with the 300ml washing once, added anhydrous sodium sulfate drying 1 hour, suction filtration, the evaporate to dryness methylene dichloride adds the dehydrated alcohol recrystallization, suction filtration namely gets this product 31.8g after the drying.Yield is 95.0%.
Claims (5)
1. the synthetic method of a loteprednol may further comprise the steps:
I .(1) with 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1,4-diene-17 β-carboxylic acid ethyl carbonate acid anhydride is added to the water, and stirs 30 minutes;
(2) in above-mentioned solution, drip triethylamine, until solution clarification, room temperature reaction 2 hours;
(3) drip acid after reaction finishes in solution, adjust pH 2～4 stirred 30 minutes, made the pH value constant;
(4) suction filtration is washed to pH5～7, namely gets 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1 after the drying, 4-diene-17 β-carboxylic acid;
II. (1) with 17 α-ethoxycarbonyl-oxygen base-11 beta-hydroxy-3-oxy-androstane-1,4-diene-17 β-carboxylic acid joins and contains in weak base and the IodineSodium Solution stirring and dissolving;
(2) add methylene dichloride and phase-transfer catalyst 4-butyl ammonium hydrogen sulfate, room temperature drips the dichloromethane solution of chlorsulfonic acid chloromethyl ester, drips off reaction 2～3 hours;
(3) organic phase washing, evaporate to dryness after the siccative drying;
(4) add dehydrated alcohol, after the heating for dissolving, cooling crystallization, suction filtration gets loteprednol after the drying.
2. according to the synthetic method of claim 1 loteprednol, it is characterized in that: the acid described in the I (3) refers to hydrochloric acid, sulfuric acid or phosphoric acid.
3. according to the synthetic method of claim 1 loteprednol, it is characterized in that: the weak base described in the II (1) and IodineSodium Solution refer to 10%～15% saleratus or sodium bicarbonate and IodineSodium Solution.
4. according to the synthetic method of claim 1 loteprednol, it is characterized in that: the weak base described in the II (1) and IodineSodium Solution refer to contain 3%～4% IodineSodium Solution.
5. according to the synthetic method of claim 1 loteprednol, it is characterized in that: the siccative described in the II (3) refers to anhydrous magnesium sulfate, anhydrous sodium sulphate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104504507A CN103183714A (en) | 2011-12-29 | 2011-12-29 | Synthetic method for loteprednol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104504507A CN103183714A (en) | 2011-12-29 | 2011-12-29 | Synthetic method for loteprednol |
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| Publication Number | Publication Date |
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| CN103183714A true CN103183714A (en) | 2013-07-03 |
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| CN2011104504507A Pending CN103183714A (en) | 2011-12-29 | 2011-12-29 | Synthetic method for loteprednol |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279325A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106279324A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and crystal formation thereof and preparation method |
| CN106892952A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106892953A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and its crystal formation and preparation method |
| CN108659083A (en) * | 2017-03-31 | 2018-10-16 | 天津药业研究院有限公司 | A kind of synthetic method of Loteprednol etabonate |
| CN108659084A (en) * | 2017-03-31 | 2018-10-16 | 天津药业研究院有限公司 | A kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds |
| CN110041391A (en) * | 2019-04-01 | 2019-07-23 | 江苏远大仙乐药业有限公司 | A kind of synthetic method of Limethason |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2079755A (en) * | 1980-07-10 | 1982-01-27 | Otsuka Pharma Co Ltd | Androstene 17 alpha -carbonate 17 beta -carboxylates (and carbothioates) |
-
2011
- 2011-12-29 CN CN2011104504507A patent/CN103183714A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2079755A (en) * | 1980-07-10 | 1982-01-27 | Otsuka Pharma Co Ltd | Androstene 17 alpha -carbonate 17 beta -carboxylates (and carbothioates) |
Non-Patent Citations (2)
| Title |
|---|
| P.DRUZGALA ETAL: "Drugs-10.Blanching Activity and Receptor Binding Affinity of A New Type of Glucocorticoid:Loteprednol Etabonate", 《J.STEROID BIOCHEM.MOLEC.BIOL.》, vol. 38, no. 2, 31 December 1991 (1991-12-31) * |
| 陈爱军等: "氯替泼诺的合成工艺改进", 《中国药物化学杂志》, vol. 13, no. 5, 20 October 2003 (2003-10-20), pages 299 - 300 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279325A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106279324A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and crystal formation thereof and preparation method |
| CN106892952A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106892953A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and its crystal formation and preparation method |
| CN108659083A (en) * | 2017-03-31 | 2018-10-16 | 天津药业研究院有限公司 | A kind of synthetic method of Loteprednol etabonate |
| CN108659084A (en) * | 2017-03-31 | 2018-10-16 | 天津药业研究院有限公司 | A kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds |
| CN110041391A (en) * | 2019-04-01 | 2019-07-23 | 江苏远大仙乐药业有限公司 | A kind of synthetic method of Limethason |
| CN110041391B (en) * | 2019-04-01 | 2021-12-07 | 江苏远大仙乐药业有限公司 | Synthetic method of dexamethasone palmitate |
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Application publication date: 20130703 |