CN105481933B - A kind of method for synthesizing momestasone furoate - Google Patents
A kind of method for synthesizing momestasone furoate Download PDFInfo
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- CN105481933B CN105481933B CN201510996544.2A CN201510996544A CN105481933B CN 105481933 B CN105481933 B CN 105481933B CN 201510996544 A CN201510996544 A CN 201510996544A CN 105481933 B CN105481933 B CN 105481933B
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- momestasone furoate
- dichloromethane
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- hydrochloric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention belongs to the synthetic method of medicine, and in particular to a kind of method of synthesis momestasone furoate is to carry out chloro while carrying out esterification with furoyl chloride using compound 1 to obtain compound 2, and open loop generates momestasone furoate to compound 2 in presence of hydrochloric acid.It is long that the present invention efficiently solves former process route, and reaction system is complicated, and time-consuming waits not enough.Present invention process is simple, and reaction condition is gentle, and high income, cost is low, and quality is high, and supplementary material is cheap and easy to get, is adapted to industrialized production.
Description
Technical field
The invention belongs to the synthetic method of medicine, and in particular to a kind of method of synthesis momestasone furoate.
Background technology
Momestasone furoate is the glucocorticoid typically synthesized, is led to anti-inflammatory, antiallergy, vasoconstriction, reduction blood vessel
Permeability, suppress cell division and the effect such as antipruritic, its feature shows action intensity increase and side effect disproportionately increases,
And be used only once daily.The momestasone furoate skin disease effective to corticosteroid therapy, such as neurodermatitis, eczema, dystopy
Scytitis and pruitus have good therapeutic effect caused by property dermatitis, seborrhea and psoriasis etc..Current furancarboxylic acid
There is the shortcomings of process is complicated, time-consuming in Mometasone production technology.
The content of the invention
The problems existed for existing momestasone furoate synthetic method, furancarboxylic acid not rice is synthesized the invention provides one kind
The method of pine.
The present invention uses following technical scheme：A kind of method for synthesizing momestasone furoate, is entered using compound 1 and furoyl chloride
Chloro is carried out while row esterification and obtains compound 2, reaction equation is as follows：
；
Step is：Dichloromethane, compound 1, organic base are added into reactor, furoyl chloride is added dropwise in cooling, and heating is stirred
Reaction to TLC monitoring reactions are mixed to complete（Dichloromethane solution using compound 1 is as comparison liquid, and it is for trying to take a small amount of reaction solution
Liquid, point sample uses volume ratio dichloromethane in GF254 silica gel plates：Methanol=20：Examined under 1 mixed solvent expansion, 254nm uviol lamps
Depending on test liquid does not contain the spot of comparison liquid, is completed for reaction）；Acid solution is added dropwise, regulation reaction solution is associated with acidity, extraction
Machine phase, organic phase contains compound 2.
Specifically step is as follows：
Chloro is carried out while carrying out esterification using compound 1 and furoyl chloride and obtains compound 2, and compound 2 is in salt
Open loop generates compound 3 in the presence of acid（Momestasone furoate）.It is as follows that it specifically prepares reaction equation：
Above-mentioned G=alkane（CnH2n+1）Sulfonyl or aromatic hydrocarbons（Ar）Sulfonyl, in the sulfonyl of alkane, preferred methylsulfonyl
Base；Preferred p-toluenesulfonyl in the sulfonyl of aromatic hydrocarbons.The preferred p-toluenesulfonyls of wherein G.
It is comprised the following steps that：（1）Dichloromethane, compound 1, organic base are added into reactor.Be cooled to 5 DEG C with
Under, furoyl chloride is added dropwise, is warming up to 25~30 DEG C and stirs 6 hours, TLC detection reactions are completed（With the dichloromethane solution of compound 1
As comparison liquid, it is test liquid to take a small amount of reaction solution, and point sample is in GF254 silica gel plates, with volume ratio Er Lv Jia Wan ︰ methanol=20：1
Mixed solvent expansion, inspect under 254nm uviol lamps, test liquid does not contain the spot of comparison liquid, completed for reaction）；And then will
It is incubated at 10~20 DEG C and 1N hydrochloric acid is added dropwise, and adjusts pH to 1~2, and extraction merges organic phase, and organic phase contains compound 2,
Directly carry out next step reaction.
（2）Glacial acetic acid is added into above-mentioned organic phase, less than 5 DEG C are cooled to, concentration is added dropwise and is stirred for 37% concentrated hydrochloric acid
3h, and then 20~25 DEG C of stir about 5h, TLC detection reaction completions are warming up to (using the dichloromethane solution of compound 2 as control
Liquid, takes and takes lower organic layer to be test liquid after a small amount of reaction solution, standing, and point sample uses volume ratio dichloromethane in GF254 silica gel plates
Alkane：Methanol=20：Inspected under 1 mixed solvent expansion, 254nm uviol lamps, test liquid does not contain the principal spot of comparison liquid, is anti-
It should complete)；Divide liquid, extraction merges organic phase, and washed and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filter, wash
Wash, merge organic phase, distillation；Solution turned cloudy is treated, 0~5 DEG C is cooled to, insulated and stirred 6h, filtering, Washing of Filter Cake is dried, obtained
Compound 3（That is momestasone furoate）；Compound 3 can be used directly according to purposes or improve pure using the methods such as recrystallization are refined
Degree.
The step（1）In organic base be diethylamine, triethylamine, ethamine, dimethylamine, trimethylamine, propylamine, isopropylamine,
One or more in butylamine, isobutyl amine, tert-butylamine, hexylamine, pyridine, 4- dimethylamino pyridines, preferably triethylamine；
The step（1）The mass volume ratio of middle compound 1 and dichloromethane is 1:4-1:15(g:ML), it is preferred that institute
The mass volume ratio for stating compound 1 and dichloromethane is 1:6(g:mL)；
The step（1）Middle compound 1 and the mol ratio of organic base are 1:2-1:8, it is preferred that the compound 1 is with having
The mol ratio of machine alkali is 1:4；
The step（1）Middle compound 1 and the mol ratio of furoyl chloride are 1:1.5-1:4, it is preferred that the compound 1 with
The mol ratio of furoyl chloride is 1:2；
The step（1）In be cooled to less than 5 DEG C, preferably -5~5 DEG C；
The step（2）The addition and step of middle glacial acetic acid（1）The mass ratio of middle compound 1 is 0.5: 1 -2: 1
(g:G), it is preferred that step（2）The addition and step of middle glacial acetic acid（1）The mass ratio of middle compound 1 is 1:1(g:g)；
The step（2）The addition and step of middle concentrated hydrochloric acid（1）The mass ratio of middle compound 1 is 0.5: 1 -4: 1
(g:G), it is preferred that step（2）The addition and step of middle concentrated hydrochloric acid（1）The mass ratio of middle compound 1 is 2: 1 (g:g)；
Existing preparation method is mostly with 9 β, and 11 beta epoxide -17 α, 21- dihydroxy -16 Alpha-Methyls-Isosorbide-5-Nitrae-is pregnant（Steroid）Diene-
3,2- diketone are starting material, carry out sulfonylation and obtain compound 1,21- chlorinations are then carried out again, obtain chloro production
Thing.Then chloro-product and furoyl chloride are obtained into compound 2 into ester.Existing preparation method prepares compound 2 by compound 1
Two-step reaction need to be passed through.
This preparation method directly can be entered by improving reaction condition with compound 1 and furoyl chloride reaction while esterification
Row chlorination, prepares compound 2 by compound 1 by a step, saves the reaction time, improve reaction yield, section
About cost.
Beneficial effects of the present invention：Efficiently solve former process route long, reaction system is complicated, time-consuming waits not enough.This
Invented technology is simple, and reaction condition is gentle, and high income, cost is low, and quality is high, and supplementary material is cheap and easy to get, is adapted to industrialized production.
Brief description of the drawings
Fig. 1 is the infared spectrum using the compound 2 prepared by the present invention；
Fig. 2 is the HPLC collection of illustrative plates using the compound 2 prepared by the present invention；
Fig. 3 is to use known technology（US 4472393）Prepare the HPLC collection of illustrative plates of gained compound 2.
Embodiment
With reference to embodiment, the present invention will be further described, and described is only several specific implementation shapes of the present invention
Formula, to those skilled in the art, can also make many deformations with improving.It is all without departing from described in claim
Deformation or improvement be regarded as the scope of the present invention.
Embodiment 1：
（1）The preparation of compound 1
9 β are added into reactor, 11 beta epoxide -17 α, 21- dihydroxy -16 Alpha-Methyls-Isosorbide-5-Nitrae-is pregnant（Steroid）Diene -3,2-
Diketone 50g, pyridine 300ml.Question response liquid is cooled to -5~5 DEG C, paratoluensulfonyl chloride 30g is added in reactor, temperature control -5
~5 DEG C of reaction 9h；It will pour into 3000ml water, stirring separates out solid, by water layer discarded, added in residue in reaction solution
380ml dichloromethane, is stirred 10 minutes, and point liquid, water layer is extracted twice with dichloromethane 380ml.Organic phase is adjusted with 1N hydrochloric acid
PH=6~7, point liquid, organic phase adjusts pH=7~8 with saturated sodium bicarbonate solution；Organic phase is washed with saturated aqueous common salt 400ml；
Treat that organic phase is concentrated to dryness, add 150ml dichloromethane, isopropyl ether 250ml is added dropwise at room temperature, continue to stir 3h, filter, dry
It is 66g, yield 93% to obtain the mass of compound 1.
（2）The preparation of compound 2
Dichloromethane 4.2kg is added into reactor, the lower mass of compound 1 that adds of stirring is 526.6g, triethylamine quality
For 404.8g, question response kettle is cooled to -5~5 DEG C, and it is 261.1g that furoyl chloride quality, which is added dropwise,.Completion of dropping, reactor is warming up to
25~30 DEG C of stirring 6h, TLC detection reactions are completed（Dichloromethane solution using compound 1 takes a small amount of reaction solution as comparison liquid
For test liquid, point sample is deployed, 254nm is ultraviolet with the ︰ 1 of volume ratio Er Lv Jia Wan ︰ methanol=20 mixed solvent in GF254 silica gel plates
Inspect, test liquid does not contain the spot of comparison liquid, completed for reaction under lamp）；And then it is incubated at 10~20 DEG C and 1N is added dropwise
Hydrochloric acid, adjusts pH=1~2, and aqueous phase is extracted 2 times with dichloromethane 1400g respectively；Merge in organic phase, organic phase and contain compound
2；A small amount of organic phase is taken, at room temperature after nitrogen drying, the detection of infrared and liquid phase is carried out, it is as a result as follows：
Fig. 1 is the infared spectrum of the compound 2 prepared by the present invention, and data are：IR（KBr, cm-1）2941,2874,
1725,1661,1621,1451,1391,887, understood by Fig. 1, Fig. 2, Fig. 3, the compound 2 prepared by the present invention, infrared test
As a result it is consistent with structure, retention time is with using known technology under identical liquid-phase condition（US 4472393）Prepare gained compound
2 retention time is consistent, therefore the present invention can pass through single step reaction prepare compound 2.
（3）The preparation of compound 3
Above-mentioned product is placed in 10L reactors, the lower addition glacial acetic acid 527g of stirring is cooled to -5~5 DEG C.Concentration is added dropwise
For 37% concentrated hydrochloric acid 1053g, completion of dropping, insulated and stirred 3h；And then 20~25 DEG C of stirring 5h are warming up to, TLC, which is detected, to have reacted
Into（Using the dichloromethane solution of compound 2 as comparison liquid, take and take lower organic layer to be test liquid, point after a small amount of reaction solution, standing
Sample uses volume ratio dichloromethane in GF254 silica gel plates：Methanol=20：Inspect, supply under 1 mixed solvent expansion, 254nm uviol lamps
Test solution does not contain the principal spot of comparison liquid, is completed for reaction）；Divide liquid, water layer is extracted 2 times with dichloromethane 770g, is merged organic
Phase, is washed 4 times with saturated nacl aqueous solution 3800g, organic to be added to anhydrous magnesium sulfate 250g dryings.Filtering, filter cake dichloro
Methane 300g is washed.Merge organic phase, distillation to muddiness；It is cooled to 0~5 DEG C, insulated and stirred 6h, filtering, a small amount of first of filter cake
Alcohol is washed, and 38~42 DEG C of dry 4h obtain compound 3（That is momestasone furoate）.
Product weighs about 494g, molar yield 95%（In terms of compound 1）, purity 99.9%.
Embodiment 2：
（1）The preparation of compound 1
9 β are added into reactor, 11 beta epoxide -17 α, 21- dihydroxy -16 Alpha-Methyls-Isosorbide-5-Nitrae-is pregnant（Steroid）Diene -3,2-
Diketone 50g, pyridine 300ml.Question response liquid is cooled to -5~5 DEG C, mesyl chloride 15g is added in reactor, temperature control -5~5 DEG C
9h is reacted, TLC detection reactions are completed；It will be poured into reaction solution in 3000ml water, stirring separates out solid；It is remaining by water layer discarded
380ml dichloromethane is added in thing, is stirred 10 minutes, point liquid, water layer is extracted twice with dichloromethane 380ml；Organic phase 1N
Salt acid for adjusting pH=6~7, point liquid, organic phase adjusts pH=7~8 with saturated sodium bicarbonate solution；Organic phase saturated aqueous common salt
400ml is washed；Treat that organic phase is concentrated to dryness, add 150ml dichloromethane, isopropyl ether 250ml is added dropwise at room temperature, continue to stir
3h, filtering is dry that the mass of compound 1 is 57g, yield 94%.
（2）The preparation of compound 2
It is 3.6kg that dichloromethane quality is added into reactor, and the lower mass of compound 1 that adds of stirring is 450.6g, three second
Amine quality is 404.8g, and question response kettle is cooled to -5~5 DEG C, and it is 261.1g that furoyl chloride quality, which is added dropwise, in insulation.Completion of dropping, will be anti-
Answer kettle to be warming up to 25~30 DEG C of stirring 6h, TLC detection reactions to complete（Dichloromethane solution using compound 1 takes as comparison liquid
A small amount of reaction solution is test liquid, and point sample uses volume ratio dichloromethane in GF254 silica gel plates：Methanol=20：1 mixed solvent exhibition
Open, inspected under 254nm uviol lamps, test liquid does not contain the spot of comparison liquid, completed for reaction）；And then by it at 10~20 DEG C
It is incubated and 1N hydrochloric acid is added dropwise, adjust pH=1~2, aqueous phase is extracted 2 times with dichloromethane 1400g, merges organic phase, under directly carrying out
Single step reaction.
（3）The preparation of compound 3
The dichloromethane solution of above-mentioned product is placed in 10L reactors, the lower addition glacial acetic acid 451g of stirring is cooled to -5
~5 DEG C.The concentrated hydrochloric acid 902g that concentration is 37%, completion of dropping, insulated and stirred 3h is added dropwise；It is warming up to 20~25 DEG C of stirring 5h.TLC
Detection（Using the dichloromethane solution of compound 2 as comparison liquid, take and take lower organic layer to be test liquid after a small amount of reaction solution, standing,
Point sample uses volume ratio dichloromethane in GF254 silica gel plates：Methanol=20：Inspected under 1 mixed solvent expansion, 254nm uviol lamps,
Test liquid does not contain the principal spot of comparison liquid, is completed for reaction）；Divide liquid, water layer is extracted 2 times with dichloromethane 770g, is associated with
Machine phase, is washed 4 times with saturated nacl aqueous solution 3800g, organic to be added to anhydrous magnesium sulfate 250g dryings, and filtering, filter cake uses two
Chloromethanes 300g is washed；Merge organic phase, distillation to muddiness；0~5 DEG C is cooled to, insulated and stirred 6h, filtering, filter cake is used on a small quantity
Methanol is washed, and 38~42 DEG C of dry 4h obtain compound 3（That is momestasone furoate）.
Product weighs about 500g, molar yield 96%（In terms of compound 1）, purity 99.9%.
Claims (5)
1. a kind of method for synthesizing momestasone furoate, it is characterised in that：Comprise the following steps that：
Chloro is carried out while carrying out esterification using compound 1 and furoyl chloride and obtains compound 2, and compound 2 is deposited in hydrochloric acid
The momestasone furoate of compound 3 is generated in lower open loop；Its specific preparation process is as follows：
G wherein in compound 1 is mesyl or p-toluenesulfonyl；
Wherein step one is：Dichloromethane, compound 1, organic base are added into reactor, cooling is added dropwise furoyl chloride, is warming up to
25~30 DEG C of stirring reactions are to reacting completion；Reaction solution is adjusted to acidity, extraction merges organic phase, and this organic phase contains chemical combination
Thing 2；
Wherein described organic base be diethylamine, triethylamine, ethamine, dimethylamine, trimethylamine, propylamine, isopropylamine, butylamine, isobutyl amine,
One or more in tert-butylamine, hexylamine, pyridine, 4- dimethylamino pyridines；The compound 1 and the quality volume of dichloromethane
Compare g:ML is 1:4-1:15；The compound 1 and the mol ratio of organic base are 1:2-1:8；The compound 1 is rubbed with furoyl chloride
You are than being 1:1.5-1:4.
2. the method for synthesis momestasone furoate according to claim 1, it is characterised in that：
Glacial acetic acid is added into the organic phase of step one in step 2, is cooled, it is 37% concentrated hydrochloric acid stirring 3h that concentration, which is added dropwise,；Enter
And 20~25 DEG C of stirring reactions are warming up to reacting completion；Divide liquid, extraction merges organic phase, dried after washing；Filtering, distillation
To solution turned cloudy, 0~5 DEG C of stirring and crystallizing is cooled to, is filtered, Washing of Filter Cake, dries, obtains compound 3.
3. the method for synthesis momestasone furoate according to claim 1, it is characterised in that：
Organic base in step one is triethylamine；Compound 1 and the mass volume ratio g of dichloromethane:ML is 1:6；Compound 1 with
The mol ratio of organic base is 1:4；Compound 1 and the mol ratio of furoyl chloride are 1:2；Cool as -5~5 DEG C.
4. the method for synthesis momestasone furoate according to claim 1, it is characterised in that：
Compound 1 and the mass ratio g of glacial acetic acid in the step (2) in the step (1):G is 1:0.5-1:2；The step
(1) compound 1 and the mass ratio g of concentrated hydrochloric acid in the step (2) in:G is 1:0.5-1:4.
5. the method for synthesis momestasone furoate according to claim 1, it is characterised in that：
Compound 1 and the ratio g of glacial acetic acid in the step (2) in the step (1):G is 1:1；Chemical combination in the step (1)
The ratio g of thing 1 and concentrated hydrochloric acid in the step (2):G is 1:2.
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| CN107266518B (en) * | 2016-04-08 | 2021-03-30 | 天津金耀集团有限公司 | Mometasone furoate crystal form and preparation method thereof |
| CN106834406A (en) * | 2017-01-23 | 2017-06-13 | 广西万德药业有限公司 | The preparation method of momestasone furoate intermediate |
| CN109206468B (en) * | 2017-06-30 | 2023-06-27 | 天津药业研究院股份有限公司 | Preparation method of mometasone furoate |
| CN109180767A (en) * | 2018-09-04 | 2019-01-11 | 浙江仙琚制药股份有限公司 | A method of preparing momestasone furoate |
| CN112110975A (en) * | 2019-06-21 | 2020-12-22 | 河南利华制药有限公司 | Method for synthesizing mometasone furoate by one-pot process |
| CN113024626A (en) * | 2019-12-24 | 2021-06-25 | 天津天药药业股份有限公司 | Preparation process of mometasone furoate |
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| EP0057401B1 (en) * | 1981-02-02 | 1984-08-01 | Schering Corporation | Aromatic heterocyclic esters of steroids, their preparation and pharmaceutical compositions containing them |
| US5886200A (en) * | 1996-07-01 | 1999-03-23 | Schering Corporation | Process for the preparation of 17-esters of 9 α, 21-dihalo-pregnane-11 β, 17 α-diol-20-ones |
| PT102343B (en) * | 1999-08-02 | 2003-11-28 | Hovione Farmaciencia Sa | METHOD FOR THE PREPARATION OF FUROATE MOMETHASONE |
| CN1137899C (en) * | 2000-03-16 | 2004-02-11 | 上海华联制药有限公司 | 17,21-ester substituted 1,4-diene-3-keto-9,11-epoxy steroid compound |
| CN102584521A (en) * | 2011-12-22 | 2012-07-18 | 凯莱英医药集团（天津）股份有限公司 | Synthetic method for chloroalkyne |
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Denomination of invention: A method for synthesis of mometasone furoate Effective date of registration: 20230201 Granted publication date: 20170919 Pledgee: Taixi sub branch of Taian Bank Co.,Ltd. Pledgor: JEWIM PHARMACEUTICAL (SHANDONG) CO.,LTD. Registration number: Y2023980031838 |
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Effective date of registration: 20230309 Address after: 271400 No. 668, Hengxin Street, Ningyang County Economic Development Zone, Tai'an City, Shandong Province Patentee after: Shandong Ruishun Pharmaceutical Co.,Ltd. Address before: 271000 peitianmen street, high tech Industrial Development Zone, Tai'an City, Shandong Province Patentee before: JEWIM PHARMACEUTICAL (SHANDONG) CO.,LTD. |