CN103833635B - A kind of preparation method of the Dimemorfan phosphate of cough medicine safely and effectively - Google Patents
A kind of preparation method of the Dimemorfan phosphate of cough medicine safely and effectively Download PDFInfo
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- CN103833635B CN103833635B CN201410104046.8A CN201410104046A CN103833635B CN 103833635 B CN103833635 B CN 103833635B CN 201410104046 A CN201410104046 A CN 201410104046A CN 103833635 B CN103833635 B CN 103833635B
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- dextrorphan
- thebaine
- sulfonyl ester
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
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Abstract
The present invention relates to the preparation method of cough medicine Dimemorfan phosphate safely and effectively, the method is: reacted with trifluoromethanesulfchloride chloride in triethylamine by dextrorphan and generate dextrorphan fluoroform sulfonyl ester; Dextrorphan fluoroform sulfonyl ester reacts with tin tetramethide and generates (9s in toluene, 13s, 14s)-3,17-thebaine is muttered (or dextrorphan fluoroform sulfonyl ester joins in the mixed solvent of THF and METHYLPYRROLIDONE, add methyl ethyl diketone iron catalyst and methyl-magnesium-bromide stirring heating to reflux 12 hours obtained (9s, 13s, 14s)-3,17-thebaine is muttered), target product (9s, 13s, 14s)-3 is made further again with phosphatase reaction salify, 17-thebaine phosphoric acid salt, i.e. Dimemorfan phosphate.The present invention, to methylate and salify three-step reaction can the preparation of realize target product through over-churning for raw material with commercially available dextrorphan.This operational path has the advantage that raw material is easy to get, synthesis step is few, technique is simple, with low cost, yield is high, product purity is high and economic and practical is strong, is applicable to suitability for industrialized production.
Description
Technical field
What the present invention relates to is a kind of suppression medulla oblongata coughing centre, is the preparation method of non-additive maincenter cough medicine Dimemorfan phosphate, belongs to technical field of medicine synthesis.
Background technology
Cough is a kind of strong respiratory movement that happens suddenly, and this action is because the respiratory centre irriate of medulla oblongata causes.Cough medicine is divided into central antitussive and peripheral antitussive drugs by its site of action difference.Central antitussive plays antitussive effect by suppressing oblongata coughing centre, and this type of medicine is applicable to the dry cough without phlegm.Peripheral antitussive drugs plays antitussive effect by suppressing any link in susceptor, esodic nerve, exodic nerve or the effector in the coughreflex arc outside coughing centre.
Dimemorfan phosphate is developed by Japanese Fujisawa Pharmaceutical Co., Ltd, is merged by Yamanouchi pharmacy afterwards, traded commodity name Astomin, Dimemorfan phosphate went on the market in 1974 in Japan, within more than 30 year, have no the report of its serious untoward reaction, determined curative effect, safe and reliable.Domestic not yet approval is gone on the market, without import.Dimemorfan phosphate suppresses medulla oblongata coughing centre, is non-additive maincenter cough medicine.Effect is slightly better than Dextromethorphane Hbr, be about 2 times of morphine monomethyl ether, but toxicity is lower, and application can not habituation repeatedly, and security is larger.Take and to take effect rapidly afterwards, and the time length is long, also can not cause constipation, and domesticly there is no producer's approval listing, there is very large market potential, develop this product at home and there are wide market outlook.Chemistry (9s, 13s, 14s) by name-3, the 17-thebaine monophosphate of Dimemorfan phosphate, its chemical structural formula is as follows:
。
The Dimemorfan phosphate preparation technology of going on the market in Japan is with 2-methyl-5,6,7,8-tetrahydroisoquinoline is starting raw material, carries out form addition, through shortening with to methyl-benzyl magnesium chloride, chiral separation, then generate Dimemorfan phosphate with phosphatase reaction cyclisation, reaction scheme is as follows:
。
This technological reaction step is long, and centre also needs chiral separation, and product yield is low, and production cost is high.
Patent (CN 102241630A) technique that Dimemorfan phosphate gets the Green Light in China is with (S)-1-(4-methyl-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9-L-mandelate, obtains (S)-1-(4-methyl-benzyl through de-L-amygdalic acid)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9, then methylate, then under heating reduced pressure, carry out annulation with phosphoric acid and obtain target product.Reaction scheme is as follows:
。
Although this technique does not need to split, long reaction time, severe reaction conditions (needing High Temperature High Pressure), product yield is low, and production cost is high.
Summary of the invention
Problem to be solved by this invention is to provide the synthetic method of one (9s, 13s, 14s)-3,17-thebaine monophosphate.This method is that a kind of technique is simple, with low cost, yield is high, product purity is high, economic and practical is strong, raw material is easy to get and is applicable to the preparation method of suitability for industrialized production.
Technical scheme provided by the invention is: (9s, 13s, 14s)-3,17-synthetic method of thebaine monophosphate, is reacted by dextrorphan generate dextrorphan fluoroform sulfonyl ester in triethylamine with trifluoromethanesulfchloride chloride; Dextrorphan fluoroform sulfonyl ester reacts with tin tetramethide and generates (9s in toluene, 13s, 14s)-3,17-thebaine (or dextrorphan fluoroform sulfonyl ester is in the mixed solvent of THF and METHYLPYRROLIDONE, add methyl ethyl diketone iron catalyst and methyl-magnesium-bromide stirring heating refluxes 12 hours, obtained (9s, 13s, 14s)-3,17-thebaines), i.e. dimemorfan crude product, directly and phosphoric acid salify, then recrystallization obtains target product (9s, 13s, 14s)-3,17-thebaine phosphoric acid salt.
Route of methylation one: dextrorphan fluoroform sulfonyl ester adds (PPh after joining and dissolving completely in toluene
3)
2pdCl
2, LiCl and PPh
3to in reaction flask, after mixing fully, stirred at ambient temperature 5min, then add (CH
3)
4sn is in reaction flask, and reaction solution reacts 12h in the reaction flask of sealing, after reacting completely, adds 10% NaHCO
3solution cancellation is reacted, and filters, filtrate CH
2cl
2extraction, merges organic phase, organic phase anhydrous magnesium sulfate drying, filters, adds the H of 1.5 times of molar weights in filtrate
3pO
4reaction salify, stirring reaction 0.5h is until no longer include white solid generation in solution, white solid obtains white crystal, i.e. Dimemorfan phosphate sterling 2 times with volume fraction 95% ethyl alcohol recrystallization again.
Route of methylation two: dextrorphan fluoroform sulfonyl ester joins in THF, stirred at ambient temperature, after dissolving completely, adds N-methyl-2-pyrrone (NMP), pass into the air in 10min nitrogen replacement reaction flask after mixing, then add ferric acetyl acetonade (Fe (acae)
3) and methyl-magnesium-bromide in reaction flask, react 12h at reflux, after reacting completely, reaction solution be cooled to room temperature, slowly drip 10mL shrend and to go out reaction, separation organic phase, aqueous phase CH
2cl
2extraction, merges organic phase.Organic phase is poured in reaction flask, add the H of 1.5 times of molar weights
3pO
4reaction salify, stirring reaction 0.5h is until no longer include white solid generation in solution, white solid obtains white crystal, i.e. Dimemorfan phosphate sterling 2 times with volume fraction 95 % ethyl alcohol recrystallization again.
Embodiment
The present invention take dextrorphan as raw material, only need through over-churning, methylate and salify three-step reaction, thus be prepared into target product Dimemorfan phosphate, each step reaction yield all arrives more than 80%, and simple to operate, economically feasible.Its method is as follows:
1. esterification take dextrorphan as raw material, under the condition of nitrogen protection, with CF
3sO
2cl reaction generates dextrorphan fluoroform sulfonyl ester;
2. methylate, take toluene as solvent, dextrorphan fluoroform sulfonyl ester reacts with tin tetramethide and generates dimemorfan or dextrorphan fluoroform sulfonyl ester under the effect of catalyst acetyl acetone iron under the katalysis of bi triphenyl phosphorus palladium chloride, take THF as solvent, generate dimemorfan with methyl bromide reactive magnesium;
3. salify, dimemorfan becomes salt formation target product Dimemorfan phosphate with phosphoric acid.Synthetic route is as follows:
Reaction conditions: a, CF
3sO
2cl (Tf=CF
3sO
2), Et
3n, CH
2cl
2b, Me
4sn, (PPh
3)
2pdCl
2, PPh
3, LiCl, toluene, 120 DEG C, H
3pO
4c, Fe (acae)
3, NMP, MeMgBr, H
3pO
4.
Feature of the present invention: with the dextrorphan that market can be bought for raw material, only need through over-churning, methylate and salify three-step reaction, thus be prepared into target product Dimemorfan phosphate, chiral separation is not needed in reaction process, reaction times is short, reaction conditions is gentle, and product yield is high, is applicable to suitability for industrialized production.
Test the preparation of 1 dextrorphan fluoroform sulfonyl ester
By raw material dextrorphan (3.56g, 13.8mmol) and Et
3n(2.1g, 20.7mmol) join 200mL CH
2cl
2in, be filled with nitrogen protection, after stirred at ambient temperature fully dissolves, then add CF
3sO
2cl(2.78g, 16.5mmol), after mixing fully, stirring reaction 12h.After question response is complete, in reaction solution, add 15mL 10% NaHCO
3aqueous solution cancellation is reacted.Organic phase anhydrous magnesium sulfate drying, filters, and filter vacuum concentrates to obtain dextrorphan fluoroform sulfonyl ester 4.59g, yield 85.34%.
Test the preparation of 2 Dimemorfan phosphates
Compound dextrorphan fluoroform sulfonyl ester (4.7g, 12mmol) joins in toluene by route one, after dissolving completely, adds (PPh
3)
2pdCl
2(1.0g, 1.4mmol), LiCl(4.2g, 99mmol) and PPh
3(1.9g, 7.2mmol), stirred at ambient temperature 5min, then add (CH
3)
4sn (6.7mL, 48mmol), sealed reaction 12h.After reacting completely, add 50mL 10% NaHCO
3solution cancellation is reacted, and filters, filtrate CH
2cl
2extraction (3 × 30mL), merges organic phase, organic phase anhydrous magnesium sulfate drying, filters, adds the H of 1.5 times of molar weights in filtrate
3pO
4reaction salify, stirring reaction 0.5h is until no longer include white solid generation in solution.Filter out white solid, then obtain white crystal, i.e. Dimemorfan phosphate sterling 3.4g 2 times with 95% ethyl alcohol recrystallization, yield is 80.07%.
Route two
1. the preparation of ferric acetyl acetonade
95% methanol solution is joined in reaction flask; Stirred at ambient temperature, adds Iron(III) chloride hexahydrate (27.03g, 0.1mol), after Iron(III) chloride hexahydrate dissolves completely in reaction flask; In reaction flask, add 0.001mol hydrochloric acid again, then slowly in solution, drip methyl ethyl diketone (30.63g, 0.3mol) (acetoneand ethyl acetate be raw material preparation), temperature controls at 50 DEG C, terminates until drip; Be warming up to 70 DEG C, at 70 DEG C of insulation reaction 0.5h, by solution concentrated 2/3, after cooling, separate out reddish orange precipitation, this i.e. raw product.Filter, with cold water washing, dry, then recrystallization obtains ferric acetyl acetonade sterling 30.38g in methanol solution, yield is 86%, fusing point: 178-182 DEG C;
2. by compound dextrorphan fluoroform sulfonyl ester (4.7g, 12mmol), join in THF, stirred at ambient temperature, after dissolving completely, add METHYLPYRROLIDONE (NMP) (7.5mL, 42mmol), pass into the air in nitrogen replacement reaction flask after mixing, then add ferric acetyl acetonade (Fe (acae)
3) diethyl ether solution (5mL, 15mmol) of methyl-magnesium-bromide of (450mg, 1.2mmol) and 3M, reaction backflow 12h.After reacting completely, reaction solution is cooled to room temperature, slowly drips 50mL shrend and to go out reaction, separation organic phase, aqueous phase CH
2cl
2extraction (3 × 30mL), merges organic phase.Organic phase is poured in reaction flask, add the H of 1.5 times of molar weights
3pO
4reaction salify, stirring reaction is until no longer include white solid generation in solution.Filter out white solid, then obtain white crystal, i.e. Dimemorfan phosphate sterling 3.5g 2 times with 95 % ethyl alcohol recrystallization, yield is 82.13%.
Claims (3)
1. the synthetic method of Dimemorfan phosphate, comprises the steps:
A () dextrorphan and trifluoromethanesulfchloride chloride are reacted and are generated dextrorphan fluoroform sulfonyl ester;
(b) dextrorphan fluoroform sulfonyl ester and tin tetramethide react generate (9s, 13s, 14s)-3,17-thebaine or
C () dextrorphan fluoroform sulfonyl ester and methyl-magnesium-bromide are obtained by reacting (9s, 13s, 14s)-3,17-thebaine;
D () (9s, 13s, 14s)-3,17-thebaine and phosphatase reaction salify obtain target product (9s, 13s, 14s)-3,17-thebaine phosphoric acid salt;
Wherein, in described step (b), the catalyzer of methylation reaction is bi triphenyl phosphorus palladium chloride; In described step (c), the catalyzer of methylation reaction is ferric acetyl acetonade.
2. synthetic method according to claim 1, is characterized in that: in described step (c), the amount of methylation catalyst ferric acetyl acetonade is 1/10 of dextrorphan fluoroform sulfonyl ester molar weight, and methyl-magnesium-bromide is stored in ether, and concentration is 3mol/L.
3. synthetic method according to claim 1, is characterized in that: the Dimemorfan phosphate that described step (d) synthesizes gained will be refined by following steps: filtrate directly adds the H of 1.5 times of molar weights
3pO
4in, be stirred in solution and no longer include white solid generation, filter, 95% ethanol 2 times recrystallization obtains white crystal, i.e. Dimemorfan phosphate sterling.
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| CN108484502A (en) * | 2018-03-12 | 2018-09-04 | 合肥医工医药有限公司 | A method of preparing Dimemorfan phosphate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008137474A1 (en) * | 2007-05-01 | 2008-11-13 | Concert Pharmaceuticals Inc. | Morphinan compounds |
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|---|---|---|---|---|
| WO2008137474A1 (en) * | 2007-05-01 | 2008-11-13 | Concert Pharmaceuticals Inc. | Morphinan compounds |
Non-Patent Citations (2)
| Title |
|---|
| Ao Zhang等.10-Ketomorphinan and 3-Substituted-3-desoxymorphinan Analogues as Mixed κ and µ * |
| Opioid Ligands:Synthesis and Biological Evaluation of Their Binding Affinity at Opioid Receptors.《J.Med.Chem.》.2003,第47卷(第1期),第165-174页. * |
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Effective date of registration: 20230921 Address after: 430000 No. a5-2, building 1, Wuhan Optical Valley International Biomedical enterprise accelerator, No. 388, Gaoxin Second Road, Donghu New Technology Development Zone, Wuhan, Hubei Province Patentee after: LONGLY BIOTECHNOLOGY (WUHAN) Co.,Ltd. Address before: 430079, 3rd Floor, East Side, Building A2-2, Accelerator Phase I, Biopharmaceutical Industrial Park, No. 858 Gaoxin Avenue, Donghu High tech Zone, Wuhan City, Hubei Province Patentee before: WUHAN YAOGU BIOLOGICAL ENGINEERING CO.,LTD. |
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