CN103833635A - Method for preparing safe and effective antibechic dimimorfan phosphate - Google Patents
Method for preparing safe and effective antibechic dimimorfan phosphate Download PDFInfo
- Publication number
- CN103833635A CN103833635A CN201410104046.8A CN201410104046A CN103833635A CN 103833635 A CN103833635 A CN 103833635A CN 201410104046 A CN201410104046 A CN 201410104046A CN 103833635 A CN103833635 A CN 103833635A
- Authority
- CN
- China
- Prior art keywords
- methyl
- dextrorphan
- reaction
- phosphate
- dextrorphane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing a safe and effective antibechic dimimorfan phosphate. The method comprises steps of reacting dextrorphane with trifluoro-methylsulfonyl chloride in triethylamine so as to generate dextrorphane trifluoro-methyl sulfone chloride ester; reacting the dextrorphane trifluoro-methyl sulfone chloride ester with tetramethyltin in methylbenzene so as to generate (9s, 13s, 14s)-3, 17-dimethyl morphinan (or adding the dextrorphane trifluoro-methyl sulfone chloride ester into mixed solvent of THF and N-methyl-2-pyrrolidone, adding catalyst ferric acetylacetonate and methyl magnesium bromide, stirring and heating reflux for 12 hours, so as to prepare (9s, 13s, 14s)-3, 17-dimethyl morphinan), furthermore, reacting with phosphoric acid so as to salify to prepare target product (9s, 13s, 14s)-3, 17-dimethyl morphine phosphate-dimimorfan phosphate. The method takes commercially available dextrorphane as the raw material, and prepares the target product through three steps of esterification, methylation and salification. The method has advantages of easily obtained raw materials, few synthesis steps, simple technology, low cost, high yield, high purity of the product and strong economic practicability, and is applicable to industrial production.
Description
Technical field
What the present invention relates to is a kind of medulla oblongata coughing centre that suppresses, and for the preparation method of non-habituation sexual centre 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 is by suppressing any link performance antitussive effect 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 afterwards traded commodity name Astomin by Yamanouchi pharmacy, Dimemorfan phosphate went on the market in Japan in 1974, within more than 30 year, have no the report of its serious untoward reaction, determined curative effect, safe and reliable.Domestic not yet approval listing, without import.Dimemorfan phosphate suppresses medulla oblongata coughing centre, is non-habituation sexual centre cough medicine.Effect is slightly better than Dextromethorphane Hbr, be about 2 times of morphine monomethyl ether, but toxicity is lower, and application can habituation repeatedly, and security is larger.Take and 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 at home this product and there are wide market outlook.Chemistry (9s, 13s, 14s)-3 by name of Dimemorfan phosphate, 17-thebaine monophosphate, its chemical structural formula is as follows:
Dimemorfan phosphate preparation technology in Japan's listing is with 2-methyl-5,6,7,8-tetrahydroisoquinoline is starting raw material, and methyl-benzyl magnesium chloride is carried out to form addition, through shortening, 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 one (9s, 13s, 14s)-3, the synthetic method of 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, and the synthetic method of 17-thebaine monophosphate is reacted dextrorphan and is generated dextrorphan fluoroform sulfonyl ester in triethylamine with trifluoromethanesulfchloride chloride; Dextrorphan fluoroform sulfonyl ester reacts generation (9s in toluene with tin tetramethide, 13s, 14s)-3, (or dextrorphan fluoroform sulfonyl ester is in the mixed solvent of THF and METHYLPYRROLIDONE for 17-thebaine, add methyl ethyl diketone iron catalyst and methyl-magnesium-bromide stirring heating to reflux 12 hours, make (9s, 13s, 14s)-3,17-thebaine), it is dimemorfan crude product, directly and phosphoric acid salify, then recrystallization makes target product (9s, 13s, 14s)-3,17-thebaine phosphoric acid salt.
Route of methylation one: dextrorphan fluoroform sulfonyl ester adds (PPh after joining in toluene and dissolving completely
3)
2pdCl
2, LiCl and PPh
3in reaction flask, after mixing fully, under room temperature, stir 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 reaction, filters filtrate CH
2cl
2extraction, merges organic phase, and organic phase anhydrous magnesium sulfate drying filters, and 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 and generate in solution, white solid again with volume fraction 95% ethyl alcohol recrystallization 2 times white crystal, i.e. Dimemorfan phosphate sterling.
Route of methylation two: dextrorphan fluoroform sulfonyl ester joins in THF, under room temperature, stir, after dissolving completely, add N-methyl-2-pyrrone (NMP), after mixing, pass into the air in 10min nitrogen replacement reaction flask, then add ferric acetyl acetonade (Fe (acae)
3) and methyl-magnesium-bromide in reaction flask, under reflux state, react 12h, after reacting completely, reaction solution is cooled to room temperature, slowly drip the 10mL shrend reaction of going out, separate organic phase, water CH
2cl
2extraction, merges organic phase.Organic phase is poured in reaction flask, added the H of 1.5 times of molar weights
3pO
4reaction salify, stirring reaction 0.5h is until no longer include white solid and generate in solution, white solid again with volume fraction 95 % ethyl alcohol recrystallization 2 times white crystal, i.e. Dimemorfan phosphate sterling.
Embodiment
The present invention is take dextrorphan as raw material, only need be through over-churning, methylate and salify three-step reaction, thus be prepared into target product Dimemorfan phosphate, respectively walk reaction yield and all arrive 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 catalyzer ferric acetyl acetonade under the katalysis of bi triphenyl phosphorus palladium chloride, take THF as solvent, react with methyl-magnesium-bromide and generate dimemorfan;
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 ℃, H
3pO
4c, Fe (acae)
3, NMP, MeMgBr, H
3pO
4.
Feature of the present invention: take the dextrorphan that can buy on market as raw material, only need be through over-churning, methylate and salify three-step reaction, thereby be prepared into target product Dimemorfan phosphate, in reaction process, do not need chiral separation, reaction times is short, reaction conditions gentleness, 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, under room temperature, stir after fully dissolving, 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 reaction.Organic phase anhydrous magnesium sulfate drying, filters, and filtrate vacuum concentration obtains dextrorphan fluoroform sulfonyl ester 4.59g, yield 85.34%.
Test the preparation of 2 Dimemorfan phosphates
Route one joins compound dextrorphan fluoroform sulfonyl ester (4.7g, 12mmol) in toluene, after dissolving completely, adds (PPh
3)
2pdCl
2(1.0g, 1.4mmol), LiCl(4.2g, 99mmol) and PPh
3(1.9g, 7.2mmol), stirs 5min under room temperature, then adds (CH
3)
4sn (6.7mL, 48mmol), sealed reaction 12h.After reacting completely, add 50mL 10% NaHCO
3solution cancellation reaction, filters filtrate CH
2cl
2extraction (3 × 30mL), merges organic phase, and organic phase anhydrous magnesium sulfate drying filters, and 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 with 95% ethyl alcohol recrystallization 2 times white crystal, i.e. Dimemorfan phosphate sterling 3.4g, yield is 80.07%.
Route two
1. the preparation of ferric acetyl acetonade
95% methanol solution is joined in reaction flask; Under room temperature, stir, in reaction flask, add Iron(III) chloride hexahydrate (27.03g, 0.1mol), after Iron(III) chloride hexahydrate dissolves completely; In reaction flask, add 0.001mol hydrochloric acid again, then slowly in solution, drip methyl ethyl diketone (30.63g, 0.3mol) (acetoneand ethyl acetate is raw material preparation), temperature is controlled at 50 ℃, finishes until drip; Be warming up to 70 ℃, at 70 ℃ of insulation reaction 0.5h, by concentrated solution 2/3, cooling after, separate out reddish orange precipitation, this is raw product.Filter, with cold water washing, dry, then recrystallization makes ferric acetyl acetonade sterling 30.38g in methanol solution, yield is 86%, fusing point: 178-182 ℃;
2. by compound dextrorphan fluoroform sulfonyl ester (4.7g, 12mmol), join in THF, under room temperature, stir, after dissolving completely, add METHYLPYRROLIDONE (NMP) (7.5mL, 42mmol), after mixing, pass into the air in nitrogen replacement reaction flask, 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 the 50mL shrend reaction of going out, separate organic phase, water CH
2cl
2extraction (3 × 30mL), merges organic phase.Organic phase is poured in reaction flask, added 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 with 95 % ethyl alcohol recrystallization 2 times white crystal, i.e. Dimemorfan phosphate sterling 3.5g, yield is 82.13%.
Claims (6)
1. the synthetic method of Dimemorfan phosphate comprises the steps
(a) dextrorphan reacts with trifluoromethanesulfchloride chloride and generates dextrorphan fluoroform sulfonyl ester;
(b) dextrorphan fluoroform sulfonyl ester reacts generation (9s, 13s, 14s)-3 with tin tetramethide, 17-thebaine or (c) dextrorphan fluoroform sulfonyl ester react with methyl-magnesium-bromide and obtain (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.
2. synthetic method according to claim 1, is characterized in that: the selection of catalyzer when methylating reagent and methylation reaction in step (b), and the selection of catalyzer when methylating reagent and methylation reaction in step (c).
3. according to the synthetic method described in claim 1 and 2, it is characterized in that: in described step (b), the catalyzer of methylation reaction is bi triphenyl phosphorus palladium chloride, and methylating reagent is tin tetramethide.
4. according to the synthetic method described in claim 1 and 2, it is characterized in that: in described step (c), the catalyzer of methylation reaction is ferric acetyl acetonade, and methylating reagent is methyl-magnesium-bromide.
5. according to the synthetic method described in claim 1 and 2, it 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.
6. synthetic method according to claim 1, is characterized in that: the Dimemorfan phosphate of the synthetic gained of described step (d) will be refined by following steps: filtrate directly adds the H of 1.5 times of equimolar amounts
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410104046.8A CN103833635B (en) | 2014-03-20 | 2014-03-20 | A kind of preparation method of the Dimemorfan phosphate of cough medicine safely and effectively |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410104046.8A CN103833635B (en) | 2014-03-20 | 2014-03-20 | A kind of preparation method of the Dimemorfan phosphate of cough medicine safely and effectively |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103833635A true CN103833635A (en) | 2014-06-04 |
| CN103833635B CN103833635B (en) | 2015-10-14 |
Family
ID=50797575
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410104046.8A Active CN103833635B (en) | 2014-03-20 | 2014-03-20 | A kind of preparation method of the Dimemorfan phosphate of cough medicine safely and effectively |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103833635B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104086486A (en) * | 2014-07-02 | 2014-10-08 | 杭州澳医保灵药业有限公司 | Preparation method of dimemorfan phosphate |
| 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 |
-
2014
- 2014-03-20 CN CN201410104046.8A patent/CN103833635B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008137474A1 (en) * | 2007-05-01 | 2008-11-13 | Concert Pharmaceuticals Inc. | Morphinan compounds |
Non-Patent Citations (1)
| 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.》, vol. 47, no. 1, 9 December 2003 (2003-12-09), pages 165 - 174 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104086486A (en) * | 2014-07-02 | 2014-10-08 | 杭州澳医保灵药业有限公司 | Preparation method of dimemorfan phosphate |
| CN104086486B (en) * | 2014-07-02 | 2016-06-08 | 杭州澳医保灵药业有限公司 | The preparation method of a kind of Dimemorfan phosphate |
| CN108484502A (en) * | 2018-03-12 | 2018-09-04 | 合肥医工医药有限公司 | A method of preparing Dimemorfan phosphate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103833635B (en) | 2015-10-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103664769B (en) | Synthesis method of dipyridyl derivative or analogue | |
| CN103833635B (en) | A kind of preparation method of the Dimemorfan phosphate of cough medicine safely and effectively | |
| CN108558635B (en) | Preparation method of 3-aryl propiolic acid and 3-aryl propiolic acid ester compound | |
| CN107915757B (en) | Using trans cvclohexvl glycol as bidentate phosphite ester ligand of connection structure and preparation method thereof | |
| CN103936656A (en) | Preparation method of 4-bromocarbazole | |
| Chen et al. | CuI catalyzed domino coupling–cyclization of 2-iodo-phenols and 1-alkynes to the synthesis of 2-substituted benzo [b] furans/furo-pyridines | |
| IT201800000667A1 (en) | PROCEDURE FOR THE PREPARATION OF DISPLACED DIARYLOXYHETERODIAZOLIC COMPOUNDS | |
| CN102372707B (en) | The synthetic method of 6-methyl-4-bromo-1,6-pyrrolin [2,3-c] pyridin-7-one | |
| CN106892826A (en) | A kind of preparation method and application of amine and imines N-methyl | |
| CN105153013A (en) | Synthesis method of 6-bromoisoindolinyl-1-one | |
| Thirupathaiah et al. | Indium triflate-catalyzed stereoselective tandem intramolecular conjugate addition of secondary amines to α, β-bisenones | |
| CN104529960A (en) | Preparation method of prucalopride intermediate | |
| CN103880675B (en) | Improved catalyzed synthesis method for 1,4-dicarbonyl compound | |
| CN103242378B (en) | Ferrocenyl pyrimidine pincer ligand and preparation method thereof | |
| CN105294573A (en) | Method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine | |
| CN105130982A (en) | Imidazo heterocyclic amino dithiocarbamate and preparation method therefor | |
| CN109912661A (en) | Pyrimidine with catalytic performance-pyrazoles ruthenium complex and preparation method thereof | |
| CN104557799B (en) | A kind of synthetic method of the pharmaceutical intermediate ketone compounds containing heterocycle | |
| CN102040563B (en) | Preparation method for 3-aryl benzo [d] isothiazole | |
| CN108947900A (en) | The method of carbon arylation tandem reaction synthesizing heterocyclic compound of the photoinduction without metal catalytic | |
| CN104710345B (en) | For preparing 4（2‑（4 aminomethyl phenyl sulfenyls））Compound, its preparation method and the application of Phenylpiperidine | |
| Havránková et al. | Comparative studies of catalytic application of cerium (III) chloride and resin supported cerium (III) in domino syntheses of 1, 5-benzodiazepine and 1, 3-diazine skeletons | |
| CN108794470B (en) | 6-hydrazino-1H-pyrazolo [3,4-b ] pyridine and synthesis method of downstream product thereof | |
| CN108503578B (en) | Synthetic method of indeno- [1,2-b ] indole-10 (5H) -ketone compound | |
| CN105949209A (en) | Synthesis method of triphenylene dodecyloxy bridged dodecyloxy phenyl porphyrin metal Zn complex |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
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. |