CN108484502A - A method of preparing Dimemorfan phosphate - Google Patents
A method of preparing Dimemorfan phosphate Download PDFInfo
- Publication number
- CN108484502A CN108484502A CN201810199587.1A CN201810199587A CN108484502A CN 108484502 A CN108484502 A CN 108484502A CN 201810199587 A CN201810199587 A CN 201810199587A CN 108484502 A CN108484502 A CN 108484502A
- Authority
- CN
- China
- Prior art keywords
- methyl
- magnesium
- bromide
- dextrorphan
- dimemorfan
- 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.)
- Pending
Links
- MKXZASYAUGDDCJ-NJAFHUGGSA-N CN(CC1)[C@@H]2[C@@H](CCCC3)[C@@]13c1cc(OC)ccc1C2 Chemical compound CN(CC1)[C@@H]2[C@@H](CCCC3)[C@@]13c1cc(OC)ccc1C2 MKXZASYAUGDDCJ-NJAFHUGGSA-N 0.000 description 1
- KBEZZLAAKIIPFK-NJAFHUGGSA-N Cc1ccc(C[C@@H]2N(C)CC[C@]34[C@@H]2CCCC3)c4c1 Chemical compound Cc1ccc(C[C@@H]2N(C)CC[C@]34[C@@H]2CCCC3)c4c1 KBEZZLAAKIIPFK-NJAFHUGGSA-N 0.000 description 1
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)
Abstract
The present invention relates to medicinal chemistry arts, and in particular to a method of preparing non-habituation sexual centre antitussive Dimemorfan phosphate.It is characterized in that using the base dextromethorphan for having listed the dextromethorphan hydrobromide of drug for many years for starting material, Dimemorfan phosphate is made at salt with phosphoric acid after methoxymethylated.Present invention process route is succinct, product purity is high, of low cost, is suitable for industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of to prepare non-habituation sexual centre antitussive Dimemorfan phosphate
Method.
Background technology
Dimemorfan phosphate is Japanese Fujisawa Pharmaceutical Co., Ltd's research and development, is most listed early in Japan within 1974, clinical
Using have no for many years serious adverse reaction report, it is curative for effect, securely and reliably.Existing domestic not yet approval listing, also without import, because
This develops this product at home certain market prospects.Entitled (9S, 13S, the 14S) -3,17- diformazans of chemistry of Dimemorfan phosphate
Base is muttered phosphate, and chemical structural formula is as follows：
Company documents Chem.Pharm.Bull.1972,20 (8), 1706-1710 and patent US3786054 are ground referring to original,
It is with 5,6,7,8- tetrahydroisoquinolines for raw material in the Dimemorfan phosphate preparation process of Japan's listing, and to methylbenzyl chlorination
Magnesium is into row format addition reaction, through sodium borohydride reduction, chiral resolution, under the conditions of 85% phosphoric acid ring-closure reaction and with phosphoric acid at
Salt generates Dimemorfan phosphate, and the synthetic route is as follows：
The technological reaction step is long, and during preparing dimemorfan using 85% phosphoric acid cyclization, the reaction time is up to
75h, impurity content is big, and (product and different mutter of two major impurities are with the ratio of 10- methyl-N-methyl hexahydro aporphines
83%：7%：9%) high vacuum vacuum distillation (0.3mmHg), is needed to remove impurity, to equipment requirement height, then again with acetone weight
Crystallization obtains dimemorfan, finally obtains Dimemorfan phosphate at salt with phosphoric acid.
Chinese patent CN 102241630A are with (S) -1- (4- methylbenzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin -
L- mandelates are starting material, it is neutralized, methylate, obtained Dimemorfan phosphate, the process route such as cyclization it is as follows：
The technique there are still phosphoric acid cyclization step in above-mentioned process route there are the shortcomings that.
Chinese patent CN 103833635A using dextrorphan as starting material, through at ester, methylate, phosphoric acid be made at salt
Dimemorfan, the process route are as follows：
a.CF3SO2Cl (Tf=CF3SO2),Et3N,CH2Cl2；b.Me4Sn,(PPh3)2PdCl2,Ph3P, LiCl, toluene,
120℃,H 3PO4；
C.Fe(acae)3,NMP,MeMgBr,H3PO4
The technique starting material dextrorphan is commercially available seldom, and need to pass through two-step reaction could be made dimemorfan, cause to receive
Rate is general (total recovery about 60~70%).The first step needs the trifluoro methylsulphur high using price, irritation is strong simultaneously in being reacted at ester
Acyl chlorides is reacted, and is genotoxicity impurity by the triflate that the substance is formed, at this stage in pharmaceutical industry
Need extremely stringent control.
Chinese patent CN 104086486A using 2- (2- alkene -4- oxo-cyclohex alkyl) ethamine as starting material, through with it is right
The condensation of methyl phenyllacetyl chloride three oxyhalogen phosphorus cyclizations, carbonyl-protection, methylates, is deprotected, restoring, cyclization, at salt di(2-ethylhexyl)phosphate being made
First coffee alkane, the process route are as follows：
The process route step is longer, and intermediate 1- has been made by a kind of new process route in the focusing on of technique
(4- methylbenzyls)-N- methyl-1s, 2,3,4,5,6,7,8- octahydro isoquinolin, and be that phosphoric acid has been made in cyclization without splitting
Dimemorfan (should be raceme).
Invention content
The invention discloses a kind of preparation processes of Dimemorfan phosphate.Using the right U.S. of drug hydrobromic acid listed for many years
The base dextromethorphan of Sha Fen is starting material, and Dimemorfan phosphate is made at salt with phosphoric acid after methoxymethylated.This hair
Bright process route is succinct, product purity is high, of low cost, is suitable for industrialized production.
Preparation method of the present invention in turn includes the following steps：
A, 3- methoxyl groups -17- methyl Dextrorphan is reacted with methyl-magnesium-bromide is made 3,17- dimethyl Dextrorphans,
B, 3,17- dimethyl Dextrorphan obtains Dimemorfan phosphate with phosphoric acid at salt again.
Reaction equation is as follows：
It is preferred addition methylating reagent methyl-magnesium-bromide, bis- (tricyclohexyl phosphine) the dichloride nickel bars of catalyst in a steps
It is carried out under part.
The mole dosage of methyl-magnesium-bromide is preferably 1.0~3.0 times of 3- methoxyl group -17- methyl Dextrorphans.More preferably
1.0~1.5 times.
The mole dosage of bis- (tricyclohexyl phosphine) Nickel Chlorides be preferably 3- methoxyl group -17- methyl Dextrorphans 1%~
10%.
The mole dosage of bis- (tricyclohexyl phosphine) Nickel Chlorides is more preferably the 5% of 3- methoxyl group -17- methyl Dextrorphans.
Reaction condition of the present invention is mild, and reaction can be carried out in different temperature.
The tricyclohexyl phosphine of post-treated generation is not necessarily to additional purification in stepb in step a, can be when preparing phosphate
It is removed.
The present invention is more preferably following preparation method：
Under nitrogen protection, 3- methoxyl groups -17- methyl Dextrorphan and bis- (tricyclohexyl phosphine) Nickel Chlorides are added non-proton
Property solvent in stirring and dissolving, methyl magnesium bromide solution is added dropwise, after completion of the reaction, is quenched reaction, organic layer is eaten by washing, saturation
Salt is washed, and removing solvent is evaporated under reduced pressure after dry and obtains dimemorfan；It is directly added into water-soluble solvent dissolving without further purification, then
White solid is precipitated after 85% phosphatase reaction is added, it is preferred through being filtered, washed, being dried to obtain the above-mentioned phosphoric acid of Dimemorfan phosphate
85% phosphoric acid
The preferred toluene of non-protonic solvent in above-mentioned reaction.
Wherein water-soluble solvent is preferably 95% ethyl alcohol.
The present invention can be prepared by target product using commercially available dextromethorphan as raw material, through methylating, at salt.Process route letter
It is clean, product purity is high, of low cost, be suitable for industrialized production.
Specific implementation mode
Embodiment 1
Under nitrogen protection, by starting material 3- methoxyl group -17- methyl Dextrorphans (5.71g, 20mmol) and bis- (three hexamethylenes
Base phosphine) stirring and dissolving in 100ml toluene is added in Nickel Chloride (0.70g, 1mmol), and it is warming up to 65 DEG C, methyl-magnesium-bromide is added dropwise
(tetrahydrofuran solution) (1mol/L, 20ml, 20mmol), is added dropwise insulation reaction, and TLC detection raw materials are down to after completion of the reaction
Room temperature is added dropwise a small amount of saturated ammonium chloride solution and reaction is quenched, water washing is added to be layered, and divides and takes organic layer；Organic layer saturated salt solution
Washing, then after drying, vacuum distillation removes toluene and obtains dimemorfan；It is directly added into 25ml95% ethyl alcohol room temperatures without further purification
White solid is precipitated after 85% phosphoric acid (2.3g, 20mmol) reaction is then added, through being filtered, washed, being dried to obtain in stirring and dissolving
Dimemorfan phosphate 5.46g, yield 77.4%, purity 96.2%.
Embodiment 2
Under nitrogen protection, by starting material 3- methoxyl group -17- methyl Dextrorphans (5.71g, 20mmol) and bis- (three hexamethylenes
Base phosphine) stirring and dissolving in 100ml toluene is added in Nickel Chloride (0.14g, 0.2mmol), and it is warming up to 65 DEG C, methyl-magnesium-bromide is added dropwise
(tetrahydrofuran solution) (1mol/L, 20ml, 20mmol), is added dropwise insulation reaction, and TLC is detected after reaction.According to reality
The method for applying example 1 carries out subsequent reactions and obtains Dimemorfan phosphate 3.76g, yield 53.3%, purity 93.7%.
Embodiment 3
Under nitrogen protection, by starting material 3- methoxyl group -17- methyl Dextrorphans (5.71g, 20mmol) and bis- (three hexamethylenes
Base phosphine) stirring and dissolving in 100ml toluene is added in Nickel Chloride (0.70g, 1mmol), and it is warming up to 65 DEG C, methyl-magnesium-bromide is added dropwise
(tetrahydrofuran solution) (1mol/L, 60ml, 60mmol), is added dropwise insulation reaction, and TLC detects raw material after completion of the reaction, presses
1 method carries out subsequent reactions and obtains Dimemorfan phosphate 5.51g, yield 78.1%, purity 97.4% as usual.
Embodiment 4
Under nitrogen protection, by starting material 3- methoxyl group -17- methyl Dextrorphans (5.71g, 20mmol) and bis- (three hexamethylenes
Base phosphine) stirring and dissolving in 100ml toluene is added in Nickel Chloride (0.70g, 1mmol), and it is warming up to 65 DEG C, methyl-magnesium-bromide is added dropwise
(tetrahydrofuran solution) (1mol/L, 24ml, 24mmol), is added dropwise insulation reaction, and TLC detects raw material after completion of the reaction, presses
Dimemorfan phosphate 5.79g, yield 82.0%, purity 99.1% are obtained according to the method progress subsequent reactions of embodiment 1.
Embodiment 5
Under nitrogen protection, by starting material 3- methoxyl group -17- methyl Dextrorphans (5.71g, 20mmol) and bis- (three hexamethylenes
Base phosphine) stirring and dissolving in 100ml toluene is added in Nickel Chloride (0.70g, 1mmol), it is warming up to reflux (about 120 DEG C), dropwise addition first
Base magnesium bromide (n-butyl ether solution) (1mol/L, 24ml, 24mmol), is added dropwise insulation reaction, and TLC detection raw material reactions finish
Afterwards, subsequent reactions are carried out according to the method for embodiment 1 and obtains Dimemorfan phosphate 5.72g, yield 81.0%, purity 97.9%.
Embodiment 6
Under nitrogen protection, by starting material 3- methoxyl group -17- methyl Dextrorphans (5.71g, 20mmol) and bis- (three hexamethylenes
Base phosphine) Nickel Chloride (0.70g, 1mmol) be added 100ml toluene in stirring and dissolving, room temperature be added dropwise methyl-magnesium-bromide (tetrahydrofuran
Solution) (1mol/L, 24ml, 24mmol), insulation reaction is added dropwise, after the completion of TLC detects raw material reaction, according to embodiment 1
Method carry out subsequent reactions obtain Dimemorfan phosphate 4.8g, yield 68.0%, purity 94.8%.
Claims (9)
1. a kind of method preparing Dimemorfan phosphate, in turn includes the following steps：
A, 3- methoxyl groups -17- methyl Dextrorphan is reacted with methyl-magnesium-bromide is made 3,17- dimethyl Dextrorphans,
B, 3,17- dimethyl Dextrorphan obtains Dimemorfan phosphate with phosphoric acid at salt again.
2. it is to be added to the bis- (thricyclohexyls of methylating reagent methyl-magnesium-bromide, catalyst in a steps method of claim 1
Phosphine) it carries out under the conditions of Nickel Chloride.
3. the method for claim 2, the wherein mole dosage of methyl-magnesium-bromide be 3- methoxyl group -17- methyl Dextrorphans 1.0~
3.0 again.
4. the method for claim 3, the wherein mole dosage of methyl-magnesium-bromide are the 1.2 of 3- methoxyl group -17- methyl Dextrorphans
Times.
5. the method for claim 2, wherein the mole dosage of bis- (tricyclohexyl phosphine) Nickel Chlorides is 3- methoxyl group -17- methyl
The 1%~10% of Dextrorphan.
6. the method for claim 5, wherein the mole dosage of bis- (tricyclohexyl phosphine) Nickel Chlorides is 3- methoxyl group -17- methyl
The 5% of Dextrorphan.
7. method of claim 1, including：Under nitrogen protection, by 3- methoxyl groups -17- methyl Dextrorphan and bis- (thricyclohexyls
Phosphine) Nickel Chloride be added non-protonic solvent in stirring and dissolving, be added dropwise methyl magnesium bromide solution reaction is quenched after completion of the reaction,
Organic layer passes through washing, and saturated common salt washing is evaporated under reduced pressure removing solvent and obtains dimemorfan after dry；Directly add without further purification
Enter water-soluble solvent dissolving, white solid is precipitated after phosphatase reaction then is added, through being filtered, washed, being dried to obtain phosphoric acid diformazan
Coffee alkane.
8. the method for claim 7, non-protonic solvent is toluene in a steps.
9. the method for claim 7, water-soluble solvent is 95% ethyl alcohol in b step.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810199587.1A CN108484502A (en) | 2018-03-12 | 2018-03-12 | A method of preparing Dimemorfan phosphate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810199587.1A CN108484502A (en) | 2018-03-12 | 2018-03-12 | A method of preparing Dimemorfan phosphate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108484502A true CN108484502A (en) | 2018-09-04 |
Family
ID=63338436
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810199587.1A Pending CN108484502A (en) | 2018-03-12 | 2018-03-12 | A method of preparing Dimemorfan phosphate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108484502A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3786054A (en) * | 1970-06-20 | 1974-01-15 | Yamanouchi Pharma Co Ltd | 3-methyl-n-methylmorphinans |
| CN103833635A (en) * | 2014-03-20 | 2014-06-04 | 武汉药谷生物工程有限公司 | Method for preparing safe and effective antibechic dimimorfan phosphate |
-
2018
- 2018-03-12 CN CN201810199587.1A patent/CN108484502A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3786054A (en) * | 1970-06-20 | 1974-01-15 | Yamanouchi Pharma Co Ltd | 3-methyl-n-methylmorphinans |
| CN103833635A (en) * | 2014-03-20 | 2014-06-04 | 武汉药谷生物工程有限公司 | Method for preparing safe and effective antibechic dimimorfan phosphate |
Non-Patent Citations (4)
| Title |
|---|
| HUI LIU ET AL.: "An Efficient Synthesis of Dimemorfan from Dextromethorphan", 《ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL》 * |
| JONG YUP KIM ET AL.: "Concise Synthesis of Dimemorfan (DF) Starting from 3-Hydroxymorphinan (3HM)", 《CHEM. PHARM. BULL.》 * |
| MAMORU TOBISU ET AL.: "Nickel-Catalyzed Cross-Coupling of Anisoles with Alkyl Grignard Reagents via C-O Bond Cleavage", 《ORGANIC LETTERS》 * |
| ZHANG-JIE GUAN ET AL.: "Methylation of arenes via Ni-catalyzed aryl C–O/F activation", 《CHEM. COMMUN.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100999522B (en) | Preparation process of palmatine | |
| US9573932B2 (en) | Synthesis of intermediates in the preparation of ALK inhibitor | |
| CN103153956A (en) | Novel processes for the manufacture of propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1h-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide | |
| CN106187852A (en) | A kind of preparation method of Vonoprazan fumarate intermediate | |
| CN104844602B (en) | A kind of preparation method of Li Gelieting | |
| Moss | A ring-closing metathesis approach to heterocycle-fused azepines | |
| CN107531677A (en) | Method for preparing Topiroxostat and its intermediate | |
| CN108484502A (en) | A method of preparing Dimemorfan phosphate | |
| Olszewski et al. | Highly diastereoselective addition of chiral H-phosphonate to tert-butylsulfinyl aldimines: a convenient approach to (R)-α-aminophosphonic acids | |
| CN104974051A (en) | Synthetic method for (1S,4R)-cis-4-amino-2-cyclopentene-1-methanol hydrochloride | |
| CN112920119B (en) | Preparation method of aporphine alkaloid | |
| CN102603597A (en) | Preparation method of (S)-oxiracetam | |
| EP2229387A1 (en) | Process for preparing chemically and chirally pure solifenacin base and its salts | |
| CN107721815A (en) | The preparation method of one kind 2 (3,5 2 (trifluoromethyl) phenyl) 2 methylpropanoic acids of synthesis | |
| KR101681954B1 (en) | Boron-Catalyzed Silylative Reduction of N-Heteroaromatics | |
| WO2011086003A1 (en) | Process for the preparation of solifenacin and solifenacin succinate | |
| CN1257166C (en) | Process for preparing tricyclic compound having antihistaminic activity | |
| CN105254646A (en) | Everolimus preparation method | |
| CN114026095A (en) | Alternative process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl ] methyl ] -3-oxo-5, 6,8,8 a-tetrahydro-1H-imidazo [1,5-a ] pyrazin-2-yl ] -carboxylic acid | |
| CN108314648A (en) | The synthetic method of the bromo- 7- fluorine isoquinolin of 4- | |
| CN101314587B (en) | Preparation for midbody of Irinotecan and preparation for Irinotecan | |
| WO2011048607A1 (en) | Processes for the preparation of solifenacin or a salt thereof | |
| CN108299301A (en) | A method of preparing high-purity dimemorfan | |
| CN102603596A (en) | Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide | |
| CN106636246A (en) | Preparation of (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine through biological method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180904 |
|
| WD01 | Invention patent application deemed withdrawn after publication |