CN103965109B - A kind of method of synthesizing codamine - Google Patents
A kind of method of synthesizing codamine Download PDFInfo
- Publication number
- CN103965109B CN103965109B CN201310046417.7A CN201310046417A CN103965109B CN 103965109 B CN103965109 B CN 103965109B CN 201310046417 A CN201310046417 A CN 201310046417A CN 103965109 B CN103965109 B CN 103965109B
- Authority
- CN
- China
- Prior art keywords
- mol ratio
- hour
- ethyl acetate
- codamine
- add
- 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.)
- Expired - Fee Related
Links
- 0 COC(*C(C=C)C=C1)=C1OC Chemical compound COC(*C(C=C)C=C1)=C1OC 0.000 description 4
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of chemical synthesis process of codamine, present method is with 3,4-dimethoxyphenylacetic acid and 4-hydroxyl, 3-methoxyphenethylamine hydrochloride is starting raw material, obtain intermediate compound I respectively through acid amide condensation, be dehydrated into intermediate II by phosphorus oxychloride, the reduction of intermediate II and then (one pot reaction) three-step reaction that methylates, total recovery is 34%.The features such as the present invention has simple to operate, and raw material is easy to get, and the reaction times is short.
Description
Technical field
The present invention relates to a kind of method preparing codamine.
Background technology
Drug problem is worldwide on the rise in recent years, causes great harm to society.Heroine is one of modal drug species, and opium (Papaver somniferum) is the starting raw material preparing heroine, and containing multiple constant and trace biology alkali in opium, these alkaloids are one of Main Means of the opium sample distinguishing different geographical.
Codamine (codamine), Laudanine (laudanine) are the important trace biology alkali in opium, and their molecular formula is C
20h
25nO
4, be difficult to when lacking reference substance or standard substance determine the retention time of two compounds in liquid chromatography.Existing market is difficult to reference substance or the standard substance of having bought codamine, therefore synthesize codamine for determining its retention time in liquid phase, and the differentiation tool realizing different geographical opium sample is of great significance.
At present, known references (Journal of Natural Products, 70 (11), 1771-1778; 2007), a kind of method of synthesizing codamine is reported: use Hydrogen bromide to carry out demethylation to DL-laudanosine (needing to be prepared through polystep reaction), and then obtain codamine.But the main drawback of the method obtains eight isomer, be separated and get up to have very high difficulty.
Summary of the invention
Unless otherwise noted, all conventional in the art according to it usage of the term in the present invention uses, and chemical is all buied from manufacturer conventional on market or method of the prior art preparation.
As used herein, term " room temperature " refers to 20-30 DEG C.
The object of the invention is to overcome the deficiencies in the prior art, providing a kind of stable, simple, raw material and be easy to get and prepare the method for codamine efficiently.
On the one hand, the invention provides a kind of method preparing codamine, said method comprising the steps of:
1) 3,4-dimethoxyphenylacetic acid and 4-hydroxyl, 3-methoxyphenethylamine hydrochloride and condensing agent are joined in pyridine, at room temperature stir 3-6 hour, obtain reaction product; In described reaction product, add ethyl acetate, aqueous ammonium chloride solution and the NaCl aqueous solution obtain organic phase to carry out extraction, after described organic phase anhydrous sodium sulfate drying, remove ethyl acetate and namely obtain intermediate compound I;
2) intermediate compound I is joined in toluene, then add phosphorus oxychloride, obtain reaction solution; Described reaction solution be heated to 85-110 DEG C and stir 2-3 hour, removing toluene and unnecessary phosphorus oxychloride, add mixture of ice and water, with aqueous sodium carbonate adjust pH to 8-9, obtain reaction product; Then by ethyl acetate, described reaction product is extracted, then use anhydrous sodium sulfate drying, namely obtain intermediate II;
3) intermediate II is joined in methyl alcohol, cool with ice bath, add sodium borohydride, then at stirring at room temperature 1-2 hour, obtain reaction solution;
4) then by massfraction be 37% formalin join in the reaction solution that step 3) obtains, stir after 0.5-2 hour, add sodium borohydride, continue to stir after 1-2 hour, cool to room temperature, is adjusted to 6-8 with aqueous ammonium chloride solution by pH value, remove methyl alcohol, obtain reaction product; Extract by ethyl acetate, carry out drying by anhydrous sodium sulphate, obtain codamine.
Preferably, in step 1), described 3,4-dimethoxyphenylacetic acids and described 4-hydroxyl, the mol ratio of 3-methoxyphenethylamine hydrochloride is 1:(1-1.2).
Preferably, in step 1), the mol ratio of described 3,4-dimethoxyphenylacetic acids and described condensing agent is 1:(1.2-1.5).
Preferably, in step 1), described condensing agent be selected from HBTU, HATU and EDCI one or more, be more preferably HBTU.
Preferably, in step 2) in, the mol ratio of described intermediate compound I and described phosphorus oxychloride is 1:(5-10).
Preferably, in step 3), the mol ratio of described intermediate II and described sodium borohydride is 1:(1-1.2).
Preferably, in step 4), the mol ratio of described intermediate II and described formalin is 1:(3-5).
Preferably, in step 4), the mol ratio of described intermediate II and described sodium borohydride is 1:(2-3).
On the other hand, the invention provides codamine prepared by a kind of method described in basis.
In one embodiment, method according to the present invention adopts following scheme:
With 3,4-dimethoxyphenylacetic acid and 4-hydroxyl, 3-methoxyphenethylamine hydrochloride is starting raw material, intermediate compound I is obtained respectively through acid amide condensation, be dehydrated into intermediate II by phosphorus oxychloride, intermediate II reduction and then (one pot reaction) three-step reaction that methylates are obtained codamine, total recovery is 34%.
Reaction process is as follows:
Compared with prior art, advantage of the present invention is:
The method preparing codamine provided by the present invention has simple to operate, raw material and is easy to get and the feature such as the reaction times is short.Method choice of the present invention is high, and eliminate the sepn process of complicated difficulty from 8 isomer, the operating time is short, and only 2 day time just can take the finished product, and experimental implementation is simple, and general laboratory technician can implement.And prior art at least needs just can take for 5 days product, experimental procedure is long, and experimental implementation is complicated, and selectivity is low, and final step can produce 8 isomer, and separating difficulty is high, differentiates that difficulty is large.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments only for illustration of object of the present invention, its scope do not limited the present invention in any way.
embodiment 1
By 3 of 196 mg, the 4-hydroxyl of 4-dimethoxyphenylacetic acid (purchased from lark prestige Science and Technology Ltd.) and 245 mg, the HBTU(of 3-methoxyphenethylamine hydrochloride (purchased from Matrix Scientifi) and 569 mg is purchased from lark prestige Science and Technology Ltd.) join in the pyridine of 3 mL, then at room temperature stir 6 hours.The ethyl acetate aqueous ammonium chloride solution and the NaCl aqueous solution that add 10 mL respectively wash 2-3 all over to extract, and obtain organic phase; By organic phase anhydrous sodium sulfate drying, revolve ethyl acetate and namely obtain intermediate compound I (LCMS purity is 92% for 350 mg, crude product).NMR test is carried out to intermediate compound I,
1h NMR (300 MHz, CDCl
3) δ 6.77 (dd, J=8.3,4.9 Hz, 2H), 6.69-6.64 (m, 2H), 6.58 (d, J=1.9 Hz, 1H), 6.49 (dd, J=8.0,1.9 Hz, 1H), 3.88 (s, 3H), 3.83 (d, J=1.3 Hz, 6H), 3.46 – 3.38 (t, J=6.9 Hz, 2H), 2.80 (s, 2H), 2.66 (t, J=6.9 Hz, 2H). ESI 346 (M+1)
+.
The intermediate compound I of 350 mg is joined in the toluene of 3mL, then adds the phosphorus oxychloride of 1.0 mL, obtain reaction solution; Reaction solution is heated to 110 DEG C and stirs cooling after 3 hours, revolve toluene and unnecessary phosphorus oxychloride, a little mixture of ice and water is added, with aqueous sodium carbonate adjust pH to 8-9, then use the extraction into ethyl acetate 2-3 time of 10mL, then use anhydrous sodium sulfate drying, be spin-dried for and namely obtain intermediate II (232 mg, crude product, LCMS purity is 81%).ESI 328 (M+H)+。
The intermediate II of 232 mg is joined in the methyl alcohol of 2 mL, cool with ice bath, then the sodium borohydride of 30 mg is slowly added, then at room temperature stir 1 hour, then be 37%(massfraction by concentration) the formalin of 288 mg add reaction solution, stir after 2 hours, the sodium borohydride of 81mg is added, continue stirring after 2 hours, cool to room temperature, aqueous ammonium chloride solution is slowly dripped into, until pH value is to 6-8, revolve methyl alcohol, with extraction into ethyl acetate 2-3 time of 10 mL, anhydrous sodium sulfate drying, be spin-dried for, namely codamine (116 mg) is obtained with silica column purification (eluant dichloromethane: methyl alcohol=20:1), total recovery is 34%.Fusing point is 172-175 DEG C.
1H NMR (300 MHz, CDCl
3) δ 6.76 – 6.69 (m, 2H), δ 6.67 – 6.60 (m, 2H), 6.13 (s, 1H), 4.75 – 4.71 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.48 (s, 3H), 3.33 – 3.20 (m, 2H), 3.16 – 3.05 (m, 2H), 3.03 – 2.95 (m, 3H), 2.93 – 2.88 (m, 1H), 2.83 (d, J = 4.9 Hz, 3H)；ESI 344 (M+H)+。
embodiment 2
By 3 of 196 mg, the 4-hydroxyl of 4-dimethoxyphenylacetic acid (purchased from lark prestige Science and Technology Ltd.) and 225 mg, the HBTU(of 3-methoxyphenethylamine hydrochloride (purchased from Matrix Scientifi) 493 mg is purchased from lark prestige Science and Technology Ltd.) join in the pyridine of 3mL and go, then at room temperature stir 3 hours.Add the ethyl acetate of 10mL, respectively wash 2-3 time with aqueous ammonium chloride solution and the NaCl aqueous solution, organic phase anhydrous sodium sulfate drying, revolve ethyl acetate and namely obtain intermediate compound I (340 mg, crude product, LCMS purity 90%).
The intermediate compound I of 340mg is joined in the toluene of 3mL, then adds the phosphorus oxychloride of 0.8 mL, obtain reaction solution; Reaction solution is heated to 110 DEG C and stirs cooling after 2 hours, revolve toluene and unnecessary phosphorus oxychloride, a little mixture of ice and water is added, with aqueous sodium carbonate adjust pH to 8-9, then use the extraction into ethyl acetate 2-3 time of 10mL, then use anhydrous sodium sulfate drying, be spin-dried for and namely obtain intermediate II (221 mg, crude product, LCMS purity 82%).ESI 328 (M+H)+。
The intermediate II of 221mg is joined in the methyl alcohol of 2mL, cool with ice bath, then the sodium borohydride of 25mg is slowly added, then at room temperature stir 2 hours, then be 37%(massfraction by concentration) the formalin of 215mg add reaction solution, stir after 1 hour, the sodium borohydride of 54mg is added, continue stirring after 1 hour, cool to room temperature, aqueous ammonium chloride solution is slowly dripped into, until pH value is to 6-8, revolve methyl alcohol, with extraction into ethyl acetate 2-3 time of 10mL, anhydrous sodium sulfate drying, be spin-dried for, namely codamine (105 mg) is obtained with silica column purification (eluant dichloromethane: methyl alcohol=20:1).Total recovery is 31%.
embodiment 3
By 3 of 196 mg, the 4-hydroxyl of 4-dimethoxyphenylacetic acid (purchased from lark prestige Science and Technology Ltd.) and 205 mg, the HBTU(of 3-methoxyphenethylamine hydrochloride (purchased from Matrix Scientifi) and 455mg is purchased from lark prestige Science and Technology Ltd.) join in the pyridine of 3mL and go, then stirring at room temperature 3 hours.Add the ethyl acetate of 10 mL, respectively wash 2-3 time with aqueous ammonium chloride solution and the NaCl aqueous solution, organic phase anhydrous sodium sulfate drying, revolve ethyl acetate and namely obtain intermediate compound I (345 mg, crude product, LCMS purity 91%), be directly used in second step reaction.
The intermediate compound I of 345mg is joined in the toluene of 3mL, then adds the phosphorus oxychloride of 0.5mL, obtain reaction solution; Reaction solution is heated to 110 DEG C and stirs cooling after 2 hours, revolve toluene and unnecessary phosphorus oxychloride, a little mixture of ice and water is added, with aqueous sodium carbonate adjust pH to 8-9, then use the extraction into ethyl acetate 2-3 time of 10mL, then use anhydrous sodium sulfate drying, be spin-dried for and namely obtain intermediate II (217 mg, crude product, LCMS purity 83%).ESI 328 (M+H)+。
The intermediate II of 217mg is joined in the methyl alcohol of 2mL, cools with ice bath, then the sodium borohydride of 30mg is slowly added, then stirring at room temperature 2 hours, obtain reaction solution; Then be that the formalin of the 165mg of 37% adds in reaction solution by concentration, stir after 0.5 hour, the sodium borohydride of 54mg is added, continue stirring after 1 hour, cool to room temperature, aqueous ammonium chloride solution is slowly dripped into, until pH value is to 6-8, revolves methyl alcohol, with extraction into ethyl acetate 2-3 time of 10mL, anhydrous sodium sulfate drying, is spin-dried for, and namely obtains the codamine of 111 mg with silica column purification (eluant dichloromethane: methyl alcohol=20:1).Total recovery is 33%.
Claims (8)
1. prepare a method for codamine, it is characterized in that, said method comprising the steps of:
1) 3,4-dimethoxyphenylacetic acid and 4-hydroxy 3-methoxybenzene ethylamine hydrochloride and condensing agent are joined in pyridine, at room temperature stir 3-6 hour, obtain reaction product; In described reaction product, add ethyl acetate, aqueous ammonium chloride solution and the NaCl aqueous solution obtain organic phase to carry out extraction, after described organic phase anhydrous sodium sulfate drying, remove ethyl acetate and namely obtain intermediate compound I;
2) intermediate compound I is joined in toluene, then add phosphorus oxychloride, obtain reaction solution, described reaction solution be heated to 85-110 DEG C and stir 2-3 hour, removing toluene and unnecessary phosphorus oxychloride, add mixture of ice and water, with aqueous sodium carbonate adjust pH to 8-9, obtain reaction product; Then by ethyl acetate, described reaction product is extracted, then use anhydrous sodium sulfate drying, namely obtain intermediate II;
3) intermediate II is joined in methyl alcohol, cool with ice bath, add sodium borohydride, then at stirring at room temperature 1-2 hour, obtain reaction solution;
4) then by massfraction be 37% formalin join step 3) in the reaction solution that obtains, stir after 0.5-2 hour, add sodium borohydride, continue to stir after 1-2 hour, cool to room temperature, with aqueous ammonium chloride solution, pH value is adjusted to 6-8, removes methyl alcohol, obtain reaction product; Extract by ethyl acetate, carry out drying by anhydrous sodium sulphate, obtain codamine.
2. method according to claim 1, is characterized in that, in step 1) in, described 3, the mol ratio of 4 dimethoxyphenylacetic acids and described 4-hydroxy 3-methoxybenzene ethylamine hydrochloride is 1: (1-1.2).
3. method according to claim 1 and 2, is characterized in that, in step 1) in, described 3, the mol ratio of 4 dimethoxyphenylacetic acids and described condensing agent is 1: (1.2-1.5).
4. method according to claim 1, is characterized in that, in step 1) in, described condensing agent be selected from HBTU, HATU and EDCI one or more.
5. method according to claim 1 and 2, is characterized in that, in step 2) in, the mol ratio of described intermediate compound I and described phosphorus oxychloride is 1: (5-10).
6. method according to claim 1 and 2, is characterized in that, in step 3) in, the mol ratio of described intermediate II and described sodium borohydride is 1: (1-1.2).
7. method according to claim 1 and 2, is characterized in that, in step 4) in, the mol ratio of described intermediate II and described formalin is 1: (3-5).
8. method according to claim 1 and 2, is characterized in that, in step 4) in, the mol ratio of described intermediate II and described sodium borohydride is 1: (2-3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310046417.7A CN103965109B (en) | 2013-02-06 | 2013-02-06 | A kind of method of synthesizing codamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310046417.7A CN103965109B (en) | 2013-02-06 | 2013-02-06 | A kind of method of synthesizing codamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103965109A CN103965109A (en) | 2014-08-06 |
| CN103965109B true CN103965109B (en) | 2015-08-19 |
Family
ID=51235168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310046417.7A Expired - Fee Related CN103965109B (en) | 2013-02-06 | 2013-02-06 | A kind of method of synthesizing codamine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103965109B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008073390A2 (en) * | 2006-12-11 | 2008-06-19 | Mallinckrodt Inc. | Preparation of 3,4-dihydroisoquinolines from an acid and an amine |
| CN101544603A (en) * | 2009-05-05 | 2009-09-30 | 南京威尔化工有限公司 | Preparation method of 3,4-dihydropapaverine and hydrochloride thereof |
-
2013
- 2013-02-06 CN CN201310046417.7A patent/CN103965109B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN103965109A (en) | 2014-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104211676B (en) | The method for obtaining olopatadine and intermediate | |
| CN104557572B (en) | Levalbuterol intermediate and levalbuterol hydrochloride synthesis method | |
| JP2017501141A5 (en) | ||
| CN105541633B (en) | open-chain chiral crown ether containing ent-Bayesian skeleton and preparation and application thereof | |
| CA2942301A1 (en) | Clomiphene synthesis using a single solvent | |
| CN109096126B (en) | Deuterium labeled D9Synthesis method of clenbuterol hydrochloride | |
| CN104478871B (en) | A kind of choline m receptor antagonist aclidinium bromide and preparation method thereof | |
| CN103787975A (en) | Huperzine A D-dibenzoyltartartrate and preparation method and application thereof | |
| CN103965109B (en) | A kind of method of synthesizing codamine | |
| CN105399644B (en) | One class with (1S, 2S) 1,2 cyclohexanediamine be isolate base, with Molecular Tweezers compound that iso steviol is chiral arm and its preparation method and application | |
| CN104478974B (en) | A kind of 20, the synthetic method of 23-dipiperidino-5-O-mycamino syl-tylono lide | |
| CN103965108B (en) | A kind of method of synthesizing Laudanine | |
| CN109988108A (en) | A kind of rich preparation method for Buddhist nun of card | |
| CN104151170A (en) | 4-nitrophenethylamine hydrochloride and preparation method thereof | |
| JP5664870B2 (en) | Novel crystal form of tricyclic benzopyran compound and method for producing the same | |
| RU2630700C2 (en) | METHODS FOR OBTAINING 5-[2-[7-(TRIFLUOROMETHYL)-5-[4-(TRIFLUOROMETHYL)PHENYL]PYRAZOLO[1,5-a]PYRIMIDINE-3-YL]ETHINYL]-2-PYRIDINAMINE | |
| CN101891731A (en) | Method for synthesizing olopatatadine E-configurational isomer | |
| CN107540564B (en) | Preparation method of Vorapaxar intermediate | |
| JPWO2015012271A1 (en) | Method for producing heterocyclic compound | |
| CN104447776A (en) | Novel heterocyclic organic compound and preparation method thereof | |
| EP1539751B1 (en) | Process for the preparation of imidazo(1,2-a)pyridine-3-acetamides | |
| CN105440030B (en) | A kind of choline m receptor antagonist aclidinium bromide and preparation method thereof | |
| CN104945399A (en) | Method for preparing Moxifloxacin impurity C | |
| CN105601640B (en) | A kind of N- tertbutyloxycarbonyls -7-（Amine methyl）The synthetic method of -6- oxa- -2- spiral shells [4.5] decane | |
| CN104876869B (en) | A kind of method for splitting of chiral fenoldpam |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150819 Termination date: 20170206 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |