CN103965108B - A kind of method of synthesizing Laudanine - Google Patents
A kind of method of synthesizing Laudanine Download PDFInfo
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- CN103965108B CN103965108B CN201310046416.2A CN201310046416A CN103965108B CN 103965108 B CN103965108 B CN 103965108B CN 201310046416 A CN201310046416 A CN 201310046416A CN 103965108 B CN103965108 B CN 103965108B
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- 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
Abstract
The invention provides a kind of synthetic method of Laudanine, present method is with 3-hydroxyl, 4-methoxyphenylacetic acid and 3,4-dimethoxy-phenylethylamine and be 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 32%.The present invention has simple to operate, and raw material is easy to get, and the reaction times is short, reaction yield high.
Description
Technical field
The present invention relates to a kind of preparation method of Laudanine.
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.
Laudanine (laudanine), codamine (codamine) are the important trace biology alkali in opium, and their molecular formula is C
20h
25nO
4, determine the retention time of two compounds in liquid chromatography to being difficult to when reference substance or standard substance when lacking.Existing market is difficult to reference substance or the standard substance of having bought Laudanine, therefore synthesize Laudanine for determining its retention time in liquid phase, and the differentiation tool realizing different geographical opium sample is of great significance.
At present, the method for the synthesis Laudanine of known references report mainly contains three kinds, the first (Polish Journal of Chemistry, 68 (12), 2665-70; 1994) method, if synthesis (Tetrahedron, 42 (24), 6669-72 of counting intermediate in; 1986; Organic Letters, 8 (1), 143-146; 2006; WO2012081031,21 Jun 2012; Bioorganic & Medicinal Chemistry Letters, 21 (19), 5934-5938; 2011), altogether need five to seven step reactions, wherein relate to 1; 3-dimercapto propylene glycol is to the protection of aldehyde radical; and Raney Ni is to its deprotection, also relate to the use of the dangerous butyllithium of tool, and total recovery unsatisfactory (<30%).
Second method (Journal of Natural Products, 70 (11), 1771-1778; 2007), be use Hydrogen bromide to carry out demethylation to DL-laudanosine, and then obtain Laudanine, the main drawback of the method obtains 8 eight isomer, has very high separating difficulty.
The third method (Indian Journal of Chemistry, Section B:Organic Chemistry Including Medicinal Chemistry, 25B (10), 1027-30; 1986; Chemical & Pharmaceutical Bulletin, 34 (5), 1946-9; 1986) also clearly, yield is extremely low, complex operation for shortcoming.
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, provide a kind of stable, simple, raw material be easy to get and efficiently prepare the method for Laudanine.
On the one hand, the invention provides a kind of method preparing Laudanine, said method comprising the steps of:
1) by 3-hydroxyl, 4-methoxyphenylacetic acid and 3,4-dimethoxy-phenylethylamine and condensing agent join in pyridine, then at room temperature stir 6-18 hour, obtain reaction product; In described reaction product, add ethyl acetate and add aqueous ammonium chloride solution respectively and the NaCl aqueous solution obtains organic phase to carry out extraction, after described organic phase anhydrous sodium sulfate drying, removing 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 is heated to 80-110 DEG C, stirs 2-3 hour, remove 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 add 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, by aqueous ammonium chloride solution by pH value to 6-8, remove methyl alcohol, obtain reaction product; Be extracted with ethyl acetate, carry out drying by anhydrous sodium sulphate, obtain Laudanine.
Preferably, in step 1), described 3-hydroxyl, the mol ratio of 4-methoxyphenylacetic acid and described 3,4-dimethoxy-phenylethylamines is 1:(1-1.2).
Preferably, in step 1), described 3-hydroxyl, the mol ratio of 4-methoxyphenylacetic acid and described condensing agent is 1:(1.2-1.5).
Preferably, in step 1), described condensing agent is selected from one or more in HBTU, HATU and EDCI, is 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 a kind of Laudanine prepared according to method of the present invention.
In one embodiment, method according to the present invention adopts following scheme:
With 3,4-dimethoxyphenylacetic acid and 3-hydroxyl, 4-methoxyphenethylamine hydrochloride is starting raw material, obtains intermediate compound I, is dehydrated into intermediate II by phosphorus oxychloride, the reduction of intermediate II and then (one pot reaction) three-step reaction that methylates respectively through acid amide condensation, and total recovery is 32%.
Compared with prior art, advantage of the present invention is:
The method preparing Laudanine 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.Compared with prior art, the present invention has simple to operate, and general laboratory technician can operate, and be safe from danger operation, and the reaction times is short, only needs two day time to obtain the finished product, and reaction yield such as can to receive at the advantage.
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 the 3-hydroxyl of 182 mg, 3 of 4-methoxyphenylacetic acid (purchased from lark prestige Science and Technology Ltd.) and 218 mg, 4-dimethoxy-phenylethylamine (thinking bio tech ltd purchased from Tianjin Skien) and the HBTU(of 569mg are purchased from lark prestige Science and Technology Ltd.) join in the pyridine of 3mL, then stirring at room temperature 18 hours.Add the ethyl acetate of 10mL and respectively wash 2-3 all over to extract with aqueous ammonium chloride solution and the NaCl aqueous solution, obtaining organic phase; By organic phase anhydrous sodium sulfate drying, revolve ethyl acetate and namely obtain intermediate compound I (337mg, crude product, LCMS purity 92%), be directly used in second step reaction.
1H NMR (300 MHz, CDCl3) δ 6.79 – 6.69 (m, 3H), 6.66 – 6.51 (m, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.49 – 3.36 (m, 4H), 2.67 (t, J = 6.8 Hz, 2H)；ESI 346 (M+H)+。
The intermediate compound I of 337mg is joined in the toluene of 3mL, then adds the phosphorus oxychloride of 0.9 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 (212 mg, crude product, LCMS purity 83%).ESI 328 (M+H)+。
The intermediate II of 212mg is joined in the methyl alcohol of 2mL, cools with ice bath, then the sodium borohydride of 25mg is slowly added, then stirring at room temperature 1 hour, obtain reaction solution; Then be that the formalin of the 263mg of 37% adds reaction solution by concentration, stir after 2 hours, add the sodium borohydride of 85mg, continue stirring after 2 hours, 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 Laudanine (110 mg) with silica column purification (eluant dichloromethane: methyl alcohol=20:1).Total recovery is 32%.Fusing point 163-165 DEG C.
1H NMR (300 MHz, CD3OD) δ 6.94 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.72 – 6.64 (m, 2H), 6.03 (s, 1H), 4.65 – 4.56 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.52 (s, 3H), 3.36 – 3.23 (m, 2H), 3.19 – 3.10 (m, 3H), 3.03 (d, J = 0.7 Hz, 3H)；ESI 344 (M+H)+。
embodiment 2
By the 3-hydroxyl of 182mg, 3 of 4-methoxyphenylacetic acid (purchased from lark prestige Science and Technology Ltd.) and 199mg, 4-dimethoxy-phenylethylamine (thinking bio tech ltd purchased from Tianjin Skien) and the HBTU(of 493mg are purchased from lark prestige Science and Technology Ltd.) join in the pyridine of 3mL, then stirring at room temperature 8 hours.Add the ethyl acetate of 10mL, respectively wash 2-3 all over to extract with aqueous ammonium chloride solution and the NaCl aqueous solution, obtain organic phase; Drying is carried out to organic phase anhydrous sodium sulphate, revolves ethyl acetate and namely obtain intermediate compound I (343 mg, crude product, LCMS purity 90%).
The intermediate compound I of 343mg is joined in the toluene of 3mL, then adds the phosphorus oxychloride of 0.7 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 2(209 mg, crude product, LCMS purity 85%).ESI 328 (M+H)+。
The intermediate II of 209mg is joined in 2mL methyl alcohol, 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 207mg of 37% adds reaction solution by concentration, stir after 1 hour, the sodium borohydride of 55mg 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 Laudanine of 105mg with silica column purification (eluant dichloromethane: methyl alcohol=20:1).Total recovery is 31%.
embodiment 3
By the 3-hydroxyl of 182mg, 3 of 4-methoxyphenylacetic acid (purchased from lark prestige Science and Technology Ltd.) and 182mg, 4-dimethoxy-phenylethylamine (thinking bio tech ltd purchased from Tianjin Skien) and 455mg HBTU(are purchased from lark prestige Science and Technology Ltd.) join in the pyridine of 3mL, then stirring at room temperature 6 hours.Add the ethyl acetate of 10mL and respectively wash 2-3 all over to extract with aqueous ammonium chloride solution and the NaCl aqueous solution, obtaining organic phase; Drying is carried out to organic phase anhydrous sodium sulphate, revolves ethyl acetate and namely obtain intermediate compound I (332 mg, crude product, LCMS purity 93%).
The intermediate compound I of 332 mg is joined in the toluene of 3mL, then the phosphorus oxychloride of 0.5mL is added, 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 (212 mg, crude product, LCMS purity 85%).ESI 328 (M+H)+。
The intermediate II of 212mg is joined in the methyl alcohol of 2mL, cools with ice bath, then the sodium borohydride of 30mg is slowly added, at room temperature stir 2 hours, obtain reaction solution; Then be that the formalin of 158 mg of 37% adds reaction solution by concentration, stir after 0.5 hour, the sodium borohydride of 55mg 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, with anhydrous sodium sulfate drying, be spin-dried for, namely obtain the Laudanine of 108mg with silica column purification (eluant dichloromethane: methyl alcohol=20:1).Total recovery is 31%.
Claims (8)
1. prepare a method for Laudanine, it is characterized in that, said method comprising the steps of:
1) 3-hydroxyl-4-methoxyphenylacetic acid and 3,4-dimethoxy-phenylethylamine and condensing agent are joined in pyridine, then at room temperature stir 6-18 hour, obtain reaction product; In described reaction product, add ethyl acetate and add aqueous ammonium chloride solution respectively and the NaCl aqueous solution obtains organic phase to carry out extraction, after described organic phase anhydrous sodium sulfate drying, removing 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 is heated to 80-110 DEG C, stirs 2-3 hour, remove 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 add step 3) reaction solution that obtains, stir after 0.5-2 hour, add sodium borohydride, continue to stir after 1-2 hour, cool to room temperature, by aqueous ammonium chloride solution by pH value to 6-8, remove methyl alcohol, obtain reaction product; Be extracted with ethyl acetate, carry out drying by anhydrous sodium sulphate, obtain Laudanine.
2. method according to claim 1, is characterized in that, in step 1) in, described 3-hydroxyl-4-methoxyphenylacetic acid and described 3, the mol ratio of 4 dimethoxy-phenylethylamines is 1: (1-1.2).
3. method according to claim 1 and 2, is characterized in that, in step 1) in, described 3-hydroxyl, the mol ratio of 4-methoxyphenylacetic acid 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 is selected from one or more in HBTU, HATU and EDCI.
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).
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| WO2012081031A1 (en) * | 2010-12-15 | 2012-06-21 | Enaltec Labs Pvt. Ltd. | Process for preparing tetrabenazine |
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Patent Citations (4)
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| WO2008067070A2 (en) * | 2006-10-19 | 2008-06-05 | California Institute Of Technology | Compositions and methods for producing benzylisoquinolines alkaloids |
| CN101558035A (en) * | 2006-12-11 | 2009-10-14 | 马林克罗特公司 | Preparation of 3,4-dihydroisoquinolines from an acid and an amine |
| CN101665444A (en) * | 2006-12-11 | 2010-03-10 | 马林克罗特公司 | Preparation of amides from an acid and amine for intermediates in the synthesis of morphinans |
| WO2012081031A1 (en) * | 2010-12-15 | 2012-06-21 | Enaltec Labs Pvt. Ltd. | Process for preparing tetrabenazine |
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