CN103387578A - Synthesis of 4-fluorobenzyloxy-6-hydroxy morphinan alkyl - Google Patents
Synthesis of 4-fluorobenzyloxy-6-hydroxy morphinan alkyl Download PDFInfo
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- CN103387578A CN103387578A CN2012101396187A CN201210139618A CN103387578A CN 103387578 A CN103387578 A CN 103387578A CN 2012101396187 A CN2012101396187 A CN 2012101396187A CN 201210139618 A CN201210139618 A CN 201210139618A CN 103387578 A CN103387578 A CN 103387578A
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- fluorine benzyloxy
- alkane
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Abstract
The invention relates to the synthesis of a natural alkaloid derivative 4-fluorobenzyloxy-6-hydroxy morphinan alkyl with a full name of (6S, 9S, 13R, 14S)-7,8-didehydro-4-(4'-fluorobenzyloxy)-N-methyl-3,7-dimethoxy-6-hydroxy morphinan alkyl. The synthesis belongs to the field of organic chemistry. The invention aims at solving a technical problem of providing a natural sinomenine alkaloid derivative 4-fluorobenzyloxy-6-hydroxy morphinan alkyl synthesizing method with the advantages of mild reaction condition, high reaction selectivity, less side reaction, simple product separation, and high yield. The method is characterized in that 4-fluorobenzyloxy sinomenine is adopted as a raw material, an ether is adopted as a solvent, and lithium aluminum hydride is adopted as a reducing agent, such that the product 4-fluorobenzyloxy-6-hydroxy morphinan alkyl is obtained; and the product is directly rapidly separated with a column chromatography method.
Description
Technical field
The invention belongs to organic chemistry filed, it relates to a kind of natural tuduranine alcaloid-derivatives 4-to the fluorine benzyloxy-(full name is 6-hydroxyl morphinan alkane: (6
s, 9
s, 13R, 14S) and-7,8-bis-dehydrogenations-4-(4-fluorine benzyloxy)-
n-methyl-3,7-dimethoxy-6-hydroxyl morphinan alkane) synthetic.
Background technology
Tuduranine (sinomenine) is to separate the isoquinoline alkaloid obtained in natural phant, and the long-term clinical test of pesticide effectiveness proves that it has the multiple physiologically actives such as anti-inflammatory, immunity, analgesia, step-down, anti-arrhythmia.Be used for the treatment of in addition in recent years chronic nephritis, anti-oxidant, antitumor, the drug rehabilitation report.The tuduranine pharmaceutical preparation is used for the treatment of rheumatoid arthritis and irregular pulse clinically, and obtains good efficacy.The result of tuduranine gel preparation in animal Transdermal absorption and test of pesticide effectiveness research shows that tuduranine has substantial connection to the synthetic and release of local prostaglandin(PG) (GP).Tuduranine also has the effect that selectivity suppresses cyclooxygenase 2 (COX-2), and this may be that it has anti-inflammatory and analgesic effect by force and one of main mechanism of side effect less.Research shows that tuduranine is mainly by regulating the cellular inflammation medium and controlling the synthetic performance of cytokine anti-inflammatory, anti rheumatism action, but, tuduranine its dosage clinically is bigger than normal, there is obvious histamine release effect, thereby cause the supersensitivity side effect, therefore, the structure of tuduranine is modified and optimized, significant with the Sinomenine derivate of new generation of seeking high-efficiency low-toxicity.(Liu Qiang, Zhou Liling, Li Rui,
herbal medicine, 1997, 28,247.Chou Ping, Qiu Saihong, [P].
cN 1142946, 1997-02-09.Sun Xuguang, Huang Yuming, Chou Ping, [P].
cN 1216701, 1999-05-19.Pang Zhigong, Wang Baoqi, [P].
cN 1153171, 1997-07-02.Chen Chong, Xu Haiqin, Zhou Jia, [P].
cN 1149456, 1997-05-04.Huo Hairu, Che Xiping,
xian Medical Univ's journal, 1989, 10,346.Wang Wenjun, Wang Peixun,
traditional Chinese Medicine University Of Guangzhou's journal, 2002, 19,46.Tu Shenghao, Hu Yonghong, Lu Fuer,
chinese experimental clinical immunology magazine, 1998, 10,268.Li Xiaojuan, Wang Peixun, Liu Liang,
traditional Chinese Medicine University Of Guangzhou's journal, 2004, 21,34).
Summary of the invention
The technical problem to be solved in the present invention is to provide the synthetic method of a kind of novel alkaloidal derivative 4-of antirheumatic natural tuduranine to fluorine benzyloxy-6-hydroxyl morphinan alkane.
The synthetic method of 4-of the present invention to fluorine benzyloxy-6-hydroxyl morphinan alkane, it is characterized in that take that 4-is raw material to fluorine benzyloxy-tuduranine, with ether, make solvent, take lithium aluminum hydride as reductive agent, obtain product 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane, its preparation feedback process means as Fig. 1.
The new Sinomenine derivate 4-described in the invention building-up reactions to fluorine benzyloxy-6-hydroxyl morphinan alkane, it is characterized in that reacting and at first carry out under nitrogen protection, 4-is joined in reaction vessel and adds the ether solvents dissolving fluorine benzyloxy-tuduranine, add lithium aluminum hydride-5 ℃ of left and right, then make it naturally rise to room temperature, reaction 15-30 minute, with a small amount of methyl alcohol cancellation reaction, with 1N sodium hydroxide solution washing reaction mixture, by washing, dry, the solvent evaporation, column chromatography for separation obtains product 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane.
The building-up reactions of new Sinomenine derivate 4-described in the present invention to fluorine benzyloxy-6-hydroxyl morphinan alkane, is characterized in that the ratio 4-of amount of substance of reactant feed is to fluorine benzyloxy-tuduranine/lithium aluminum hydride: 1: (1 ~ 2.0).Ratio as preferred amount of substance is 1: 1.5.
The separation method of new Sinomenine derivate 4-described in the present invention to fluorine benzyloxy-6-hydroxyl morphinan alkane, it is characterized in that at first distillating recovering solvent, the chromatography column that residue is directly 4 centimetres of 2 – by length, chromatography carrier is used 100 – 400 purpose silica gel or aluminum oxide, and eluent is (V
methyl alcohol: V
methylene dichloride=1:15) developping agent separates, and air distillation obtains Sinomenine derivate 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane after reclaiming the developping agent solvent.
The present invention has following characteristics:
1, using 4-is raw material to fluorine benzyloxy-tuduranine and lithium aluminum hydride.
2, ether is reaction solvent, the reaction conditions gentleness, and speed of response is fast.
3, side reaction is less, and selectivity is higher, and yield is high, and reaction and product separation are simple to operate.
The accompanying drawing explanation
Fig. 1 is reaction process schematic diagram of the present invention.
Embodiment
Below by embodiment, technical scheme of the present invention is done more specifically bright.
The preparation process of Sinomenine derivate 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane: under nitrogen protection; in there-necked flask; adding 4-is raw material to fluorine benzyloxy-tuduranine; add anhydrous ether to dissolve; place it in ice bath be cooled to-5-0 ℃ left and right; add lithium aluminum hydride; then make it naturally rise to room temperature; reaction 15-30 minute; with a small amount of methyl alcohol cancellation reaction; with 1N sodium hydroxide solution washing reaction mixture, by washing, drying, solvent evaporation, column chromatography for separation, obtain product 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane.
Embodiment
Below by specific embodiment, technical scheme of the present invention is done more specifically bright.
Embodiment 1
Under nitrogen protection, in there-necked flask, add 4-to fluorine benzyloxy-tuduranine 0.85 gram, add 10 milliliters of anhydrous diethyl ethers, place it in ice bath and be cooled to-5 ℃, add 0.11 gram lithium aluminum hydride, then make it naturally rise to room temperature, react 15 minutes, with 2 ml methanol cancellation reactions, add 20 milliliter of 1 M NaOH solution washing reaction mixture, 15 milliliters of washed with dichloromethane three times for reaction mixture, combined dichloromethane, with the saturated aqueous common salt water washing once, which floor has separated, use anhydrous sodium sulfate drying, boil off solvent, residue directly separates with 50 gram alumina chromatographic columns, the methyl alcohol that is 1:15 by volume ratio separates with methylene dichloride mixed solvent developping agent, obtain compound 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane 0.83 gram after boiling off the developping agent solvent, yield 98%, fusing point 107-109 ℃,
1h NMR (CDCl
3, ppm): (CDCl
3)
δ7.50～7.46 (q,
j 1=4.7,
j 2=8.7 Hz, 2H), 7.10～7.04 (t,
j=8.4 Hz, 2H), 6.79～6.76 (d,
j=9.0 Hz, 1H), 6.75～6.73 (d,
j=9.0 Hz, 1H), 5.40～5.36 (d,
j=10.8 Hz, 1H), 5.03～4.99 (d,
j=11.4 Hz, 1H), 4.45～4.44 (s, 1H), 4.12～4.08 (t,
j=6.6 Hz, 1H), 3.78 (s, 3H), 3.46 (s, 3H), 3.46～3.42 (d,
j=13.8 Hz, lH), 3.02～2.99 (t,
j=3.9 Hz, lH), 2.93～2.87 (d,
j=18.0 Hz, 1H), 2.80～2.72 (dd,
j=4.5,
j=17.4 Hz, lH), 2.52～2.46 (m, 2H), 2.39 (s, 3H), 2.02～1.95 (m, 2H), (1.78 s, 1H), 1.68～1.60 (m, 2H).
19f NMR (CDCl
3, ppm): 115.19 (s, 1F).
13c NMR (CDCl
3, ppm): (CDCl
3)
δ156.6,150.8,147.2,134.0,132.4,130.9,129.7,123.2,115.3,111.2,107.6,96.8,72.9,66.6,57.5,55.7,54.3,47.8,45.5,42.6,40.2,37.9,34.5,24.6. IR:
v(cm
1): 3403,3198,2994,2906,2833,1666,1602,1574,1510,1480,1435,1270,1218,1270,1153,1093,1046,1006,816,785,750 cm
-1. MS (EI, 70 ev): m/z (%) 439 ([M]
+). Anal. Calcd. (%). for C
26h
30fNO
4(
4): C, 71.05, H, 6.88, F, 4.32, N, 3.18. Found (%): C, 71.11, H, 6.59, F, 4.13, N, 3.10.
Embodiment 2
Under nitrogen protection, in there-necked flask, add 4-to fluorine benzyloxy-tuduranine 1.70 grams, add 20 milliliters of anhydrous tetrahydro furans, place it in ice bath and be cooled to 0 ℃, add 0.22 gram lithium aluminum hydride, react 15 minutes, then make it naturally rise to room temperature, stir after 20 minutes, with 3 ml methanol cancellation reactions, add 30 milliliter of 1 M NaOH solution washing reaction mixture, 30 milliliters of washed with dichloromethane three times for reaction mixture, combined dichloromethane, with the saturated aqueous common salt water washing once, which floor has separated, use anhydrous sodium sulfate drying, boil off solvent, residue directly separates with 60 gram alumina chromatographic columns, the methyl alcohol that is 1:15 by volume ratio separates with methylene dichloride mixed solvent developping agent, obtain compound 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane 1.76 grams after boiling off the developping agent solvent, yield 98%, fusing point 107-109 ℃.
Claims (5)
1.4-to the fluorine benzyloxy-(full name is 6-hydroxyl morphinan alkane: (6
s, 9
s, 13R, 14S) and-7,8-bis-dehydrogenations-4-(4-fluorine benzyloxy)-
n-methyl-3,7-dimethoxy-6-hydroxyl morphinan alkane) synthetic, it is characterized in that usining 4-to fluorine benzyloxy-tuduranine as reactant, and make solvent with ether, take lithium aluminum hydride as reductive agent, under-5-25 ℃ reaction conditions, obtain product, product is directly by the column chromatography method sharp separation.
2. according to the described method of claim 1; it is characterized in that reacting and at first carry out under nitrogen protection; 4-is joined in reaction vessel and adds the ether solvents dissolving fluorine benzyloxy-tuduranine; add lithium aluminum hydride-5 ℃ of left and right; then make it naturally rise to room temperature; reaction 15-30 minute; with a small amount of methyl alcohol cancellation reaction; with 1N sodium hydroxide solution washing reaction mixture, by washing, drying, solvent evaporation, column chromatography for separation, obtain product 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane.
3. according to the described synthetic method of claim 1 or 2, it is characterized in that the ratio 4-of amount of substance of reactant feed is to fluorine benzyloxy-tuduranine/lithium aluminum hydride: 1: (1 ~ 2.0) is 1: 1.5 as the ratio of preferred amount of substance.
4. according to claim 1,2,3, described synthetic method, it is characterized in that new Sinomenine derivate 4-described in the present invention to fluorine benzyloxy-6-hydroxyl morphinan alkane separation method is, at first distillating recovering solvent, the chromatography column that residue is directly 4 centimetres of 2 – by length, chromatography carrier is used 100 – 400 purpose silica gel or aluminum oxide, and eluent is (V
methyl alcohol: V
methylene dichloride=1:15) developping agent separates, and air distillation obtains Sinomenine derivate 4-to fluorine benzyloxy-6-hydroxyl morphinan alkane after reclaiming the developping agent solvent.
5. according to claim 1,2,3,4, described synthetic method, it is characterized in that the solvent adopted in reaction is a kind of in tetrahydrofuran (THF), ether, isopropyl ether, n-butyl ether, Isosorbide-5-Nitrae-dioxy six alkane.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1785976A (en) * | 2005-12-15 | 2006-06-14 | 南京大学 | N-alkyl diversine and its preparation method |
| WO2009155259A1 (en) * | 2008-06-17 | 2009-12-23 | Mallinckrodt Inc. | Processes for the preparation of 6- beta-hydroxy morphinan compounds |
| CN101973938A (en) * | 2010-09-01 | 2011-02-16 | 南京大学 | C-ring hydrogenated sinomenine derivative and preparation method and application thereof |
-
2012
- 2012-05-08 CN CN2012101396187A patent/CN103387578A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1785976A (en) * | 2005-12-15 | 2006-06-14 | 南京大学 | N-alkyl diversine and its preparation method |
| WO2009155259A1 (en) * | 2008-06-17 | 2009-12-23 | Mallinckrodt Inc. | Processes for the preparation of 6- beta-hydroxy morphinan compounds |
| CN101973938A (en) * | 2010-09-01 | 2011-02-16 | 南京大学 | C-ring hydrogenated sinomenine derivative and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ZHENG XING-LIANG，等: "Synthesis and Crystal Structure of (7R,8S,9S,12S)-13,14-dehydro-1-(4′-fluorobenzyloxy)-N-methyl-2,13-dimethoxy-12-hydroxymorphinane", 《CHINESE J. STRUCT. CHEM.》 * |
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Application publication date: 20131113 |