CN103387539A - Synthesis of 4-benzyloxy-17-acetylmorphinan-6-one - Google Patents
Synthesis of 4-benzyloxy-17-acetylmorphinan-6-one Download PDFInfo
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- CN103387539A CN103387539A CN2012101395112A CN201210139511A CN103387539A CN 103387539 A CN103387539 A CN 103387539A CN 2012101395112 A CN2012101395112 A CN 2012101395112A CN 201210139511 A CN201210139511 A CN 201210139511A CN 103387539 A CN103387539 A CN 103387539A
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- benzyloxy
- dimethoxy
- morphinan
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Abstract
The invention relates to the synthesis of a novel sinomenine derivative 4-benzyloxy-17-acetylmorphinan-6-one with a full name of (9S,13R,14S)-7,8-dehydro-4-benzyloxy-3,7-dimethoxy-17-acetylmorphinan-6-one). The invention belongs to the fields of organic chemistry and medical chemistry, and aims at solving a technical problem of providing a novel sinomenine derivative 4-benzyloxy-3,7-dimethoxy-17-acetylmorphinan-6-one synthesis process with mild reaction condition, high reaction selectivity, less side effect, simple product separation, and high yield. The process is characterized in that 7,8-dehydro-4-benzyloxy-3,7-dimethoxy-17-methyl-morphinan-6-one is adopted as a reactant, and is subjected to a reaction with methanol and chloroformate-1-chloroethyl in a 1,2-dichloroethane solvent, such that a 17-demethylated intermediate is obtained. The 17-demethylated intermediate is subjected to a reaction with benzenesulfonyl chloride, such that 4-benzyloxy-3,7-dimethoxy-17-acetylmorphinan-6-one is obtained.
Description
Technical field
The invention belongs to organic chemistry and pharmaceutical chemistry field, it relates to a kind of novel Sinomenine derivate 4-benzyloxy-17-ethanoyl morphinan-6-ones synthetic, and (full name is: (9
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3,7-dimethoxy-17-ethanoyl morphinan-6-ones) synthetic, this novel compound is hopeful the medicine for rheumatism, rheumatism treatment.
Background technology
Tuduranine (sinomenine) is to separate the isoquinoline alkaloid obtained from the plant Stem of Orientoine, 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 Sinomenine derivate 4-benzyloxy-17-ethanoyl morphinan-6-ones.
Synthesizing of novel Sinomenine derivate 4-benzyloxy described in the invention-17-ethanoyl morphinan-6-ones, it is characterized in that reaction divides two steps to carry out, the first step: under nitrogen protection, first by (9
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3, the 17-methyl in 7-dimethoxy-17-methylmorphinan-6-ketone molecule is taken off, and obtains demethylation intermediate (9
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3,7-dimethoxy-17-demethyl morphinan-6-ones, second step: 17-demethylation intermediate and excess acetyl chloride are obtained to 4-benzyloxy-17-ethanoyl morphinan-6-ones, and its preparation feedback process means as Fig. 1.
Novel Sinomenine derivate 4-benzyloxy described in the present invention-17-ethanoyl morphinan-6-ones synthetic, is characterized in that the ratio (9 of the amount of substance of reactant feed in the first step reaction
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3,7-dimethoxy-17-methylmorphinan-6-ketone/chloroformate-1-chloro-ethyl ester/NaHCO
3for: 1: (1 ~ 5): (2 ~ 10) are 1: 4: 10 as the ratio of preferred amount of substance; The ratio (9 of the amount of substance of reactant in the second step reaction
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3,7-dimethoxy-17-demethyl morphinan-6-ones/Acetyl Chloride 98Min. is: 1: (1.5 ~ 2) are 1: 1.5 as the ratio of preferred amount of substance.
The preparation of novel Sinomenine derivate 4-benzyloxy described in the present invention-17-ethanoyl morphinan-6-ones; it is characterized in that the solvent reacted in the first step demethylation step selects 1; 2-ethylene dichloride better effects if; demethylation also will just can complete under pure promotion; the methyl alcohol better effects if, the second step reaction selects methylene dichloride better as solvent, and crude product separates the employing column chromatography method; the chromatography column carrier is used 100 – 400 purpose silica gel or aluminum oxide, and eluent is (V
methyl alcohol: V
methylene dichloride=1:10) developping agent separates, and air distillation obtains Sinomenine derivate 4-benzyloxy-17-ethanoyl morphinan-6-ones after reclaiming the developping agent solvent.
The present invention has following characteristics:
1, reaction conditions gentleness, speed of response is very fast, and side reaction is less, and selectivity is higher, and yield is high.
2, 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-benzyloxy-17-ethanoyl morphinan-6-ones: N
2under protection, in reaction flask, add 4-benzyloxy tuduranine and NaHCO
3, then adding solvent 1, the 2-ethylene dichloride, be cooled to 0 ℃ with frozen water by temperature of reaction system, slowly drips chloroformate-1-chloro-ethyl ester, after dropwising, at room temperature stirs 0.5-1 hour, then the 1-2 hour that refluxes, and by the solvent evaporate to dryness, uses CH
3oH dissolves residuum, then the 1-2 hour that refluxes, solvent evaporated, and residue fully washs dissolving with saturated sodium bicarbonate solution, use again chloroform extraction 2-3 time, combining extraction liquid, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, directly carry out column chromatography separation, CH
3oH/DCM(1:7) make developping agent, developping agent is steamed on rotatory evaporator, obtain demethylation product (9
s, 13
r, 14
s)-7, 8-dehydrogenation-4-benzyloxy-3, 7-dimethoxy-17-demethyl morphinan-6-ones, the demethylation thing is joined in another reaction flask, under nitrogen protection, add methylene dichloride or chloroform, the toluene equal solvent, add the acylating reagent Acetyl Chloride 98Min., be total to thermal response under agitation condition, thin-layer chromatography TLC follows the tracks of reaction, react after 3-6 hour, cool to room temperature, the saturated sodium bicarbonate washing, dichloromethane extraction, combining extraction liquid, anhydrous sodium sulfate drying, boil off solvent, residue directly separates with silica gel or alumina chromatographic column, the methyl alcohol that is 1:10 by volume ratio separates with methylene dichloride mixed solvent developping agent, obtain compound 4-benzyloxy-17-ethanoyl morphinan-6-ones after boiling off the developping agent solvent.
Embodiment
Below by specific embodiment, technical scheme of the present invention is done more specifically bright.
Embodiment 1
In 25 mL three-necked bottles, after vacuum is substituted gas, add 4-benzyloxy tuduranine 2 mmol, NaHCO
320 mmol, then add 1,2-ethylene dichloride 15mL as solvent, with frozen water, temperature of reaction system is cooled to 0 ℃, N
2under protection, slowly drip 0.55g(4.5 mmol) chloroformate-1-chloro-ethyl ester, after dropwising, at room temperature stir 0.5 hour, then reflux 2 hours, by the solvent evaporate to dryness, with 10 mL CH
3oH dissolves residuum, then refluxes 1 hour, solvent evaporated, and residue dissolves with methylene dichloride, saturated sodium bicarbonate solution fully washs, then uses chloroform extraction 3 times (15 mL * 3), combining extraction liquid, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, and directly carries out column chromatography separation, CH
3oH/DCM(1:7) make developping agent, by product component evaporate to dryness on rotatory evaporator, obtain 17-demethylation product 0.76 gram (94%), fusing point 78-80 ℃, the demethylation thing is joined in another reaction flask, under nitrogen protection, add methylene dichloride as solvent, add acylating reagent Acetyl Chloride 98Min. 3 mmol, under agitation condition, 60-65 ℃ of reaction, thin-layer chromatography TLC follows the tracks of reaction, react after 4 hours, cool to room temperature, 20 milliliters of saturated sodium bicarbonate solution washings, dichloromethane extraction (15 mL * 3), combining extraction liquid, anhydrous sodium sulfate drying, boil off solvent, residue directly separates with silica gel column chromatography, the methyl alcohol that is 1:10 by volume ratio separates with methylene dichloride mixed solvent developping agent, obtain compound 4-benzyloxy-17-ethanoyl morphinan-6-ones 0.58 gram after boiling off the developping agent solvent, yield 69%, fusing point 83-85 ℃,
1h-NMR (CDCl
3, 300MHz): δ 7.61-7.59 (d, J=8.0 Hz, 2H), 7.41-7.34 (m, 3H), (6.73-6.71 d, J=8.2 Hz, 1H), (6.58-6.56 d, J=8.2 Hz, 1H), (5.52 s, 1H), 5.35-5.31 (d, J=14.8 Hz, 1H), 5.09-5.06 (d, J=14.8 Hz, 1H), 4.19-4.15 (d, J=20.8 Hz, 1H), 3.82 (s, 3H), 3.52 (s, 3H), 3.21-3.14 (dd, J
1=6.0, J
2=24.4 Hz, 1H), 2.72-2.20 (m, 4H), 2.06 (s, 3H), 1.97-1.94 (d, J=13.6 Hz, 2H), 1.75-1.66 (ddd, 2H),
13c-NMR (CDCl
3, 300MHz): δ 194.1,171.3, and 151.5,146.4,142.9,136.7,132.3,128.4,127.4, 127.1,125.6,121.5,116.4,113.7,74.3,56.2,55.2,50.5, 49,2,43, Isosorbide-5-Nitrae 1.2,39.5,37.1,28.5,21.4, MS-EI(m/z): 447 ([M]
+), C
27h
29nO
5ultimate analysis: C, 72.46, H, 6.53, N, 3.13. measured value: C, 72.21, H, 6.43, N, 2.86.
Claims (4)
1.4-(full name is benzyloxy-17-ethanoyl-morphinan-6-ones: (9
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3,7-dimethoxy-17-ethanoyl-morphinan-6-ones) synthetic, it is characterized in that reaction minute two steps carry out, the first step: under nitrogen protection, first will (9
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3, the 17-methyl in 7-dimethoxy-17-methylmorphinan-6-ketone molecule is taken off, and obtains demethylation intermediate (9
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3,7-dimethoxy-17-demethyl morphinan-6-ones, second step: 17-demethylation intermediate and excess acetyl chloride are obtained to 4-benzyloxy-17-ethanoyl-morphinan-6-ones.
2. according to the described method of claim 1, it is characterized in that the ratio (9 of the amount of substance of reactant feed in the first step reaction
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3,7-dimethoxy-17-methylmorphinan-6-ketone/chloroformate-1-chloro-ethyl ester/NaHCO
3for: 1: (1 ~ 5): (2 ~ 10) are 1: 4: 10 as the ratio of preferred amount of substance; The ratio (9 of the amount of substance of reactant in the second step reaction
s, 13
r, 14
s)-7,8-dehydrogenation-4-benzyloxy-3,7-dimethoxy-17-demethyl morphinan-6-ones/Acetyl Chloride 98Min. is: 1: (1.5 ~ 2) are 1: 1.5 as the ratio of preferred amount of substance.
3. according to the described method of claim 1 or 2, the solvent that it is characterized in that reacting in the first step demethylation step selects chloroform, benzene, toluene, tetrahydrofuran (THF), isopropyl ether, n-butyl ether, 1,4-dioxy six alkane, 1, a kind of in the 2-ethylene dichloride, 1, the 2-ethylene dichloride is the best reaction solvent of effect, and demethylation also will just can complete under the promotion of alcohol (as: methyl alcohol, ethanol, propyl alcohol, butanols etc.), and wherein the methyl alcohol effect is best.
4. according to claim 1,2,3, described method, it is characterized in that second step reaction selection chloroform, N, dinethylformamide, benzene, toluene, tetrahydrofuran (THF), 1,4-dioxy six alkane, 1, the 2-ethylene dichloride is as solvent, and chloroform is that the solvent effect is best, and crude product separates the employing column chromatography method, chromatography carrier is used 100 – 400 purpose silica gel or aluminum oxide, and eluent is (V
methyl alcohol: V
methylene dichloride=1:10) developping agent separates, and air distillation obtains Sinomenine derivate 4-benzyloxy-17-ethanoyl-morphinan-6-ones after reclaiming the developping agent solvent.
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Citations (6)
| 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 |
| CN1821244A (en) * | 2006-03-15 | 2006-08-23 | 南京大学 | A class of 17-acyl diversine derivatives and its preparing method |
| CN101265266A (en) * | 2008-04-23 | 2008-09-17 | 南京大学 | Sinomenine derivative, preparation method and application thereof |
| CN101578101A (en) * | 2005-12-15 | 2009-11-11 | 自然医学公司 | Sinomenine derivatives and preparation and uses thereof |
| US20100210843A1 (en) * | 2009-02-17 | 2010-08-19 | Mallinckrodt Inc. | Process for the Reductive Alkylation of Normorphinans |
| WO2011009015A1 (en) * | 2009-07-16 | 2011-01-20 | Mallinckrodt Inc. | (+) - morphinans as antagonists of toll-like receptor 9 and therapeutic uses thereof |
-
2012
- 2012-05-08 CN CN2012101395112A patent/CN103387539A/en active Pending
Patent Citations (6)
| 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 |
| CN101578101A (en) * | 2005-12-15 | 2009-11-11 | 自然医学公司 | Sinomenine derivatives and preparation and uses thereof |
| CN1821244A (en) * | 2006-03-15 | 2006-08-23 | 南京大学 | A class of 17-acyl diversine derivatives and its preparing method |
| CN101265266A (en) * | 2008-04-23 | 2008-09-17 | 南京大学 | Sinomenine derivative, preparation method and application thereof |
| US20100210843A1 (en) * | 2009-02-17 | 2010-08-19 | Mallinckrodt Inc. | Process for the Reductive Alkylation of Normorphinans |
| WO2011009015A1 (en) * | 2009-07-16 | 2011-01-20 | Mallinckrodt Inc. | (+) - morphinans as antagonists of toll-like receptor 9 and therapeutic uses thereof |
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Application publication date: 20131113 |