CN103387539A - Synthesis of 4-benzyloxy-17-acetyl morphinan-6-one - Google Patents

Abstract

The present invention relates to a novel sinomenine derivative 4-benzyloxy-3,7-dimethoxy-17-acetylmorphinan-6-one (full name: (9 S ,13 R ,14 S The invention discloses a method for synthesizing 4-benzyloxy-3,7-dimethoxy-17-acetylmorphinan-6-one, which belongs to the field of organic chemistry and medicinal chemistry. The technical problem to be solved is to provide a synthesis process of a new sinomenine derivative 4-benzyloxy-3,7-dimethoxy-17-acetylmorphinan-6-one, which has mild reaction conditions, high reaction selectivity, few side reactions, simple product separation and high yield. The method is characterized in that 7,8-dehydro-4-benzyloxy-3,7-dimethoxy-17-methyl-morphinan-6-one is used as a reactant, and in a 1,2-dichloroethane solvent, 1-chloroethyl chloroformate and methanol are reacted to obtain a 17-demethylated intermediate, and then the 17-demethylated intermediate is reacted with acetyl chloride to obtain 4-benzyloxy-3,7-dimethoxy-17-acetylmorphinan-6-one.

Description

Synthesis of 4-Benzyloxy-17-acetylmorphinan-6-one

technical field

The invention belongs to the field of organic chemistry and medicinal chemistry, and it relates to the synthesis of a novel sinomenine derivative 4-benzyloxy-17-acetylmorphinan-6-one (full name is: ( 9S , 13R , 14 S )-7,8-dehydro-4-benzyloxy-3,7-dimethoxy-17-acetylmorphinan-6-one), this new structure compound is promising for rheumatism , Drugs for the treatment of rheumatoid diseases.

Background technique

Sinomenine (sinomenine) is an isoquinoline alkaloid isolated from the plant S. sinomenine. Long-term clinical drug efficacy tests have proved that it has various physiological functions such as anti-inflammatory, immune, analgesic, antihypertensive, and antiarrhythmic. active. In recent years, there are also reports on the treatment of chronic nephritis, anti-oxidation, anti-tumor, and detoxification. Sinomenine pharmaceutical preparations are clinically used to treat rheumatoid arthritis and arrhythmia, and have achieved good results. The results of sinomenine gel preparation in animal transdermal absorption and drug efficacy test show that sinomenine is closely related to the synthesis and release of local prostaglandins (GP). Sinomenine also has the effect of selectively inhibiting cyclooxygenase 2 (COX-2), which may be one of the main mechanisms for its strong anti-inflammatory and analgesic effects and relatively small side effects. Studies have shown that sinomenine mainly exerts anti-inflammatory and anti-rheumatic effects by regulating cell inflammatory mediators and controlling cytokine synthesis. However, the clinical dosage of sinomenine is too large, and it has obvious histamine release effect, thus causing allergic reactions. Therefore, it is of great significance to modify and optimize the structure of sinomenine to find a new generation of sinomenine derivatives with high efficiency and low toxicity. (Liu Qiang, Zhou Liling, Li Rui, Chinese herbal medicine, 1997, 28, 247. Qiu Ping, Qiu Saihong, [P]. CN 1142946, 1997-02-09 . Sun Xuguang, Huang Yuming, Qiu 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, Journal of Xi'an Medical University, 1989, 10, 346. Wang Wenjun, Wang Training, Journal of Guangzhou University of Traditional Chinese Medicine, 2002, 19, 46. Tu Shenghao, Hu Yonghong, Lu Fuer, Chinese Journal of Experimental Clinical Immunology, 1998, 10, 268. Li Xiaojuan , Wang Training, Liu Liang, Journal of Guangzhou University of Traditional Chinese Medicine, 2004, 21, 34).

Contents of the invention

The technical problem to be solved by the present invention is to provide a synthetic method of a novel sinomenine derivative 4-benzyloxy-17-acetylmorphinan-6-one.

The synthesis of novel sinomenine derivative 4-benzyloxy-17-acetylmorphinan-6-one described in the present invention is characterized in that the reaction is carried out in two steps, the first step: under nitrogen protection, First , the 17- The methyl group is removed to obtain the demethylated intermediate (9 S , 13 R , 14 S )-7,8-dehydro-4-benzyloxy-3,7-dimethoxy-17-normorphine Pyran-6-one, the second step: reacting the 17-demethylated intermediate with acetyl chloride to obtain 4-benzyloxy-17-acetylmorphinan-6-one, the preparation reaction process is shown in Figure 1.

The synthesis of novel sinomenine derivative 4-benzyloxy-17-acetylmorphinan-6-ketone described in the present invention is characterized in that the ratio of the amount of substance of the reactant raw material in the first step reaction ( 9 S ,13 R ,14 S )-7,8-dehydro-4-benzyloxy-3,7-dimethoxy-17-methylmorphinan-6-one/chloroformic acid-1-chloroethyl Ester/NaHCO ₃ is: 1: (1 ~ 5): (2 ~ 10), the ratio of the amount of substance as preferred is 1: 4: 10; The ratio of the amount of substance of the reactant in the second step reaction (9 S ,13 R ,14 S )-7,8-dehydro-4-benzyloxy-3,7-dimethoxy-17-normethylmorphinan-6-one/acetyl chloride: 1:( 1.5~2), the preferred ratio of the amount of substances is 1:1.5.

The preparation of the novel sinomenine derivative 4-benzyloxy-17-acetylmorphinan-6-one described in the present invention is characterized in that the solvent in the first demethylation step of the reaction is selected from 1,2 -Ethylene dichloride effect is better, demethylation also can be finished under the promotion of alcohol, methanol effect is better, the second step reaction selects methylene chloride as solvent better, crude product separation adopts column chromatography method, layer Use 100–400 mesh silica gel or alumina as the carrier of the analysis column, and the eluent is (V _methanol : V _{dichloromethane} = 1:10) for separation, and the solvent of the developer is recovered by atmospheric distillation to obtain the sinomenine derivative 4- Benzyloxy-17-acetylmorphinan-6-one.

The present invention has the following characteristics:

1. The reaction conditions are mild, the reaction speed is fast, the side reactions are less, the selectivity is high, and the yield is high.

2. The operation of reaction and product separation is simple.

Description of drawings

Figure 1 is a schematic diagram of the reaction process of the present invention.

Detailed ways

Below through embodiment, the technical solution of the present invention is described further in detail.

The preparation process of sinomenine derivative 4-benzyloxy-17-acetylmorphinan-6-one: under the protection of N ₂ , in the reaction flask, add 4-benzyloxysinomenine and NaHCO ₃ , and then add Solvent 1, 2-dichloroethane, cool the temperature of the reaction system to 0°C with ice water, slowly add 1-chloroethyl chloroformate dropwise, after the dropwise addition, stir at room temperature for 0.5-1 hour, then Reflux for 1-2 hours, evaporate the solvent to dryness, dissolve the residue with CH ₃ OH, then reflux for 1-2 hours, evaporate the solvent to dryness, wash and dissolve the residue with saturated sodium bicarbonate solution, and then extract 2-3 times with chloroform, The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and directly separated by column chromatography, CH ₃ OH/DCM (1:7) was used as the developing solvent, and the developing solvent was evaporated on a rotary evaporator. out, the demethylated product (9 S ,13 R ,14 S )-7,8-dehydro-4-benzyloxy-3,7-dimethoxy-17-normorphinan-6- Ketone, add the demethylated product into another reaction flask, under the protection of nitrogen, add dichloromethane or chloroform, toluene and other solvents, add the acylating reagent acetyl chloride, and heat the reaction under stirring conditions, TLC tracking After reacting for 3-6 hours, cool to room temperature, wash with saturated sodium bicarbonate, extract with dichloromethane, combine the extracts, dry over anhydrous sodium sulfate, evaporate the solvent, and the residue is directly separated by silica gel or alumina chromatography column, Use methanol and dichloromethane mixed solvent developer with a volume ratio of 1:10 to separate, and evaporate the developer solvent to obtain the compound 4-benzyloxy-17-acetylmorphinan-6-one.

Detailed ways

The technical solutions of the present invention will be further specifically described below through specific examples.

Example 1

In a 25 mL three-necked flask, after vacuum ventilation, add 2 mmol of 4-benzyloxysinomenine, 20 mmol of NaHCO ₃ , and 15 mL of 1,2-dichloroethane as a solvent, and dissolve the reaction with ice water The temperature of the system was cooled to 0°C, and under the protection of _N2 , slowly added 0.55g (4.5 mmol) of chloroformic acid-1-chloroethyl ester dropwise. Evaporate to dryness, dissolve the residue with 10 mL CH ₃ OH, and reflux for 1 hour, evaporate the solvent to dryness, dissolve the residue with dichloromethane, wash thoroughly with saturated sodium bicarbonate solution, and extract with chloroform three times (15 mL×3), The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and directly separated by column chromatography, using CH ₃ OH/DCM (1:7) as a developing solvent, and the product components were separated on a rotary evaporator Evaporate to dryness to obtain 0.76 g (94%) of the 17-demethylated product, melting point 78-80 ° C, the demethylated product was added to another reaction flask, under the protection of nitrogen, dichloromethane was added as a solvent, and the acylated Reagent acetyl chloride 3 mmol, under stirring conditions, react at 60-65°C, follow the reaction by TLC, react for 4 hours, cool to room temperature, wash with 20 ml saturated sodium bicarbonate solution, extract with dichloromethane (15 mL× 3), combined extracts, dried over anhydrous sodium sulfate, evaporated to remove solvent, the residue was directly separated by silica gel column chromatography, separated with methanol and dichloromethane mixed solvent with a volume ratio of 1:10, and evaporated to remove the developer solvent Finally, 0.58 g of compound 4-benzyloxy-17-acetylmorphinan-6-one was obtained, the yield was 69%, the melting point was 83-85°C, ¹ H-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); ¹³ C-NMR (CDCl ₃ , 300MHz): δ 194.1, 171.3, 151.5, 142.9, 142.9, 136.7, 132.3, 128.4, 127.1, 125.6, 121.5, 113.7, 74.3, 56.2, 50.5, 49,2, 41.2, 37.1, 28.5, 28.5, 28.5, 28.5 21.4; MS-EI (m/z): 447 ([M] ⁺ ); C ₂₇ H ₂₉ NO ₅ Elemental Analysis: C, 72.46; H, 6.53; N, 3.13. Found: 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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