CN1785977A - 17-sulfonyl diversine and its preparation method - Google Patents

Abstract

The invention discloses a class of 17-sulfonylsinomenine, which has potential drug application prospects. Its structural formula is as shown in the figure. In the structural formula, R=R ₁ S(OO)-, R ₁ =methyl, ethyl, propyl , hydrocarbon groups and substituted hydrocarbon groups of trifluoromethyl; R ₁ =phenyl and substituted phenyl groups. In the synthesis process of the 17-position compound of sinomenine, the method of protecting the phenolic hydroxyl group with benzyloxybenzyl group is used, and the deprotection is carried out at room temperature with trifluoroacetic acid. The conditions are mild and the reaction speed is fast. The synthesis process has less side reactions, The advantage of high yield, the average yield is about 90%, and compared with the benzyl protection method does not produce double bond hydrogenation and other phenomena.

Description

A class of 17-sulfonyl sinomenine and its preparation method

1. Technical field

The present invention relates to a class of organic compounds and a preparation method thereof, in particular to a class of 17-sulfonyl sinomenine and a preparation method thereof.

2. Background technology

Sinomenine (sinomenine) is a morphine alkaloid extracted from the rhizomes of S. chinensis and S. tomentosa. According to relevant literature records (CN98120549, 1142946, 1149456, US9903753), it has pharmacological activities such as anti-inflammatory, analgesic, antihypertensive, antiarrhythmic, etc. It is mainly used clinically to treat rheumatoid arthritis, cerebral ischemia, neurological dysfunction, etc. symptom.

A recent study (WO2004048340) found that sinomenine and its derivatives (using mouse Morris watermaze test, Social recognition test, NaNO ₂ induced anoxia test) also have the effects of nootropic, anti-drug, and neuroprotective.

In the patent CN.1153171, it is reported that the sinomenine complex of cyanogermanium-metal germanium is used as a broad-spectrum anticancer drug, which has the advantages of less toxic and side effects, no reduction in human immune function, and effective tumor suppression. CN.02137445.7 reports that sinomenine phospholipid complex is used for treating rheumatoid arthritis and arrhythmia. The patent pointed out that the complex has stronger lipophilicity than the parent drug, and its anti-inflammatory activity is significantly improved.

The research on N-desmethyl sinomenine shows that N-desmethyl sinomenine has higher physiological activity compared with sinomenine and points out that its activity has a certain relationship with hydrophilicity. Its salt, phenolic ester Derivatives have the functions of treating dysfunction, rheumatoid arthritis and the like. (US9903753, US6372756).

Ye Xianrong et al. (Acta Pharmacologica Sinica, 2004, 39(3), 180-183) modified the carbonyl-containing ring to obtain a series of compounds. Compared with sinomenine, it was found that it was conjugated with carbonyl by croton oil-induced mouse ear swelling method. The activity of (7-methoxyl-dihydrosinomenine) is maintained when the double bond is saturated, and the analgesic activity of this compound is better than that of sinomenine in the acetic acid writhing test of mice.

3. Contents of the invention

The object of the present invention is to provide a class of 17-sulfonyl sinomenine; and the method of protecting the phenolic hydroxyl group by benzyloxybenzyl, and carry out at room temperature with dilute trifluoroacetic acid/dichloromethane liquid during deprotection, with mild conditions and fast reaction speed , and provide a method for preparing 17-sulfonyl sinomenine.

The purpose of the present invention is achieved by the following technical solutions:

A class of 17-sulfonyl sinomenine, its structural formula is as follows:

Wherein R=R ₁ S(O0)-, R ₁ = methyl, ethyl, propyl, trifluoromethyl and other hydrocarbon groups and substituted hydrocarbon groups; or R ₁ = phenyl and substituted phenyl groups.

The reaction process of the preparation method of a class of 17-sulfonyl sinomenine that the present invention relates to is as follows:

A kind of preparation method of 17-sulfonyl sinomenine, its preparation steps are as follows:

(1), the preparation of 4-benzyloxybenzylsinomenine (IV): take sinomenine (III), triphenylphosphine, and 4-benzyloxybenzyl alcohol and dissolve them in a sufficient amount of solvent, and dissolve them at 0-20°C Add diethyl azodicarboxylate dropwise, finish adding within 0.5-2hr, continue to stir until the end of the reaction to obtain 4-benzyloxybenzyl sinomenine with a yield of 80.0-99.0%; wherein triphenylphosphine, benzyl alcohol, The consumption of diethyl azodicarboxylate is 1.5-5.0 times (mol) the same as that of cyantium (III), and the solvent is tetrahydrofuran, toluene or a mixture of the two;

(2), the preparation of 17-demethyl-4-benzyloxybenzyl sinomenine (V): the 4-benzyloxybenzyl sinomenine is dissolved in

Dissolving agent, then react with chloroformic acid-1-chloroethyl ester in the presence of acid-binding agent to obtain N-(1-chloroethoxyformyl)-4-benzyloxybenzyl sinomenine; wherein the solvent used is 1, Aprotic solvents such as 2-dichloroethane, chloroform, dichloromethane, acetone, toluene; Described acid binding agent is alkali metal carbonate, as sodium bicarbonate, sodium carbonate, potassium carbonate etc., and its consumption is 4- 1.0-6.0 times (quality) of benzyloxybenzyl sinomenine; chloroformic acid-1-chloroethyl ester consumption is 0.1-3.0 times (quality) of benzyloxybenzyl sinomenine;

The residue of the last step reaction is directly added in a sufficient amount of methanol, and heated under nitrogen to reflux to obtain 17-demethyl-4-benzyloxybenzyl sinomenine (V) and its hydrochloride mixture, and this mixture is dissolved in chloroform Disperse and neutralize with sodium bicarbonate solution to obtain 17-desmethyl-4-benzyloxybenzyl sinomenine;

(3), the preparation of 17-sulfonyl-4-benzyloxybenzyl sinomenine (VI): take the above-mentioned 17-demethyl-4-benzyloxybenzyl sinomenine (V), after melting with a solvent, React with sulfonyl chloride in the presence of an acid-binding agent to obtain 17-sulfonyl-4-benzyloxybenzyl sinomenine (VI); the acid-binding agent is an organic base, such as triethylamine, pyridine, etc., or an inorganic base, Such as sodium carbonate, sodium bicarbonate, etc.;

(4), the preparation of 17-sulfonyl sinomenine (I): get 17-sulfonyl-4-benzyloxybenzyl sinomenine at room temperature with 2-20% trifluoroacetic acid/dichloromethane solution to obtain 17-sulfonylsinomenine.

Beneficial effect:

In the synthetic process of the 17-position derivative of sinomenine, we refer to literature (Bruce C.Hamper, Tetrahedron Letters, 37(21), 3671-3674.M.Mergler, Tetrahedron Letters, 29(32), 4005-8. ) method, using benzyloxybenzyl to protect the phenolic hydroxyl group; removing the protecting group is a more critical step, we use dilute trifluoroacetic acid/dichloromethane solution to remove the protection at room temperature, and found that the conditions are mild and the reaction speed is fast (2 -10min), less side reactions, high yield (yields are all above 90%), deprotection under this condition does not produce double bond hydrogenation phenomenon.

A class of 17-sulfonyl sinomenine such as part of the compound name number of the structural formula and its physical and chemical constants are shown in the following table:

4. Specific implementation

The preparation of embodiment 1 17-propanesulfonyl sinomenine (compound 3), its preparation steps are as follows:

(1) Preparation of 4-benzyloxybenzylsinomenine (IV): refer to (Yukiohitotsuyanagi, J.Org.Chem., 1995, 60, 4549-58.);

Add 1.65g of sinomenine, 4.08g of PPh ₃ , 2.97g of benzyloxybenzyl alcohol and 40.0ml of absolute tetrahydrofuran into a 100ml three-necked flask in sequence, start stirring, and add 2.65g of DEAD dropwise under ice-cooling to 0°C. The addition is completed within 30min, and the Remove from the ice bath, continue to stir, and check the progress of the reaction with TLC. After about 10 hours, the reaction is complete. Remove the solvent under reduced pressure, pack it into a silica gel chromatography column, and wash it with ethyl acetate and 6:1 chloroform/methanol in sequence to obtain a light yellow product. , recrystallized from diethyl ether to obtain 2.6g white solid 4-benzyloxybenzyl sinomenine (IV); mp 72°C; [α] ²⁵ _D -69.0°(c=0.28 CH ₂ Cl ₂ ); ¹ HNMR (300MHz, DCCl ₃ ) δ7.56(d, 2H, J=8.6Hz.), 7.48-7.34(m, 4H), 7.02(d, 2H, J=8.6Hz.), 6.77(dd, 2H, J=8.4Hz. ), 5.52(d, 1H, J=1.5Hz.), 5.23(d, 1H,=10.5Hz.), 5.11(s, 2H), 5.01(d, 1H, J=10.5Hz), 4.20(d, 1H, J=16.1Hz.), 3.83(s, 3H), 3.53(s, 3H), 3.18-3.16(m, 1H), 3.05-2.97(m, 2H), 2.82-2.73(m, 1H), 2.49-2.37(m, 2H), 2.43(s, 3H), 1.97(ddd, 1H, J=4.3, 11.4, 11.4Hz.), 1.87-1.80(m, 2H);

(2), preparation of 17-desmethyl-4-benzyloxybenzylsinomenine (V): refer to (R.A.Olofson, J.Org.Chem.49(11), 2081-2082);

Dissolve 1.0g of 4-benzyloxybenzylsinomenine in 10.0ml of dichloroethane, add 1.0g of sodium bicarbonate, cool to 0°C under stirring, add dropwise 0.3g of chloroformic acid-1-chloroethyl ester, and keep warm for 1- 2hr, remove the ice-water bath, raise the temperature to slight reflux for 0.5-1hr, cool to room temperature, filter, spin off the solvent, the obtained intermediate product is not refined, directly added to 20ml of methanol, heated to reflux for 15min under nitrogen protection, and the solvent is removed under reduced pressure , the resulting product is 17-desmethyl-4-benzyloxybenzyl sinomenine and its hydrochloride mixture, dispersed with chloroform, neutralized by sodium bicarbonate to obtain 17-propanesulfonyl-4-benzyloxybenzyl sinomenine alkali;

(3), preparation of 17-propanesulfonyl-4-benzyloxybenzyl sinomenine (VI, R=propanesulfonyl);

100mg 17-desmethyl-4-benzyloxybenzylsinomenine, 10ml dichloromethane, 0.1ml triethylamine, 50mg propanesulfonyl chloride was added dropwise in an ice-water bath, followed by TLC until the reaction was complete, washed with water, and the solvent was removed under reduced pressure Purified by silica gel column to obtain 105mg 17-propanesulfonyl-4-benzyloxybenzyl sinomenine; [α] ²⁵ _D +210.5°(c=0.06CH ₂ Cl ₂ ) ¹ HNMR (300MHz, DCCl ₃ ) 7.56 (d, 1H, J=8.7Hz), 7.48-7.34(m, 4H), 7.03(d, 1H, J=8.7Hz), 6.81(d, 1H, J=8.7Hz), 6.78(d, 1H, J=8.7Hz), 5.47(s, 1H), 5.27(d, 1H, J=10.5Hz), 5.11(s, 1H), 5.01(d, 1H, J=10.5Hz), 4.37(s, 1H) , 4.21(d, 1H, J=15.9Hz), 3.85(s, 3H), 3.53(s, 3H), 3.52-3.44(m, 1H), 3.28-3.20(m, 1H), 2.97-2.85(m , 4H), 2.74-2.55(m, 1H), 2.47(d, 1H, J=15.9Hz), 1.94-1.83(m, 3H), 1.80-1.65(m, 1H), 1.07(t, 3H, J= 7.2Hz);

(4), the preparation of 17-propanesulfonylsinomenine (compound 3): refer to (Bruce C.Hamper, Tetrahedron Letters, 37 (21), 3671-3674.M.Mergler, Tetrahedron Letters, 29 (32), 4005-8.) preparation;

50mg of 17-propanesulfonyl-4-benzyloxybenzyl sinomenine was treated with 5ml of 5% trifluoroacetic acid/dichloromethane solution for 5min, and 20ml of 10% sodium bicarbonate solution was added to neutralize, the organic layer was separated, and anhydrous sulfuric acid Dry over sodium, remove the solvent under reduced pressure and purify by silica gel column chromatography to obtain compound 3; mp 110.0-113.0°C; [α] ²⁵ _D +48.2°(c=0.35 CH ₂ Cl ₂ ); ¹ HNMR (300MHz, DCCl ₃ ) δ _H 6.69(d, 1H, J=8.4Hz.), 6.57(d, 1H, J=8.4Hz.), 6.04(s, 1H), 5.44(d, 1H, J=1.8Hz.), 4.40- 4.35(m, 2H.), 3.84(s, 3H), 3.56-3.54(m, 1H), 3.51(s, 3H), 3.18-3.16(m, 1H), 3.02-2.95(m, 3H), 2.91 -2.85(m, 1H), 2.83-2.76(m, 1H), 2.48(d, 1H, J=16.0Hz.), 2.07-2.01(m, 1H), 1.90-1.82(m, 3H), 1.08( t, 3H, J=7.4Hz.).

Embodiment 2: the preparation of 17-p-toluenesulfonyl sinomenine (compound 4), its preparation steps are as follows:

(1), the preparation of 17-(p-methylbenzenesulfonyl)-4-benzyloxybenzyl sinomenine

100mg 17-desmethyl-4-benzyloxybenzyl sinomenine, 10ml dichloromethane, 0.1ml triethylamine, 50mg p-toluenesulfonyl chloride was added dropwise in an ice-water bath, TLC tracked the reaction until complete, washed with water, and dried The solvent was evaporated under reduced pressure, and the product was directly used in the next step without purification;

(2), the preparation of 17-p-toluenesulfonyl sinomenine

The crude product of 100mg 17-(p-toluenesulfonyl)-4-benzyloxybenzylsinomenine was treated with 5ml 5% trifluoroacetic acid/dichloromethane solution at room temperature for 5min, washed with water, dried, and the solvent was evaporated under reduced pressure. The product was Compound 4 was obtained by silica gel chromatography; mp 141.0-143.0°C; [α] ²⁵ _D +92.4° (c=0.49 CH ₂ Cl ₂ ); ¹ HNMR (300MHz, DCCl ₃ ) δ _H 7.74 (d, 2H, J= 7.6Hz.), 7.33(d, 2H, J=7.6Hz.), 6.62(d, 1H, J=8.3Hz.), 6.38(d, 1H, J=8.3Hz.), 6.00(s, 1H) , 5.40(s, 1H), 4.49(s, 1H), 4.32(d, 1H, J=15.70Hz.), 3.80(s, 3H), 3.71-3.67(m, 1H), 3.49(s, 3H) , 3.05-2.99(m, 1H), 2.84(s, 1H), 2.74-2.59(m, 2H), 2.46(s, 3H), 2.37(d, 1H, J=15.7Hz.), 1.97-1.93( m, 1H), 1.75-1.70 (m, 1H).

Claims (5)

1, a class of 17-sulfonyl sinomenine, its structural formula is as follows:

Wherein R=R ₁ S(O0)-, R ₁ = methyl, ethyl, propyl, trifluoromethyl hydrocarbon group and substituted hydrocarbon group; R ₁ = phenyl group and substituted phenyl group. 2. A method for preparing 17-sulfonylsinomenine according to claim 1, the preparation steps of which are as follows: (1), the preparation of 4-benzyloxybenzyl sinomenine (IV): take sinomenine (III), triphenylphosphine, and 4-benzyloxybenzyl alcohol and dissolve them in a solvent, and add distillate dropwise at 0-20° C. Add diethyl azodicarboxylate within 0.5-2 hr, and continue to stir until the end of the reaction to obtain 4-benzyloxybenzyl sinomenine, with a yield of 80.0-99.0%; (2), the preparation of 17-demethyl-4-benzyloxybenzyl sinomenine (V): 4-benzyloxybenzyl sinomenine is dissolved in a solvent, and then mixed with chloroformic acid- 1-chloroethyl ester reaction to obtain N-(1-chloroethoxyformyl)-4-benzyloxybenzyl sinomenine; the residue of the previous step reaction was directly added to methanol, heated to reflux under nitrogen protection to obtain 17 -Demethyl-4-benzyloxybenzyl sinomenine (V) and its hydrochloride are generated, the mixture is dispersed with chloroform, neutralized with sodium bicarbonate solution to obtain 17-demethyl-4-benzyloxybenzyl cyanine Phine; (3), the preparation of 17-sulfonyl-4-benzyloxybenzyl sinomenine (VI): take above-mentioned 17-demethyl-4-benzyloxybenzyl sinomenine (V), after dissolving with solvent, Reaction with sulfonyl chloride in the presence of an acid-binding agent to obtain 17-sulfonyl-4-benzyloxybenzyl sinomenine (VI); (4), the preparation of 17-sulfonyl sinomenine (I): get 17-sulfonyl-4-benzyloxybenzyl sinomenine at room temperature with 2-20% trifluoroacetic acid/dichloromethane solution to obtain 17-sulfonylsinomenine. 3. The preparation method of 17-sulfonylsinomenine according to claim 2 is characterized in that in step (1), the consumption of triphenylphosphine, benzyl alcohol and diethyl azodicarboxylate is the same as Qingteng The amount of base (III) is 1.5-5.0 times (mol), and the solvent is tetrahydrofuran, toluene or a mixture of the two. 4. The preparation method of 17-sulfonylsinomenine according to claim 2 is characterized in that the solvent described in step (2) is 1,2-dichloroethane, chloroform, dichloromethane, acetone , toluene is an aprotic solvent; the acid-binding agent is an alkali metal carbonate, such as sodium bicarbonate, sodium carbonate, salt of wormwood, etc., and its consumption is 1.0-6.0 times of 4-benzyloxybenzyl sinomenine (mass ); chloroformic acid-1-chloroethyl ester consumption is 0.1-3.0 times (quality) of benzyloxybenzyl sinomenine. 5. The preparation method of 17-sulfonylsinomenine according to claim 2, characterized in that the acid-binding agent described in step (3) has organic bases such as triethylamine, pyridine, or sodium carbonate, sodium bicarbonate and other inorganic bases.