CN104140412B - For preparing the intermediate of Bruguiesulfurol, its synthetic method, intermediate and purposes - Google Patents

Abstract

The present invention relates to prepare the new intermediate of natural product Bruguiesulfurol, its synthetic method and the intermediate thereof with anti-type ii diabetes activity, and the method preparing Bruguiesulfurol.The synthetic method of the Bruguiesulfurol that the present invention provides, synthetic route is novel, easy and simple to handle, and yield is high, and safety is good, applicable industrialized production, and solution this compound at present is only capable of and is separated, by extremely inefficient extracting in mangrove plant extractum, the problem prepared.Formulas I.

Description

Intermediates for the preparation of new oledithiols, their synthesis methods, intermediates and uses

technical field

The present invention relates to the field of chemical synthesis, more specifically, the present invention relates to the preparation of novel intermediates of natural product bruguiesulfurol (bruguiesulfurol) with anti-type II diabetes activity, its synthetic method and its intermediates, and the preparation of new The method of ladenithiol.

Background technique

New clover dithiol is a five-membered ring disulfide compound with a new skeleton structure isolated from the mangrove plant clover (Phytochemistry2009, 70, 2096-2100), and its structural formula is as follows:

(Formula I).

Studies have shown that this compound has good inhibitory activity on type II diabetes target protein tyrosine phosphatase 1B (proteintyrosine phosphatase1B, PTP1B) (its inhibitory concentration is IC ₅₀ =17.5μM), and it is effective in the treatment of type II diabetes and its complications It has good application value. However, the amount that can be obtained by means of separation is limited, thus limiting the in-depth activity research and druggability evaluation of the compound.

Contents of the invention

In view of the above and other problems existing in the prior art, the present inventor has conducted extensive and in-depth research, and finally completed the present invention.

Therefore, an object of the present invention is to provide a compound shown in the following formula II, which can be used for the preparation of neoclamedithiol.

Formula II wherein, R is a protecting group.

Another object of the present invention is to provide a preparation method of the compound represented by the above formula II.

Still another object of the present invention is to provide a kind of synthetic method of new oledithiol.

Another object of the present invention is to provide a compound represented by the following formula III, which can be used to prepare the compound represented by the above formula II.

Formula III wherein R is a protecting group and X is chlorine, bromine or iodine.

According to a first aspect of the present invention, a kind of compound shown in following formula II is provided:

Formula II wherein, R is a protecting group.

In the present invention, preferably, the protecting group can be p-bromobenzoyl, p-chlorobenzoyl, p-iodobenzoyl, tetrahydropyranyl, more preferably p-bromobenzoyl, tetrahydropyranyl group, most preferably tetrahydropyranyl.

According to a second aspect of the present invention, there is provided a method for preparing a compound represented by the above formula II, the method comprising:

c) reacting the compound of formula III with sodium disulfide under the action of a phase transfer catalyst to obtain the compound of formula II, wherein R is a protecting group, and X is chlorine, bromine or iodine.

In the present invention, in step c), preferably, the molar ratio of the compound of formula III to sodium disulfide is 1:1-5, more preferably 1:1-2; preferably, the phase transfer catalyst is benzyl Triethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or Tetraalkyltrimethylammonium chloride; Preferably, the solvent used for the reaction is a mixed solvent of dichloromethane or chloroform and water; Preferably, the reaction temperature is 0°C to 50°C, more preferably 0°C to 20°C; and/ Or, preferably, the reaction time is 1-40 hours, more preferably 2-15 hours.

In the preparation method of the compound shown in the above formula II, preferably, the compound of the formula III can be prepared by the following steps:

a) making the compound of formula V undergo a ring-opening reaction to obtain a compound of formula IV, wherein X is as defined above;

b) Protecting the hydroxyl group of the compound of formula IV to obtain the compound of formula III, wherein R is as defined above.

In the present invention, in step a), the reaction conditions for the ring-opening reaction are not particularly limited, as long as the ring-opening reaction can be performed. As an example, the ring-opening reaction can be performed in the presence of, for example, hydrochloric acid, hydrobromic acid or hydroiodic acid. Preferably, the molar ratio of the compound of formula V to hydrochloric acid, hydrobromic acid or hydroiodic acid is 1:1 to 5, more preferably 1:1 to 3; preferably, the solvent used for the reaction can be tetrahydrofuran, ether, dioxane , benzene, toluene, water or a mixture thereof; preferably, the reaction temperature may be -40°C to room temperature, more preferably -20°C to 0°C, most preferably -10°C to 0°C; and/or, preferably, the reaction time It may be 1 to 10 hours, more preferably 1 to 5 hours.

In the present invention, in step b), there is no special limitation on the type of the hydroxyl protection reaction, as long as the hydroxyl group can be protected. The hydroxyl protection reaction can be carried out by using any hydroxyl protection reaction in the art. As an example, the compound of formula IV can be combined with 3,4-dihydropyran under the action of a catalyst to obtain a compound of formula III whose hydroxyl group is protected by tetrahydropyranyl (THP), wherein, preferably, the compound of formula The molar ratio of compound IV to 3,4-dihydropyran is 1:1-10, more preferably 1:1-3. Described catalyzer can be selected from one or more in p-toluenesulfonic acid, pyridine p-toluenesulfonic acid salt, trifluoromethanesulfonic acid, acetic acid and camphorsulfonic acid; Reaction used solvent can be methanol, ethanol, Virahol , ether, tetrahydrofuran, dioxane, benzene, toluene, chloroform, methylene chloride, dimethyl sulfoxide or a mixture thereof; preferably, the reaction time can be 2 to 10 hours; and/or, preferably, the reaction temperature can be -78°C to room temperature.

According to a third aspect of the present invention, there is provided a synthetic method of neoclamedithiol, the method comprising:

d) oxidizing and deprotecting the compound of formula II to obtain the compound of formula I, wherein R is a protecting group.

In the present invention, in step d), there is no special limitation to the oxidizing agent used in the oxidation reaction, as long as the oxidation purpose of the present invention can be realized, for example, the oxidizing agent can be m-chloroperoxybenzoic acid or peroxy tert-butanol . Preferably, the solvent used for the reaction may be dichloromethane, tetrahydrofuran, 1,4-dioxane or chloroform; preferably, the reaction temperature may be 0°C to 60°C, more preferably 0°C to 20°C; and/or, The reaction time may be 1 to 40 hours, more preferably 2 to 15 hours.

In a preferred embodiment of the present invention, in step d), the compound of formula 4 is oxidized and deprotected under the action of an oxidizing agent to obtain compound formula I, and the reaction formula is as follows:

Formula 4 Formula I.

In the present invention, for example, wherein, the compound of formula 4 as a specific example of the compound of formula II can be prepared as follows:

In step a), using epibromohydrin (compound of formula 1) as the starting material, under the action of hydrobromic acid, the epoxy is opened to obtain 1,3-dibromo-2-propanol (compound of formula 2);

In step b), 1,3-dibromo-2-propanol (compound of formula 2) and 3,4-dihydropyran are catalyzed by pyridine p-toluenesulfonate to obtain compound of formula 3 with protected hydroxyl group ,

In step c), the compound of formula 3 reacts with the aqueous solution of sodium disulfide under the action of the phase transfer catalyst tetrabutylammonium bromide to generate the compound of formula 4; wherein the aqueous solution of sodium disulfide can be obtained by making sodium sulfide containing crystal water and sulfur The powder is prepared by reaction under heating conditions.

Above-mentioned specific synthetic method can represent with following reaction scheme I:

Formula 1 Formula 2 Formula 3 Formula 4

Reaction Scheme I

Therefore, the synthetic method of the natural product neocladildithiol provided by the present invention has novel synthetic route, simple and convenient operation, high yield, good reproducibility, and is suitable for industrialized production. The problem of extremely inefficient extraction and separation preparation in creams.

detailed description

Hereinafter, the present invention will be described in more detail through exemplarily proposed embodiments, however, the scope of the present invention is not limited to the embodiments.

Example

NMR was measured by Bruker-AMX300 nuclear magnetic resonance instrument; EI-MS was measured by Finnigan-MAT-95 mass spectrometer; column chromatography silica gel column and thin-layer silica gel plate were column silica gel H of Qingdao Ocean Chemical Co., Ltd. or Yantai Chemical Research Institute Experimental Factory (100-200 mesh, 200-300 mesh, 10-40μM).

Epibromohydrin, sulfur powder, sodium sulfide, chemically pure, China Pharmaceutical Group Chemical Reagent Co., Ltd.

Embodiment 1: Synthesis of 1,3-dibromo-2-propanol (compound of formula IV)

Add 20 grams of epibromopropane (compound of formula V) into a three-necked bottle with a thermometer, cool down to below 0°C, slowly add 32 grams of hydrobromic acid (40%) dropwise, during the process of violent heat release, control the temperature below 5°C, after the addition was complete, keep stirring at 0°C for 4 hours, extract twice with ether, combine the organic phases, wash the organic phase with saturated aqueous sodium bicarbonate solution, and then wash the organic phase with water, dry the organic phase with anhydrous magnesium sulfate, filter and evaporate under reduced pressure The solvent was removed to obtain 27 g of a colorless oil (compound of formula IV), yield: 85%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.00 (m, 1H), 3.58 (d, 1H), 3.56 (d, 1H), 2.6 (br, 1H).

Example 2: Synthesis of 2-(1,3-dibromo-2-propoxy)-tetrahydropyran (compound of formula III)

1.09 g of 1,3-dibromo-2-propanol (compound of formula IV) was dissolved in 10 ml of tetrahydrofuran, then 0.84 g of 3,4-dihydropyran was added, followed by 125 mg of pyridine p-toluenesulfonate , stirred at room temperature for 2 hours, added 30 milliliters of ethyl acetate for dilution, washed twice with 30 milliliters of water, and then washed with 30 milliliters of saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was washed with petroleum ether: ethyl acetate The ester (volume ratio 100:1) was used as the eluent, and 1.20 g of a colorless oil (compound of formula III) was obtained by silica gel column chromatography, with a yield of 80%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.76-4.79 (m, 1H), 3.88-4.04 (m, 2H), 3.51-3.71 (m, 5H), 1.53-1.87 (m, 6H).

Embodiment 3: the synthesis of formula II compound

Dissolve 2.85 grams of sodium sulfide nonahydrate in 10 milliliters of water, add 380 milligrams of sulfur powder, heat to 50 ° C, and wait until the sulfur powder is completely dissolved in the solution to obtain a light yellow solution, cool to room temperature, add this solution to the dissolved 1.20 grams In the chloroform solution of 30 milliliters of the compound of formula III, add a small amount of phase transfer catalyst tetrabutylammonium bromide, the solution turns black, stir at room temperature for 12 hours, add 20 milliliters of water, separate layers, extract the aqueous layer with chloroform, combine organic phase, Dry over anhydrous magnesium sulfate, filter, concentrate, and the residue uses petroleum ether:ethyl acetate (volume ratio 200:1) as the eluent, and obtains 500 mg of a colorless oil (compound of formula II) through silica gel column chromatography, Yield 61%.

¹ H NMR (400MHz, CDCl ₃ ): δ4.78-4.84(m,1H),4.69-4.72(m,1H),3.82-3.89(m,1H),3.49-3.56(m,1H),3.11- 3.28(m,4H),1.54-1.86(m,6H).

EI-MS: 206[M] ⁺ .

Embodiment 4: the synthesis of formula I compound

170 mg of the compound of formula II was dissolved in 10 ml of dichloromethane, cooled to 0°C, added 300 mg of m-chloroperoxybenzoic acid, kept stirring at 0°C for 1 hour, stirred at room temperature for 2 hours, added 10 ml of water, and separated layers. The aqueous layer was extracted with dichloromethane, the organic phases were combined, dried with anhydrous magnesium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography with petroleum ether:ethyl acetate (volume ratio 2:1) as the eluent to obtain white Solid (compound of formula I) 30 mg, yield 24%.

¹ H NMR (400MHz, CDCl ₃ ): δ4.93(m,1H),3.98(dd,1H),3.78(dd,1H),3.67(dd,1H),3.58(dd,1H);

¹³ C NMR (100MHz, CDCl ₃ ): δ68.15, 64.87, 45.04;

HR-EI-MS: 153.9761[M] ⁺ .

Claims (22)

1. A compound shown in the following formula II: Wherein, R is a protecting group and is not 2-methacryloyl. 2. The compound according to claim 1, wherein the protecting group is p-bromobenzoyl, p-chlorobenzoyl, p-iodobenzoyl or tetrahydropyranyl. 3. The compound according to claim 1, wherein the protecting group is p-bromobenzoyl or tetrahydropyranyl. 4. The compound of claim 1, wherein the protecting group is tetrahydropyranyl. 5. A preparation method of the compound according to claim 1, the method comprising: c) reacting the compound of formula III with sodium disulfide under the effect of a phase transfer catalyst to obtain the compound of formula II, Wherein, the definition of R is as described in claim 1, and X is chlorine, bromine or iodine. 6. The method according to claim 5, wherein, in step c), The molar ratio of the compound of formula III to sodium disulfide is 1:1～5; The phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctylmethylammonium chloride, dodecyl tri Methylammonium chloride or tetradecyltrimethylammonium chloride; The solvent used for reaction is the mixed solvent of dichloromethane or chloroform and water; The reaction temperature is 0°C to 50°C; and/or, The reaction time is 1 to 40 hours. 7. The method according to claim 5, wherein, in step c), The molar ratio of the compound of formula III to sodium disulfide is 1:1～2; The reaction temperature is 0°C to 20°C; and/or, The reaction time is 2 to 15 hours. 8. The method according to claim 5, wherein, also comprising the step of preparing the compound of formula III by the following steps: a) making the compound of formula V undergo a ring-opening reaction to obtain the compound of formula IV, wherein the definition of X is as described in claim 5; b) protecting the hydroxyl group of the compound of formula IV to obtain the compound of formula III, wherein the definition of R is as described in claim 1. 9. The method according to claim 8, wherein, in step a), the ring-opening reaction is carried out in the presence of hydrochloric acid, hydrobromic acid or hydroiodic acid. 10. The method according to claim 9, wherein, in step a), The molar ratio of the compound of formula V to hydrochloric acid, hydrobromic acid or hydroiodic acid is 1:1～5; The solvent used for the reaction is tetrahydrofuran, ether, dioxane, benzene, toluene, water or a mixture thereof; The reaction temperature is -40°C to room temperature; and/or, The reaction time is 1 to 10 hours. 11. The method according to claim 10, wherein, in step a), The molar ratio of the compound of formula V to hydrochloric acid, hydrobromic acid or hydroiodic acid is 1:1～3; The reaction temperature is -20°C to 0°C; and/or, The reaction time is 1 to 5 hours. 12. The method according to claim 10, wherein, in step a), the reaction temperature is -10°C to 0°C. 13. The method according to claim 8, wherein, in step b), the compound of formula IV and 3,4-dihydropyran are reacted by a catalyst to obtain the formula in which the hydroxyl group is protected by tetrahydropyranyl III compound. 14. The method of claim 13, wherein, in step b), The molar ratio of the compound of formula IV to 3,4-dihydropyran is 1:1-10; The catalyst is one or more selected from p-toluenesulfonic acid, pyridine p-toluenesulfonic acid salt, trifluoromethanesulfonic acid, acetic acid and camphorsulfonic acid; The solvent used for the reaction is methanol, ethanol, Virahol, ether, tetrahydrofuran, dioxane, benzene, toluene, chloroform, methylene chloride, dimethyl sulfoxide or a mixture thereof; The reaction time is 2 to 10 hours; and/or, The reaction temperature is -78°C to room temperature. 15. The method according to claim 14, wherein, in step b), the molar ratio of the compound of formula IV to 3,4-dihydropyran is 1:1-3. 16. A synthetic method of new oledithiol, the method comprising: d) oxidizing and deprotecting the compound of formula II to obtain the compound of formula I, wherein R is a protecting group. 17. The method of claim 16, wherein, in step d), Described oxidizing agent is m-chloroperoxybenzoic acid or peroxy tert-butyl alcohol; The solvent used for the reaction is dichloromethane, tetrahydrofuran, 1,4-dioxane or chloroform; The reaction temperature is 0°C to 60°C; and/or, The reaction time is 1 to 40 hours. 18. The method of claim 17, wherein, in step d), The reaction temperature is 0°C to 20°C; and/or, The reaction time is 2 to 15 hours. 19. The method according to claim 16, wherein, in step d), the compound of formula 4 is oxidized and deprotected under the action of an oxidizing agent to obtain compound formula I, and the reaction formula is as follows: Here, THP means tetrahydropyranyl. 20. The method according to claim 19, wherein, also comprising the step of preparing the compound of formula 4 as follows: In step a), the compound of formula 1 is used as the starting material, and under the action of hydrobromic acid, the epoxy is opened to obtain the compound of formula 2; In step b), the compound of formula 2 and 3,4-dihydropyran are catalyzed by pyridine p-toluenesulfonate to obtain the compound of formula 3 whose hydroxyl group is protected, In step c), the compound of formula 3 is reacted with an aqueous sodium disulfide solution under the action of a phase transfer catalyst tetrabutylammonium bromide to generate a compound of formula 4. 21. The method of claim 16, wherein the protecting group is p-bromobenzoyl, p-chlorobenzoyl, p-iodobenzoyl or tetrahydropyranyl. 22. The method of claim 16, wherein the protecting group is p-bromobenzoyl or tetrahydropyranyl.