CN109161016B - Preparation method of guanidine polymer heterogeneous catalyst and its application method in catalytic synthesis of warfarin and its derivatives - Google Patents

Abstract

The invention discloses a preparation method of a guanidine polymer heterogeneous catalyst and an application method thereof in catalytic synthesis of warfarin and derivatives thereof, the method takes a plurality of primary amine compounds and benzene isothiocyanate as raw materials, thiourea is firstly synthesized, then 2-chloro-1-methyl iodopyridine is used for converting the thiourea into corresponding carbodiimide, then the carbodiimide and branched polyethyleneimine are stirred and reacted at room temperature to synthesize the guanidine polymer based on the polyethyleneimine, the obtained guanidine polymer can be purified only by washing in a solvent, the guanidine polymer prepared by the invention can efficiently catalyze the addition reaction of 4-hydroxycoumarin and α -unsaturated ketone, the anticoagulant warfarin and derivatives thereof can be obtained at room temperature with yield of more than 90 percent, and the catalyst can be recycled at the same time, thereby achieving the effects of high efficiency and environmental protection.

Description

Preparation method of guanidine polymer heterogeneous catalyst and its catalytic synthesis of warfarin and its use Methods of application in derivatives

technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of a guanidine polymer heterogeneous catalyst and an application method thereof in the catalytic synthesis of warfarin and derivatives thereof.

Background technique

Guanidine is a general term for a class of organic compounds containing HNC(NH ₂ ) ₂ structural motifs, and guanidine functional groups exist in organisms and in many drug molecules, such as L-arginine, and the drug metformin for the treatment of diabetes. In organic chemistry, guanidine is more used as a strong base, and guanidine is one of the strongest organic bases. It is called "superbase" and has strong nucleophilicity. As a strong base or catalyst, it has Used in many types of organic reactions. However, due to their high polarity, guanidine compounds are difficult to separate and purify, and the synthesis methods of guanidine are few and complicated, and the synthesis cost is relatively high, all of which limit the application of guanidine compounds in organic reactions.

One idea to solve the above problems is to immobilize the guanidine compound to make a heterogeneous catalyst, in order to recycle the catalyst for multiple times, thereby reducing the reaction cost. At present, there have been reports on the immobilization of guanidine on silica gel and polyethylene glycol, but the problem of reduced catalyst activity after immobilization has been reported. There are also reports on the immobilization of guanidine on Fe ₃ O ₄ nanoparticles. The catalyst activity is reduced, and there are problems of metal residues. Therefore, it is still of great significance to synthesize a new type of guanidine-based solid-supported catalyst, realize the recycling of the catalyst, and overcome the problem of reducing the catalyst activity.

Warfarin is one of the most widely used anticoagulant drugs, which can only treat thromboembolic diseases in a variety of situations, so the study of its synthesis has broad application prospects. The earliest warfarin synthesis required multi-step reactions, while the existing warfarin production process was carried out by Michael reaction between 4-hydroxycoumarin and cinnamone (benzylidene acetone) under the action of an alkaline catalyst. Synthesized to obtain warfarin and its derivatives, see the following reaction formula:

Commonly used catalysts for catalytic synthesis of warfarin include some small molecular primary amine catalysts and thiourea catalysts. These catalysts are all homogeneous catalysts. After the reaction, the catalyst needs to be separated from the product, which increases the reaction cost and operation steps. Research on new catalytic systems to reduce the synthesis cost of warfarin and realize simple, efficient and green synthesis of warfarin still has important industrial application prospects.

SUMMARY OF THE INVENTION

The technical problem solved by the present invention is to synthesize a new type of amine-guanidine-functionalized polymer based on branched polyethylene (referred to as guanidine polymer), and apply the guanidine polymer as a catalyst to 4-hydroxycoumarin and cinnamon The Michael reaction of ketone (benzylidene acetone) to synthesize warfarin and its derivatives under mild and green conditions can improve the catalytic performance and conversion rate, and the catalyst guanidine polymer can be reused, thereby reducing the synthesis cost.

The present invention adopts the following technical scheme in order to solve the above-mentioned technical problems: 1. the preparation method of guanidine polymer heterogeneous catalyst, comprises the following steps:

(1), weigh equimolar amounts of primary amine compound (1) and phenyl isothiocyanate (2), dissolve in solvent acetonitrile, stir at room temperature for 6 hours, the reaction generates a large amount of white solid, filter and dry The product thiourea (3) can be obtained, and the reaction equation of this synthesis is as follows:

Wherein, R is phenyl, benzyl, n-hexyl or cyclohexyl;

(2) Dissolve 1 equivalent of thiourea (3) in dichloromethane, add 2 equivalents of 2-chloro-1-methyliodopyridine (4) and 3 equivalents of triethylamine, and stir at room temperature for 30 The product carbodiimide (5) can be obtained after column purification, and the synthetic reaction equation is as follows:

；

;

(3) Dissolve carbodiimide (5) and branched polyethyleneimine (6) in methylene chloride according to a certain molar ratio, stir at room temperature for 24 hours, remove the solvent in a rotary evaporator, and the obtained After the white solid was washed with ethanol, water and ethyl acetate in turn, it was dried in an oven at 60 degrees to obtain the guanidine polymer heterogeneous catalyst (7). The synthetic reaction equation is as follows:

。

.

The molar ratio of the carbodiimide (5) to the branched polyethyleneimine (6) described in step (3) is 1:1, 4:1 or 8:1.

The application method of the guanidine polymer heterogeneous catalyst in the catalytic synthesis of warfarin and its derivatives comprises the following steps: adding α,β-unsaturated ketone (9), 4-hydroxycoumarin (8) and a solvent into a container After the reaction is completed, the reaction solution is centrifuged, the supernatant is separated and dried, and recrystallized to obtain warfarin and its derivatives, and the precipitated guanidine polymer heterogeneous catalyst (7) is treated with methanol and water. After washing, drying can be reused again, and the reaction equation of this synthesis is as follows:

The solvent is a 1:1 mixture of ethanol and deionized water, the mass of the guanidine polymer heterogeneous catalyst (7) is 10% of the mass of the α,β-unsaturated ketone (9), and the reaction temperature is room temperature 20 ℃. -30 degrees, the reaction time is 12-24 hours, the guanidine polymer heterogeneous catalyst (7) can be reused at most 3 times after drying, and the R' group of the α,β-unsaturated ketone (9) is phenyl Or substituted phenyl, the molar ratio of α,β-unsaturated ketone (9) and 4-hydroxycoumarin (8) is 1:1.05.

With the above technical solution, the reagents used in the present invention are all commercially available. Compared with the prior art, the present invention has the following advantages:

(1) The final step of synthesizing guanidine polymer is the reaction of guanidine precursor carbodiimide and polymer carrier branched polyethyleneimine. After the synthesis, only need to wash to wash off the unreacted carbodiimide, Purification of guanidine polymers is very simple.

(2) The present invention uses guanidine polymer as a catalyst to catalyze the synthesis of warfarin. Since one repeating unit contains 7 guanidine groups, the catalyst activity is high, and the complete conversion of the reaction raw materials can be achieved in only 12 hours, and the purity of the crude product >95%.

(3) The catalyst used is insoluble in the reaction solvent, and can be quickly separated from the product and recycled after the reaction is completed.

(4) The reaction uses ethanol as a solvent, which is environmentally friendly and has mild conditions.

(5) The substrate has a wide range of applications.

As always stated, the present invention provides a simple, efficient, green and practical new method for the synthesis of warfarin and its analogs, and has broad application prospects.

Detailed ways

The present invention is further described below through the examples, but it does not mean that the protection scheme of the present invention is limited to the examples.

Example 1: Synthesis of Diphenyl-Substituted Guanidine Polymers

Dissolve 1.86 g of aniline and 2.71 g of phenyl isothiocyanate in 50 mL of acetonitrile, stir at room temperature for 6 hours, a large amount of white precipitates appear, filter and dry to obtain 4.22 g of white solid with a yield of 92.5%.

Take 2.28 g of N,N'-diphenylthiourea obtained in the previous step, dissolve it in 50 mL of dichloromethane, then add 3.03 g of triethylamine, and finally add 5.11 g of 2-chloro-1-methyliodopyridine, Stir at room temperature for 30 minutes, filter, and after the filtrate is spun to remove the solvent, column chromatography (eluent: petroleum ether) is used for separation and purification to obtain 1.57 g of a colorless transparent liquid with a yield of 81.0%.

1.57 g (about 8 mmol) of diphenylcarbodiimide obtained in the previous step was dissolved in 20 mL of dichloromethane, 0.473 g of branched polyethyleneimine (1 mmol equivalent, molecular weight 10000) was added, and stirred at room temperature for 24 hours, followed by The dichloromethane was removed under reduced pressure to obtain a white solid, which was washed with distilled water and methanol, respectively, and dried to obtain a diphenyl-substituted guanidine-functionalized polymer.

Example 2: Synthesis of Phenyl, Benzyl Substituted Guanidine Polymers

Dissolve 2.14 g of benzylamine and 2.71 g of phenyl isothiocyanate in 50 mL of acetonitrile, stir at room temperature for 6 hours, a large number of white precipitates appear, filter and dry to obtain 4.56 g of white solid with a yield of 94.0%.

Take 2.42 g of the thiourea obtained in the previous step, dissolve it in 50 mL of dichloromethane, then add 3.03 g of triethylamine, and finally add 5.11 g of 2-chloro-1-methyliodopyridine, stir at room temperature for 30 minutes, filter, After the filtrate was spun to remove the solvent, column chromatography (eluent: petroleum ether) was used for separation and purification to obtain 1.66 g of a colorless transparent liquid with a yield of 79.8%.

1.66 g (about 7.9 mmol) of the carbodiimide obtained in the previous step was dissolved in 20 mL of dichloromethane, 0.473 g of branched polyethyleneimine (1 mmol equivalent, molecular weight 10,000) was added, and the mixture was stirred at room temperature for 24 hours, and then decompressed. The dichloromethane was removed to obtain a white solid, which was washed with distilled water and methanol, respectively, and dried to obtain a phenyl- and benzyl-substituted guanidine-functionalized polymer.

Example 3: Synthesis of phenyl, n-hexyl substituted guanidine polymers

Dissolve 2.02 g of n-hexylamine and 2.71 g of phenyl isothiocyanate in 50 mL of acetonitrile, stir at room temperature for 6 hours, a large amount of white precipitates appear, filter and dry to obtain 4.12 g of white solid with a yield of 87.1%.

Take 2.36 g of the thiourea obtained in the previous step, dissolve it in 50 mL of dichloromethane, then add 3.03 g of triethylamine, and finally add 5.11 g of 2-chloro-1-methyliodopyridine, stir at room temperature for 30 minutes, filter, After the filtrate was spun to remove the solvent, column chromatography (eluent: petroleum ether) was used for separation and purification to obtain 1.26 g of a colorless transparent liquid with a yield of 62.3%.

1.26 g (about 6.23 mmol) of the carbodiimide obtained in the previous step was dissolved in 20 mL of dichloromethane, 0.368 g of branched polyethyleneimine (0.78 mmol equivalent, molecular weight 10000) was added, and the mixture was stirred at room temperature for 24 hours, and then decompressed. The dichloromethane was removed to obtain a white solid, which was washed with distilled water and methanol, respectively, and dried to obtain a phenyl- and n-hexyl-substituted guanidine-functionalized polymer.

Example 4: Synthesis of phenyl, cyclohexyl substituted guanidine polymers

Dissolve 1.98 g of cyclohexylamine and 2.71 g of phenyl isothiocyanate in 50 mL of acetonitrile, stir at room temperature for 6 hours, a lot of white precipitates appear, filter and dry to obtain 3.63 g of white solid with a yield of 77.5%.

Take 2.34 g of the thiourea obtained in the previous step, dissolve it in 50 mL of dichloromethane, then add 3.03 g of triethylamine, and finally add 5.11 g of 2-chloro-1-methyliodopyridine, stir at room temperature for 30 minutes, filter, After the filtrate was spun to remove the solvent, column chromatography (eluent: petroleum ether) was used for separation and purification to obtain 1.43 g of a colorless transparent liquid with a yield of 71.5%.

1.43 g (about 7.1 mmol) of the carbodiimide obtained in the previous step was dissolved in 20 mL of dichloromethane, 0.422 g of branched polyethyleneimine (0.89 mmol equivalent, molecular weight 10000) was added, and the mixture was stirred at room temperature for 24 hours, and then decompressed. The dichloromethane was removed to obtain a white solid, which was washed with distilled water and methanol, respectively, and dried to obtain a guanidine-functionalized polymer substituted with phenyl and cyclohexyl.

Example 5: Synthesis of warfarin.

In a 25mL round-bottom flask, add 146mg cinnamone, 170mg 4-hydroxycoumarin, 10mg diphenyl substituted guanidine polymer, 10mL absolute ethanol, and stir at room temperature for 12 hours. After the reaction of cinnamone is analyzed by thin layer chromatography , filtered, the filtrate was removed under reduced pressure and the solvent was purified by silica gel column (developing solvent: petroleum ether, ethyl acetate = 3:1) to obtain 296 mg of white solid with a yield of 96.1%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 1.68 (s, 1.59 H), 1.73 (s, 1.52 H), 1.98-2.05 (m, 0.57H), 2.30 (s, 0.3 H), 2.40- 2.58 (m, 1.49H), 3.20 (br s, 0.99H), 3.30 (dd, 0.10H), 3.86 (dd, J = 10.4, 19.6 Hz, 0.1H), 4.16 (dd, J =6.8, 11.2 Hz) , 0.5H), 4.29 (dd, J = 3.2, 6.8 Hz, 0.5H), 4.69 (dd, J = 2.4, 10.0 Hz, 0.1H), 7.22-7.37 (m, 7 H), 7.49 (m, 0.6 H), 7.55 (dt, J = 1.6, 8.4Hz, 0.33H), 7.81 (dd, J =1.2, 7.6 Hz, 0.5H), 7.90 (dd, J =1.2, 7.6 Hz, 0.5H), 7.95 ( dd, J =1.6, 8.0 Hz, 0.1H), 9.48(br s, 0.1H);

Example 6: Synthesis of 4-methoxy-substituted warfarin analogs.

In a 25mL round-bottom flask, add 196mg 4-methoxycinnamone, 170mg 4-hydroxycoumarin, 10mg diphenyl substituted guanidine polymer, 10mL absolute ethanol, stir at room temperature for 16 hours, TLC analysis After the reaction of cinnamone was completed, it was filtered, and the solvent was removed from the filtrate under reduced pressure, and then purified by silica gel column (developing solvent: petroleum ether, ethyl acetate = 3:1) to obtain 321 mg of white solid with a yield of 95.0%.

¹ H NMR (400 MHz, CDCl ₃ ) ä (ppm) 1.67 (s, 1.87H), 1.70 (s, 1.50H), 1.95- 2.01 (m, 0.54H), 2.27 (s, 0.35 H), 2.34- 2.53 (m, 1.61H), 3.40 (s, 0.5H), 3.60 (s, 0.5H), 3.76 (d, 3.2H), 3.80 (m, 0.2H), 4.10 (dd, J = 6.9, 11.3 Hz ,0.5H), 4.22 (dd, J = 3.1, 6.7 Hz, 0.5H), 4.65 (dd, J = 2.3, 10.0 Hz, 0.1H), 6.81-6.86 (m, 2.3H), 7.11-7.35 (m , 5H), 7.47 (dt, J = 4.6, 8.2 Hz, 0.68H), 7.55 (dt, J = 1.6, 7.4 Hz, 0.27H), 7.80 (dd, J = 1.3, 6.9 Hz, 0.25H), 7.89 (dd, J = 1.5, 7.9 Hz, 0.25H), 9.44(br s, 0.1H);

Example 7: Synthesis of 4-Methyl Substituted Warfarin Analogs.

In a 25mL round bottom flask, add 160 mg 4-methyl cinnamone, 170 mg 4-hydroxycoumarin, 10 mg diphenyl substituted guanidine polymer, 10 mL absolute ethanol, stir at room temperature for 16 hours, TLC Analysis: After the reaction of cinnamone was completed, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure, and then purified by silica gel column (developing solvent: petroleum ether, ethyl acetate = 5:1) to obtain 297 mg of white solid with a yield of 92.2%.

¹ H NMR (600 MHz, CDCl ₃ ) ä (ppm) 1.67 (s, 1.4H), 1.72 (s, 1.3H), 2.0 (dd, J = 13.9, 26.3 Hz, 0.49H), 2.29 (s, 0.28 H), 2.30 (d, J = 4.7, 2.9H), 2.39 (dd, J = 6.9, 14.2 Hz, 0.53H), 2.16 (dd, J = 6.9, 14.0 Hz, 0.44H), 2.53(dd, J = 3.0, 14.1 Hz, 0.5H), 3.2 (s, 0.39H), 3.23 (s, 0.5H), 3.31 (d, J =2.2, 0.08H), 3.84 (m, 0.12H), 4.13 (dd, J = 6.9, 11.5 Hz, 0.45H), 4.26 (dd, J = 2.6, 6.7 Hz, 0.45H), 4.66 (d, J = 8.5 Hz, 0.08H), 7.08-7.19 (m, 4.2H), 7.21 -7.36 (m, 2.5H), 7.49-7.57 (m, 1.0H), 7.81 (dd, J = 1.14, 6.7 Hz, 0.27H), 7.90 (dd, J = 1.26, 7.92 Hz, 0.29H), 7.94 (dd, J = 1.08, 7.9 Hz, 0.13H), 9.43(s, 0.1H);

Example 8: Synthesis of 4-Fluorosubstituted Warfarin Analogs.

Add 164 mg 4-fluorocinnamone, 170 mg 4-hydroxycoumarin, 10 mg diphenyl substituted guanidine polymer, 10 mL absolute ethanol to a 25 mL round bottom flask, stir at room temperature for 16 hours, and analyze by thin layer chromatography After the reaction of cinnamone ketone was completed, it was filtered, and the solvent was removed from the filtrate under reduced pressure, and then purified by silica gel column (developing solvent: petroleum ether, ethyl acetate = 5:1) to obtain 291 mg of pale yellow solid with a yield of 89.3%.

¹ H NMR (400 MHz, CDCl ₃ ) ä (ppm) 1.69 (s, 1.2H), 1.72 (s, 1.7H), 1.95 (dd, J = 11.6, 13.8 Hz, 0.5H), 2.29 (s, 0.3 H), 2.37 (dd, J = 7.0, 14.2 Hz, 0.4H), 2.46 (m, 0.9H), 3.25-3.30 (dd, J = 2.4, 19.4 Hz, 0.1H), 3.37 (s, 0.32H) , 3.79 (s, 0.48H), 3.85 (dd, J = 10.3, 19.4 Hz, 0.1H), 4.16 (dd, J =6.8, 11.5 Hz, 0.6H), 4.21 (dd, J = 3.8, 6.9 Hz, 0.5H), 4.67 (d, J = 8.6 Hz, 0.1H), 6.94-7.02 (m, 1.9H), 7.15-7.34 (m, 4.1H), 7.47-7.59 (m, 1H), 7.80 (dd, J = 1.64, 8.52 Hz, 0.5H), 7.87 (dd, J = 1.52, 7.88 Hz, 0.33H), 7.95 (dd, J =1.44, 7.96 Hz, 0.1H), 9.60 (s, 0.07H);

Example 9: Synthesis of 3-chloro-substituted warfarin analogs.

Add 180 mg 3-chlorocinnamone, 170 mg 4-hydroxycoumarin, 10 mg diphenyl substituted guanidine polymer, 10 mL absolute ethanol to a 25 mL round bottom flask, stir at room temperature for 16 hours, and analyze by thin layer chromatography After the reaction of cinnamone was completed, it was filtered, and the solvent was removed from the filtrate under reduced pressure, and then purified by silica gel column (developing solvent: petroleum ether, ethyl acetate = 4:1) to obtain 312 mg of pale yellow solid with a yield of 91.2%.

1H NMR (400 MHz, CDCl3) δ (ppm) 1.71 (s, 1.03H), 1.76 (s, 1.51H), 2.00 (m, 0.82H), 2.31 (s, 0.28H), 2.42-2.51 (m, 1.19H), 3.06 (s, 0.33H), 3.21(s, 0.47H), 3.86 (dd, J = 10.6, 19.7 Hz, 0.09H), 4.13 (m, 0.72H), 4.22 (m, 0.39H) , 4.67 (dd, J = 1.8, 10.4 Hz, 0.06H), 7.13-7.38 (m, 6.66H), 7.50-7.61(m, 1.04H), 7.82 (dd, J = 1.44, 8.2 Hz, 0.37H) , 7.88 (dd, J = 1.56, 7.92 Hz, 0.25H, 7.97 (dd, J = 1.48, 8.0 Hz, 0.09H), 9.57 (s, 0.07H).

Claims (4)

1. The preparation method of the guanidine polymer heterogeneous catalyst is characterized by comprising the following steps:

(1) weighing equimolar primary amine compound (1) and phenyl isothiocyanate (2), dissolving in solvent acetonitrile, stirring at room temperature for 6 hours, reacting to generate a large amount of white solid, filtering, and drying to obtain the product thiourea (3), wherein the reaction equation of the synthesis is as follows:

wherein R is phenyl, benzyl, n-hexyl or cyclohexyl;

(2) dissolving 1 equivalent of thiourea (3) in dichloromethane, adding 2 equivalents of 2-chloro-1-methyl iodopyridine (4) and 3 equivalents of triethylamine, stirring at room temperature for 30 minutes, and purifying by passing through a column to obtain the product carbodiimide (5), wherein the reaction equation of the synthesis is as follows:

；

(3) dissolving carbodiimide (5) and branched polyethyleneimine (6) in dichloromethane according to a certain molar ratio, stirring at room temperature for 24 hours, removing the solvent in a rotary evaporator, washing the obtained white solid with ethanol, water and ethyl acetate in sequence, and drying at 60 ℃ in an oven to obtain the guanidine polymer heterogeneous catalyst (7), wherein the reaction equation of the synthesis is as follows:

。

2. the method for preparing the guanidine polymer heterogeneous catalyst according to claim 1, wherein the feeding molar ratio of the carbodiimide (5) to the branched polyethyleneimine (6) in the step (3) is 1:1, 4:1 or 8: 1.

3.α -unsaturated ketone (9), 4-hydroxy coumarin (8) and solvent are added into a container, stirred and reacted, after the reaction is finished, reaction liquid is centrifuged, supernatant liquid is separated and dried, and the warfarin and the derivative are obtained after recrystallization, the precipitated guanidine polymer heterogeneous catalyst (7) is washed by methanol and water and dried for reuse, the guanidine polymer heterogeneous catalyst (7) is obtained by the preparation method of claim 1, and the synthetic reaction equation is as follows:

the R' group is phenyl or substituted phenyl.

4. The application method of the guanidine polymer heterogeneous catalyst in catalytic synthesis of warfarin and derivatives thereof according to claim 3 is characterized in that the solvent is a mixture of ethanol and deionized water in a ratio of 1:1, the mass of the guanidine polymer heterogeneous catalyst (7) is 10% of the mass of α -unsaturated ketone (9), the reaction temperature is 20-30 ℃, the reaction time is 12-24 hours, the guanidine polymer heterogeneous catalyst (7) is dried and recycled for 3 times at most, the R' group of α -unsaturated ketone (9) is phenyl or substituted phenyl, and the feeding molar ratio of α -unsaturated ketone (9) to 4-hydroxycoumarin (8) is 1: 1.05.