CN112778214A - Intermediate for synthesizing rilpivirine, synthesis method thereof and rilpivirine synthesis method - Google Patents
Intermediate for synthesizing rilpivirine, synthesis method thereof and rilpivirine synthesis method Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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Abstract
The invention relates to the technical field of drug synthesis, in particular to an intermediate for synthesizing rilpivirine, a synthesis method thereof and a synthesis method of rilpivirine. Intermediates were synthesized according to the following synthetic route:
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to an intermediate for synthesizing rilpivirine, a synthesis method thereof and a synthesis method of rilpivirine.
Background
Rilpivirine is a novel non-nucleoside reverse transcription inhibitor (NNRTI) developed by Tibotec pharmaceutical. To date, only 5 NNRTI anti-HIV agents are marketed, namely nevirapine, efavirenz, delavirdine, etravirine, and rilpivirine. Compared with the old medicines such as nevirapine, delavirdine, etravirine and the like, the rilpivirine has the advantages of 1 tablet every day, first-line medication, extremely low drug resistance and high safety. It has the same curative effect as efavirenz and better safety, so that rilpivirine can be used as a new treatment method for HIV-1 infected patients. Rilpivirine has been approved by the U.S. Food and Drug Administration (FDA) in 5 months of 2011 for the treatment of HIV-1 infected patients Rilpivirine can also be used in combination with other antiretroviral drugs for the treatment of HIV-1 infected adult patients who have never undergone HIV treatment (treatment naive).
Rilpivirine has the chemical name: 4- [ [4- [ [4- [ (1E) -2-cyanoethenyl ] -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile, having the structure shown below:
there are many reports on the synthesis of rilpivirine, for example, the amino protection of 2-amino-4-chloropyrimidine, the subsequent reaction with 4- [ (1E) -2-cyanovinyl ] -2, 6-dimethylaniline under alkaline conditions, deamination protection, purification, impurity and cis-isomer removal to obtain an intermediate with a desired configuration, and the subsequent reaction of the intermediate to obtain rilpivirine.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide an intermediate for synthesizing rilpivirine, a synthesis method thereof and a synthesis method of rilpivirine. By adopting the method provided by the embodiment of the invention, the intermediate for synthesizing rilpivirine can be efficiently synthesized, amino protection, deamination protection and isomer separation are not required, and the overall synthesis yield of rilpivirine can be improved.
The invention is realized by the following steps:
in a first aspect, the invention provides a synthesis method of an intermediate for synthesizing rilpivirine, wherein the intermediate is synthesized according to the following synthesis route:
In alternative embodiments, M is a strong acid; preferably a strong organic or inorganic acid; preferably, the organic strong acid is p-toluenesulfonic acid or methanesulfonic acid, and the inorganic strong acid is hydrochloric acid or sulfuric acid;
preferably, X is chlorine or bromine, preferably chlorine.
In an alternative embodiment, the molar ratio of the compound of formula II to the compound of formula I is 1: 1-2, preferably 1:1-1.5, more preferably 1: 1.1.
In an alternative embodiment, the conditions under which the reaction is carried out according to the synthetic route are: the time is 1-10 hours, and the temperature is 0-120 ℃;
preferably, the time is 2-8 hours, the temperature is 10-90 ℃ or 20-80 ℃ or 50-70 ℃;
preferably, the solvent used in the reaction is a solvent capable of dissolving the compound represented by formula I and the compound represented by formula II, but not participating in the reaction;
preferably, the solvent is selected from at least one of dioxane, tetrahydrofuran or 2-methyltetrahydrofuran, DMF, DMSO, and NMP, and the solvent is an anhydrous solvent;
preferably, the reaction system is an acidic environment, preferably a weakly acidic environment.
In a second aspect, the invention provides an intermediate for synthesizing rilpivirine, which is prepared by the synthesis method of any one of the intermediates for synthesizing rilpivirine described in the previous embodiments,
preferably, the intermediate represented by formula III is a mixture of cis and trans isomers,
preferably, the intermediate of formula III comprises the following two compounds:
In a third aspect, the invention provides a synthesis method of rilpivirine, which comprises the following steps of synthesizing rilpivirine according to the following synthesis route:
In alternative embodiments, the molar ratio of intermediate of formula | V to compound of formula | V is 1: 1-2, preferably 1:1-1.5, more preferably 1: 1.1.
In an alternative embodiment, the intermediate of formula III is reacted with the compound of formula IV under the conditions: for a period of from 1 to 10 hours, preferably from 4 to 8 hours, at a temperature of from 25 to 130 ℃, preferably from 50 to 80 ℃ or from 90 to 100 ℃.
In an alternative embodiment, the intermediate of formula III is reacted with the compound of formula IV under basic conditions.
In an alternative embodiment, the alkaline substance used to form the alkaline condition is selected from any one of an alkali metal hydride, an alkali metal carbonate, an alkali metal phosphate, an alkali metal acetate, or an alkali metal hydroxide.
The invention has the following beneficial effects: the embodiment of the invention provides a new idea for synthesizing rilpivirine intermediates, which utilizes the fact that a compound shown in a formula II can generate acid by itself and then provides an acid environment for reaction, so that the compound shown in the formula I and the compound shown in the formula II can directly perform autocatalytic reaction on the basis of not performing amino protection on the compound shown in the formula I, the compound shown in the formula I and the compound shown in the formula II react to form a required intermediate, and the overall yield of rilpivirine synthesis is improved.
Meanwhile, when the rilpivirine is synthesized, the intermediate shown in the formula | | | | is not separated but directly reacted, the Z configuration in the intermediate shown in the formula III can be partially converted into the E configuration, and then the yield of the rilpivirine with physiological activity can be improved.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The embodiment of the invention provides a synthesis method of an intermediate for synthesizing rilpivirine, which comprises the following steps of:
The reaction environment provided by the embodiment of the invention is acidic, preferably weakly acidic, and the pH is generally 5-6. If the reaction environment of the example of the present invention is changed to an alkaline environment, the reaction proceeds very slowly, a reaction time needs to be greatly prolonged, and only a small amount of raw materials undergo the reaction even if the reaction time is greatly prolonged, resulting in an extremely low yield.
Further, X is chlorine or bromine, preferably chlorine. The use of the halogen can further facilitate the synthesis of the intermediate of formula III.
Further, the molar ratio of the compound represented by the formula II to the compound represented by the formula I is 1: 1-2, preferably 1:1-1.5, more preferably 1: 1.1. For example, the molar ratio of the compound represented by formula I to the compound represented by formula II may be any value such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, and 1:2, or any value within a range formed between the above values. The conditions for carrying out the reaction according to the synthetic route are: the time is 1-10 hours, and the temperature is 0-120 ℃; the time is 2-8 hours, and the temperature is 10-90 ℃, or 20-80 ℃, or 50-70 ℃. For example, the time may be any value such as 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 8.5 hours, 9 hours, and 10 hours, or any value within a range between the above values. The temperature may be any value or any value within a range defined between any of the above values, such as 0 ℃,5 ℃,10 ℃, 15 ℃, 20 ℃, 22 ℃, 27 ℃, 30 ℃, 35 ℃, 38 ℃, 40 ℃, 45 ℃, 47 ℃, 50 ℃, 60 ℃, 63 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃,100 ℃, 110 ℃, 115 ℃ and 120 ℃.
The compound shown in the formula | and the compound shown in the formula II can be promoted to react under the conditions, so that the synthesis yield of the intermediate shown in the formula III is improved.
Further, the solvent used in the reaction is a solvent capable of dissolving the compound represented by formula I and the compound represented by formula | |, but does not participate in the reaction; wherein the solvent is at least one of dioxane, tetrahydrofuran or 2-methyltetrahydrofuran, DMF, DMSO and NMP, and the solvent is anhydrous.
The embodiment of the invention also provides an intermediate for synthesizing rilpivirine, which is prepared by the synthesis method of the intermediate for synthesizing rilpivirine, wherein the prepared intermediate represented by the formula I is a cis-trans isomer mixture and comprises the following two compounds:
The embodiment of the invention also provides a synthesis method of rilpivirine, which synthesizes rilpivirine according to the following synthesis path:
The intermediate shown in the formula | | | | only has an intermediate with an E configuration (namely, the compound shown in the formula | | | -1) and can be synthesized to obtain rilpivirine with biological and physiological activities, so the intermediate is generally required to be separated and purified to obtain a simple substance with the E configuration, and then rilpivirine is synthesized, but the E configuration can be partially converted into a Z configuration (namely, the compound shown in the formula III-2) in the subsequent rilpivirine synthesis process, and therefore, the rilpivirine is required to be separated and purified again after being synthesized. In the process of integrally synthesizing rilpivirine, twice separation and purification are needed, and meanwhile, amino protection and deamination protection of the compound shown in the formula I are carried out, so that the yield of the whole rilpivirine process is low.
In the embodiment of the invention, the intermediate (namely, the cis-trans isomer mixture) shown in the formula III is directly reacted, so that the step of separating the intermediate shown in the formula III is omitted, and meanwhile, part of Z-type configuration can be converted into E-type configuration in the reaction process, so that the synthesis yield of rilpivirine is improved. Meanwhile, the rilpivirine is purified only after the synthesis of the rilpivirine is finished, namely, the rilpivirine is separated and purified only once in the embodiment of the invention without amino protection and deamination, so that the synthesis yield of the rilpivirine is further improved.
Further, the molar ratio of the intermediate shown in the formula III to the compound shown in the formula IV is 1: 1-2, preferably 1:1-1.5, more preferably 1: 1.1. For example, the molar ratio of the intermediate of formula III to the compound of formula IV may be any value such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, and 1:2, or any value within the range formed between the above values. The conditions for carrying out the reaction according to the synthetic route are: the time is 1-10 hours, and the temperature is 25-130 ℃; the time is 4-8 hours, and the temperature is 50-80 ℃ or 90-100 ℃. For example, the time may be any value such as 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 8.5 hours, 9 hours, and 10 hours, or any value within a range between the above values. The temperature may be any value or any value within a range defined between the above values, such as 25 ℃, 30 ℃, 35 ℃, 38 ℃, 40 ℃, 45 ℃, 47 ℃, 50 ℃, 55 ℃, 60 ℃, 63 ℃, 68 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃,100 ℃, 110 ℃, 115 ℃, 120 ℃, 125 ℃ and 130 ℃.
And the intermediate shown in the formula III and the compound shown in the formula IV react under the alkaline condition. The alkaline substance used for the alkaline condition is selected from any one of alkali metal hydride, alkali metal carbonate, alkali metal phosphate, alkali metal acetate or alkali metal hydroxide, and may be NaH, NaOH, KOH, potassium phosphate, potassium acetate or K2CO and the like which can form an alkaline reaction system.
The embodiment of the invention adopts the reaction conditions, the temperature and the reaction environment, can further ensure that the intermediate shown in the formula III and the compound shown in the formula IV fully react, and is favorable for the synthesis of rilpivirine.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
The embodiment of the invention provides a method for synthesizing 3- (4- (2-aminopyrimidine-4-yl) -3, 5-dimethylphenyl) -acrylonitrile, which comprises the following steps:
see the following synthetic route:
DMF (40ml) was charged into a reaction flask, and the compound represented by formula I (14.3g, 110mmol) and the compound represented by formula II-1 (20.9g,100mmol) were added under nitrogen, stirred, and heated to 90 ℃ to 95 ℃. The temperature was maintained for 3 hours. After the reaction is finished, the temperature is reduced to 20 +/-5 ℃ at room temperature, and 120ml of 10% potassium carbonate aqueous solution is added dropwise. Solid is separated out, filtered and washed by water. Filtering until no filtrate is dripped, scraping out a filter cake, refluxing and pulping by using 30ml of acetonitrile for 1 hour, cooling to room temperature of 20 +/-5 ℃, filtering, leaching by using a proper amount of acetonitrile, and drying at 50 ℃ to obtain an intermediate shown in the formula III (21.3g, 80.5 percent, the purity of 98.7 percent, and the E/Z (87: 12)), and directly using in the next reaction without further purification.
In order to verify that the intermediate shown in formula III has the desired E configuration capable of forming rilpivirine, in this example, 1g of the intermediate shown in formula III is taken, purified, and then characterized, specifically as follows: 1g of the intermediate of formula III was purified by silica gel column separation (eluent dichloromethane: methanol 10:1) to give the pure E configuration intermediate, i.e. the compound of formula III-1 (350mg) and E/Z mixture (640 mg).
A compound of formula III-1:1h NMR (400MHz, DMSO-d6) δ:8.39(s,1H), 7.71(d, J ═ 5.5Hz,1H), 7.56(d, J ═ 16.5Hz,1H),7.40(s,2H),6.38(d, J ═ 16.5Hz,1H),5.97(s,2H),2.15(s, 6H); ms (+ C, ESI): M265, found: (266, M + 1).
Example 2
The embodiment of the invention provides a method for synthesizing 3- (4- (2-aminopyrimidine-4-yl) -3, 5-dimethylphenyl) -acrylonitrile, which comprises the following steps:
see the following synthetic route:
DMF (50ml) was charged into a reaction flask, and the compound represented by formula I (14.3g, 110mmol) and the compound represented by formula II-2 (27g,100mmol) were added under nitrogen, stirred, and heated to 90 ℃ to 95 ℃. The temperature was maintained for 3 hours. After the reaction is finished, the temperature is reduced to 20 +/-5 ℃ at room temperature, and 150ml of 10% potassium carbonate aqueous solution is added dropwise. Solid is separated out, filtered and washed by water. Filtering until no filtrate is dripped, scraping out a filter cake, refluxing and pulping by using 30ml of acetonitrile for 1 hour, cooling to room temperature of 20 +/-5 ℃, filtering, leaching by using a proper amount of acetonitrile, and drying at 50 ℃ to obtain an intermediate (19.9g, 75%, the purity of 97.5%, and the E/Z (82: 15)) shown in the formula III, wherein the intermediate is directly used for the next reaction without further purification.
In order to verify that the intermediate shown in the formula III has the required E configuration capable of forming rilpivirine, 1g of the intermediate shown in the formula III is separated and purified by a silica gel column (eluent is dichloromethane: methanol: 10:1), and the pure intermediate shown in the formula E is obtained, namely the compound shown in the formula I-1 (310mg) and an E/Z mixture (660 mg).
A compound of formula III-1:1h NMR (400MHz, DMSO-d6) δ:8.39(s,1H), 7.71(d, J ═ 5.5Hz,1H), 7.56(d, J ═ 16.5Hz,1H),7.40(s,2H),6.38(d, J ═ 16.5Hz,1H),5.97(s,2H),2.15(s, 6H); ms (+ C, ESI): M265, found: (266, M + 1).
Example 3
The embodiment of the invention provides a method for synthesizing 3- (4- (2-aminopyrimidine-4-yl) -3, 5-dimethylphenyl) -acrylonitrile, which comprises the following steps:
see the following synthetic route:
DMF (70ml) was charged into a reaction flask, and the compound represented by formula I (14.3g, 110mmol) and the compound represented by formula II-3 (34.4g,100mmol) were added under nitrogen, stirred, and heated to 90 ℃ to 95 ℃. The temperature was maintained for 3 hours. After the reaction is finished, the temperature is reduced to 20 +/-5 ℃ at room temperature, and 200ml of 10% potassium carbonate aqueous solution is dripped. Solid is separated out, filtered and washed by water. Filtering until no filtrate is dripped, scraping out a filter cake, refluxing and pulping by 30ml of acetonitrile for 1 hour, cooling to room temperature of 20 +/-5 ℃, filtering, leaching by using a proper amount of acetonitrile, and drying at 50 ℃ to obtain an intermediate (22.5g, 85 percent, the purity of 98.3 percent, and the E/Z (89/9)) shown in the formula III, wherein the intermediate is directly used for the next reaction without further purification.
To verify that the intermediate of formula III has the desired E configuration to form rilpivirine, 1g of the intermediate of formula III was purified by silica gel column separation (eluent dichloromethane: methanol: 10:1) to give the pure E configuration intermediate, i.e., the compound of formula III-1 (620mg) and the E/Z mixture (360 mg). The nuclear magnetic results and mass spectrum results of the compound represented by the formula III-1 were consistent with those of example 2.
Example 4
The embodiment of the invention provides a method for synthesizing 3- (4- (2-aminopyrimidine-4-yl) -3, 5-dimethylphenyl) -acrylonitrile, which comprises the following steps:
see the following synthetic route:
DMF (50ml) was charged into a reaction flask, and the compound represented by formula I (14.3g, 110mmol) and the compound represented by formula III-4 (26.8g,100mmol) were added under nitrogen, stirred, and heated to 90 ℃ to 95 ℃. The temperature was maintained for 3 hours. After the reaction is finished, the temperature is reduced to 20 +/-5 ℃ at room temperature, and 150ml of 10% potassium carbonate aqueous solution is added dropwise. Solid is separated out, filtered and washed by water. Filtering until no filtrate is dripped, scraping out a filter cake, refluxing and pulping by using 30ml of acetonitrile for 1 hour, cooling to room temperature of 20 +/-5 ℃, filtering, leaching by using a proper amount of acetonitrile, and drying at 50 ℃ to obtain an intermediate (18g, 68 percent, the purity is 95 percent, and E/Z is 79; 16) shown in the formula III, wherein the intermediate is directly used for the next reaction without further purification.
In order to verify that the intermediate shown in the formula III has the required E configuration capable of forming rilpivirine, 1g of the intermediate shown in the formula III is separated and purified by a silica gel column (eluent is dichloromethane: methanol: 10:1), and the pure intermediate shown in the formula E is obtained, namely the compound shown in the formula I-1 (290mg) and an E/Z mixture (680 mg). The nuclear magnetic results and mass spectrum results of the compound represented by the formula III-1 were consistent with those of example 2.
Example 5
The embodiment of the invention provides a synthesis method of rilpivirine (a compound shown in a formula V). See the following synthetic route:
the intermediate of formula III prepared in example 1 (26.5g, 1eq, E/Z87: 12) was dissolved in DMF (110ml) and K was added2CO3(27.6g, 2eq), the compound represented by the formula IV-1 (21.8g, 1.2eq), cuprous iodide (1.9g, 0.1eq), and argon gas were used to displace the air in the reaction system. Then, the temperature was raised to 110 ℃ and the reaction was maintained at the reaction temperature for 5 hours. After cooling to room temperature, 200ml of water were added to the reaction mixture, which was extracted with 1L of ethyl acetate, and the organic phase was dried, filtered and concentrated to give the crude product.
The crude product was recrystallized twice from ethanol and acetonitrile, respectively, to give the compound represented by formula V (21.9g, yield 60%, E/Z99.5: 0.5). The characterization data are as follows:1H NMR(400MHz,DMSO-d6)δ9.62(s,br，1H),8.95(s,br，1H),8.04(s,br，1H),7.73(s,2H),7.64(d,J＝16.5Hz,1H),7.50(s,br，4H),6.46(d,J＝16.5Hz,1H),6.35(s,br, 1H),2.21(s, 6H); ms (+ C, ESI): M ═ 366, found: (367, M + 1).
Example 6
The embodiment of the invention provides a synthesis method of rilpivirine (a compound shown in a formula V). See the following synthetic route:
the intermediate of formula III (26.5g, 1eq, E/Z87: 12) was dissolved in toluene (110ml) and K was added3PO4(31.8g, 1.5eq), the compound represented by the formula IV-1 (21.8g, 1.2eq), tris (dibenzylideneacetone dipalladium (1.83g, 0.02eq), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (1.15g, 0.02eq), and the air in the reaction system was replaced with argon, followed by heating to 100 ℃ and maintaining the reaction at the reaction temperature for 4 hours, cooling to room temperature, adding 200ml of water to the reaction mixture, extracting with 1L of ethyl acetate, drying, filtering, and concentrating the organic phase to obtain a crude product, and recrystallizing the crude product with ethanol and acetonitrile, respectively, to obtain the compound represented by the formula V (28.5g, yield 76%, E/Z ═ 99.6: 0.3).
Example 7
The embodiment of the invention provides a synthesis method of rilpivirine (a compound shown in a formula V). See the following synthetic route:
the intermediate of formula III (26.5g, 1eq, E/Z83: 15) was dissolved in toluene (110ml) and K was added3PO4(31.8g, 1.5eq), the compound represented by the formula IV-1 (21.8g, 1.2eq), tris (dibenzylideneacetone dipalladium (1.83g, 0.02eq), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (1.15g, 0.02eq), and the air in the reaction system was replaced with argon, then the temperature was raised to 100 ℃ and the reaction was maintained at this temperature for 4 hours, the reaction mixture was cooled to room temperature, 200ml of water was added to the reaction mixture, extraction was performed with 1L of ethyl acetate, and the organic phase was dried, filtered and concentrated to obtain a crude productThe compound represented by the formula V was obtained by secondary recrystallization from ethanol and acetonitrile (27.4g, yield 75%, E/Z99.4: 0.4).
Example 8
The embodiment of the invention provides a synthesis method of rilpivirine (a compound shown in a formula V). See the following synthetic route:
the intermediate of formula III (26.5g, 1eq, E/Z87: 12) was dissolved in toluene (110ml) and K was added3PO4(31.8g, 1.5eq), a compound represented by the formula IV-2 (16.5g, 1.2eq), tris (dibenzylideneacetone dipalladium (1.83g, 0.02eq), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (1.15g, 0.02eq), and the air in the reaction system was replaced with argon, followed by heating to 100 ℃ and maintaining the reaction at the reaction temperature for 8 hours, cooling to room temperature, adding 200ml of water to the reaction mixture, extracting with 1L of ethyl acetate, drying, filtering, and concentrating the organic phase to obtain a crude product, and recrystallizing the crude product with ethanol and acetonitrile, respectively, to obtain a compound represented by the formula V (23g, yield 63%, E/Z99: 1).
It should be noted that the compound represented by the formula V prepared in examples 6 to 8 and the compound represented by the formula V prepared in example 5 have the same characterization results, and the inventors do not supplement the characterization results.
Comparative example 1
The invention provides a synthesis method of rilpivirine (a compound shown in a formula V). See the following synthetic route:
the intermediate of formula III (26.5g, 1eq, E/Z99.1: 0.9) was dissolved in DMF (110ml) and K was added2CO3(27.6g, 2eq), the compound represented by the formula IV-1 (21.8g, 1.2eq), cuprous iodide (1.9g, 0.1eq), and argon gas were used to displace the air in the reaction system. Then the temperature is raised to 110 ℃, in the reactionThe reaction was maintained at temperature for 5 hours. After cooling to room temperature, 200ml of water were added to the reaction mixture, which was extracted with 1L of ethyl acetate, and the organic phase was dried, filtered and concentrated to give the crude product. The crude product was recrystallized twice from ethanol and acetonitrile, respectively, to give the compound represented by formula V (22.7g, yield 62%, E/Z99.5: 0.3).
The reaction conditions of the comparative example are consistent with those of the example 5, the difference is only that the mixture ratio of the E/Z configuration of the intermediate shown in the formula III is different, the content of the E configuration in the intermediate shown in the formula III of the comparative example is obviously different from that in the intermediate shown in the formula III of the example 5, but the yields of the E configuration and the E configuration are basically the same, which indicates that the E configuration and the Z configuration of the intermediate shown in the formula III are interconverted in the process of forming rilpivirine.
Comparative example 2
The embodiment of the invention provides a synthesis method of rilpivirine (a compound shown in a formula V). See the following synthetic route:
the intermediate of formula III (26.5g, 1eq, E/Z87: 12) was dissolved in DMF (110ml) and K was added3CO3(27.6g, 2eq), the compound represented by the formula IV-1 (21.8g, 1.2eq), followed by heating to 100 ℃ and maintaining the reaction at the reaction temperature for 10 hours. After cooling to room temperature, 200ml of water were added to the reaction mixture, which was extracted with 1L of ethyl acetate, and the organic phase was dried, filtered and concentrated to give the crude product. The crude product was recrystallized twice from ethanol and acetonitrile, respectively, to give the compound of formula V (12.8g, yield 35%, E/Z98: 2).
This comparative example, which did not employ a catalyst, had a yield that was reduced by at least a factor of 1, indicating that the catalyst had a significant effect on the reaction of the present invention.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthetic method of an intermediate for synthesizing rilpivirine is characterized in that the intermediate is synthesized according to the following synthetic route:
2. The process of claim 1, wherein M is a strong acid; preferably a strong organic or inorganic acid; preferably, the organic strong acid is p-toluenesulfonic acid or methanesulfonic acid, and the inorganic strong acid is hydrochloric acid or sulfuric acid;
preferably, X is chlorine or bromine, preferably chlorine.
3. The synthesis method of an intermediate for the synthesis of rilpivirine according to claim 1 or 2, wherein the molar ratio of the compound represented by formula II to the compound represented by formula I is 1: 1-2, preferably 1:1-1.5, more preferably 1: 1.1.
4. A synthesis process of an intermediate for the synthesis of rilpivirine according to claim 1, characterized in that the reaction conditions according to the synthesis route are: the time is 1-10 hours, and the temperature is 0-120 ℃;
preferably, the time is 2-8 hours, the temperature is 10-90 ℃ or 20-80 ℃ or 50-70 ℃;
preferably, the solvent used in the reaction is a solvent capable of dissolving the compound represented by formula I and the compound represented by formula II, but not participating in the reaction;
preferably, the solvent is selected from at least one of dioxane, tetrahydrofuran or 2-methyltetrahydrofuran, DMF, DMSO, and NMP, and the solvent is an anhydrous solvent;
preferably, the reaction system is an acidic environment, preferably a weakly acidic environment.
5. An intermediate for synthesizing rilpivirine, which is an intermediate represented by the formula III prepared by the synthesis method of an intermediate for synthesizing rilpivirine according to any one of claims 1 to 4,
preferably, the intermediate is a mixture of cis and trans isomers,
preferably, the intermediates include the following two compounds:
6. A synthesis method of rilpivirine is characterized in that rilpivirine is synthesized according to the following synthesis route:
wherein X is a halogen atom and M is an acid.
7. The method for synthesizing rilpivirine according to claim 6, wherein the molar ratio of the intermediate represented by formula III to the compound represented by formula IV is 1: 1-2, preferably 1:1-1.5, more preferably 1: 1.1.
8. The method for synthesizing rilpivirine according to claim 6, wherein the reaction conditions of the intermediate shown in formula III and the compound shown in formula IV are as follows: for a period of from 1 to 10 hours, preferably from 4 to 8 hours, at a temperature of from 25 to 130 ℃, preferably from 50 to 80 ℃ or from 90 to 100 ℃.
9. The method for synthesizing rilpivirine according to claim 6, wherein the intermediate represented by formula III is reacted with the compound represented by formula IV under alkaline conditions.
10. The method of claim 9, wherein the alkaline conditions are provided by an alkaline substance selected from the group consisting of alkali metal hydrides, alkali metal carbonates, alkali metal phosphates, alkali metal acetates, and alkali metal hydroxides.
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