WO2013159286A1 - Etravirine and method for preparing intermediate thereof - Google Patents

Description

 Preparation method of etravirine and its intermediates

 Technical field

 The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of escitalin and an intermediate thereof. Background technique

 Etravirine (-165335, TMC-125) is marketed under the trade name Intelence, chemical name 4-[6-amino-5-bromo-2-(4-cyanophenolamine)pyrimidine-4 -Oxo] -3,5-dimethylbenzonitrile, the structural formula is as follows:

 Etravirine is a new generation of non-nucleoside reverse transcriptase inhibitor (NN-RTI) developed by Tibotec, a subsidiary of Johnson & Johnson, which has anti-HIV infection effects. Clinical studies have shown that etravirine shows strong antiviral activity in patients treated with NN-RTI for the first time; this product is also effective and long-lasting in patients who have previously used anti-viral drugs. In addition, HIV-1 infected patients have a good drug metabolism profile after taking etravirine and are well tolerated. January 18, 2008 US FDA approves Tibotec Therapeutics's etravirine tablets in combination with other anti-HIV drugs to treat adult HIV-infected people with other antiretroviral drugs.

 At present, there are mainly the following synthetic methods for etravirine:

First, WO0027825A1 first disclosed the following synthetic route of etravirine:

 The above-mentioned route raw materials are not easily available, and the amination reaction of the last step has a long time and a low conversion rate, and is not suitable for industrial production.

 2. Bioorg. Med. Chem. Lett., 2001, 11(17), 2235-9 reported the following methods of etravirine:

 The method not only has a long synthesis route (a total of five steps of reaction), the raw material 4-cyanophenyl hydrazine is expensive and difficult to obtain, and the selectivity of the condensation reaction in the fourth step is poor, and the conversion of the aminolysis reaction in the fifth step is incomplete, resulting in The total yield is less than 10% and is not suitable for industrial production.

Third, WO2010150279A2 reported the following synthesis methods:

 Although the method has only four steps of reaction, the raw materials of each step are relatively easy to obtain, the conversion rate of the ammoniation reaction is improved, and the total yield of the crude product of etravirine can reach 40%. However, in the second step, up to 12% of the by-products (ie, the compound of the formula (3)) must be purified before the next amination reaction, and the compound of the formula (3) is the same as the compound of the formula (2). The isomers are structurally and physicochemically similar, and therefore, the purification of the compound of the formula (2) is difficult.

The yield of the condensation reaction in the fourth step of the method is still only 48%, and the yield of the amination reaction in the fifth step is only 44%. The yield of the two steps is low, and the purity of the product is not high, resulting in the final step of bromine. The yield of the reaction is also low, as low as 43%. The total yield of these three steps is only 9%, which is not suitable for industrial production. Therefore, there is an urgent need to develop a preparation method of etravirine which is simple in operation and low in production cost. Summary of the invention

 An object of the present invention is to provide an intermediate of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxo, which is simple in operation and low in production cost. A method for preparing -3,5-dimethylbenzonitrile.

 Another object of the present invention is to provide a preparation method of etravirine which is simple in operation and low in production cost.

In a first aspect of the invention, there is provided a process for the preparation of an intermediate of escitalin of formula IV, comprising the steps of:

 (i) a condensation reaction of 3,5-dimethyl-4-hydroxybenzonitrile with a compound of formula II in an inert solvent in the presence of a base to provide a reaction mixture of a compound III or a compound of formula III;

 (ii) subjecting a reaction mixture of a compound of formula III or a compound of formula III with an amination reagent as follows to give formula IV

 Wherein steps (i) and (ii) are carried out in the same or substantially the same inert solvent.

In a second aspect of the present invention, there is provided a method for preparing an intermediate of the escitalin of the formula IV, comprising the steps of: (1) a condensation reaction of 3,5-dimethyl-4-hydroxybenzonitrile with a compound of formula II in the presence of a base in an inert solvent to provide a reaction mixture of the compound III;

 (2) The reaction mixture containing the compound of the formula III obtained in the step (1) is subjected to the following amination reaction with the aminating agent without isolation (similar to "direct use for subsequent reaction"), thereby obtaining a compound of the formula IV (ie, Quvilin intermediate).

 In another preferred embodiment, the steps (1) and (2) are carried out in the same or substantially the same inert solvent.

 In another preferred embodiment, the separating comprises a treatment selected from the group consisting of: filtration, decantation, drying, crystallization, |3⁄4 core.

 In another preferred embodiment, the step ω or the step (1) further includes the steps of:

(1.1) reacting 3,5-dimethyl-4-hydroxybenzonitrile with a base in an inert solvent to obtain a reaction mixture containing a compound of formula I;

(1.2) The reaction mixture containing the compound of the formula I obtained in the step (1.1) is subjected to a condensation reaction with a compound of the formula II to obtain a reaction mixture containing the compound of the formula III.

CI

III

 In another preferred embodiment, the reaction mixture containing the compound of the formula I obtained in the step (1.1) is used directly in the step (1.2).

 In another preferred embodiment, the yield of the compound of formula IV is 65%, preferably 70%, more preferably 75%, most preferably 85%, based on the compound of formula II.

 In another preferred embodiment, the inert solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane Hexacyclic, tetrahydrofuran, or a combination thereof.

 In another preferred embodiment, the inert solvent is N-methylpyrrolidone, N,N-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, 1,4-dioxane or tetrahydrofuran. .

 In another preferred embodiment, the inert solvent is N-methylpyrrolidone.

 In another preferred embodiment, the base is an alkali metal salt.

 In another preferred embodiment, the alkali metal salt is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, sodium acetate, sodium t-butoxide, Potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, or a combination thereof; preferably potassium carbonate, sodium carbonate, or sodium acetate.

 In another preferred embodiment, in the step (i) or the step (1), the molar ratio of 3,5-dimethyl-4-hydroxybenzonitrile to the base is 1:1.0 to 1:10.0.

 In another preferred embodiment, the molar ratio is 1:1.0 to 1:4.0; preferably 1:2.0 to 1:4.0.

 In another preferred embodiment, in the step (i) or the step (1), the molar ratio of the 3,5-dimethyl-4-hydroxybenzonitrile to the compound of the formula II is 1:1.0 to 1:6.0.

 In another preferred embodiment, the molar ratio is 1:1.0 to 1:3.0; preferably 1:1.2 to 1:2.0.

 In another preferred embodiment, in the step (i) or the step (1), the condensation reaction temperature is 20-120 ° C; preferably 35-65 ° C;

In another preferred embodiment, in the step (i) or the step (1), the condensation reaction time is 3-20 hours; It is preferably 8-12 hours.

 In another preferred embodiment, the step (ii) or the step (2) further comprises a separation step of: mixing the reaction mixture after the amination reaction with water and crystallization to obtain a crude compound of the formula IV.

 In another preferred embodiment, the mixing comprises the steps of: adding the reaction mixture to water, or adding water to the reaction mixture.

 In another preferred embodiment, the separating step further comprises a refining step: purifying the isolated crude compound of the formula IV in a solvent for purification to obtain a compound of the formula IV having a purity of 95%.

 In another preferred embodiment, the solvent for purification is acetone or a mixed solvent of acetone and water.

 In another preferred embodiment, the reaction mixture containing the compound of the formula III obtained in the step (i) is used directly in the step (ii), or the reaction mixture containing the compound of the formula III obtained in the step (1) is directly used in the step (2). Included in the step (i) and step (ii) is further comprising the step of: filtering the reaction mixture containing the compound of formula III, and using the filtrate of the compound of formula III for step (ii).

 In a third aspect of the invention, there is provided a method of preparing etravirine according to formula V, the method comprising the steps of:

 (a) a condensation reaction of 3,5-dimethyl-4-hydroxybenzonitrile with a compound of formula II in an inert solvent in the presence of a base to provide a reaction mixture of a compound III or a compound of formula III;

(aii) subjecting a compound of formula III or a reaction mixture containing a compound of formula III to an amination reagent as described below, to give a compound of formula IV (ie, etravirine intermediate);

(aiii) subjecting the compound of the formula IV obtained in the step (aii) to a bromination reaction in the presence of a brominating reagent in an inert solvent;

 IV V

 Wherein steps (ai) and (aii) are carried out in the same or substantially the same inert solvent; or the method comprises the steps of:

 (bl) condensing 3,5-dimethyl-4-hydroxybenzonitrile with a compound of formula II in an inert solvent in the presence of a base

 III

(b2) The reaction mixture containing the compound of the formula III obtained in the step (bl) is subjected to the following amination reaction with the aminating agent without isolation (similar to "direct use for subsequent reaction"), thereby obtaining a compound of the formula IV (ie, Quvilin intermediate);

(b3) bromination reaction of the compound of the formula IV obtained in the step (b2) in the presence of a brominating reagent in an inert solvent

 In another preferred embodiment, the reaction mixture containing the compound of the formula III obtained in the step (ai) is directly used in the step (aii), or the reaction mixture containing the compound of the formula III obtained in the step (bl) is directly used in the step (b2). ); or

 Also included between the step (ai) and the step (aii) is a step of filtering the reaction mixture containing the compound of the formula III and using the filtrate of the compound of the formula III for the step (aii).

 In another preferred embodiment, the step (ai) or the step (b1) further includes the following steps:

(1.1) reacting 3,5-dimethyl-4-hydroxybenzonitrile with a base in an inert solvent to obtain a reaction mixture containing a compound of formula I;

(1.2) The reaction mixture containing the compound of the formula I obtained in the step (1.1) is subjected to a condensation reaction with a compound of the formula II to obtain a reaction mixture containing the compound of the formula III.

CI

III

 In another preferred embodiment, the reaction mixture containing the compound of the formula I obtained in the step (1.1) is used directly in the step (1.2).

 In another preferred embodiment, in the step (ai) or the step (b1), the inert solvent, the base, the molar ratio of the 3,5-dimethyl-4-hydroxybenzonitrile to the base, The molar ratio of the 3,5-dimethyl-4-hydroxybenzonitrile to the compound of the formula II, the condensation reaction temperature, or the condensation reaction time is as described in the first aspect of the invention.

 In another preferred embodiment, in the step (aii) or the step (b2), a separation step is further included: adding the reaction mixture to water or adding water to the reaction mixture, and crystallization to obtain a compound of the formula IV.

 In another preferred embodiment, the separating step further comprises a refining step: purifying the isolated crude compound of the formula IV in acetone or a mixed solvent of acetone and water to obtain a compound of the formula IV having a purity of 95%.

In another preferred embodiment, the brominating reagent of the step (aiii) or the step (b3) is: brominated succinimide (NBS) or Br ₂ .

 In another preferred embodiment, the yield of escitalin is 50%, preferably 55 %; more preferably 60%; optimally 65 %, calculated according to the compound of formula II. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (e.g., the embodiments) can be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. detailed description

Through long-term and intensive research, the inventors have unexpectedly discovered that when preparing a compound IV from a compound of formula II and 3,5-dimethyl-4-hydroxybenzonitrile, the same or substantially the same solvent system is used, the reaction process. The multi-step reaction can be carried out continuously without separate purification between the steps, and the operation is very simple, especially The obtained compound has good yield and high purity, and can be directly used for preparing emetrexate. Based on the above method, the present invention also provides a method for preparing escitalin, which significantly improves the yield of escitalin (if the yield can be increased by 5-8 times), which is remarkable compared with the prior art. Reduce its production costs and have high industrial application value. On this basis, the inventors have completed the present invention. The "same or substantially the same inert solvent", "the same or substantially the same solvent" or "the same or substantially the same solvent system" as used in the present invention means that the components contained in the inert solvent, solvent or solvent system are the same or basic. the same.

 For a first solvent system having the same total volume and a second solvent system (where at least one solvent system contains at least two solvents), the P values of the two solvent systems can be calculated as follows:

P=2X∑ AS÷ (∑S1+∑S2) X 100%

 In the formula,

 AS is the absolute value of the difference in the amount of a solvent in the first solvent system and the second solvent system; ∑S1 is the sum of all the solvents contained in the first solvent system;

 ∑S2 is the sum of all the solvents contained in the second solvent system.

 The amount of the solvent may be the number of volumes, the number of masses, or the number of moles, preferably the number of volumes.

 When the P value is 25%, preferably 20%, more preferably 10%, more preferably 5%, still more preferably 1%, it is considered that the two solvent systems are substantially the same.

 For example, for a first solvent system consisting of solvent A and solvent B in a volume ratio of 50:50, and a second solvent system consisting of solvent A, solvent B and solvent C in a volume ratio of 50:50:10, P Value = 2X10 ÷ (100+110) X 100% ^9.52%, so it can be regarded as basically the same solvent system.

 In the present invention, when a small amount of other solvent is additionally added to an inert solvent, solvent or solvent system, it can be regarded as substantially the same inert solvent, solvent or solvent system. Generally, the phrase "containing a small amount of other solvent" means that the solvent to be reacted may contain less than 20% (preferably less than 10%) of other solvent based on the total volume or total weight of the solvent.

When other solvents are brought in by the ammoniating agent (e.g., aqueous ammonia) used, the solvent (e.g., water) carried in is not considered to change the solvent component of the inert solvent, solvent or solvent system. For example, when the reaction mixture is reacted with aqueous ammonia, the water introduced from the aqueous ammonia is not counted as the solvent component in the inert solvent, solvent or solvent system. The starting materials used in the present invention are commercially available or can be carried out according to known methods. For example, the starting material 4-(4,6-dichloropyrimidin-2-amino)benzonitrile (compound of formula II) can be referred to Bioorg. Med. Chem. The method reported by Lett., 2001, ll (17), 2235-9 was prepared. Preparation method of Yiqu Weilin intermediate

 The preparation method of the intermediate of the formula (IV) of the present invention will now be further described in conjunction with the preferred embodiments, including the steps:

可将所述步骤 (il)得到的含式 I化合物的反应混合物直接用于步骤 (i2)。 (il) reacting 3,5-dimethyl-4-hydroxybenzonitrile with a base in an inert solvent at a temperature (eg, 50-100 ° C) for a period of time (eg, 1-3 hours) to obtain a reaction mixture comprising a compound of formula I;

The reaction mixture containing the compound of the formula I obtained in the step (il) can be used directly in the step (i2).

 In another preferred embodiment, the inert solvent in the step (il) is preferably selected from the group consisting of, but not limited to: N-methylpyrrolidone, N,N-dimethylformamide, N,N-di Methyl acetamide, 1,4-dioxane, tetrahydrofuran, or a combination thereof.

 In another preferred embodiment, the base in the step (il) may be an inorganic base or an organic base, preferably an alkali metal salt such as, but not limited to: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate , sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, sodium acetate, sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, or a combination thereof; preferably potassium carbonate, sodium carbonate Or sodium acetate.

 In another preferred embodiment, the molar ratio of 3,5-dimethyl-4-hydroxybenzonitrile to base in the step (il) is 1:1.0~1:10.0, preferably 1:1.0~ 1 : 4.0; more preferably 1: 2.0 to 1: 4.0.

(12) The reaction mixture of the compound of the formula I obtained in the step (il) is subjected to a condensation reaction with the compound of the formula II at a certain temperature (for example, 20-120 ° C; preferably 35-65 ° C) for a period of time ( For example, 3-20 hours; preferably 8-12 hours), a reaction mixture containing a compound of formula III is obtained.

CI

III

 In another preferred embodiment, in the step (i2), the molar ratio of the 3,5-dimethyl-4-hydroxybenzonitrile to the compound of the formula II is 1:1.0 to 1:6.0, preferably 1: 1.0 to 1:3.0; more preferably 1:1.2 to 1:2.0.

 In another preferred embodiment, the step (i2) may further comprise the steps of: filtering the reaction mixture containing the compound of the formula III, removing the solid (such as removing excess salt), collecting the filtrate, and using the filtrate for the next step; or The reaction mixture containing the compound of formula III was used directly in the next step.

(ii) subjecting the reaction mixture containing the compound of the formula III obtained in the step (i2) to amination reaction for a certain period of time (for example, 8-20 hours) at a certain temperature (for example, 100 to 150 ° C, preferably 110 to 130 ° C) Or 10-18 hours), thereby obtaining a compound of formula IV (ie

在另一优选例中， 所述氨化反应中采用的氨化试剂可选自氨气或氨水。 所 述氨水可以是市售的任意浓度的氨水溶液， 例如浓度为 1%至饱和的氨水溶液。

In another preferred embodiment, the ammoniating agent used in the amination reaction may be selected from ammonia gas or ammonia water. The aqueous ammonia may be any commercially available aqueous ammonia solution of any concentration, for example, a 1% to saturated aqueous ammonia solution.

 Wherein the steps (il), (i2) and (ii) are carried out in the same or substantially the same solvent.

 In another preferred embodiment, the step (ii) further comprises the step of separating: adding the reaction mixture to water, or adding water to the reaction mixture, and crystallization to obtain a crude compound of the formula IV.

In another preferred embodiment, the separating step further comprises a refining step: purifying the isolated crude compound of the formula IV in a purified solvent to obtain a compound of the formula IV having a purity of 95%. Place The purification step is a purification step such as recrystallization, and the purification solvent may be any solvent suitable for purification, such as a mixed solvent preferably mixed from acetone or acetone and water in any ratio; wherein the volume content of water is preferably not more than 60%. , preferably no more than 40%.

 The yield of the compound of the formula IV obtained by the process of the present invention is 65%, preferably 70%, more preferably 75%, most preferably 85%, calculated according to the compound of the formula II.

 Preparation method of Yiqu Weilin

 The preparation method of the escitalin represented by the formula (V) of the present invention is preferably based on the preparation steps (il), (i2) and (ii) of the escitalin intermediate of the present invention, and the steps ( Ii) The compound of formula IV obtained is further subjected to the following bromination step:

 (iii) the compound of the formula IV obtained in the step (ii) in an inert solvent in the presence of a brominating reagent at room temperature (e.g., 25-28 ° C).

In another preferred embodiment, the reagent or solvent used in the bromination reaction of the step (iii) may be a reagent or a solvent commonly used by those skilled in the art, and the brominating reagent is preferably brominated succinimide (NBS). Or Br ₂ , the inert solvent used is a solvent commonly used for bromination, preferably acetone.

 The yield of the etoxetine obtained by the method of the present invention is 50%, preferably 55%; more preferably 60%; most preferably 65%, calculated according to the compound of the formula II. The main advantages of the invention are:

 1. A method for preparing an intermediate of the escitalin of the formula IV, which uses the same or substantially the same solvent system, can carry out a multi-step reaction continuously, without separation and purification between the steps, and the operation is very simple, the compound The yield is much higher than the existing method, and the obtained compound has high purity and can be directly used for preparing emetrexate.

2. Provided a preparation method of escitalin represented by formula V, which is based on the preparation method of the escitalin intermediate provided by the invention, and significantly improves the yield of escitalin, thereby significantly reducing His life Production cost, industrial application value is high. The invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Example 1

Preparation of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile 3,5-dimethyl- 4-Hydroxybenzonitrile (1 1.8 g, 0.080 mol) was dissolved in 100 mL of N-methylpyrrolidone (ΝΜΡ), followed by K ₂ CO ₃ (ll.Og, 0.080 mol). The temperature was raised to 90 ° C and the reaction was kept for 2 hours.

 After the reaction mixture was cooled to 25 ° C, 4-(4,6-dichloropyrimidin-2-amino)benzonitrile (21.3 g, 0.081 mol) was added, and the reaction was kept for 3 hours. The temperature was raised to 50 ° C, and the reaction was continued for another 10 hours. Filter and solid wash twice with 30 mL of NMP.

 The filtrate was combined, ammonia gas was introduced to saturation, and the temperature was raised to 120 ° C, and the reaction was kept for 10 hours.

 500 mL of water was added to the system. Crystallization, filtration, and filter cake were rinsed with 50 mL of water.

 The obtained wet cake was added to a mixed solvent of 90 mL of acetone and 15 mL of water, and heated under reflux for 30 minutes. Cool to room temperature, filter and vacuum dry to give 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile 25.0 g , yield 87.8%.

 HPLC purity 98.7%. MS (ESI) m/z: (M+H) 357.4, (M+Na) 379.4. Example 2

Preparation of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile 3,5-dimethyl- 4-Hydroxybenzonitrile (6.0 g, 0.041 mol) was dissolved in 75 mL of N,N-dimethylformamide (DMF) and then Na ₂ CO ₃ (5.2 g, 0.049 mol). The temperature was raised to 80 ° C, and the reaction was kept for 2 hours.

 After cooling the above reaction mixture to 25 ° C, 4-(4,6-dichloropyrimidin-2-amino)benzonitrile was added.

(13.0 g, 0.049 mol), the reaction was kept for 4 hours. The temperature was raised to 55 ° C, and the reaction was continued for another 8 hours. Filter and solid wash twice with 20 mL DMF.

The filtrates were combined and 30 ml of 25% ammonia water was slowly added. The temperature was raised to 110 ° C, and the reaction was kept for 15 hours. 300 mL of water was added to the system. Crystallization, filtration, and filter cake were rinsed with 30 mL of water.

 The obtained wet cake was added to 50 mL of acetone, and heated under reflux for 1 hour. Cool to room temperature, filter and vacuum dry to give 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile 12.3 g , the yield was 84.3%.

 HPLC purity was 98.2%. The mass spectrum data was identical to Example 1. Example 3

 Preparation of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile 3,5-dimethyl- 4-Hydroxybenzonitrile (6.0 g, 0.041 mol) was dissolved in 60 mL of tetrahydrofuran (THF), followed by sodium acetate (13.5 g, 0.16 mol). The temperature was raised to reflux, and the reaction was kept for 3 hours.

 After the reaction mixture was cooled to 30 ° C, 4-(4,6-dichloropyrimidin-2-amino)benzonitrile (21.6 g, 0.082 mol) was added, and the reaction was kept for 3 hours. The temperature was raised to 60 ° C, and the reaction was continued for another 12 hours.

 Then, to the reaction mixture of the previous step, ammonia gas was passed to saturation. The temperature was raised to 120 ° C and the reaction was allowed to stand for 12 hours.

 300 mL of water was added to the system. Crystallization, filtration, and filter cake were rinsed with 30 mL of water.

 The obtained wet cake was added to a mixed solvent of 40 mL of acetone and 20 mL of water, and heated under reflux for 30 minutes. Cool to room temperature, filter and vacuum dry to give 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile 11.3 g , yield 77.2%.

 The HPLC purity was 97.7 %. The mass spectrum data was identical to Example 1. Example 4

 Preparation of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile 3,5-dimethyl- 4-hydroxybenzonitrile (6.0 g, 0.041 mol) was dissolved in 60 mL of 1,2-dioxane, followed by sodium ethoxide (2.8 g, 0.041 mol). The temperature was raised to 75 ° C and the reaction was kept for 1 hour.

 After the reaction mixture was cooled to 20 ° C, 4-(4,6-dichloropyrimidin-2-amino)benzonitrile was added.

( l l .Og, 0.042 mol), heat preservation reaction for 3 hours. The temperature was raised to 45 ° C, and the reaction was continued for another 10 hours.

 Then, to the reaction mixture of the previous step, 30 ml of 25% aqueous ammonia was slowly added. Warm up to

The reaction was kept at 120 ° C for 15 hours.

 300 mL of water was added to the system. Crystallization, filtration.

The obtained wet cake was added to a mixed solvent of 35 mL of acetone and 15 mL of water, and the mixture was heated under reflux for 30 minutes. Cool to room temperature, filter and vacuum dry to give 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl] Oxygen] -3,5-dimethylbenzonitrile 11.8 g, yield 80.8%.

 The HPLC purity was 98.1%. The mass spectrum data was identical to Example 1. Example 5

 Preparation of Yiqu Weilin

 4-[[6-Amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile (35.6 g, obtained in Example 1, O.lOmol) was dissolved in 300 ml of acetone, and N-bromosuccinimide (NBS) (17.8 g, 0.1 mol) was added in portions at room temperature. After the addition was completed, stirring was continued for 2 hours at room temperature.

 Then, 140 mL of a 0.5 M sodium hydroxide solution was added thereto with stirring, stirring was continued for 30 minutes, and then filtered, and the filter cake was dried under vacuum to obtain crude etravirine.

 The crude product was recrystallized from acetone to give elubrinine 35.0 g, yield 80.4%.

 The HPLC purity was 99.3%. MS (ESI) m/z: (M+H) 436.3, (M+Na) 458.3. Comparative example

 Preparation of different solvent systems 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile

 The compound of formula IV is prepared by two steps using 3,5-dimethyl-4-hydroxybenzonitrile and a compound of formula II as a starting material. For the preparation method, see Example 1 and Example 2 on pages 11-12 of the specification of WO2012001695. Calculated according to the compound of formula II, 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile The yield was about 21%. in conclusion:

 1. The preparation method of the compound of the formula IV of the present invention, although the compound of the formula IV is obtained by a plurality of reactions, the same or substantially the same solvent system is used throughout the whole process, and the multi-step reaction is continuously carried out without separation and purification between the steps. The operation is very simple, the yield of the compound of the formula IV is very high (the yield is not less than 77%), far exceeds the yield of 21% in the prior art, and the purity is high, and can be directly used without a purification step. Preparation of estrovir.

2. The preparation method of the escitalin according to the present invention is based on the preparation of the compound of the formula IV, wherein the compound of the formula IV is further subjected to a bromination reaction. The method significantly improves the yield of the esculin: according to the compound of the formula II, the yield of the method of the invention can reach 60-70%, which is much higher than the prior art. The yield of eucommia, such as Bioorg. Med. Chem. Lett., 2001, 11(17), The method disclosed in 2235-9, which yields about 14% of the yield of escitalin in three steps, and the total yield of the three steps is only 9% in the method disclosed in WO2012001695A1, thereby significantly reducing the production thereof. Cost, industrial application value is high. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art after the above-described teachings of the present invention.

Claims

Rights request A method for preparing an intermediate of escitalin according to formula IV, which comprises the steps of:  (i) a condensation reaction of 3,5-dimethyl-4-hydroxybenzonitrile with a compound of formula II in the presence of a base in an inert solvent to provide a reaction mixture of a compound of formula III or a compound of formula III;

 III  (ii) subjecting a compound of formula III or a reaction mixture containing a compound of formula III to an amination reagent as described below, to give a compound of formula IV;

Wherein steps (i) and (ii) are carried out in the same or substantially the same inert solvent. 2. A method for preparing an intermediate of escitalin according to formula IV, which comprises the steps of: (1) 3,5-dimethyl-4- in an inert solvent in the presence of a base Hydroxybenzonitrile is subjected to a condensation reaction with a compound of formula II to provide a reaction mixture comprising a compound of formula III;

(2) The reaction mixture containing the compound of the formula III obtained in the step (1) is subjected to the following amination reaction with an aminating agent without isolation to obtain a compound of the formula IV.

3. The method according to claim 1 or 2, wherein the inert solvent is selected from the group consisting of: N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, tetrahydrofuran, or a combination thereof.  4. Process according to claim 1 or 2, characterized in that the base is an alkali metal salt.  The method according to claim 1 or 2, wherein in the step (i) or the step (1), the molar ratio of the 3,5-dimethyl-4-hydroxybenzonitrile to the base is 1. : 1.0~1 : 10.0.  The method according to claim 1 or 2, wherein the molar ratio of 3,5-dimethyl-4-hydroxybenzonitrile to the compound of the formula II in the step (i) or the step (1) For 1: 1.0~1: 6.0.  The method according to claim 1 or 2, wherein the step (ii) or the step (2) further comprises a separation step: mixing the reaction mixture after the amination reaction with water, and crystallization, thereby obtaining Crude compound of formula IV. 8. The method according to claim 7, wherein the separating step further comprises a refining step of: purifying the isolated crude compound of the formula IV in a solvent for purification to obtain a purity of 95%. IV compound. 9. The method of claim 1 or 2, wherein  The reaction mixture containing the compound of the formula III obtained in the step (i) is directly used in the step (ii), or the reaction mixture containing the compound of the formula III obtained in the step (1) is directly used in the step (2);  Further included between the step (i) and the step (ii) is the step of: filtering the reaction mixture containing the compound of the formula III, and using the filtrate containing the compound of the formula III for the step (ii).  10. A method for preparing etravirine according to formula V, characterized in that  The method includes the steps of:  (a) a condensation reaction of 3,5-dimethyl-4-hydroxybenzonitrile with a compound of formula II in an inert solvent in the presence of a base to provide a reaction mixture of a compound of formula III or a compound of formula III;

 (aii) subjecting a compound of formula III or a reaction mixture containing a compound of formula III to an amination reagent as described below to give a compound of formula IV;

(aiii) bromination of the compound of the formula IV obtained in the step (aii) in the presence of a brominating reagent in an inert solvent to give the formula V.

Wherein steps (ai) and (aii) are carried out in the same or substantially the same inert solvent; or the method comprises the steps of:  (bl) a condensation reaction of 3,5-dimethyl-4-hydroxybenzonitrile with a compound of formula II in the presence of a base in an inert solvent to provide a reaction mixture comprising a compound of formula III;

 III  (b2) The reaction mixture containing the compound of the formula III obtained in the step (bl) is subjected to the following amination reaction with the amination catalyst without isolation, thereby obtaining a compound of the formula IV;

(b3) The compound of the formula IV obtained in the step (b2) is subjected to a bromination reaction in an inert solvent in the presence of a brominating reagent to give the formula V. 〇 〇