WO2013159286A1 - Étravirine et procédé de préparation d'un intermédiaire correspondant - Google Patents

Étravirine et procédé de préparation d'un intermédiaire correspondant Download PDF

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Publication number
WO2013159286A1
WO2013159286A1 PCT/CN2012/074609 CN2012074609W WO2013159286A1 WO 2013159286 A1 WO2013159286 A1 WO 2013159286A1 CN 2012074609 W CN2012074609 W CN 2012074609W WO 2013159286 A1 WO2013159286 A1 WO 2013159286A1
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Prior art keywords
compound
formula
reaction mixture
reaction
formula iii
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PCT/CN2012/074609
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English (en)
Chinese (zh)
Inventor
李金亮
赵楠
熊毅
阮洪亮
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上海迪赛诺药业有限公司
上海迪赛诺化学制药有限公司
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Priority to PCT/CN2012/074609 priority Critical patent/WO2013159286A1/fr
Publication of WO2013159286A1 publication Critical patent/WO2013159286A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • 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.
  • N-RTI non-nucleoside reverse transcriptase inhibitor
  • 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.
  • 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.
  • 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%.
  • up to 12% of the by-products ie, the compound of the formula (3)
  • 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.
  • Another object of the present invention is to provide a preparation method of etravirine which is simple in operation and low in production cost.
  • steps (i) and (ii) are carried out in the same or substantially the same inert solvent.
  • 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;
  • 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).
  • the steps (1) and (2) are carried out in the same or substantially the same inert solvent.
  • the separating comprises a treatment selected from the group consisting of: filtration, decantation, drying, crystallization,
  • step ⁇ or the step (1) further includes the steps of:
  • 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.
  • reaction mixture containing the compound of the formula I obtained in the step (1.1) is used directly in the step (1.2).
  • 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.
  • 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.
  • the inert solvent is N-methylpyrrolidone, N,N-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, 1,4-dioxane or tetrahydrofuran. .
  • the inert solvent is N-methylpyrrolidone.
  • the base is an alkali metal salt.
  • 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.
  • the molar ratio of 3,5-dimethyl-4-hydroxybenzonitrile to the base is 1:1.0 to 1:10.0.
  • the molar ratio is 1:1.0 to 1:4.0; preferably 1:2.0 to 1:4.0.
  • 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.
  • the molar ratio is 1:1.0 to 1:3.0; preferably 1:1.2 to 1:2.0.
  • the condensation reaction temperature is 20-120 ° C; preferably 35-65 ° C;
  • the condensation reaction time is 3-20 hours; It is preferably 8-12 hours.
  • 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.
  • the mixing comprises the steps of: adding the reaction mixture to water, or adding water to the reaction mixture.
  • 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%.
  • the solvent for purification is acetone or a mixed solvent of acetone and water.
  • 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).
  • 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).
  • steps (ai) and (aii) are carried out in the same or substantially the same inert solvent; or the method comprises the steps of:
  • 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);
  • 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
  • step (ai) 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).
  • step (ai) or the step (b1) further includes the following steps:
  • 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.
  • reaction mixture containing the compound of the formula I obtained in the step (1.1) is used directly in the step (1.2).
  • the inert solvent, the base, the molar ratio of the 3,5-dimethyl-4-hydroxybenzonitrile to the base is as described in the first aspect of the invention.
  • 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.
  • 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%.
  • the brominating reagent of the step (aiii) or the step (b3) is: brominated succinimide (NBS) or Br 2 .
  • the yield of escitalin is 50%, preferably 55 %; more preferably 60%; optimally 65 %, calculated according to the compound of formula II.
  • 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.
  • the P values of the two solvent systems can be calculated as follows:
  • 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.
  • the two solvent systems are substantially the same.
  • a small amount of other solvent 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.
  • 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.
  • the solvent e.g., water
  • the solvent carried in is not considered to change the solvent component of the inert solvent, solvent or solvent system.
  • 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.
  • the starting material 4-(4,6-dichloropyrimidin-2-amino)benzonitrile can be referred to Bioorg. Med. Chem. The method reported by Lett., 2001, ll (17), 2235-9 was prepared.
  • step (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).
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • a certain temperature for example, 20-120 ° C; preferably 35-65 ° C
  • a period of time For example, 3-20 hours; preferably 8-12 hours
  • 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.
  • 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.
  • 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.
  • steps (il), (i2) and (ii) are carried out in the same or substantially the same solvent.
  • 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.
  • 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%.
  • 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.
  • 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:
  • 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:
  • 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.
  • 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.
  • the reaction was kept at 120 ° C for 15 hours.
  • Example 5 The HPLC purity was 98.1%.
  • the mass spectrum data was identical to Example 1.
  • Example 5 The HPLC purity was 98.1%.
  • the mass spectrum data was identical to Example 1.
  • 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.
  • a compound of formula II for the preparation method, see Example 1 and Example 2 on pages 11-12 of the specification of WO2012001695.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de l'étravirine et un procédé de préparation d'un intermédiaire correspondant et, en particulier, elle concerne un procédé de préparation d'un intermédiaire d'étravirine représenté dans une formule IV. Le procédé adopte un système de solvant identique ou essentiellement identique, aucune séparation ou purification n'est nécessaire entre les étapes de réaction, de multiples étapes de réaction peuvent être réalisées consécutivement, l'exploitation est simple et le composé préparé de formule IV peut être directement utilisé pour la préparation d'étravirine. Un procédé de préparation d'étravirine est en outre décrit et le procédé est basé sur le procédé susmentionné de préparation de l'intermédiaire, de manière à améliorer significativement le rendement en étravirine.
PCT/CN2012/074609 2012-04-24 2012-04-24 Étravirine et procédé de préparation d'un intermédiaire correspondant WO2013159286A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009051782A1 (fr) * 2007-10-18 2009-04-23 Concert Pharmaceuticals Inc. Étravirine deutérée
WO2010150279A2 (fr) * 2009-06-22 2010-12-29 Emcure Pharmaceuticals Limited Procédé pour la synthèse d'inhibiteur non nucléosidique de la transcriptase inverse diarylpyrimidine
WO2011017079A1 (fr) * 2009-07-27 2011-02-10 Teva Pharmaceutical Industries Ltd. Procédé de préparation et de purification d'etravirine et intermédiaires de celui-ci
WO2012001695A1 (fr) * 2010-06-28 2012-01-05 Hetero Research Foundation Procédé de préparation d'intermédiaire de l'étravirine et de polymorphes de l'étravirine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009051782A1 (fr) * 2007-10-18 2009-04-23 Concert Pharmaceuticals Inc. Étravirine deutérée
WO2010150279A2 (fr) * 2009-06-22 2010-12-29 Emcure Pharmaceuticals Limited Procédé pour la synthèse d'inhibiteur non nucléosidique de la transcriptase inverse diarylpyrimidine
WO2011017079A1 (fr) * 2009-07-27 2011-02-10 Teva Pharmaceutical Industries Ltd. Procédé de préparation et de purification d'etravirine et intermédiaires de celui-ci
WO2012001695A1 (fr) * 2010-06-28 2012-01-05 Hetero Research Foundation Procédé de préparation d'intermédiaire de l'étravirine et de polymorphes de l'étravirine

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