4-[6-Amino-5-bromo-2- [(4-cyanophenyl)amino] pyrimidin-4-yl]oxy-3,5-dimethylbenzonitrile

EMA:Link, US FDA:link

269055-15-4

It was originally developed and launched by Johnson & Johnson, for the treatment of HIV-1 infection. Family members of the product case, WO0027825, hold SPC protection in the EU until 2023 and expire in the US in 2020.

Etravirine (ETR,^[1] brand name Intelence, formerly known as TMC125) is a drug used for the treatment of HIV. Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Etravirine works by reducing the amount of HIV and increasing the number of CD4 or T cells in the blood. Unlike the currently available agents in the class, resistance to other NNRTIs does not seem to confer resistance to etravirine.^[2] Etravirine is marketed by Tibotec, a subsidiary of Johnson & Johnson. In January 2008, the Food and Drug Administration approved its use for patients with established resistance to other drugs, making it the 30th anti-HIV drug approved in the United States and the first to be approved in 2008.^[3] It was also approved for use in Canada on April 1, 2008.^[4]

Etravirine is licensed in the United States, Canada, Israel, Russia and the European Union,^[5] and is under regulatory review in Switzerland and Australia.^[6]

Indications and dosage

Etravirine, in combination with other anti-retrovirals, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

The recommended dose of etravirine is 200 mg (2 x 100 mg tablets, or 1 x 200 mg tablet as of 03/18/2011) taken twice daily following a meal. The type of food does not affect the exposure to etravirine.^[7]

Contraindication

Each 100 mg etravirine tablet contains 160 mg of lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.^[8]

Mechanism of action

Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), designed to be active against HIV with mutations that confer resistance to the two most commonly prescribed first-generation NNRTIs, mutation K103N for efavirenz and Y181C for nevirapine.^[9] This potency appears to be related to etravirine’s flexibility as a molecule. Etravirine is a diarylpyrimidine (DAPY), a type of organic molecule with some conformational isomerism that can bind the enzyme reverse transcriptase in multiple conformations, allowing for a more robust interaction between etravirine and the enzyme, even in the presence of mutations.^[10] Other diarylpyrimidine-analogues are currently being developed as potential anti-HIV agents, notably rilpivirine.

Warnings and risks

In 2009, the prescribing information for etravirine was modified to include “postmarketing reports of cases of Stevens–Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, as well as hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Intelence therapy should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop.”^[11]

Etravirine (I), formerly TMC 125 and chemically known as 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile, is an NNRTI approved in 2008 for use in combination with other antiretroviral agents in treatment- experienced adult patients with multidrug-resistant HIV infections. Etravirine is marketed worldwide as an oral tablet and was first disclosed by De Corte et al in US 7,037,917.

Etravirine (I)

De Corte et al in US 7,037,917 provides a method for manufacturing of diarylpyrimidine compounds wherein a compound of formula (II) is heated with ammonia in presence of a inert solvent such as 1,4-dioxane in a pressure vessel at 150⁰C for 4 days.

(H) (I) X – halogen

Davies et al in Drugs of the Future 2005, 30(5): 462-468 discloses that the intermediate compound (II) can be prepared in two different routes. The first route discloses that 5-bromo-2,4,6-trichloropyrimidine is reacted with 4- aminobenzonitrile by means of diisopropylethylamine in refluxing dioxane giving a diarylamine which is then reacted with 4-hydroxy-3,5- dimethylbenzonitrile to give intermediate of formula (II) (Scheme – 1).

Scheme – 1 ^lll)

The second method for synthesis of compound of formula (II) discloses that 4-guanidinobenzonitrile is cyclized with diethylmalonate by means of sodium ethoxide to give 4-(4,6-dihydroxypyrimidine-2-yl-amino)- benzonitrile, which upon treatment with POCI₃ yields the corresponding dichloro derivative. Further bromination with bromine and sodium bicarbonate in aqueous methanol affords 4-(5-bromo-4,6-dichloropyrimidin- 2-ylamine)-benzonitrile, which on condensation with the sodium salt of cyano-2,6-dimethylphenolate in presence of N-methylpyrrolidone and dioxane gives intermediate of formula (II) (Scheme – II).

However, the abovementioned procedure for synthesis of diarylpyrimidine NNRTIs suffers from the disadvantage that the conversion of compound of formula II to the final compound is very slow. The reaction of compound of formula (II) with ammonia, even in refluxing dioxane requires four days for completion and the yields obtained are not very satisfactory.

Recently, De Kock et al, in US 2008/0194602 has reported that diarylpyrimidine oxide derivatives possesses HIV replication inhibiting properties. The diarylpyrimidine oxide derivatives are prepared from corresponding diarylpyrimidine derivatives of formula III by N-oxidation of the tertiary nitrogen of pyrimidine ring.

(III)

There are various method reported for synthesis of diarylpyrimidine derivatives of formula III, as summarized in Scheme – 3.

One of the most preferred processes reported for synthesis of diarylpyrimidine derivatives of formula (III), is by halogenating a compound of formula (IV). Further, the compound of formula (IV) is reported to be prepared from 4-aminobenzonitrile and cyanamide. This reaction is conducted in water in the presence of a strong acid, to yield 4-cyanophenyl guanidine, which is then reacted with an alkyl malonic ester, in the presence of a strong base and at increased temperature. The obtained 4,6- dihydroxypyrimidine is then treated with a halogenating agent. The pyrimidine derivative is then reacted with a 4-substituted benzonitrile and then further with ammonia to yield the intermediates (IV).

Although, the process disclosed herein relates to synthesis of N-oxide derivatives and not particularly etravirine, the same method could be used for synthesis of etravirine. However, the said process again suffers from the limitation that it utilizes cyanamide, which is a highly toxic compound. Thus, from the above, it would be evident, that though NNRTIs, such as etravirine, are the main-stay therapy for treatment of HIV infections,

……………………………….

http://www.google.com/patents/EP2342186A2?cl=en

Scheme – 4.

aq. ammonia

Halogenation

(I) (IV)

EXAMPLES:

Example 1

Synthesis of 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5 dimethylbenzonitrile (Compound-V):

2,4,6-Trichloropyrimidine (100 g, 0.545 m) was dissolved in 1,4-dioxane (300 ml) and 3,5,-dimethyl-4-hydroxybenzonitrile (80.1 g, 0.545m) was added under stirring. Addition of N,N-diisopropylethylamine (141.0Og, 1.09m) was carried to this solution over a period of 30 minutes. Reaction mass was heated at 70⁰C and stirred for 2.0 hours. The reaction mass was cooled slowly to 15°C and obtained product was filtered at 12-15°C followed by washing the cake with 50 ml of 1,4-dioxane. Finally the cake was washed with water (200ml) to get the desired product. Melting point: 208-210⁰C.

Yield: 128 g, %Yield=80%;

Example 2

Synthesis of 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]- 3,5-dimethylbenzonitrile (Compound-VT) Compound-V (100 g, 0.34 m) was dissolved in N-methylpyrrolidone (500 ml) and 4-Aminobenzonitrile (40.12 g, 0.34m) was added under stirring. The reaction mass was cooled to 0⁰C. To this solution, addition of potassium t- butoxide was carried out (76.3g, 0.68m) in lots over a period of 1.0 hour at 0 to 10⁰C. The reaction mass was allowed to come at room temperature gradually over 1 to 2 hours. Then slowly the reaction mass was added in chilled water (2.0L) by maintaining the reaction mass temperature below 2O⁰C. The reaction mass was filtered and washed the cake with 200 ml water. Wet cake was again dissolved in 1.0L water below 20⁰C and filtered. The obtained product was purified by using ethyl acetate (2×300 ml) at 60- 7O⁰C followed by filtration at 10-15⁰C. Yield: 50 g.

Example 3

Synthesis of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]- 3,5-dimethylbenzonitriIe (Compound – IV)

Aqueous ammonia (25%) (600 ml) was added to a solution of Compound- VI (100 g, 0.266 m) in 1,4-Dioxane (1000 ml) and the reaction mass was heated in pressure autoclave at 12O⁰C and maintain at 120-125⁰C forlO-12 hours. The reaction mass was allowed to cool to 50⁰C, and again heated to 70-80⁰C, at which water (200 ml) was added slowly. The reaction mass gradually cooled to 10⁰C and filtered to obtain wet cake, which was dried to get desired product.

Yield: 75 g, %Yield= 80%. Example 4

Synthesis of Etravirine

Compound-IV (100 g, 0.28 m) was taken in methylene dichloride (800 ml) and cooled to a temperature of 0 to 5°C. Slowly liquid bromine (47.2 g, 0.294 m) was added at 0 to 5⁰C by dissolving in 200 ml of methylene dichloride. The reaction mass was stirred at 0 to 5⁰C for 2 to 4 hrs. Chilled water (800 ml) was added in to the reaction mass and pH was adjusted at 9 to 10 by slow addition of sodium hydroxide solution at 0 to 5°C. Sodium metabisulphite solution was added at 0 to 5⁰C and the reaction mass was stirred at 0-10⁰C for 1 hour by maintaining the reaction mass pH at 8 to 9. The reaction mass was filtered and washed the cake with 200 ml water. Dry the wet product at 50-60⁰C & recrystallize from acetone. Yield: 100 g, Melting point: 252 to 254°C.

………………………………………..

http://www.google.com/patents/EP2212298B1?cl=en

• The synthesis of compounds of Formula I can be readily achieved by synthetic chemists of ordinary skill. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Relevant procedures and intermediates are disclosed, for instance in PCT patent publication WO2000/27825 ; European Patent 1 002 795 ; United State patent 7,241,458 ; and Ludovici, DW et al, Biorg Med Chem Lett 2001, 11:2235. The compounds may be prepared as illustrated in the schemes shown below.

Exemplary Synthesis

• [0043]
  

  
• [0044]
  Scheme 1 shows a general route for preparing compounds of Formula I. An appropriately deuterated benzonitrile 10 is converted to the corresponding aryl guanidine compound 11 by refluxing in ethanol with cyanamide and nitric acid. Reaction with diethylmalonate and sodium ethoxide in ethanol produces the cyanophenylamino-4-dihyroxypyrimidine 12, which is then chlorinated by treatment with POCl₃, and brominated by treatment with bromine gas and aqueous sodium bicarbonate in methanol to yield compound 13. Compound 13 is combined with appropriately deuterated 4-cyanophenol 14 in the presence of N-methylpyrrolidone (“NMP”) and dioxane to form tricyclic compound 15. Compound 15 is then treated with ammonia in isopropyl alcohol (“IPA”) to form a compound of Formula I.

  

  
• [0045]
  Scheme 2 shows how various deuterated benzonitriles 10, useful in Scheme 1, may be prepared. Reaction A, starting with compound 20, illustrates the preparation of the 4-amino-2,3,5,6-d₄-benzonitrile reagent 10a. Treatment of commercially available 4-chloro-2,3,5,6-d ₄-aniline (20) with palladium(II) trifluoroacetate, 2-di-tert-butylphosphino-1,1 ‘-binaphthyl, zinc flakes, and zinc cyanide according to the procedure described by Littke, A et al., Org Lett, 2007, 9:1711-1714 affords 10a.
• [0046]
  Scheme 2B shows the preparation of an alternative benzonitrile intermediate 4-amino-2,6-d₂-benzonitrile 10b, starting with commercially available 4-nitroaniline (21). Treatment of 21 with commercially available deuterium chloride in deuterated water according to the procedure described by Suehiro, T et al., Bull Chem Soc Jap, 1987, 60:3321-3330 affords the 2,6-d₂-4-nitroaniline 22, which can be elaborated through nitrochloro intermediate 23 and chloroaniline intermediate 24 to the necessary d₂-benzonitrile building block 10b using the procedures described in Suehiro, T et al., Bull Chem Soc Jap, 1987, 60:3321-3330.

  
• [0047]
  Scheme 3 shows the synthesis of appropriately deuterated.cyanophenols 14 useful in Scheme 1. Sequence A, starting with commercially available ortho-cresol-d ₇ 30, shows the preparation of the 2,6-d₂-4-hydroxy-3,5-bis(methyl-d₃)benzonitrile intermediate 14a (R¹, R² = CD₃; Y¹, Y² = D). Treatment of 30 with commercially available d ₂-diiodomethane and diethylzinc according to the procedure described by Macdonald, TL et al., Tet Lett, 1989, 39:5215-5218 affords the 2,6-bis(methyl-d₃)phenol 31. Subsequent bromination of the phenol with N-bromosuccinimde (NBS) in carbon tetrachloride using the protocol described by Srinivasan, KV et al., TetLett, 1994, 35:7055-7056 affords the 4-bromo-substituted phenol 32 Treatment of the bromophenol 32 with copper(I) cyanide in refluxing DMF according to the procedure described in Chinese patent publication 1687060 affords the requisite benzonitrile 14a.
• [0048]
  Scheme 3B, starting with commercially available 1-(methoxymethoxy)benzene (33), illustrates the preparation of 4-hydroxy-3,5-bis(methyl-d₃)benzonitrile 14b (R¹, R² = CD₃; Y¹ Y² = H). Treatment of 33 with n-butyllithium followed by treatment of the in situ generated organolithium with commercially available d₃-iodomethane according to the procedure described by Hayes, RN et al., Aus J Chem, 1989, 42:865-874 affords the 2-(methyl-d₃)phenol 34, which can then be processed as shown to afford the desired bis(methyl-d₃)benzonitrile (14b: R¹, R² = CD₃; Y¹, Y² = H).

Examples

• [0102]
  Example 1. Synthesis of 2,6-d₂-4-hydroxy-3,5-bis(methyl-d₃)benzonitrile (14b). Intermediate 14b was prepared as outlined in Scheme 4 below. Details of the synthesis follow.

  

  
• [0103]
  Synthesis of 3,4,5-d₃-2,6-bis(methyl-d₃)phenol (31). To a sealed tube containing a suspension of 2,6-dimethylphenol 40 (2.0 g, 16.4 mmol) in D₂O (25 mL), was added 5% Pt/C (20 wt%, 0.40 g). The mixture was purged with nitrogen then placed under an H₂ atmosphere and stirred at ambient temperature for 15 minutes (min). The tube was then sealed and the mixture heated to 180 °C for a period of 24 hours (h). After cooling to ambient temperature, the mixture was diluted with. Et₂O and filtered through Celite. The aqueous phase was extracted with Et₂O (3 x 25 mL) and the organic extracts were dried, (MgSO₄), filtered, and concentrated in vacuo to afford 1.8 g (84%) of pure 31 as a white solid; 98% D incorporation by ¹H NMR.
• [0104]
  Synthesis of 4-bromo-3,5-d₂2,6-bis(methyl-d₃)phenol (32). To a solution of 31 (1.6 g, 12.2 mmol) in AcOH (12 mL) at ambient temperature, was added 4,4-dibromo-3-methyl-pyrazol-5-one (3.1 g, 12.2 mmol, 1.0 equiv). The mixture was stirred at ambient temperature for period of 20 h then filtered through Celite and washed with cold AcOH (5 mL). The mixture was then concentrated in vacuo and the residue obtained was diluted with H₂O (15 mL) and neutralized with a saturated aqueous NaHCO₃ solution. The aqueous mixture was then extracted with hexane/Et₂O (1:1, 3 x 15 mL) and the organic extracts were dried, (MgSO₄), filtered, and concentrated in vacuo. Purification of the crude mixture on SiO₂ (10%-20% EtOAc/Hex) afforded 1.4 g (79 %) of pure 32 as a white solid;
• [0105]
  Synthesis of 2,6-di-4-hydroxy-3,5-bis(methyl-d₃)benzonitrile (14b). To a sealed vessel containing a solution of phenol 32 (1.45 g, 6.93 mmol) in DMF (15 mL), was added zinc cyanide (0.98 g, 8.32 mmol, 1.2 equiv), Pd₂(dba)₃ (0.36 g, 0.35 mmol, 5 mol%), dppf (0.19 g, 0.35 mmol, 5 mol%), polymethylhydrosiloxane (PMHS, 0.15 g, 10 wt%) and water (0.35 mL). The vessel was sealed and heated to 120 °C for a period of 18 h. After cool ing to ambient temperature, the mixture was diluted with H₂O (20 mL) and Et₂O (20 mL). The aqueous phase was further extracted with Et₂O (3 x 20 mL) and the organic extracts were dried, (MgSO₄) filtered, and concentrated in vacuo. Purification of the crude mixture on SiO₂ (10%-20% EtOAc/Hex) afforded 1.0 g (92%) of pure 14b as an off-white solid.
• [0106]
  Example 2. Synthesis of 104. Compound 104 was prepared as outlined in Scheme 5 below. Details of the synthesis follow. Pyrimidine 42 was prepared as set forth in Ludovici, DW et al., Biorg. Med. Chem. Lett. 2001, 11:2235-2239.

  
• [0107]
  Synthesis of 4-(5-bromo-6-cbloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-2,6-d₂ –3,5-bis(methyl-d₃)benzonitrile (43). To a sealed tube containing a solution of nitrile 41 (100 mg, 0.64 mmol, 1.1 equiv) in 1,4-dioxane (0.6 mL), was added NaH (26 mg, 0.64 mmol, 1,1 equiv). The mixture was stirred at ambient temperature for a period of 2 min, NMP (0.6 mL) was added, and the resulting mixture was stirred for an additional 10 min at ambient temperature. Pyrimidine 42 (0.20 g, 0.58 mmol, 1.0 equiv) was added to the mixture, and the vessel was sealed and heated to 155 °C for a period of 16 h. After cooling to ambient temperature, the mixture was diluted with H₂O (4 mL) and the crude product was filtered off and washed with additional water. Purification of the crude solid on SiO₂ (70% CH₂Cl₂/Hexanes) afforded 72 mg (27%) of pure 43 as a white solid.
• [0108]
  Synthesis of 4-(6-amino-5-bromo-2-(4-cyanopheaylamino)pyrimidin-4-yloxy)-2,6-dideutero-3,5-bis(trideuteromethyl)benzonitrile (104) Pyrimidine 43 (72 mg, 0.16 mmol) was dissolved in a 0.5 M solution of 1,4-dioxane (4 mL) in a sealed tube. The vessel was heated to 130 °C for a period of 24 h. After cooling to ambient temperature, the mixture was concentrated in vacuo. Purification of the crude mixture on SiO₂ (0.25%-0.5% MeOH*/ CH₂Cl₂) (*2.0 M NH₃ in MeOH) afforded 12.1 mg (17%) of pure 104 as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (d, J=8.8, 2H), 7.30 (d, J=8.8, 2H), 6.82 (br s, 1H), 5.33 (br s, 2H). HPLC (method: 150 mm C18-RP column-gradient method 5-95% ACN; Wavelength: 254 nm): retention time: 5.39 min; purity: 97.8%. MS (M+H): 443.0, 445.1.

http://www.google.com/patents/EP2212298B1?cl=en

…………………………………

http://www.google.com/patents/WO2012001695A1?cl=en

Etravirine can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

Etravirine and its salts were described in US patent nos. 7,037,917. According to the patent also described a process for the preparation of etravirine which comprises treating 4-[[6-chloro-5-bromo-2[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethylbenzonitrile with ammonia.

Process for the preparation of etravirine was described in Drugs of the Future 2005, 30(5): 462-468. According to the process of etravirine which comprises treating 4- [[6-chloro-5 -bromo-2 [(4-cyanophenyl)amino] -4-pyrimidinyl] oxy] -3 ,5 -dimethylbenzonitrile with ammonia.

Process for the preparation of 4-[[6-^‘chloro-2-[(4-cyanophenyl)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile was described in Organic process research & development., 2010, 14(3); 657-660. According to the process of 4-[[6-chloro-2-[(4- cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile which comprises reacting 4-aminobenzonitrile in N-methylpyrrolidone with 4-[(2,6-dichloro)-4- pyrimidinyloxy]-3,5-dimethylbenzonitrile in the presence of potassium tert-butoxide. Process for the preparation of etravirine was described in Organic process research & development., 2010, 14(3); 657-660. According to the publication, crystalline solid of etravirine was obtained by dissolving crude etravirine in acetone at 50 to 55°C and was treated with activated charcoal, and isolating. The crystalline etravirine obtained by the process of the prior art is herein after designated as etravirine crystalline form I. The powdered x-ray diffractogram (PXRD) of etravirine crystalline Form I is shown in figure 1. Crystalline Form I is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 8.7, 9.1, 13.0, 19.4, 19.6, 23.5, 26.5, 26.8 and 28.5 ± 0.2 degrees.

preparation of 4- [[6-chloro-2- [(4-cyanophenyl)amino] -4-pyrimidinyl] oxy] -3 ,5 -dimethylbenzonitrile of formula I:

which comprises reacting the 4-(4,6-dichloropyrimidine-2-yl-amino)benzonitrile of formula II:

with 4-hydroxy-3,5-dimethylbenzonitrile of formula III:

in the presence of a base to obtain a compound of formula I.

Examples

Preparation of l-(4-cvanophenyl)guanidine

Preparative example 1 :

A solution of P-aminobenzonitrile (100 gm), ethanol (500 ml), concentrated nitric acid (36 ml) and aqueous cyanamide (50%, 54 ml) was heated at reflux. The solution was maintained for 16 hours at reflux. The reaction mass was further cooled to 0°C and then added methyl tert-butyl ether (500 ml) at 0 to 5°C. The reaction mass was maintained for 5 hours at 0 to 5°C and separated solid obtained was collected by filtration to obtain 59 gm of guanidine nitrate.

Guanidine nitrate (59 gm) was dissolved in water (590 ml) and then added sodium hydroxide solution (1M, 325 ml). The separated solid obtained was filtered and dried to obtain 33 gm of l-(4-cyanophenyl)guanidine. Preparation of 4-(4,6-dihvdroxypyrimidine-2-yl-amino)benzonitrile

Preparative example 2: Diethyl malonate (30 gm) was added to l-(4-cyanophenyl)guanidine (30 gm) at room temperature. A solution of sodium (17.2 gm) in ethanol (450 ml) was added to the above reaction mass. The contents were heated to reflux and maintained for 12 hours. Distilled off the solvent completely under vacuum and then added water (500 ml). The reaction mass was stirred for 30 minutes and filtered. The solid obtained was dried to obtain 40 gm of 4-(4,6-dihydroxypyrimidine-2-yl-amino)benzonitrile.

Preparation of 4-(4,6-dichloropyrimidine-2-yl-amino)benzonitrile

Preparative example 3 :

Phosphoryl chloride (159 ml), Ν,Ν-dimethyl aniline (1 18 ml) and 4-(4,6- dihydroxypyrimidine-2-yl-amino)benzonitrile (40 gm) are added and heated to reflux. The reaction mass was maintained for 6 hours at reflux and then poured into ice water (1000 ml). The reaction mass stirred for 2 hours at room temperature and filtered. The solid obtained was dried to obtain 35 gm of 4-(4,6-dichloropyrimidine-2-yl- amino)benzonitrile.

Preparation of 4- [ [6-chloro-2- [(4-cyanophenyl)aminol -4-pyrimidinyl] oxyl -3,5- dimethylbenzonitrile

Example 1 :

4-(4,6-Dichloropyrimidine-2-yl-amino)benzonitrile (35 gm) as obtained in preparative example 3 was added to 4-hydroxy-3,5-dimethylbenzonitrile (22 gm) and then added a mixture of N-methylpyrrolidone and potassium carbonate (22 gm ) at 45°C. The reaction mass was stirred for 12 hours at 45°C and then added water (1000 ml). The reaction mass was cooled to 25°C and stirred for 2 hours at 25°C, filtered. The wet solid obtained was dissolved in acetone (140 ml) under stirring and the separated solid was filtered, and then dried at 50°C to obtain 24 gm of 4-[[6-chloro-2-[(4- cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile.

Preparation of 4-ff6-amino-2-[(4-cvanophenyl)aminol-4-pyrimidinylloxyl-3,5- dimethylbenzonitrile

Example 2: 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrin idinyl]oxy]-3,5-dimethyl- benzonitrile (24 gm) was dissolved in aqueous ammonia (240 ml) and 1,4-dioxane (274 ml) at room temperature. The contents were heated to 120°C and maintained for 12 hours at 120°C. To the reaction mass was added water (360 ml) and the reaction mass was slowly cooled to 50 to 60°C. The reaction mass was further cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C, filtered. The wet solid obtained was dissolved in toluene (150 ml) under stirring. The separated solid was filtered and dried at 50°C to obtain 10 gm of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethylbenzonitrile.

Preparation of etravirine

Example 3 :

4- [ [6-amino-2- [(4-cyanophenyl)amino] -4-pyrimidinyl]oxy] -3 ,5 -dimethyl – benzonitrile (10 gm) was dissolved in dichloromethane (100 ml) at 0 to 5°C and then added bromine solution (4.7 gm in 50 ml of dichloromethane). The reaction mass was stirred for 4 hours at 0 to 5°C and then added water (100 ml). The pH of the reaction mass was adjusted to 9 to 10 with sodium hydroxide solution (4N, 10 ml). Sodium metabisulphite solution (0.5 gm in 2 ml of water) was added to the reaction mass and pH of the reaction mass was maintained between 7.5 to 8.5 with sodium hydroxide solution (4N, 10 ml). The separated solid was filtered and dried at 50 to 55°C to obtain crude etravirine.

Crude etravirine obtained above was dissolved in acetone (200 ml) at 50 to 55°C and then treated with activated charcoal (1.5 gm). The reaction mass was filtered through celite and the filtrate was distilled off acetone completely to obtain residue. The residue was cooled to 5 to 10°C and filtered. The solid obtained was dried at 60°C to obtain 5.2 gm of pure etravirine.

………………………………..

http://www.google.com/patents/WO2013159286A1?cl=en

Etravirine (Etravirine, -165335, TMC-125) under the trade name British Terai (Intelence), chemical name 4 – [6 – amino-5 – bromo-2 – (4 – cyanide Diaminodiphenol) pyrimidine-4 – oxy] -3, 5 – dimethyl-benzonitrile, the following structural formula:

Etravirine is a Johnson & Johnson subsidiary Tibotec has developed a next-generation non-nucleoside reverse transcriptase inhibitors (NN-RTI), with anti-HIV-infection. Clinical studies have shown that patients with the first use of NN-RTI drug therapy, etravirine showed strong antiviral activity; patients previously used antiviral drugs, this product also has the characteristics of rapid and long-lasting effect. In addition, HIV-1-infected patients with oral ribavirin according to the song has a good distribution of drug metabolism and is well tolerated. January 18, 2008 the FDA approved Tibotec Therapeutics’s priority review program by etravirine tablets combined with other anti-HIV drugs for the treatment of other antiretroviral drugs ineffective in adult HIV-infected patients.

Currently on the synthesis of etravirine have the following main categories:

One, WO0027825A1 etravirine first disclosed the following synthetic route:

The above line is not easy to get raw materials, and the last step amination exist for a long time, conversion rate of defects, is not suitable for industrial production.

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

This method not only synthetic route length (total of 5-step reaction), starting 4 – cyanophenyl guanidine expensive and difficult to obtain, and the condensation reaction selectivity in step 4, ammonolysis step 5 incomplete conversion, resulting in The total yield of less than 10%, is not suitable for industrial production.

Three, WO2010150279A2 reported the following synthetic methods:

This method, although only four steps, each step is also more readily available raw materials, the reaction rate is improved amination, etravirine total crude yield of 40%. However, with the second reaction step up to nearly 12% of the byproduct [i.e. a compound of formula (3)], can be purified after the amination reaction of the next step, the compound (3) with a compound of formula (2) and the same formula isomers, very similar structures and physicochemical properties, and therefore, the formula (2) the difficulty of purification of the compounds higher.

This method yields a condensation reaction of step 4 is only 48% ammoniated reaction yield of step 5 is also only 44%, the yield is low this two-step reaction, the product purity is not high, leading to the final step of bromine on behalf of the reaction yield is also low, as low as 43%, only 9% of the total yield of these three steps, not suitable for industrial production. Therefore, an urgent need to develop a simple, low cost of production etravirine preparation.

Preparation methods according to Qu Wei Lin

Qu Wei Lin preparation method according to the present invention is shown in the formula (V), preferably based preparation steps according to Qu Wei Lin intermediates of the present invention (il), (i2) and (ii), the step ( ii) to obtain a compound of formula IV, the following bromination step further:

(Iii) at room temperature (eg 25 – 28 ° C) in an inert solvent, in the presence of bromide reagents, step (ii) of the resulting compound of formula IV).

In another preferred embodiment, the reagent or the solvent in step (iii) of the bromination reaction can be used by those of ordinary skill in the reagents or solvents used, preferably bromination reagent bromosuccinimide (NBS ) or Br _2, the inert solvent used for the bromination reaction solvent, preferably acetone.

Compounds of formula II is calculated by the method according to Qu Wei obtained a 50% yield of the forest of the present invention, preferably 55%; better to 60%; optimally 65%. The main advantages of the present invention are:

1 provides a method for preparing formula IV as shown by curved intermediate Wei Lin, the method using the same or substantially the same solvent system, can be performed continuously multistep reaction without separation and purification between steps, the operation is very simple, compound The yield is much higher than existing methods, and high-purity compounds obtained can be directly used in the preparation according to Qu Wei Lin.

2 provides a method for preparing formula V according to Qu Wei Lin, the method based on production method according to Qu Wei Lin intermediates in the present invention provides a significantly improved yield according to Qu Wei Lin, thereby significantly reducing its production cost, high value industrial applications. Below with reference to specific embodiments, further illustrate the present invention. It should be understood that these embodiments are merely illustrative of the invention and are not intended to limit the scope of the invention. Example experimental method does not indicate the specific conditions of the following examples, usually in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight. Example 1

4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile A mixture of 3,5 – dimethyl – 4 – hydroxybenzonitrile (1 1.8g, 0.080mol) was dissolved in lOOmL N-methylpyrrole embankment ketone (ΝΜΡ) was then added K ₂ CO ₃ (ll Og, 0.080mol.). Warmed to 90 ° C, incubated for 2 hours.

The above reaction mixture was cooled to 25 ° C, the solution of 4 – (4,6 – dichloro-pyrimidin-2 – amino) benzonitrile (21.3g, 0.081mol), incubated for 3 hours. Heated to 50 ° C, and then continue to heat for 10 hours. Filtered and the solid rinsed two times with 30mL NMP.

The combined filtrates were saturated with ammonia gas was heated to 120 ° C, the reaction was kept for 10 hours.

Thereto was added water 500mL. Crystallization, filtration, the filter cake was 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 was heated at reflux for 30 minutes. Cooling to room temperature, filtered and dried in vacuo to give 4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile 25.0g yield of 87.8%.

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

4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile A mixture of 3,5 – dimethyl – 4 – hydroxybenzonitrile (6.0g, 0.041mol) was dissolved in 75mL N, N-dimethylformamide (DMF) was then added Na ₂ CO ₃ (5.2g, 0.049mol). Heated to 80 ° C, incubated for 2 hours.

The above reaction mixture was cooled to 25 ° C, the solution of 4 – (4,6 – dichloro-pyrimidin-2 – amino) benzonitrile

(13.0g, 0.049mol), incubated for 4 hours. Heated to 55 ° C, and then continue to heat for 8 hours. Filtered and the solid rinsed two times with 20mL DMF.

The combined filtrate was slowly added 25% aqueous ammonia 30ml. Heated to 110 ° C, the reaction was kept for 15 hours. Water was added to the system 300mL. Crystallization, filtration, the filter cake was rinsed with 30 mL of water.

The obtained wet cake was added into a 50 mL of acetone was heated at reflux for 1 hour. Cooling to room temperature, filtered and dried in vacuo to give 4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile 12.3 g yield of 84.3%.

HPLC purity 98.2%. An example of mass spectral data consistent with the implementation. Example 3

4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile A mixture of 3,5 – dimethyl – 4 – hydroxybenzonitrile (6.0g, 0.041mol) was dissolved in 60mL of tetrahydrofuran (THF), and then sodium acetate (13.5 g, 0.16mol). Warmed to reflux, the reaction was kept for 3 hours.

The above reaction mixture was cooled to 30 ° C, the solution of 4 – (4,6 – dichloro-pyrimidin-2 – amino) benzonitrile (21.6g, 0.082mol), incubated for 3 hours. Heated to 60 ° C, and then continue to heat for 12 hours.

Then, the reaction mixture up one step, the ammonia gas until saturation. Heated to 120 ° C, the reaction was kept for 12 hours.

Water was added to the system 300mL. Crystallization, filtration, the filter cake was 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 was heated at reflux for 30 minutes. Cooling to room temperature, filtered and dried in vacuo to give 4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile 11.3 g yield of 77.2%.

HPLC purity 97.7%. An example of mass spectral data consistent with the implementation. Example 4

4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile A mixture of 3,5 – dimethyl – 4 – hydroxybenzonitrile (6.0g, 0.041mol) was dissolved in 60mLl, 4 – dioxane, and then added sodium ethoxide (2.8g, 0.041mol). Heated to 75 ° C, the reaction was kept for 1 hour.

The above reaction mixture was cooled to 20 ° C, the solution of 4 – (4,6 – dichloro-pyrimidin-2 – amino) benzonitrile

(Ll. Og, 0.042mol), incubated for 3 hours. Warmed to 45 ° C, and then incubation was continued for 10 hours.

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

120 ° C, the reaction was kept for 15 hours.

Water was added to the system 300mL. Crystallization, filtration.

The obtained wet cake was added to a mixed solvent of acetone and 15mL 35mL of water, heated at reflux for 30 minutes. Cooling to room temperature, filtered and dried in vacuo to give 4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile 11.8g The yield was 80.8%.

HPLC purity 98.1%. An example of mass spectral data consistent with the implementation. Example 5

Preparation according to Qu Wei Lin

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

Then, stirring was added 0.5M sodium hydroxide solution 140mL, stirring was continued for 30 minutes, filtered, and the filter cake was dried under vacuum, the crude product may, in accordance etravirine.

The crude product is recrystallized from acetone, may, in accordance etravirine 35.0g, yield 80.4%.

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

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

3,5 – dimethyl-4 – hydroxybenzonitrile as starting material a compound of formula II, the preparation of compounds of formula via a two-step IV, the preparation methods, see WO2012001695 Example specification of a page 11-12 and Example 2, calculated by the compound of formula II, in the present Comparative Example 4 – [[6 – amino-2 – [(4 – cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethyl benzene carbonitrile yield of approximately 21%. Conclusion:

1 The present invention is a method for preparing the compound of formula IV, although the reaction of a compound prepared by a plurality of formula IV, however, use the same or substantially the same throughout the solvent system, multi-step continuous reaction without separation and purification between steps, operation is very simple, and the resulting compound of formula IV is very high yield (yield not less than 77%), far exceeding the prior art, 21% yield and high purity, used directly without purification step Preparation according to Qu Wei Lin.

(2) Preparation method according to Qu Wei Lin of the present invention is a system of law based on the compound of formula IV, is a compound of formula IV further bromination. The method significantly improves the yield according to Qu Wei Lin: A compound of formula II according to the calculation of the starting material, the method according to the present invention, Qu Wei Lin yield up to 60-70%, much higher than the existing technology By Qu Wei Lin in yield, as Bioorg. Med. Chem. Lett., 2001, 11 (17), revealed 2235-9 method through a three-step system may, in accordance yield about Qu Wei Lin 14%, WO2012001695A1 disclosed method, three-step total yield of only 9%, thereby significantly reducing the cost of production, high industrial value. All documents mentioned in the present invention are incorporated by reference as if each reference was individually incorporated by reference, as cited in the present application. It should also be understood that, after reading the foregoing teachings of the present invention, those skilled in the art that various modifications of the present invention or modifications, and these equivalents falling as defined by the appended claims scope of claims of the present application.

………………………………………………..

Organic process research & development., 2010, 14(3); 657-660

http://pubs.acs.org/doi/abs/10.1021/op9003289

Etravirine (1) is a novel diarylpyrimidine non-nucleoside reverse transcriptase inhibitor and has recently been approved by the U.S. Federal Drug Administsration for the treatment of AIDS. Its reported synthesis is fraught with many difficulties, the foremost being the poor yield and long reaction time required at the aminolysis stage. We attributed this problem to the presence of a bromide group adjacent to the reaction site of the advance intermediate (6). In order to circumvent this issue, we proposed to defer the installation of the bromide group at a later stage, preferably after aminolysis. Indeed, this protocol has worked well. However, in the process of installation of diarylether and diarylamine functionalities at appropriate positions, we had to reverse the sequence of displacement reactions of the dichloride intermediate (9) with 3,5-dimethyl-4-hydroxybenzonitrile (5) and 4-aminobenzonitrile (3). The classical bromination led to the completion of etravirine synthesis.

References

NEW PATENT

WO-2014068588

Biophore India Pharmaceuticals Pvt Ltd

Process for preparing etravirine by reacting 4-((6-amino-5-bromo-2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile with 4-hydroxy-3,5-dimethyl benzonitrile in presence of a base such as N-methylpyrrolidone. Also claims the preparation of intermediates involved in synthesis of etravirine. Useful for treating HIV infection.