WO2016059646A2 - Procédé amélioré pour la préparation de 4-[6-amino-5-bromo-2-[(4-cyanophényl)aminol]-4-pyrimidinyl]oxy]-3,5-diméthylbenzonitrile - Google Patents

Procédé amélioré pour la préparation de 4-[6-amino-5-bromo-2-[(4-cyanophényl)aminol]-4-pyrimidinyl]oxy]-3,5-diméthylbenzonitrile Download PDF

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WO2016059646A2
WO2016059646A2 PCT/IN2015/000385 IN2015000385W WO2016059646A2 WO 2016059646 A2 WO2016059646 A2 WO 2016059646A2 IN 2015000385 W IN2015000385 W IN 2015000385W WO 2016059646 A2 WO2016059646 A2 WO 2016059646A2
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formula
compound
amino
dimethylbenzonitrile
benzonitrile
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PCT/IN2015/000385
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WO2016059646A3 (fr
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Gutta Madhusudhan
Peri Seetha Rama Sarma
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Msn Laboratories Private Limited
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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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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 present invention provides an improved process for the preparation of 4-[[6- amino-5 -bromo-2- [(4-cyanophenyl)amino] -4-pyrimidinyl] oxy] -3 , 5 -dimethyl benzonitrile compound of formula- 1, which is represented by the following structural formula:
  • the present invention also provides salts of intermediate compounds useful in the preparation of compound of formula- 1.
  • Etravirine 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl benzonitrile is commonly known as Etravirine, and was formerly known as TMC-125, and marketed under the brand name Intelence® by Tibotec.
  • Etravirine is a drug used for the treatment of HIV and it is non-nucleoside reverse transcriptase inhibitor (NNRTIs). Unlike the currently available agents in the class, resistance to other NNRTIs does not seem to confer resistance to Etravirine.
  • NNRTIs non-nucleoside reverse transcriptase inhibitor
  • Etravirine is prepared by reacting a tetra halogenated pyrimidine derivative and an aminobenzene derivative, and optionally brominating the obtained product to obtain Etravirine.
  • This process includes two Steps which require chromatographic purification of intermediates which in turn reduces the yield of the final product.
  • WO2012/001695 Al discloses the preparation of 4-[[6-amino-5-bromo-2-[(4-cyano phenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile compound of formula- 1 by reacting 4-(4,6-dihydroxypyrimidin-2-ylamino)benzonitrile compound of formula-4 with phosphorus oxychloride in ⁇ , ⁇ -dimethyl aniline to provide 4-(4,6-dichloro pyrimidin-2- ylamino)benzonitrile compound of formula-5.
  • the said process suffers from several draw backs including the usage of carcinogenic substance i.e, ⁇ , ⁇ -dimethyl aniline for the chlorination of compound of formula-4. Further, it is also observed that when the reaction was carried out in the presence of N,N-dimethyl aniline, the yield of the compound of formula-5 is decreased with increased level of impurities and requires tedious purification process to get pure compound. Therefore the said process is not cost-effective, not amenable for commercial synthesis on industrial scale and thereby making the process commercially unviable.
  • the first aspect of the present invention is to provide an improved process for the preparation of pure 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethylbenzonitrile compound of formula- 1.
  • the second aspect of the present invention is to provide a process for the preparation of 4-(4,6-dichloropyrimidin-2-ylamino)benzonitrile compound of formula-5.
  • the third aspect of the present invention relates to 4-(4,6-dichloropyrimidin-2- ylamino)benzonitrile p-toluene sulfonic acid salt compound of formula-5a.
  • the fourth aspect of the present invention is to provide a process for the purification of 4-(6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile compound of formula-7.
  • the fifth aspect of the present invention relates to crystalline form of 4-(6-amino-2- (4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile dihydrochloric acid salt compound of formula-8a hereinafter designated as form-M.
  • the sixth aspect of the present invention is to provide an alternate process for the preparation of 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethylbenzonitrile compound of formula- 1.
  • the seventh aspect of the present invention is to provide a process for the preparation of 4- [ [6-amino-5 -bromo-2- [(4-cyanophenyl)amino] -4-pyrimidinyl] oxy] -3 , 5 -dimethyl benzonitrile compound of formula- 1.
  • Figure-1 Illustrates the P-XRD pattern of crystalline form-M of 4-(6-amino-2-(4- cyanophenyl amino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile dihydrochloric acid salt.
  • Figure-2 Illustrates the P-XRD pattern of crystalline form ⁇ S of 4-(4,6-Dichloropyrimidin-2- yl-amino)benzonitrile p-toluene sulfonic acid.
  • Figure-3 Illustrates the P-XRD pattern of crystalline form-N of 4-(4,6-Dichloropyrimidin-2- yl-amino)benzonitrile p-toluene sulfonic acid.
  • the present invention deals with an improved process for preparation of 4-[[6-amino-
  • suitable solvent is selected from “alcoholic solvent” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, ethylene glycol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butylether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chlor
  • base is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tert- butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonate?
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like
  • alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tert- butoxide, potassium tert-butoxide and the like
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like
  • alkali metal bicarbonate alkali metal bicarbonate?
  • TAA triethylamine
  • DIPA diisopropylamine
  • DIPEA diisopropylethylamine
  • DIBA diisobutylamine
  • piperidine pyridine, tributyl amine, 4- dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), N-methyl pyrrolidone (NMP), 1,8-diazabycyclo [5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1.4diazabycyclo [2.2.2] octane and the like.
  • TAA triethylamine
  • DIPA diisopropylamine
  • DIPEA diisopropylethylamine
  • DIBA diisobutylamine
  • DMAP 4- dimethylaminopyridine
  • NMM N-methyl morpholine
  • NMP N-methyl pyrrolidone
  • brominating agents include but are not limited to l,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide, N-bromoacetamide, thionyl bromide and bromine and the like.
  • chlorinating agents include but are not limited to chlorine, oxalyl chloride, sulfuryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, pivaloyl chloride, antimony pentachloride, iodine trichloride, sulfur dichloride, disulfur dichloride, manganese tetrachloride and the like.
  • the suitable hydrochloric acid source is selected from HC1 gas, dilute HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl and the like.
  • suitable “acid” is selected from “organic acids” such as oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, camphorsulfoic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids” such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid.
  • organic acids such as oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzene
  • the first aspect of the present invention provides an improved process for the preparation of pure 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethylbenzonitrile compound of formula- 1, comprising of the following steps:
  • step-a) the chlorination is carried out using suitable chlorinating agent in combination with suitable base selected from organic base preferably N-methyl pyrrolidone and suitable solvent selected from chloro solvents, ketone solvents, ester solvents, ether solvents, polar aprotic solvents, alcoholic solvents, hydrocarbon solvents and polar solvents such as water or mixture thereof; preferably polar aprotic solvents;
  • suitable base selected from organic base preferably N-methyl pyrrolidone
  • suitable solvent selected from chloro solvents, ketone solvents, ester solvents, ether solvents, polar aprotic solvents, alcoholic solvents, hydrocarbon solvents and polar solvents such as water or mixture thereof; preferably polar aprotic solvents;
  • the suitable solvent is selected from ketone solvents, ester solvents, ether solvents, alcohol solvents, hydrocarbon solvents preferably ketone solvents and the conversion of salt compound of formula-5a to compound of formula-5 is carried out by using an inorganic base;
  • the suitable base is selected from organic or inorganic bases and suitable solvent selected from alcohol solvents, ketone solvents, polar aprotic solvents, ether solvents, ester solvents, polar solvents such as water or mixture thereof;
  • the suitable amine source is selected from ammonium salts, ammonium hydroxide, anhydrous ammonia, amines, organic compounds containing at least one amine functional group, and compounds with at least one terminal amine; and a suitable solvent is selected from ketone solvents, ether solvents, ester solvents, alcohol solvents, chloro solvents and polar solvents such as water or mixtures thereof; in step-e) tn% i: suitable acid is selected from ethylacetate-hydrochloric acid and p- toluene sulfonic acid; and the suitable base is selected from inorganic base; and a suitable solvent is selected from ketone solvents, ether solvents, ester solvents, alcohol solvents, chloro solvents and polar solvents such as water or mixtures thereof;
  • step-f) the bromination is carried out in presence of a suitable base selected from inorganic or organic bases and the suitable solvent is selected from chloro solvents, ketone solvents, ether solvents, ester solvents, alcohol solvents, hydrocarbon solvents, polar solvents such as water or mixture thereof; at a suitable temperature ranging from 0°C to the reflux temperature of the solvent used in the reaction; preferably 0-5°C.
  • a suitable base selected from inorganic or organic bases and the suitable solvent is selected from chloro solvents, ketone solvents, ether solvents, ester solvents, alcohol solvents, hydrocarbon solvents, polar solvents such as water or mixture thereof.
  • the preferred embodiment of the present invention provides an improved process for the preparation of pure 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]- 3,5-dimethylbenzonitrile compound of formula-1, comprising of the following steps:
  • One of the embodiments of the present invention provides an alternate process for the preparation of formula-1 comprising of conversion of the compound of formula-8 into its p- toluene sulfonic acid salt compound of formula-8b followed by converting it into dihydrochloric acid salt compound of formula- 8 a thereby converting it into pure compound of formula-1.
  • the second aspect of the present invention provides a process for the preparation of 4- (4,6-dichloropyrimidin-2-ylamino)benzonitrile compound of formula-5, comprising of the following steps:
  • the third aspect of the present invention relates to 4-(4,6-dichloropyrimidin-2- ylamino)benzonitrile p-toluene sulfonic acid salt compound of formula-5 a.
  • the present invention also relates to crystalline form-S of 4-(4,6-dichloropyrimidin-2- ylamino)benzonitrile p-toluene sulfonic acid salt compound of formula-5 a, characterized by its powder X-ray diffractogram having peaks at 4.7, 4.8, 9.1, 9.3, 10.8, 1 1.8, 14.3, 16.1, 16.3, 16.9, 18.8, 19.2, 21.4, 22.0, 22.5, 22.7, 23.9, 24.7, 25.3, 26.0, 26.7, 27.7, 28.6, 21.4, 32.1, 32.4, 33.3, 33.6, 35.6, 36.2, 36.8, 37.8, 45.9, 47.2 and 48.9 ⁇ 0.2 degrees of two-theta and the P-XRD pattern is depicted in figure-2.
  • the present invention also relates to crystalline form-N of 4-(4,6- dichloropyrimidin-2-ylamino)benzonitrile p-toluene sulfonic acid salt compound of formula- 5a, characterized by its powder X-ray diffractogram having peaks at 4.9, 9.1, 10.9, 1 1.9, 14.3, 21.4, 22.0, 23.9, 25.3, 26.0 and 28.5 ⁇ 0.2 degrees of two-theta and the P-XR pattern is depicted in figure-3.
  • the 4-(4,6-dichloropyrimidin-2-ylamino)benzonitrile p-toluene sulfonic acid salt compound of formula-5a is useful in the preparation of pure compound of formula-5 which further enhance the purity in subsequent stages and final drug substance.
  • the fourth aspect of the present invention provides a process for the purification of 4- (6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile compound of formula-7, comprising of the following steps:
  • the suitable solvent is selected from alcohol solvents, preferably methanol; in step-b) the suitable temperature is ranging from 35°C to reflux temperature of the solvent used in the reaction;
  • the suitable temperature is ranging from 0°C to 35°C.
  • the conversion of compound of formula-7 into compound of formula-8 involves the reaction with ammonia at a high pressure which undergo degradation and leading to the formation of unknown impurities and 'chloro impurity' .
  • the fifth aspect of the present invention relates to crystalline form-M of 4-(6-amino- 2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile dihydrochloric acid salt compound of formula-8a, characterized by its powder X-ray diffractogram having peaks at 10.0, 11.1, 12.3, 13.1, 13.7, 17.0, 17.4, 18.3, 20.0, 20.2, 20.9, 22.5, 23.0, 23.4, 24.4, 24.8, 25.3, 27.0, 28.1, 29.4, 29.7, 32.9 and 33.9 ⁇ 0.2 degrees of two-theta and the P-XRD pattern was depicted in figure- 1.
  • 3,5-dimethylbenzonitrile dihydrochloric acid salt compound of formula-8a of the present invention is useful in the preparation of pure compound of formula-8 as well as in the preparation of pure compound of formula- 1.
  • the sixth aspect of the present invention provides an alternate process for the preparation of 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethylbenzonitrile compound of formula- 1, comprising of the following steps:
  • step-(b) or (c) reacting the compound of formula-7 obtained in step-(b) or (c) with a suitable amine source in a suitable solvent to provide 4-(6-amino-2-(4-cyanophenylamino)pyrimidin- 4-yloxy)-3,5-dimethylbenzonitrile compound of formula-8,
  • step-a) the suitable chlorinating agent is same as defined above in combination with
  • suitable base selected from organic base preferably N-methyl pyrrolidone;
  • the suitable base is selected from organic and inorganic base; preferably inorganic base;
  • the suitable amine source is selected from ammonium salts, ammonium hydroxide, anhydrous ammonia, amines, ammonia gas;
  • the suitable acid is selected from p-toluene sulfonic acid; and the suitable base is selected from inorganic base;
  • step-f) the bromination is carried out in presence of a suitable base selected from inorganic or organic bases at a suitable temperature ranging from 0°C to the reflux temperature of the solvent used in the reaction; preferably 0-5°C;
  • the suitable solvent is selected from chloro solvents, ketone solvents, ether solvents, ester solvents, alcohol solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents such as water or mixture thereof.
  • the preferred embodiment of the present invention provides an alternate process for the preparation of 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethyl benzonitrile compound of formula- 1, comprising of the following steps:
  • the seventh aspect of the present invention provides a process for the preparation of 4- [[6-amino- 5 -bromo-2- [(4-cyanophenyl)amino] -4-pyrimidinyl] oxy] -3 , 5 -dimethyl benzonitrile compound of formula- 1, comprising of the following steps:
  • the present inventors have overcome the problem by carrying out the bromination using a combination of liquid bromine, potassium carbonate in the presence of dichloromethane and 2-butanol at 0-5 °C. Usage of 2-butanol in the reaction will wash out all the impurities to provide the compound of formula- 1 with enhanced yield and purity. The same was illustrated in the following table: s. In put Brominating Solvent Yield of Purity of Percentage of
  • 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethyl benzonitrile compound of formula- 1 obtained according to the present invention has the chloro impurity not more than 0.05 %, preferably not more than 0.03 %, more preferably not more than 0.02 %.
  • Apparatus A liquid chromatographic system equipped with variable wavelength PDA-detector; Column: Xterra RP 18 250*4.6, 5 ⁇ ; Flow rate: 1.2 ml/min; Wavelength: 303 nm & 272 nm; Column temperature: 25°C; Injection volume: 10 ⁇ ; Run time: 45 min; Diluent: Methanol (100% v/v); Needle wash: Diluent; Elution: Gradient; Sample concentration: 0.2 mg/ml; Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile : Methanol (50 : 50 v/v); Buffer: 3.08 gm (40 mm) ammonium acetate into 1000 ml milli-Q-water and then adjust the pH ⁇ 6.0 with dilute acetic acid, Filter through 0.22 ⁇ nylon membrane filter paper.
  • Apparatus A liquid chromatographic system equipped with variable wavelength PDA-detector; Column: Xterra RP 18 125*4.0, 5 ⁇ ; Flow rate: 0.8 ml/min; Wavelength: 303 nm; Column temperature: 4Q°C; Injection volume: 10 ⁇ ; Run time: 42 min; Diluent: Methanol (100% v/v); Needle, wash: Diluent; Elution: Gradient; Sample concentration: 0.2 mg/ml; Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile : Methanol (50 : 50 v/v); Buffer: 3.08 gm (40 mm) ammonium acetate into 1000 ml milli-Q-water and then adjust the pH ⁇ 6.0 with dilute acetic acid, Filter through 0.45 ⁇ nylon membrane filter paper.
  • Apparatus A liquid chromatographic system equipped with variable wavelength PDA-detector; Column: Xterra RP 18 125*4.0, 5 ⁇ ; Flow rate: 0.8 ml/min; Wavelength: 303 nm & 245 nm; Column temperature: 40°C; Injection volume: 10 ⁇ ,; Run time: 36 min; Diluent: Methanol (100% v/v); Needle wash: Diluent; Elution: Gradient; Sample concentration: 0.2 mg/ml; Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile : Methanol (50 : 50 v/v); Buffer: 40 mm of ammonium acetate into 1000 ml milli-Q-water and then adjust the pH ⁇ 6.0 with dilute acetic acid, Filter through 0.45 ⁇ nylon membrane filter paper.
  • 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl benzonitrile produced by the present invention can be further micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • Example-1 Preparation of l-(4-cyanophenyI)guanidine (Formula-3)
  • Aqueous cyanamide (889 ml) was added to a mixture of 4-aminobenzonitrile (250 gms) compound of formula-2 and isopropanol (1000 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 75-80°C. Hydrochloric acid (250 ml) was added to the reaction mixture at 75-80°C and stirred the reaction mixture for 2 hours at the same temperature. Another lot of hydrochloric acid (125 ml) was slowly added to the reaction mixture at 75-80°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 50-55°C Nitric acid (200 gms) was slowly added to the reaction mixture at 50-55°C.
  • Dimethyl malonate (302 gms) was added to the mixture of l-(4-cyanophenyl) guanidine (150 gms) compound of formula-3 and methanol (801 ml) at 25-30°C.
  • Slowly sodium methoxide solution (494 ml) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65 °C and stirred for 10 hours at the same temperature. 80-90%) of the solvent was distilled off from the reaction mixture under reduced pressure at below 60°C. Cooled the reaction mixture to 25-30°C. Water (750 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature.
  • Example-4 Purification of 4-(4,6-Dichloropyrimidin-2-yl-amino)benzonitriIe (Formula-5)
  • Example-8 Preparation of 4-(6-amino-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5- dimethylbenzonitrile dihydrochloric acid salt
  • Forma-8a A mixture of 4-(6-amino-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethyl benzonitrile (11 1 gms) compound of formula-8 and tetrahydrofuran (880 ml) were stirred for 15 minutes at 25-30°C.
  • Example-10 Preparation of 4-(6-amino-2-(4-cyanophenylamino)pyrimidin-4-yloxy)- 3,5-dimethylbenzonitriIe (Formula-8) via PTSA salt
  • Tetrahydrofuran (240 ml) was added to 4-(6-amino-2-(4-cyanophenylan ino) pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (80 gms) at 25-3Q°C.
  • tetrahydrofuran (240 ml) was added at 25-30°C and cooled the reaction mixture to 10-15°C.
  • Aqueous sodium hydroxide solution (13.4 gms of sodium hydroxide in 134 ml of water) was slowly added to the reaction mixture at 10-15°C and stirred for 1 hour at the same temperature.
  • Water 1000 ml was added to the reaction mixture. Raised the temperature of the reaction mixture to 25-3Q°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
  • Example-12 Purification of 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile (Formula-l)
  • Amino CPP dimethyl benzonitrile impurity Not detected; N-Oxide impurity: Not detected; 3-aminobromo impurity: Not detected; Desamino impurity: Not detected; Bromo dimer impurity: Not detected.
  • Aqueous cyanamide (53.25 ml) was added to a mixture of isopropyl alcohol (100 ml) and 4-amino benzonitrile (25 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 75-80°C. Hydrochloric acid was slowly added to the reaction mixture at 75-80°C and stirred for 2 hours at the same temperature. Again hydrochloric acid was added to the reaction mixture at 75-80°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 25-30°C . Aqueous sodium hydroxide solution was slowly added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 5-10°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 32 gms.
  • N-methyl pyrrolidone (43.3 gms) was added to a solution of 4-(4,6- dihydroxypyrimidin-2-ylamino)benzonitrile and dichloromethane (250 ml) at 25-3Q°C. Cooled the reaction mixture to 0-15°C. Phosphorus oxychloride (168 gms) was slowly added to the reaction mixture at 0-15°C under nitrogen atmosphere. Slowly raised the temperature of the reaction mixture to 25-30°C and the heated to 40-45°C. Stirred the reaction mixture for 6 hours at 40-45°C. Cooled the reaction mixture to 5-10°C. Reaction mixture was quenched with pre-cooled water at below 15°C and stirred for 45 minutes at the same temperature.
  • Example-19 Purification of 4-[[6-amino-5-bromo-2-[(4-cyanophenyI)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile (Formula-1)
  • Acetone (1500 ml) was added to 4-(6-amino-5-bromo-2-(4-cyano phenyl )amino pyrimidin-4-yloxy)-3,5-dimethyl benzonitrile (50 gms) at 25-30°C Heated the reaction mixture to 45-50°C and stirred for 30 minutes at the same temperature. Carbon was added to the reaction mixture at 45-50°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and washed with acetone. Distilled off the solvent completely from the reaction mixture under reduced pressure. Acetone (15 ml) was added to the reaction mixture. Heated the reaction mixture to 50-55 and stirred for 45 minutes at the same temperature.
  • Amino CPP dimethyl benzonitrile impurity Not detected; N-Oxide impurity: Not detected; 3-aminobromo impurity: Not detected; Desamino impurity: Not detected; Bromo dimer impurity: Not detected.
  • ⁇ , ⁇ -dimethyl aniline (265 gms) was added to a pre-cooled mixture of phosphorus oxychloride (768 ml) and 4-(4,6-dihydroxypyrimidin-2-yl-amino) benzonitrile (250 gms) at 0-5°C under nitrogen atmosphere. Heated the reaction mixture to 50-55°C and stirred for 5 hours at the same temperature. Distilled off the excess phosphorus oxychloride from the reaction mixture under reduced pressure. Cooled the reaction mixture to 0-5°C. Quenched the reaction mixture into ice cold water at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 216.5 gms; Purity by HPLC: 83.63%; Trichloro impurity: 10.44%.

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Abstract

La présente invention concerne un procédé amélioré pour la préparation du composé 4-[[6-amino-5-bromo-2- [(4-cyanophényl)amino] -4-pyrimidinyl]oxy]-3,5-diméthylbenzonitrile de formule 1, qui est représenté par la formule structurelle 1 suivante : Formule 1
PCT/IN2015/000385 2014-10-13 2015-10-13 Procédé amélioré pour la préparation de 4-[6-amino-5-bromo-2-[(4-cyanophényl)aminol]-4-pyrimidinyl]oxy]-3,5-diméthylbenzonitrile WO2016059646A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108218795A (zh) * 2016-12-21 2018-06-29 上海医药工业研究院 一种2,4-二氨基嘧啶类衍生物、其制备方法、中间体及应用
CN113480483A (zh) * 2021-08-17 2021-10-08 浙江致新医药科技有限公司 一种依曲韦林氯代杂质的制备方法

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CA2803848A1 (fr) * 2010-06-28 2012-01-05 Hetero Research Foundation Procede de preparation d'intermediaire de l'etravirine et de polymorphes de l'etravirine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108218795A (zh) * 2016-12-21 2018-06-29 上海医药工业研究院 一种2,4-二氨基嘧啶类衍生物、其制备方法、中间体及应用
CN113480483A (zh) * 2021-08-17 2021-10-08 浙江致新医药科技有限公司 一种依曲韦林氯代杂质的制备方法

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