WO2012021446A2 - Procédé pour préparer l'aliskirène et ses intermédiaires - Google Patents

Procédé pour préparer l'aliskirène et ses intermédiaires Download PDF

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WO2012021446A2
WO2012021446A2 PCT/US2011/046929 US2011046929W WO2012021446A2 WO 2012021446 A2 WO2012021446 A2 WO 2012021446A2 US 2011046929 W US2011046929 W US 2011046929W WO 2012021446 A2 WO2012021446 A2 WO 2012021446A2
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formula
reaction
compound
give
dimethyl
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PCT/US2011/046929
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WO2012021446A3 (fr
Inventor
Naveen Kumar Kolla
Kaliyaperumal Srinivasan Appaye
Srinivas Gangula
Rajeshwar Reddy Govindapur
Nagaraju Manne
Satish Pandurang Nikumbh
Uday Kumar Neelam
Suju Chuttippari Joseph
Sudhakar Reddy Baddam
Shyam Kumar Unniaranpurakkal Kunhimon
Mohan Moovendan
Vilas Dahanukar
Kiran Kumar Doniparthi
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Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
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Publication of WO2012021446A2 publication Critical patent/WO2012021446A2/fr
Publication of WO2012021446A3 publication Critical patent/WO2012021446A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/32—Decarboxylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Definitions

  • the present application relates to a process for the preparation of aliskiren and its pharmaceutically acceptable salts.
  • the present application relates to a process for the preparation of intermediates for aliskiren, and their conversion to aliskiren or its salts.
  • Aliskiren hemifumarate is described chemically as 5(S)-amino-4(S)- hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)phenyl] octanoic acid A/-(2-carbamoyl-2,2-dimethylethyl) amide hemifumarate and is represented structurally by Formula I.
  • Aliskiren is first in a class of drugs called direct rennin inhibitors and is useful in the treatment of primary hypertension. Aliskiren is commercially available in the USA, in the form of its hemifumarate salt, as the active ingredient in TEKTURNATM products.
  • U.S. Patent No. 5,559,1 1 1 discloses aliskiren, its pharmaceutically acceptable salts. The patent also gives processes for its preparation. Various processes for the preparation of aliskiren, its salts, and its intermediates have been described in subsequent patents and applications. Most of the references relate to convergent synthetic routes for the preparation of aliskiren wherein two intermediates, which are referred to as synthons are prepared separately and coupled together to give aliskiren in the course of entire synthesis.
  • the present application relates to processes for the preparation of known synthons 3-amino-2,2,-dimethylpropanamide of Formula HA, and (2S,4E)-5- chloro-2-isopropyl-N,N-dimethylpent-4-enamide of Formula MB which are used in a convergent synthetic process for the preparation of aliskiren and its salts.
  • US 7,550,626 B2 provides a process for the preparation of the racemic compound of Formula VB involving the reaction of dialkyl malonate of Formula 1MB with 1 ,3 dihalopropene, wherein the reaction is conducted in the presence of a metal alkoxide in an organic solvent to form the compound of Formula IVB. This is followed by addition of an inorganic salt and an alcohol to form the racemic compound of Formula VB.
  • US 2007/0191630 A1 covers an in-situ process for preparation of the compound of Formula VB by reacting dimethyl-2-isopropyl malonate of Formula 1MB with a base in the presence of an aprotic solvent and then with a 1 , 3 dihalopropene followed by replacement of one of the ester groups with a hydrogen atom in the same reaction vessel.
  • the present applicants have developed an improved process for the preparation of the synthon of Formula IIB resulting in better chiral purity and better yields of the product at various stages of the process and therefore overall improvement in the yield of the intermediate of Formula IIB. Also the present applicants have developed an improved process for the recovery of the racemic compound of Formula VB from the unwanted isomer generated during selective enzymatic hydrolysis reaction of the racemic compound of Formula VB. The present applicants have also developed a novel process for the preparation of the intermediate of Formula VB which involves lesser number of steps and is easily scalable.
  • the synthons of Formula IIA and MB can be converted to aliskiren or its salts via a common intermediate of Formula IVC:
  • X is CI, Br, I, NH 2 , or NH-P, and P is an amine-protecting group.
  • the present application provides alternate processes for the preparation of aliskiren and its salts, which are cost effective, safe, can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield based on the starting materials employed.
  • the present application provides a process for the preparation of the synthon 3-amino-2,2-dimethylpropanamide of Formula IIA comprising:
  • Formula IMA Formula IVA wherein R 1 is Ci -6 alkyl, C 3 -C 8 cycloalkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 6 -
  • Another aspect of the present application provides a process for the preparation of (2S,4£)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide of Formula MB comprising the steps of:
  • Formula 1MB Formula IVB conversion of the compound of Formula IVB to the racemic pound (£)-methyl 5-chloro-2-isopropylpent-4-enoate of Formula VB;
  • the present application also provides processes for the preparation of aliskiren or its salts of Formula I using the synthons of Formula IIA or MB.
  • the present application provides a process for the preparation of the synthon 3-amino-2,2-dimethylpropanamide of Formula IIA comprising:
  • Formula IIIA Formula IVA wherein R 1 is Ci -6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 - Ci 4 aryl, (C 6 -Ci aryl)alkyl-, or Ci-Cgheteroaryl-;
  • Suitable alkylating agents which can be used in step a) include, but are limited to dimethyl sulfate, dimethyl carbonate, methyl iodide, or the like.
  • Suitable bases which can be used in step a) include but are not limited to inorganic bases such as an alkali metal hydroxide or an alkali metal alkoxide.
  • the alkali metal hydroxides include lithium hydroxide, sodium hydroxide or potassium hydroxide and the alkali metal alkoxides include sodium methoxide, sodium ethoxide or potassium tertiary-butoxide.
  • Suitable phase transfer catalysts which can be used in step a) include, but are not limited to, a tetraalkylammonium halide or a tetraalkylphosphonium halide such as tetrabutylammonium bromide, tetrabutylammonium fluoride, or tetrabutylammonium hydrogen sulfate; crown ethers like 15-crown-5 or 18-crown-6; or the like.
  • a tetraalkylammonium halide or a tetraalkylphosphonium halide such as tetrabutylammonium bromide, tetrabutylammonium fluoride, or tetrabutylammonium hydrogen sulfate
  • crown ethers like 15-crown-5 or 18-crown-6; or the like.
  • Suitable solvents which can be used for the reaction steps a), b) and c) include, but are limited to alcohol solvents such as methanol, ethanol, 2-propanol, 1 -butanol, or 2-butanol; nitriles solvents such as acetonitrile or propionitrile; halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane or the like; ketone solvents; aliphatic hydrocarbon solvents; aromatic hydrocarbon solvents like toluene or xylene; dimethyl sulfone; dimethyl sulfoxide; or mixtures thereof.
  • alcohol solvents such as methanol, ethanol, 2-propanol, 1 -butanol, or 2-butanol
  • nitriles solvents such as acetonitrile or propionitrile
  • halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachlor
  • the dialkylation is carried out by mixing a first solution of ethyl-2-cyano acetate in a suitable solvent to a freshly prepared solution of a suitable base and phase transfer catalyst in a suitable solvent.
  • Mode of addition of solutions can be reversed for better yield and purity of ⁇ , ⁇ -dimethyl ester of Formula IVA. It is advantageous to maintain the temperature of the solution at about 5 °C to about 15 °C during the addition of first solution to the second solution and addition can be rapid or slow. It is advantageous to mix solution in from about 1 hour to about 4 hours while maintaining the internal temperature at from about 5 °C to about 15 °C.
  • ⁇ , ⁇ -dimethyl ester of Formula IVA obtained is purified by any known techniques.
  • the ester is purified by vacuum distillation at about 100 °C to about 160 °C.
  • Purified intermediate of Formula IVA is amidated either by passing ammonia gas into the solution of ⁇ , ⁇ -dimethyl ester or by treating it with an ammonical solution.
  • An ammonical solution is prepared by dissolving ammonia in a suitable solvent.
  • the solution is prepared in Ci-6 aliphatic alcohols like methanol, ethanol, or the like. The amidation process is completed in about 7 to about 20 hours by stirring the solution at about ambient temperature to about 40 °C.
  • solvent can be removed by suitable techniques and obtained residue may optionally be purified by suitable techniques.
  • a Ci -6 aliphatic hydrocarbon solvent such as hexane; a C 6 -ioaromatic hydrocarbon solvent; or a C 3-6 ester solvent such as ethyl acetate or butyl acetate for a period of few hours at about 0 °C to about 30 °C.
  • the reduction conditions employed for reducing compound of Formula VA may be selected from the known reduction methods and in one aspect can be performed by using known reducing agent selected from, but not limited to metal hydrides such as lithium aluminium hydride, or the like, metal catalysts, for example Raney® nickel or platinum or palladium catalysts supported on active carbon.
  • metal hydrides such as lithium aluminium hydride, or the like
  • metal catalysts for example Raney® nickel or platinum or palladium catalysts supported on active carbon.
  • the reduction of compound of Formula VA is conducted in presence of hydrogen gas at temperature of about 40°C to about 80°C for a period of about 5 to about 20 hours in an appropriate solvent and in the presence or absence of suitable base such as ammonia or its solution with any suitable solvent such as Ci- 6 aliphatic alcohols or the like.
  • hydrogen is applied at a pressure of about 5 kg/cm 2 to about 12 kg/cm 2 during reduction.
  • the compound of Formula 11 A can be purified by any well known techniques of prior art before its isolation.
  • it can be purified by dissolving the crude material in C-3 -6 esters such as ethyl acetate or butyl acetate followed by addition of an anti solvent such as an ether solvent like tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, diethyl ether, diisopropyl ether, t-butyl methyl ether or the like.
  • C-3 -6 esters such as ethyl acetate or butyl acetate
  • an anti solvent such as an ether solvent like tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, diethyl ether, diisopropyl ether, t-butyl methyl ether or the like.
  • Isolation and purification of the synthon of Formula IIA and the intermediates described above can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent- extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.
  • the synthon of Formula IIA is obtained in substantially high yields by using the process of the present application and has a purity of more than about 95% by GC, or more than about 98% by GC.
  • Another aspect of the present application provides a process for the preparation of (2S,4£)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide of Formula I IB comprising the steps of:
  • Formula 1MB Formula IVB conversion of the compound of Formula IVB to the racemic pound (£)-methyl 5-chloro-2-isopropylpent-4-enoate of Formula VB;
  • Suitable aprotic polar solvents which can be used in step a) include, but are not limited to dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N- dimethylacetamide, tetrahydrofuran (THF), acetone, acetonitrile, ethyl acetate, hydrocarbons like toluene, xylene, hexane, heptanes, pentane, cyclopentane cyclohexane, methylcyclohexane, ethereal solvents like 1 , 4-dioxane, MTBE or the like or mixtures thereof.
  • DMSO dimethylsulfoxide
  • DMF N-dimethylformamide
  • THF tetrahydrofuran
  • acetone acetonitrile
  • ethyl acetate hydrocarbons like toluene
  • xylene hexane
  • Suitable bases which can be used in steps a) include, but are not limited to alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, or the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; carbonates of alkali metals such as lithium carbonate, sodium carbonate, potassium carbonate, or the like; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; ammonia; or mixtures thereof.
  • the hydroxides, carbonates, and bicarbonates can be used in the form of solids or in the form of their aqueous solutions.
  • aqueous solutions containing about 5% to 50%, or about 10% to 20%, (w/v) of the corresponding base can be used.
  • Suitable catalysts which can be used in step a) include, but are not limited to, phase transfer catalysts like tetraalkylammonium or phosphonium halides such as tetrabutylammonium bromide, tetrabutylammonium fluoride, tetraalkylammonium acetates, tetraalkylphosphonium acetates, tetrabutylammonium hydrogen sulfate, alkali metal acetate like sodium acetate or 1 ⁇ their hydrates like sodium acetate trihydrate, crown ethers like 15-crown-5 or 18- crown-6, or the like.
  • phase transfer catalysts like tetraalkylammonium or phosphonium halides such as tetrabutylammonium bromide, tetrabutylammonium fluoride, tetraalkylammonium acetates, tetraalkylphosphonium acetates
  • Step b) can be carried out either by dealkoxycarbonylating one of the ester in the presence of a solvent and optionally a catalyst to replace one of the ester groups with a hydrogen, or by hydrolysis in the presence of a base of both the ester linkages and monodecarboxylation of the resulting dicarboxylic acid.
  • Suitable bases and catalysts which can be used in steps b) are similar to those given for step a).
  • the presence of catalyst in the reaction helps in reducing the reaction completion time and the temperature at which the reaction is conducted, thus providing some process-engineering advantages.
  • Suitable solvents which can be used for the reactions of steps b) and c) include, but are not limited to, aprotic polar solvents such as dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide, acetone, acetonitrile, ethyl acetate, or the like; hydrocarbon solvents such as toluene, xylene, ortho-xylene, heptanes, hexanes, cyclohexane, methylcyclohexane, or the like; alcoholic solvents like methanol, ethanol, ethylene glycol, isopropyl alcohol, 2-methoxyethanol, or the like; ester solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, or the like; ethereal solvents like 1 ,4- dioxane
  • Enzymatic resolution in step c) involves combining a suitable enzyme with the ester of Formula VB, wherein the suitable enzyme is capable of selectively hydrolyzing the ester.
  • suitable enzymes include hydrolase,
  • the enzyme is an esterase, lipase, or a protease.
  • the enzymatic hydrolysis reaction is carried out in a buffer or aqueous basic medium with pH range from about 7 to about 14 or in an aqueous acetic medium with pH range of from about 1 to about 7.
  • Dimethylamine can be used as its solution in an organic solvent or in the form of its salts such as hydrochloride for the reaction in step d).
  • the Grignard reagents of Formula R 3 -Mg-X used in step d) are known products, sold in solution in ethers such as THF, 2-methyl THF, or dialkyl ethers, or in hydrocarbons like hexanes and heptanes at concentrations of between 0.25 and 4M, or can be prepared in-situ in the reaction medium by adaptation of methods known from the literature.
  • R 3 is a C C 6 alkyl group and X is halogen.
  • the Grignard reaction is suitably carried out in the presence of ether solvents such as THF, 2-methyl THF, 1 ,4-dioxane, or dialkyl ethers; halogenated hydrocarbon solvents such as CH 2 CI 2 ; hydrocarbon solvents such as toluene, xylene, ortho-xylene, heptane, hexane, cyclohexane, methylcyclohexane.
  • ether solvents such as THF, 2-methyl THF, 1 ,4-dioxane, or dialkyl ethers
  • halogenated hydrocarbon solvents such as CH 2 CI 2
  • hydrocarbon solvents such as toluene, xylene, ortho-xylene, heptane, hexane, cyclohexane, methylcyclohexane.
  • the molar ratio of the Grignard reagent may range between 1 to 4 molar equivalents per mole of the
  • the amount of side products arising from the reaction is significantly lower.
  • the reaction can be conducted at a temperature of lower than about 25 °C or lower than about 100 °C, and the compound of Formula IIB can be obtained in almost quantitative yield.
  • the Grignard reaction involves a direct amidation of the corresponding ester using isopropyl magnesium chloride and dimethylamine or its salt thereby avoiding racemization which occurs during the processes described in the prior art which involve hydrolysis of ester group of the compound of Formula VIB followed by formation of acid chloride before reaction with the dimethylamine.
  • the isolation of products at each stage may involve classical methods like extraction of the product into an organic layer followed by vacuum evaporation of the organic layer to isolate the product, filtration of the product from the reaction mass, or evaporation of the reaction mass directly after quenching the reaction mass appropriately.
  • the compound of Formula IIB can be further purified by employing conventional methods such as extraction, recrystallization, column chromatography, or by washing with an organic solvent or with an aqueous solution.
  • the present application provides a process comprising reaction of the compound of Formula VIB with dimethylamine in the presence of Grignard reagent to give the compound of Formula IIB:
  • Formula VIB Formula MB wherein R 3 is a d-C 6 alkyl group and X is halogen.
  • the present application provides a process for the recovery of racemic (£)-methyl 5-chloro-2-isopropylpent-4-enoate of Formula V from the corresponding acid of the unwanted isomer ⁇ R, £)-5-chloro-2- isopropylpent-4-enoic acid of Formula VIIB without isolating the acid of Formula VIIB from the reaction mixture.
  • the recovery is suitably carried out without isolation of unwanted isomer of the acid of Formula VIIB.
  • the acid is esterified in-situ and racemized.
  • the acid of the unwanted isomer can be esterified using esterification agents such as diazoalkanes, dialkyl sulfates like dimethyl sulfate or acetals, or especially activated acetals such as ⁇ , ⁇ -dimethylformamide dialkyl acetals, dialkylcarbonates which may be used alone or together with appropriate alkali metal alcoholates.
  • the esterification reaction is suitably carried out at temperatures from about 20 °C to about 150 °C.
  • the reaction is suitable carried out in chlorinated solvents like dichloromethane, CHCI 3 or hydrocarbons like toluene, xylene, hexane, or cyclohexane, or their mixtures optionally in the presence of a phase transfer catalyst.
  • chlorinated solvents like dichloromethane, CHCI 3 or hydrocarbons like toluene, xylene, hexane, or cyclohexane, or their mixtures optionally in the presence of a phase transfer catalyst.
  • the racemization may be performed in the same reaction vessel following esterification. Racemization may be carried out suitably by heating to high temperatures or by adding strong bases. Suitable bases which can be used for the racemization process include, but are not limited to, metal alkoxides such as - - sodium methoxide, sodium ethoxide, sodium tert-pentoxide, sodium tert-butoxide, sodium trimethylsilanolate, potassium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-pentoxide, potassium trimethylsilanolate, lithium ethoxide, lithium isopropoxide, lithium methoxide, lithium tert-butoxide, lithium trimethylsilanolate, or the like, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, or the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; carbonates of al
  • Suitable aprotic polar solvents which can be used in step a) include, but are not limited to dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide, tetrahydrofuran (THF), acetone, acetonitrile, ethyl acetate, Protic solvent like methanol, ethanol or the like, or their mixtures.
  • the racemic carboxylic ester may be isolated by extraction into organic solvents.
  • the carboxylic esters are obtained in yields of 97% or more, the carboxylic acid being quantitatively converted to the corresponding racemic carboxylic ester.
  • the present application provides a novel process for the preparation of racemic (£)-methyl 5-chloro-2-isopropylpent-4-enoate of Formula VB comprising the steps of:
  • Suitable solvents which can be used for the alkylation reaction include, but are not limited to, aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N- dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide, tetrahydrofuran (THF), acetone, acetonitrile, ethyl acetate, or the like; hydrocarbon solvents such as toluene, xylene, ortho-xylene, heptanes, hexanes, cyclohexane, methylcyclohexane, or the like; alcoholic solvents like methanol, ethanol, isopropyl alcohol, 2-methoxy ethanol, ethylene glycol, or the like; ester solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, or the like; or mixtures thereof in various proportions.
  • Suitable bases which can be used include, but are not limited to, metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-pentoxide, sodium tertiary butoxide, sodium trimethylsilanolate, potassium tertiary butoxide, potassium methoxide, potassium ethoxide, potassium tert-pentoxide, potassium trimethylsilanolate, lithium ethoxide, lithium isopropoxide, lithium methoxide, lithium tertiary butoxide, lithium trimethylsilanolate, or the like, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, or the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; carbonates of alkali metals such as lithium carbonate, sodium carbonate, potassium carbonate, or the like; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate, potassium
  • the intermediate of Formula MB and Formula VB prepared according to the processes of the present application are substantially pure.
  • substantially pure it is meant that the intermediates have a purity of more than about 95%, or more than about 98%, or more than about 99%, or more than about 99.5%, and contain less than about 1 %, or less than about 0.5%, or less than about 0.1 % by weight of individual process related impurities, as characterized by GC.
  • the compounds of Formula VB and Formula MB obtained above can be converted to aliskiren or its pharmaceutically acceptable salts by processes described in the art.
  • the present application relates to a process for the preparation of aliskiren or its salts starting from the synthons of Formula 11 A or IIB.
  • the synthon of Formula 11 A can be converted to aliskiren using processes known in the art which further comprising reaction of the synthon of Formula IIB:
  • X is CI, Br, I, NH 2 , or NH-P, and P is an amine-protecting group.
  • the compound of Formula INC can be converted to a compound of Formula IVC by processes known in the art such as disclosed in U.S. Patent No. 5,559,1 1 1 , U.S. Patent No. 6,730,798, and U.S. Patent No. 7,009,078.
  • the compound of Formula IVC upon condensation with the intermediate of Formula IIA followed by subsequent conversion of X to amino group provides aliskiren.
  • X in the compound of Formula IVC is an amine- protecting group, which can be prepared by a process involving:
  • the reduction of azide group of Formula IVC(i) is carried out with a suitable reducing agent in a suitable solvent and under suitable reaction conditions.
  • suitable reducing agents include, but are not limited to the catalysts palladium, platinum, nickel, ruthenium, rhodium, or derivatives thereof, including in supported form or in oxide form, and a source of hydrogen.
  • the reduction is carried out with hydrogen gas in the presence of metal catalysts, for example Raney® nickel, platinum, or palladium catalysts supported on active carbon.
  • Suitable solvents which can be used for the reduction reaction include, but are not limited to, Ci-ealiphatic alcohols selected form methanol, ethanol, 2- propanol, 1 -propanol, or mixtures thereof. Additionally one can also add a solvent selected from ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran or dioxane; aromatic hydrocarbons such as toluene or xylene; aliphatic halogenated hydrocarbons such as methylene chloride, chloroform or 1 ,2-ethane dichloride; aliphatic hydrocarbons such as pentane, hexane or heptane; esters such as ethyl acetate or butyl acetate; or nitriles such as acetonitrile; miscellaneous solvents such as N,N- dimethylformamide
  • Suitable amine base include, but are not limited to ammonia, methylamine, ethanolamine, dimethylamine, methylethanolamine, trimethylamine, diisopropylamine or the like.
  • hydrogen is applied at a pressure of about 4 kg/cm 2 to about 16 kg/cm 2 for a period of few minutes to few hours and the temperature maintained during the hydrogenation is about 20 °C to about 50 °C.
  • the amine intermediate of Formula IVC (ii) can be purified by any well known techniques of prior art before its isolation. In one aspect it can be purified by acid-base treatment, that is by treating it with an acid addition salt such as hydrochloric acid salt followed by neutralization with a suitable base to give purified compound of formula IVC (iii).
  • acid-base treatment that is by treating it with an acid addition salt such as hydrochloric acid salt followed by neutralization with a suitable base to give purified compound of formula IVC (iii).
  • Another aspect of the present application is protection of amine group in the compound of Formula IVC (ii) with a suitable amine protecting reagent by treating the compound of Formula IVC (ii) with a suitable protecting reagent in presence of tertiary amine base in a suitable solvent.
  • Suitable amine protecting reagents include, but are not limited to carbobenzyloxy (Cbz) group, p- methoxybenzyl carbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, 9-fluorenylmethyloxycarbonyl (FMOC) group, acetyl (Ac)- group, benzoyl (Bz) group, benzyl (Bn) group, p-methoxybenzyl (PMB) group, 3,4- dimethoxybenzyl (DMPM) group, p-methoxyphenyl (PMP) group, tosyl (Ts) group, other sulfonamides (Nosyl & Nps) groups, or the like.
  • a suitable amine protecting reagent is tert-butyloxycarbonyl (BOC).
  • Suitable solvents for the protection reaction include, but are not limited to, halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, methylene chloride, or the like.
  • the protection of amine group is carried out by reacting the compound of Formula IVC (ii) with a suitable protecting reagent for a period of few minutes to few hours at 20 °C to 150 °C.
  • the protected compound of Formula IVC(ii) obtained can be isolated by techniques known in the art and can be further purified by recrystallization or slurrying in a suitable solvent.
  • the compound of Formula IVC can be converted to aliskiren by a process further comprising:
  • P is an amine-protecting group
  • the reaction can be carried out in presence of a base such as triethylamine, diisopropylethyl amine, 2-hydroxypyridine, N,N- dimethylaminopyridine, or the like, or the reaction can be carried out in the presence of metal triplets or a Lewis acid.
  • a base such as triethylamine, diisopropylethyl amine, 2-hydroxypyridine, N,N- dimethylaminopyridine, or the like, or the reaction can be carried out in the presence of metal triplets or a Lewis acid.
  • Suitable solvents which can be used for the reaction include but are not limited to aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide, acetonitrile or the like; hydrocarbons such as toluene or the like; or mixtures thereof; or their combination with water in various proportions without limitation.
  • aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide, acetonitrile or the like
  • hydrocarbons such as toluene or the like
  • the solvent is recovered under vacuum.
  • the open chain compound of Formula VC is treated with a strong acid such as hydrochloric acid, trifluoroacetic acid, ortho phosphoric acid or the like in a suitable solvent to remove the amine amine-protecting group.
  • a strong acid such as hydrochloric acid, trifluoroacetic acid, ortho phosphoric acid or the like
  • the product can be isolated as an acid addition salt of the same acid which is used for the deprotection and further neutralized with a suitable base to give aliskiren.
  • Aliskiren in neutral form can be purified by any known technique of the prior art before converting it to a pharmaceutically acceptable salt.
  • Suitable solvent which can be used for the deprotection reaction include, but are not limited to C 1-6 aliphatic alcohols selected form methanol, ethanol, 2- propanol, or 1 -propanol; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran or dioxane; or aromatic hydrocarbons such as toluene or xylene.
  • C 1-6 aliphatic alcohols selected form methanol, ethanol, 2- propanol, or 1 -propanol
  • ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran or dioxane
  • aromatic hydrocarbons such as toluene or xylene.
  • Aliskiren is treated with a suitable pharmaceutically acceptable acid. In one embodiment, it is treated with fumaric acid, in a suitable solvent or mixtures thereof to give pharmaceutically acceptable salt of aliskiren. In one embodiment, aliskiren base is dissolved along with a suitable pharmaceutically acceptable acid in a suitable solvent and stirred at ambient temperature.
  • the solvent employed is selected from the Ci- 6 aliphatic alcohols methanol, ethanol, 2-propanol, or 1 - propanol; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, 1 ,2- dimethoxy ethane, tetrahydrofuran or dioxane; aromatic hydrocarbons such as toluene or xylene; aliphatic halogenated hydrocarbons such as methylene chloride, chloroform or 1 ,2-ethane dichloride, aliphatic hydrocarbons such as pentane, hexane or heptane; esters such as ethyl acetate or butyl acetate; or nitriles such as acetonitrile; or mixtures thereof.
  • the quantity of solvent/s taken is about one to about twenty times with respect to the starting material. In one embodiment, quantity of solvent taken is about five to fifteen times.
  • Aliskiren or its salts obtained above can be further purified by recrystallization or slurrying in a suitable solvent.
  • suitable organic solvents which can be used for recrystallization or slurry formation include but are not limited to: esters such as ethyl acetate, n-butyl acetate, tertiary-butyl acetate, isopropyl acetate or the like; ketone solvents such as acetone, ethyl methyl ketone, or the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane or the like; nitrile solvents such as acetonitrile, propionitrile or the like; or mixtures thereof in various proportions.
  • Aliskiren or its salts obtained using the process of the present application have a purity of more than about 99.5% or more than about 99.9 % by HPLC.
  • the present applicants have developed an improved process for the preparation of the synthon of Formula 11 A involving the use of a safer base during alkylation thus providing a process which is safe to use and is cost effective.
  • Still another aspect of the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising aliskiren or its salts prepared according to the process of the present application along with one or more pharmaceutically acceptable carriers, excipient, or diluents.
  • compositions comprising aliskiren or its salts and its combination with a pharmaceutically acceptable carrier of this application may further formulated as solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions.
  • solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules
  • liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions
  • injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions.
  • Formulations may be in the form of immediate release, delayed release or modified release.
  • immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems.
  • the compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization.
  • Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.
  • Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
  • compositions that find use in the present application include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch or the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants
  • compositions of present application include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants or the like.
  • aliskiren or its salts is a useful active ingredient in the range of 100 mg to 200 mg, per dosage unit.
  • Celite ® is flux-calcined diatomaceous earth.
  • Celite ® is a registered trademark of World Minerals Inc.
  • Raney® nickel is a sponge-metal catalyst produced when a block of nickel-aluminum alloy is treated with concentrated sodium hydroxide. Raney® is a registered trademark of W. R. Grace and Company.
  • the acronyms DMSO, MTBE, GC, and TBAB stand for dimethylsulfoxide, methyl tertiary-butyl ether, gas chromatography, and tetrabutyl ammonium bromide respectively.
  • the abbreviation % e. e. means the enantiomeric excess of a substance, which is defined as the absolute difference between the mole fraction of each enantiomer.
  • amine base is any of a class of nitrogen-containing compounds derived, either in principle or in practice, from ammonia.
  • Amine bases include, but are not limited to ammonia, methylamine, ethanolamine, dimethylamine, methylethanolamine, trimethylamine, diisopropylamine, or the like.
  • Amine-protecting group refers to a radical when attached to a nitrogen atom in a target molecule is capable of surviving subsequent chemical reactions applied to the target molecule i.e. hydrogenation, reaction with acylating agents, alkylation etc.
  • the amine-protecting group can later be removed.
  • Amine protecting groups include, but are not limited to, fluorenylmethoxycarbonyl
  • FMOC FMOC
  • tert-butoxycarbonyl t-BOC
  • benzyloxycarbonyl Cbz or Z
  • p- methoxybenzyl carbonyl Moz or MeOZ
  • those of the acyl type ⁇ e.g., formyl, acetyl (Ac), benzoyl (Bz), trifluoroacetyl, p-tosyl (Ts), sulfonamide (Nosyl & Nps) groups, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o- nitrophenylsulfenyl, o-nitrophenoxyacetyl), those of the ether type (e.
  • Amino-protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule.
  • an amine-protecting agent examples include, but are not limited to, Ci-C 6 aliphatic acid chlorides or anhydrides, C 6 - Ci 4 arylcarboxylic acid chlorides or anhydrides, t-butyl chloroformate, di-tert-butyl dicarbonate, butoxycarbonyloxyimino-2-phenylacetonitrile, t-butoxycarbonyl azide, t-butyl fluoroformate, fluorenylmethoxy carbonyl chloride,
  • a suitable amine protecting reagent is tert-butyloxycarbonyl (BOC).
  • Alcohol solvent is an organic solvent containing a carbon bound to a hydroxyl group.
  • Alcohol solvents include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, Ci -6 alcohols, or the like.
  • Alkyl refers to a hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C Ci 2 alkyl group may have from 1 to 12 (inclusive) carbon atoms in it.
  • C-i-Cealkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • Alkenyl refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond, and may exist in the E or Z conformation.
  • Examples of a C 2 -C 6 alkenyl group include, but are not limited to, ethylenyl (vinyl), propylenyl, 1 -butylenyl, 2-butylenyl, isobutylenyl, sec-butylenyl, 1 -pentenyl, 2- pentenyl, isopentenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, and isohexenyl.
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond.
  • Examples of a C 2 -C 6 alkynyl group include, but are not limited to, acetylenyl, propynyl, 1 -butynyl, 2-butynyl, isobutynyl, sec- butynyl, 1 -pentynyl, 2-pentynyl, isopentynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, and isohexyne.
  • a "aprotic polar solvent” has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMA), N- methylpyrrolidone (NMP), formamidyl acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro- based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy s
  • Aryl refers to an aromatic hydrocarbon group.
  • Examples of a C 6 -Ci 4 aryl group include, but are not limited to, phenyl, -naphthyl, ⁇ -naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenanaphthyl.
  • (Aryl)alkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with an aryl group as defined above.
  • (C 6 -C-i 4 Aryl)alkyl- moieties include benzyl, benzhydryl, 1 - 2 ⁇ _ phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1 -naphthylmethyl, 2- naphthylmethyl, and the like.
  • Cycloalkyl refers to a non-aromatic, saturated, monocyclic, bicyclic, or polycyclic hydrocarbon ring system.
  • Representative examples of a C 3 - Cscycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl.
  • halogenated hydrocarbon solvent is an organic solvent containing a carbon bound to a halogen.
  • Halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 -trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
  • “Ester solvents” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C 3-6 esters, or the like.
  • ether solvent is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms.
  • “Ether solvents” include but are not limited to diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2- ethoxyethanol, anisole, C 2 - 6 ethers, or the like.
  • Halogen refers to -F, -CI, -Br and -I.
  • Heteroaryl refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one ring atom selected from the heteroatoms oxygen, sulfur, and nitrogen.
  • C-i-Cgheteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1 ,3,4-oxadiazole, 1 ,2,4-triazole, 1 -methyl-1 ,2,4- triazole, 1 H-tetrazole, 1 -methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazo
  • Bicyclic C-i-Cghetroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring having one or two nitrogen atoms in g the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom.
  • monocyclic C C 4 heteroaryl groups include 2H-tetrazole, 3H-1 ,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, and pyrrole.
  • hydrocarbon solvent is a liquid hydrocarbon, which may be linear, branched, or cyclic and may be saturated, unsaturated, or aromatic. It is capable of dissolving a solute to form a uniformly dispersed solution.
  • hydrocarbon solvent include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3- dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooc
  • a “methoxide source” is any reagent or combination of reagents capable of transferring a methoxide anion (CH 3 0 " ) to an acceptor.
  • a “methoxide source” include, but are not limited to, sodium methoxide (also known as sodium methylate), lithium methoxide, potassium methoxide, calcium methoxide, magnesium methoxide, tetrabutylammonium methoxide solution, titanium(IV) methoxide, zinc methoxide, or the like.
  • methanol can be reacted with a base to produce methoxide. The reaction between the base and methanol can be run at ambient temperature for about 15 minutes to about 30 minutes.
  • the reaction mixture which includes methoxide, unreacted methanol, and the base, is reacted with the substrate.
  • phase transfer catalyst is a compound, which will enhance the rate of a reaction between chemical species located in different phases such as immiscible liquids, liquid/solid, or liquid/gas reactions.
  • the phase transfer catalyst extracts one of the reactants, most commonly an anion, across the interface into the other phase so that reaction can proceed.
  • These catalysts are salts of onium ions (e.g. tetraalkyl ammonium salts) or agents that complex inorganic cations (e.g. crown ethers).
  • the catalyst cation is not consumed in the reaction although an anion exchange does occur.
  • Such catalysts can be utilized in either stoichiometric or 0 catalytic, e.g. less than stoichiometric quantities. Examples of such catalysts include, but are not limited to, benzyltrimethylammonium chloride, benzyltributyl ammonium bromide, benzyltrioctyl ammonium bromide,
  • benzyltriphenylphosphonium bromide benzyltriethylammonium chloride, benzyltriethylammonium bromide, hexadecyltributylphosphonium bromide, hexadecyltrimethylammonium bromide, methyltrioctylammonium chloride, methyltrioctyl ammonium bromide, tetrabutyl ammonium bromide,
  • ammonium chloride tetraethylammonium iodide, tetraethylammonium hydrogen sulfate, tetrapropyl ammonium bromide, tetrapropylammonium chloride,
  • dodecyltrimethylammonium bromide tricetylmethyl ammonium chloride
  • crown ethers such as 18-crown-6 (1 ,4,7,10,13,16-hexaoxacyclooctadecane), and polyethylene glycols.
  • a “racemic compound” is one that has equal amounts of left- and right- handed enantiomers of a chiral molecule.
  • Resolution is a process for the separation of racemic compounds into their enantiomers. Resolution can be carried out either chemically or enzymatically.
  • Enzymes are chiral catalysts, producing either mostly one or only one of the possible stereoisomeric products.
  • Process engineering advantages refer to advantages in the handling aspects of chemical reactions wherein scale-up advantages are provided by either reducing the temperature of the reactions, use of non-toxic reagents, reduction in the duration of reaction etc.
  • substantially pure means comprising less than about 7%, less than about 5%, less than about 3%, less than about 2%, less than about 1 %, less than about 0.5%, less than about - _ 9 -
  • Step 1 Preparation of Ethyl 2-cyano-2-methylpropanoate (Formula IVA). To a mixture of sodium hydroxide (22.12 g, 0.55 mol) in dichloromethane (250 mL) was charged tetrabutyl ammonium bromide (7.12 g, 0.022 mol) at 25- 35°C and then cooled to -10 to -5°C. To the resulting heterogeneous reaction mass was added another solution containing ethyl 2-cyano acetate (Formula IMA) (25 gm, 0.223 mol) and dimethyl sulfate (64.1 g, 0.5 mol) at below 10°C over a period of 2-3 hours.
  • ethyl 2-cyano-2-methylpropanoate (Formula IVA).
  • reaction mass was heated to 35-40°C and stirred at same temperature for 2-3 hours. After reaction completion, reaction mass was cooled to 0-5°C and then quenched using water (125 mL) at below 10°C. The resulting aqueous and organic layers were separated, the aqueous layer was extracted twice with dichloromethane (2 x 50 mL). The organic layers were combined and washed twice with water (2 x 125 mL) at 25-35°C. The final organic layer was subjected to evaporation at 45°C under atmospheric pressure and finally under applied vacuum to remove the traces of dichloromethane left over in the crude compound.
  • the resulting crude material can be triturated in ethyl acetate (23.8 mL) at 0-5°C for 2-3 hours to obtain very pure material of compound of present interest.
  • the yield obtained is 14.56 g.
  • the present purification can be selectively opted to enhance the purity of present intermediate. Purity details by GC: 2-cyano-2-methylpropanamide: >99%; ethyl 2-cyano-2-methylpropanoate: not detected (starting material).
  • Step 2 Preparation of 2-Cyano-2-methylpropanamide (Formula VA).
  • ethyl 2- cyano-2-methylpropanoate (20 g) at 25-35°C and stirred for 12-14 hours at same temperature 25-35°C.
  • the reaction mass was evaporated at below 50°C under vacuum and the resulting crude material was triturated with ethyl acetate (23.8 mL) at 0-5°C for 2-3 hours.
  • the solid obtained was isolated by filtration, washed with ethyl acetate, and then dried by suction for 10-15 min. The wet solid obtained was dried to obtain 14.56 grams of desired compound.
  • Step 3 Preparation of 3-amino-2,2-dimethylpropanamide (Formula IIA).
  • a mixture of 2-cyano-2-methylpropanamide (40 g, 0.357 mol), Raney® nickel (8 g), a 10% solution of ammonia in methanol (63.75 mL, 0.375 mol) and methanol (320 mL) were placed in autoclave system at 25-35°C and stirred for 5- 10 min.
  • the resulting reaction mixture was heated to 60-65°C, hydrogen at 7-8 kg/cm 2 pressure applied, and then stirred at same temperature for 10 hours. A 7- 8 kg/cm 2 hydrogen pressure was ensured throughout the reaction time.
  • reaction mass was cooled to 25-35°C, filtered over a Hyflow bed to separate the catalyst and the recovered catalyst was washed with methanol (80 mL). Both the filtrates were combined, subjected to evaporation at below 50°C under vacuum, and chased once with ethyl acetate (80 mL) to obtain the crude material.
  • the resulting crude material was dissolved in ethyl acetate (40 mL) at 25-35°C, diisopropyl ether was added (80 mL) as an anti solvent and then stirred at same temperature for 2-3 hours.
  • Step 1 Preparation of (3S,5R)-5-((1S,3S)-1-amino-3-(4-methoxy-3-(3- methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one (Formula IVC (ii)).
  • a solution of the compound of Formula IVC (i) (1 .0 g) in ethanol (50 mL) and ethanolamine (0.13 mL) was hydrogenated under a hydrogen pressure of 10 kg/cm 2 at room temperature in the presence of Pd/C (10%) for 90 minutes. After completion of hydrogenation, the catalyst was removed by filtration and the filtrate was evaporated to obtain a residue.
  • Step 2 Preparation of tert-butyl (1 S,3S)-1-((2R,4S)-4-isopropyl-5- oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4- methyl pentylcarbamate (Formula IVC (iii).
  • dichloromethane 2.0 mL
  • triethylamine 0.1 mL
  • di-tert-butyl dicarbonate 0.1 1 mL
  • Step 3 Preparation of tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2- dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3- methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (Formula VC).
  • 3-amino-2,2- dimethylpropanamide (0.21 g).
  • the resulting solution was heated to 95-98 °C and further stirred for 18-19 hours while maintaining the same temperature. After completion of the reaction (monitored by TLC), the mixture was cooled to ambient temperature and quenched with 5% sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (2x25 ml), the combined organic layers were separated and washed with water (2x25 mL). The organic extract was evaporated to give title compound.
  • Step 4 Preparation of aliskiren (Formula I).
  • 12/V hydrochloric acid 0.1 mL
  • the resulting mixture was stirred for 3-4 hours at ambient temperature.
  • the solvent was evaporated and water (25.0 mL) was added.
  • the pH of the resulting solution was adjusted to 8-9 using aqueous sodium hydroxide solution.
  • the aqueous layer was extracted with ethyl acetate (2x25 mL) and the combined organic layers were washed with water (25 mL). The organic extract was evaporated to give the title compound.
  • Step 1 Preparation of (£)-dimethyl 2-(3-chloroallyl)-2- isopropylmalonate (Formula IVB).
  • Method I Sodium hydride (2.49 g) and THF (50 mL) were taken into a round bottom flask and a mixture of dimethyl isopropyl malonate (Formula IIIB)(10 g), trans- , 3-dichloropropene (8.28 g) in THF (10 mL) was added to it. The reaction mixture was heated to about 65° C and maintained for about 24 hours. The reaction mass was then cooled to about 25 °C and acetic acid (10 mL) and water (50 mL) was added to it.
  • Step 2 Preparation of (E)-methyl 5-chloro-2-isopropylpent-4-enoate (Formula V).
  • Method I (£)-Dimethyl 2-(3-chloroallyl)-2-isopropylmalonate of Formula IVB (2.5 g) and DMSO (10 ml_) were taken into a round bottom flask and tetraethyl ammonium acetate (9.2 g) was added to it. Temperature of the reaction mixture was raised to 10 to 130 °C and maintained for about 12 hours.
  • Method III Potassium hydroxide (39.5 g) and 2-methoxy ethanol (250 ml_) were taken into a round bottom flask and (£)-dimethyl 2-(3-chloroallyl)-2- isopropylmalonate of Formula IVB (50 g) was added to it. Temperature of the reaction mixture was raised to about 120 °C and maintained for about 3 hours. Reaction completion was checked using thin layer chromatography. After reaction completion, the reaction mixture was cooled to room temperature and diluted with water (250 mL), and then extracted into hexane (150 mL). The aqueous layer was cooled to about 10 to 20 °C and acidified with concentrated HCI to a pH of 2.0.
  • reaction mass was then extracted with hexane (150 mL) followed by extraction into dichloromethane (150 mL). The combined organic layer was washed with water and evaporated off to get a residue. The residue was taken into methanol (150 mL) and sulfuric acid (5.0 mL) was added to it. Temperature of the reaction mass was raised to about 65 °C and maintained for reaction completion. After the reaction was completed, the reaction mass was evaporated under reduced pressure and water (150 mL) was added cooled and extracted with MTBE or hexane (300 mL). The organic layer washed with bicarbonate solution. The organic layer was then evaporated under vacuum to give 25 g (65% yields) of the title compound. Purity by GC: 98.2%
  • Step 3 Preparation of (S, £)-methyl-5-chloro-2-isopropylpent-4-enoate (Formula VIB).
  • (E)-Methyl 5-chloro-2-isopropylpent-4-enoate of Formula V (25 g), 10 % sodium carbonate buffer solution (375 mL), and Esterase V enzyme (12.5 mL) were taken into a round bottom flask at 30 to 35 °C. The reaction mass was maintained to reduce the pH to about 10. The pH of the reaction mass was adjusted to about 10 using 1 M sodium hydroxide solution (50 mL). The reaction mixture was stirred for about 24 hours. After the reaction was completed, pH of the reaction mass was adjusted to about 3 with 6 N HCI solution.
  • Step 4 Recovery of (E)-methyl 5-chloro-2-isopropylpent-4-enoate of Formula VB from the filtered mother liquors obtained in step 3.
  • the aqueous layer obtained from step 3 ( 5 % aq. Sodium carbonate solution), containing the other isomer, dichloromethane (325 mL), tetrabutyl ammonium bromide (6.5 g) and dimethyl sulfate (32.41 g) were taken into a round bottom flask. Temperature of the reaction mass was raised to 35 to 45 °C and stirred for 1 -2 h and then filtered through a Celite ® bed.
  • Step 5 Preparation of (2S, 4£)-5-chloro-2-isopropyl-N, N- dimethylpent-4-enamide (Formula IIB).
  • (2S,4£)-Methyl 5-chloro-2- isopropylpent-4-enoate of Formula VI (10 g) THF (50 mL) was taken into a round bottom flask and cooled to 0 to 5°C.
  • a solution of dimethylamine (37.4 g) in THF (50 mL) was added at 30 to 35 °C under nitrogen atmosphere.
  • Isopropyl magnesium chloride (77.1 mL) was added at the same temperature and stirred for about 3 hours. The reaction mixture was then quenched with aq.
  • Step I Preparation of 5-(3-chloro-allyl)-5-isopropyl-2, 2-dimethyl-[1 , 3] dioxane-4, 6-dione (Formula IXB).
  • 5-lsopropyl-2, 2-dimethyl-[1 , 3] dioxane-4, 6- dione (4 g) (Formula VIIIB), potassium carbonate (2.9 g), triethylbenzylammonium chloride (4.9 g), and trans- ⁇ , 3-dichloropropene (4.7 g) acetonitrile (40 ml) were taken into a round bottom flask. The reaction mixture was heated to 50 to 55 °C and maintained for about 2 hours.
  • Step II Preparation of (E)-methyl 5-chloro-2-isopropylpent-4-enoate (Formula VB).
  • 5-(3-Chloro-allyl)-5-isopropyl-2, 2-dimethyl-[1 ,3]dioxane-4,6-dione (Formula IXB) 500 mg
  • sodium methoxide 155 mg
  • methanol 10 mL
  • the reaction mixture was cooled to 25 to 35 °C and extracted into hexane (25 mL).
  • the hexane layer was evaporated under reduced pressure to give 200 mg (Yield 55%) of racemic (£)- methyl 5-chloro-2-isopropylpent-4-enoate.

Abstract

La présente invention concerne un procédé pour la préparation d'aliskirène et ses sels pharmaceutiquement acceptables. En particulier, la présente demande concerne un procédé pour la préparation d'intermédiaires pour l'aliskirène, et leur conversion en aliskirène ou ses sels.
PCT/US2011/046929 2010-08-09 2011-08-08 Procédé pour préparer l'aliskirène et ses intermédiaires WO2012021446A2 (fr)

Applications Claiming Priority (8)

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IN2283/CHE/2010 2010-08-09
IN2283CH2010 2010-08-09
US41495110P 2010-11-18 2010-11-18
US61/414,951 2010-11-18
IN386CH2011 2011-02-10
IN386/CHE/2011 2011-02-10
US201161468676P 2011-03-29 2011-03-29
US61/468,676 2011-03-29

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WO2012021446A2 true WO2012021446A2 (fr) 2012-02-16
WO2012021446A3 WO2012021446A3 (fr) 2012-06-21

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CN110511141A (zh) * 2019-09-09 2019-11-29 上海凌凯医药科技有限公司 一种丙戊酰脲的合成方法

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EP2062874A1 (fr) * 2007-11-20 2009-05-27 KRKA, tovarna zdravil, d.d., Novo mesto Procédé et intermédiaires pour la préparation d'aliskiren

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EP2062874A1 (fr) * 2007-11-20 2009-05-27 KRKA, tovarna zdravil, d.d., Novo mesto Procédé et intermédiaires pour la préparation d'aliskiren

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DONG, HUA ET AL.: 'Practical Synthesis of an Orally Active Renin Inhibitor A liskiren.' TETRAHEDRON LETTERS vol. 46, 2005, pages 6337 - 6340 *
LINDSAY, KARL B. ET AL.: 'Formal Total Synthesis of the Potent Renin Inhibit or Aliskiren: Application of a SmI2-Promoted Acyl-like Radical Coupling.' J. ORG. CHEM. vol. 71, 2006, pages 4766 - 4777 *
TAMARU, YOSHINAO ET AL.: 'Et3B-promoted, Pd(O)-catalyzed Allylation of Active Methylene Compounds with Allylic Alcohols.' TETRAHEDRON LETTERS vol. 41, 2000, pages 5705 - 5709 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110511141A (zh) * 2019-09-09 2019-11-29 上海凌凯医药科技有限公司 一种丙戊酰脲的合成方法
CN110511141B (zh) * 2019-09-09 2022-04-29 上海凌凯医药科技有限公司 一种丙戊酰脲的合成方法

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