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WO2011061675A1 - Process for enantioselective preparation of nitroketone, an intermediate of protease inhibitors - Google Patents

Process for enantioselective preparation of nitroketone, an intermediate of protease inhibitors Download PDF

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Publication number
WO2011061675A1
WO2011061675A1 PCT/IB2010/055184 IB2010055184W WO2011061675A1 WO 2011061675 A1 WO2011061675 A1 WO 2011061675A1 IB 2010055184 W IB2010055184 W IB 2010055184W WO 2011061675 A1 WO2011061675 A1 WO 2011061675A1
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nitroketone
formula
tert
solution
butoxycarbonyl
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Abhay Atmaram Upare
Sushil Kumar Mishra
Santosh Crasta
Karuna Wankhede
Sandesh Vishwasrao
Hariharan Sivaramakrishnan
Mita Roy
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Piramal Enterprises Ltd
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Piramal Healthcare Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups

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  • the present invention relates to a process for the preparation of N-[(lS)-3-nitro- 2-oxo-l-(phenylmethyl)propyl]carbamic acid, 1 ,1-dimethylethyl ester, hereinafter referred to as Nitroketone, represented by formula I. More particularly, the present invention relates to an improved process for an enantioselective preparation of nitroketone, which is a key intermediate of protease inhibitors, Amprenavir, Fosamprenavir and Darunavir.
  • Amprenavir [(35')-tetrahydro-3-furyl-N-[(15',2i?)-3-(4-amino-N-isobutyl- benzenesulfonamido)- 1 -benzyl-2-hydroxypropyl] carbamate] , having the following structure, is a protease inhibitor, which is used in the treatment of HIV (Human Immunodeficiency Virus) infection.
  • HIV Human Immunodeficiency Virus
  • a prodrug of Amprenavir namely Fosamprenavir [[[(2i?,35')-l-[N-(2- methylpropyl)(4-aminobenzene)sulfonamido]-3-([[(35')-oxolan-3-yloxy]carbonyl] amino)-4-phenylbutan-2-yl]oxy]phosphonic acid] is made commercially available by GlaxoSmithKline.
  • Fosamprenavir calcium is an active ingredient of Lexiva® and Telzir®, the product currently used in the treatment of HIV infection.
  • Fosamprenavir is structurally represented as follows:
  • Darunavir [N-[3-[N-(4-aminophenylsulfonyl)-N-isobutylamino]-l(S)-benzyl- 2(R)-hydroxypropyl]carbamic acid (3i?,3a5',6ai?)-perhydrofuro[2,3-b]furan-3-yl ester] is used in the treatment of HIV infection.
  • Darunavir is an active ingredient of Prezista®, developed by Tibotec.
  • Prezista is an OARAC (Office of AIDS Research Advisory Council) recommended treatment option for treatment-nai ' ve and treatment-experienced adults and adolescents.
  • Darunavir is structurally represented as follows:
  • N-[(lS)-3-nitro-2-oxo-l-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Nitroketone) structurally represented as formula I, is a known intermediate of the protease inhibitors, Amprenavir, Fosamprenavir and Darunavir.
  • journal reference Synthesis 1978, page no. 478-479 describes a general process for the preparation of a-nitroketone (alpha-nitroketone).
  • the general process described in said journal reference is depicted as below:
  • this crude substituted imidazole solution can be used directly in the next condensation step or it can be alternatively isolated as a crystalline solid, (iv) to a preformed solution of either potassium tert-butoxide or sodium hydride in 15 volume of dry tetrahydrofuran, nitromethane was added to obtain an alkali salt of nitromethane and then charged the substituted imidazole obtained in step (iii) dropwise with stirring, (v) the resultant solution was refluxed for -16 hours and then cooled to room temperature, (vi) further work-up of the reaction mixture to obtain the product, desired a-nitroketone and typical purification of the resulting product yields desired a-nitroketone.
  • the process comprises the steps of: (i) addition of a preformed solution of 1,1 '- carbonyldiimidazole in dry tetrahydrofuran to N-(tert-butoxycarbonyl)-L- phenylalanine at room temperature and followed by stirring for 2 hours to obtain a solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III, (ii) in another reactor a solution of nitromethane in dry tetrahydrofuran is prepared and cooled to 0°C, to this solution then dropwise charged preformed solution of potassium tert-butoxide in 8 volume of dry tetrahydrofuran, (iii) subsequently the solution obtained in step (i) was added to the solution of potassium salt of nitromethane in tetrahydrofuran and the reaction mixture was stirred for 15 hours at room temperature, (iv) the reaction mixture was then treated with 7% aqueous hydrochloric acid and
  • step (iii) of the above process involves stirring for 15 hours at room temperature for the reaction to take place, which is certainly a drawback of the process for the industrial application of the process.
  • US Patent No. 5,599,994 describes a process for the preparation of nitroketone of formula I from N-(tert-butoxycarbonyl)-L-phenylalanine of formula II, wherein the process comprising the steps of: (i) reaction of a preformed solution of 1,1 '- carbonyldiimidazole in dry tetrahydrofuran with N-(tert-butoxycarbonyl)-L- phenylalanine under anhydrous conditions to obtain a solution of N-(tert- butoxycarbonyl)-L-phenylalanylimidazole of formula III, (ii) this solution was then refluxed for 1 hour and subsequently cooled to 30°C, (iii) in another reactor, to a pre-cooled solution of potassium tert-butoxide in 15 L of tetrahydrofuran, 96% of nitromethane was added dropwise to
  • nitroketone of formula I a key intermediate of protease inhibitors, Amprenavir, Fosamprenavir and Darunavir, can be improved particularly in terms of cost, by providing an enantioselective synthesis that would result in substantially enantiomerically pure nitroketone with good yield.
  • the processes for the preparation of nitroketone described in the cited prior art documents mostly yields the product, N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III with almost 50% racemization. In view of this, it is highly unlikely to obtain the nitroketone having the desired chiral purity from the compound of formula III with almost 50% racemization. Also, such prior art processes require large volume of solvents, longer reaction time and results in low yield and poor chiral purity of the desired enantiomer of nitroketone.
  • nitroketone of formula I can be obtained in good yield and substantial enantiomeric purity from N-(tert- butoxycarbonyl)-L-phenylalanine of formula II through an improved process, which although involves use of an activating agent, ⁇ , -carbonyldiimidazole and alkali nitromethane salt, avoids racemization of nitroketone.
  • the present invention provides a simple, cost-effective and industrially viable process for the preparation of nitroketone, a key intermediate of Amprenavir, Fosamprenavir and Darunavir, the protease inhibitors useful in the treatment of HIV infection.
  • An object of the present invention is to provide a process for the enantioselective preparation of N-[(lS)-3-nitro-2-oxo-l-(phenylmethyl)propyl]carbamic acid, 1,1- dimethylethyl ester (Nitroketone) of formula I from N-(tert-butoxycarbonyl)-L- phenylalanine of formula II.
  • Another object of the present invention is to provide a process for the preparation of substantially enantiomerically pure nitroketone of formula I which utilizes a simple purification method.
  • Yet another object of the present invention is to provide a process for the enantioselective preparation of nitroketone of formula I having > 89% yield and > 99% chiral purity.
  • Further object of the present invention is to provide a process for the preparation of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III having chiral purity of > 98%.
  • Yet further object of the present invention is to provide a simple, cost-effective and industrially applicable process for the enantioselective preparation of nitroketone of formula I.
  • Yet further object of the present invention is to provide a process for the enantioselective preparation of nitroketone of formula I substantially free of the undesired (1R) enantiomer and the reactant, N-(tert-butoxycarbonyl)-L- phenylalanine of formula II and the unreacted, N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III.
  • step (c) adding the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III in an organic solvent, obtained in step (a) to the solution of potassium salt of nitromethane in tetrahydrofuran, obtained in step (b) at a temperature of 25 °C to obtain the nitroketone of formula I.
  • the desired (IS) enantiomer of nitroketone of formula I is obtained in substantially pure form i.e. having a chiral purity of > 99% and with yield of > 89%.
  • N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III having chiral purity of > 98%.
  • the unreacted reactant, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is present in ⁇ 0.20% only.
  • the process for the preparation of nitroketone of formula I provides the desired (IS) enantiomer of nitroketone with good chiral purity and good yield without involving use of lengthy and tedious methods and elaborate work-up procedures, thereby making the process for the preparation of nitroketone simple, cost-effective and industrially viable.
  • the present invention relates to a process for the enantioselective preparation of N- [(1 S)-3-nitro-2-oxo- 1 -(phenylmethyl)propyl]carbamic acid, 1 , 1 -dimethylethyl ester (Nitroketone) of formula I
  • step (c) adding the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III in an organic solvent, obtained in step (a) to the solution of potassium salt of nitromethane in tetrahydrofuran, obtained in step (b) at a temperature of 25 °C to obtain the nitroketone of formula I.
  • the step (a) of the process involves reaction of N-(tert-butoxycarbonyl)-L-phenylalanine of formula II with an activating agent, ⁇ , -carbonyldiimidazole in the presence of an organic solvent to activate said compound of formula II.
  • the activating agent displaces the hydroxy group, part of the carboxyl group of the compound of formula II with a radical suitable to make the carbonyl carbon of said carboxyl group more susceptible to the nucleophilic addition.
  • ⁇ , -carbonyldiimidazole is used as an activating agent , wherein the hydroxy group, part of the carboxyl group, of the compound of formula II is replaced with the imidazole group to obtain the N- (tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III.
  • the reaction of ⁇ , ⁇ -carbonyldiimidazole with N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is carried out in the presence of an organic solvent such as methylene dichloride.
  • the N-(tert-butoxycarbonyl)-L- phenylalanine of formula II and 1,1' -carbonyldiimidazole is used in a molar ratio of 1 : 1.2.
  • the step (a) of the process involving reaction of N-(tert-butoxycarbonyl)-L-phenylalanine of formula II with 1,1 '- carbonyldiimidazole is preferably carried out at a temperature ranging from -7°C to -3°C.
  • the step (b) of the process involves reaction of the preformed solution of nitromethane in methylene dichloride with the preformed solution of potassium tert-butoxide in tetrahydrofuran at a temperature ranging from 5°C to 10°C to obtain a solution of potassium salt of nitromethane in tetrahydrofuran.
  • the step (b) of the process involving preparation of potassium salt of nitromethane is carried out using 5 volumes of tetrahydrofuran with respect to the weight of the potassium tert-butoxide.
  • the step (c) of the process involves reaction of the solution of N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III in methylene dichloride with the solution of potassium salt of nitromethane in tetrahydrofuran at a temperature of 25 °C to obtain the nitroketone of formula I.
  • the purification of nitroketone results in further improvement of the chiral purity of the desired enantiomer of nitroketone.
  • the purification of nitroketone of formula I is carried out using an organic solvent selected from methyl tert-butyl ether, ethyl acetate or a mixture thereof.
  • the purification of nitroketone is preferably carried out using methyl tert-butyl ether alone or a mixture of ethyl acetate and methyl tert-butyl ether.
  • the mixture of ethyl acetate and methyl tert- butyl ether is used in the ratio of 1 : 3 wt/vol with respect to the nitroketone of formula I.
  • a 'substantially enantiomerically pure' or 'substantially pure' nitroketone of formula I corresponds to the nitroketone having chiral purity of > 99%.
  • the nitroketone of formula I obtained using the process of the present invention contains ⁇ 1 % of the undesired (1R) enantiomer of nitroketone and said product is substantially free of the unreacted reactant, N-(tert-butoxycarbonyl)-L- phenylalanine of formula II and unreacted N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III.
  • the process is advantageous as it would further aid in providing the final product i.e. Amprenavir, Fosamprenavir or Darunavir, the protease inhibitors, in higher purity starting from the substantially pure nitroketone.
  • the enantiomeric ratio of desired (IS) enantiomer of nitroketone of formula I and undesired (1R) enantiomer of nitroketone is monitored using the chiral high performance liquid chromatography (HPLC) method of analysis. Further, the percentage of unreacted N-(tert- butoxycarbonyl)-L-phenylalanine of formula II and N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III and the percentage of product formation i.e. mixture of (IS) and (1R) enantiomers of nitroketone is monitored using the achiral HPLC method of analysis.
  • N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is dissolved in an organic solvent such as methylene dichloride to obtain a solution of N-(tert-butoxycarbonyl)-L-phenylalanine in methylene dichloride.
  • an organic solvent such as methylene dichloride
  • a solution of ⁇ , ⁇ -carbonyldiimidazole in methylene dichloride is prepared.
  • the reagent, ⁇ , ⁇ -carbonyldiimidazole acts as an activating agent, which displaces the hydroxy group, which constitutes part of the carboxyl group of N-(tert- butoxycarbonyl)-L-phenylalanine, with an imidazolyl group making the carbonyl carbon of the carboxyl group more susceptible to the nucleophilic addition.
  • ⁇ , ⁇ -carbonyldiimidazole acts as an activating agent, which displaces the hydroxy group, which constitutes part of the carboxyl group of N-(tert- butoxycarbonyl)-L-phenylalanine, with an imidazolyl group making the carbonyl carbon of the carboxyl group more susceptible to the nucleophilic addition.
  • the clear solution is maintained at a temperature of -7°C to -3°C for another 1 hour to obtain a solution of N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III in methylene dichloride.
  • the reaction mixture is monitored using chiral HPLC method of analysis, the product formed i.e., N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III having chiral purity of > 98% and the achiral HPLC method of analysis indicates the unreacted reactant, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II, present in the reaction mixture is only ⁇ 0.20%.
  • step (b) of the process the solution of potassium tert-butoxide in tetrahydrofuran is prepared and cooled to 5°-10°C.
  • a solution of nitromethane in methylene dichloride is prepared.
  • the solution of nitromethane in methylene dichloride is added drop wise at a temperature of 0° to 10°C, as the formation of nitromethane anion is typically an exothermic reaction.
  • reaction mixture After completion of the addition of the solution of nitromethane in methylene dichloride, the reaction mixture is stirred at 5°-10°C for another 30 minutes and then the reaction mixture is allowed to warm to 25 °C, and the reaction mixture is further maintained at the same temperature for 10 minutes to obtain the solution of potassium salt of nitromethane in tetrahydrofuran.
  • step (c) of the process to the reactor containing the solution of potassium salt of nitromethane in tetrahydrofuran, the solution of N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III in methylene dichloride is added through cannula over a period of 1 hour at a temperature of 25 °C and stirred for another 10 minutes. Then the reaction mixture is heated to 35°-40°C and further the reaction mixture is maintained at this temperature for another 1 hour.
  • reaction mixture is monitored using achiral HPLC method of analysis, which indicates formation of nitroketone of formula I as > 90%, the unreacted, N-(tert- butoxycarbonyl)-L-phenylalanylimidazole of formula III as ⁇ 7% and the unreacted reactant, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II as ⁇ 3%.
  • reaction mixture is cooled to 20°C.
  • the reaction mixture is then acidified using a suitable acid to lower the pH of the reaction mixture to a sufficiently low value to prevent significant enolate formation and to avoid cleavage of the protecting group, for example tert-butoxycarbonyl (BOC).
  • BOC tert-butoxycarbonyl
  • potassium hydrogen sulphate solution is used to acidify the reaction mixture.
  • a solution of potassium hydrogen sulphate in water is prepared and cooled to a temperature of 0°-5°C. The above reaction mixture is slowly added to the previously cooled solution of potassium hydrogen sulphate by maintaining the temperature of the reaction mixture ⁇ 5°C.
  • reaction mixture is filtered through hyflo and the two layers formed, namely the aqueous layer and the organic layer are separated using separating funnel.
  • the aqueous layer is extracted twice with methylene dichloride and all the methylene dichloride layers are washed with 2.5% potassium hydrogen sulphate solution followed by washing with water at 5°-10°C and with 20% brine solution.
  • the resulting methylene dichloride layer is kept at room temperature for 12 hours.
  • the methylene dichloride layer as obtained above is transferred into a distillation assembly and the methylene dichloride layer is distilled under vacuum at 35°C till the concentrate level is 1 volume.
  • first lot of heptane is added and distillation is continued, followed by addition of second lot of heptane and the distillation is continued further, finally third lot of heptane is added and the resulting reaction mixture is cooled to room temperature. Further, the reaction mixture is cooled to 5°-10°C and maintained for 1 hour to obtain the product, nitroketone of formula I.
  • the product obtained is filtered under vacuum and then washed with heptane and dried under vacuum at 35 °C for 2 hours.
  • the chiral HPLC method of analysis indicates that the chiral purity of nitroketone is > 95%, and the undesired (1R) enantiomer is ⁇ 5%.
  • the achiral HPLC method of analysis indicates that the achiral purity of nitroketone is > 99%.
  • the nitroketone of formula I as obtained above is sufficiently pure to use it as such in the next step, but if the (IS) enantiomer of nitroketone having a chiral purity > 99% is desired then it may be required to include an additional step of purification to obtain the desired (IS) enantiomer of nitroketone having the desired chiral purity.
  • the resulting nitroketone is dissolved in an organic solvent such as methyl tert-butyl ether or a mixture of ethyl acetate and methyl tert-butyl ether under heating at a temperature of 50°C to obtain a clear solution. This clear solution is then concentrated to obtain a suspension. The resulting suspension is then stirred at room temperature for 1 hour and then filtered to obtain the nitroketone having chiral purity of > 99% and only ⁇ 1% of the undesired (1R) enantiomer is obtained.
  • N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is a known compound and can be prepared by a known method or by using the process developed by the present inventors.
  • the process developed by the present inventors involves preparing a clear solution of sodium hydroxide (NaOH) by dissolving flakes of NaOH in water. This clear solution is cooled to 25°-30°C and then L-phenylalanine is added to it.
  • phase transfer catalyst such as tetrabutyl ammonium bromide (TBAB) is added, followed by stirring for 5 minutes and subsequently the reaction mixture is cooled to 0°-5°C.
  • first lot of tert-butoxycarbonyl anhydride i.e. BOC anhydride is added to the reaction mixture and the temperature of the reaction mixture is raised to 25°-30°C and further the reaction mixture is maintained at the same temperature for 4 hours.
  • the second lot of BOC anhydride is charged at 25°-30°C and the reaction mixture is maintained at the same temperature for another 12 hours.
  • the reaction mixture is then treated twice with heptane and the two layers formed, namely the aqueous layer and the organic layer are separated.
  • the aqueous layer is cooled to 0°-5°C and then ethyl acetate is added to it, followed by addition of aqueous solution of potassium hydrogen sulphate to form an organic layer and an aqueous layer. Further, the aqueous layer is separated from the organic layer and is extracted three times with ethyl acetate. Subsequently all the ethyl acetate layers are combined and washed with 20% brine solution.
  • the ethyl acetate layer is distilled under vacuum at 35°- 40°C to yield N-(tert-butoxycarbonyl)-L-phenylalanine of formula II, having chiral purity of > 99%.
  • the compound of formula I N-[(lS)-3-nitro-2-oxo-l- (phenylmethyl)propyl]carbamic acid, 1 ,1-dimethylethyl ester (Nitroketone), the product of the process of the present invention, is a key intermediate of protease inhibitors and antiretroviral drugs, Amprenavir [(S ⁇ -tetrahydro-S-furyl-N- [(15',2i?)-3-(4-amino-N-isobutylbenzenesulfonamido)-l-benzyl-2- hydroxypropyl]carbamate], Fosamprenavir [[(2i?,35')-l-[N-(2-methylpropyl)(4- aminobenzene)sulfonamido]-3-([[(35')-oxolan-3-yloxy]carbonyl]amino)-4- phenylbutan-2-
  • the nitroalcohol which is obtained from the nitroketone, may be subsequently converted to protease inhibitors, Amprenavir, Fosamprenavir or Darunavir by following one or more processes known in the prior art.
  • the nitroketone can be converted to the nitroalcohol by the process described in our pending Indian Patent Application No. 1415/MUM/2009 incorporated herein by reference. Accordingly, the nitroketone obtained by the process of the present invention may be converted to the corresponding nitroalcohol using a reducing agent such as sodium borohydride in the presence of a mixture of methanol and methylene dichloride.
  • the nitroalcohol may be subsequently converted to Amprenavir by following the process described in the prior art, Chinese Patent Application No. 1891698.
  • Mainly the nitroalcohol may be treated with a reducing agent, followed by reaction with isobutyl chloride and 4-nitrobenzenesulfonyl chloride to obtain an intermediate namely, N-[(lS,2R)-2-hydroxy-3-[(2-methylpropyl)[(4- nitrophenyl)sulfonyl] amino] - 1 -(phenylmethyl)propyl]carbamic acid, 1,1- dimethylethyl ester, which on treatment with (S)-3-hydroxytetrahydrofuran and catalytic reduction of the resulting compound, may yield Amprenavir.
  • the nitroketone of formula I obtained by the process of the present invention may be converted to nitroalcohol as discussed above, which is subsequently converted to another protease inhibitor, Darunavir by following one or more processes known in the prior art.
  • the process for the preparation of Darunavir may involve the steps of : (i) reducing the nitroalcohol of formula I to the corresponding aminoalcohol using an appropriate reducing agent e.g , palladium on charcoal, palladium hydroxide or Raney Nickel, (ii) the resulting aminoalcohol may then be treated with isopropyl amine to obtain 3S- [N-(t-butoxycarbonyl)amino]-l-(2-methylpropyl)amino-4-phenylbutan-2R-ol, as per the method described in US Patent No.
  • the resulting compound may then be condensed with p-methoxybenzenesulfonyl chloride in the presence of sodium bicarbonate and dichloromethane to yield an intermediate, which may be further condensed with (3R,3aS,6a/?)-3- hydroxyhexahydrofuro[2,3-b]furanyl succinimidyl carbonate using 30% trifluoroacetic acid in dichloromethane solution to obtain Darunavir, as per the method described in the published International Patent Application No. WO 2008/133734.
  • the inventors of the present invention carried out the process for the preparation of nitroketone of formula I from N-(tert-butoxycarbonyl)-L-phenylalanine of formula II as per the method described in Synthetic Communication, 1998, vol. no. 28, issue 3, and page no. 395- 401.
  • the process of said prior art as practiced by the present inventors is referred to herein as a reference example.
  • Said process carried out by the inventors of the present invention is illustrated below: (3S)-3-tert-butoxycarbonylamino- 1 -nitro-2-oxo-4-phenylbutane (4) (as per reference Synthetic Communication, 1998, vol. no. 28, issue 3, page no. 395- 401):
  • the compound (4) corresponds to nitroketone of formula I of the present invention.
  • the inventors of the present invention carried out the process for the preparation of nitroketone of formula I from N-(tert-butoxycarbonyl)-L-phenylalanine of formula II as per the method described in US Patent No. 5,599,994.
  • the process of said prior art as practiced by the present inventors is referred to herein as a reference example. Said process carried out by the inventors of the present invention is illustrated below:
  • 3-N-BOC-amino-3-benzyl-2-oxo-l-nitropropane (as per US Patent No. 5,599,994):
  • the compound, 3-N-BOC-amino-3-benzyl-2-oxo-l-nitropropane corresponds to nitroketone of formula I of the present invention.
  • the carbonyldiimidazole BOC-phenylalanine solution was then added dropwise to said pale yellow solution, which was concurrently cooled in an ice bath, to form a reaction mixture.
  • the reaction mixture was allowed to stand at room temperature for 12 hours and then was refluxed for an additional 3 hours to form 3-N-BOC-amino-3-benzyl-2-oxo-l- nitropropane in solution of THF.
  • the product solution was mixed with a 125ml of aqueous solution (pH ⁇ l) containing 46.3g sulfuric acid (H 2 SO 4 ) and 26.4g potassium hydroxide (KOH) to form an organic and an aqueous phase.
  • the organic phase was concentrated to a paste, while the aqueous phase was extracted with ethyl acetate.
  • the extracted ethyl acetate and the paste of organic phase were then combined and washed twice with aqueous potassium hydrogen sulphate (KHSO 4 ) (final pH of the aqueous layer was 3) and then dried over anhydrous magnesium sulphate (MgS0 4 ), followed by evaporation of the filtered ethyl acetate, to obtain 92.4% of 3-N-BOC-amino-3-benzyl-2-oxo-l-nitropropane (nitroketone) as a yellow solid.
  • KHSO 4 potassium hydrogen sulphate
  • MgS0 4 anhydrous magnesium sulphate
  • step (i) To a reactor containing the solution of potassium salt of nitromethane in tetrahydrofuran, the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole (obtained in step (i)) was added through cannula at 25°C and stirred for 30 minutes. The reaction mixture was then heated to 35°-40°C and maintained at this temperature for another 1 hour. The reaction mixture was then cooled to 20°C.
  • the methylene dichloride layer (obtained as above) was then distilled off under vacuum at 35°C till the concentrate level was 1 volume. Then 2 x 320ml of heptane was added to the distilled methylene dichloride layer and distillation continued, followed by the second lot of 640ml of heptane was added and cooled the reaction mixture to room temperature. Further cooled the reaction mixture to 5°-10°C and maintained at the same temperature for another 1 hour. The reaction mixture was filtered and washed with heptane. Dry the product obtained under vacuum at 35°C for 2 hour to yield nitroketone.
  • step (i) To a reactor containing the solution of potassium salt of nitromethane in tetrahydrofuran, the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole (obtained in step (i)) was added through cannula at 25°C and stirred for 30 minutes. The reaction mixture was then heated to 35°-40°C and maintained at this temperature for another 1 hour. The reaction mixture was then cooled to 20°C.
  • the resulting reaction mixture was then filtered through hyflo bed and washed with methylene dichloride. The filtrate was transferred into separating funnel and the two layers formed were separated. The methylene dichloride layer was washed with 2.5% potassium hydrogen sulphate solution and water at 5°-10°C, followed by washed with 20% brine solution. The methylene dichloride layer was then maintained at room temperature for another 12 hours.
  • the methylene dichloride layer (obtained as above) was then distilled off under vacuum at 35°C till the concentrate level was 1 volume. Then 2 x 100ml of heptane was added to the distilled methylene dichloride layer and distillation continued, followed by the second lot of 200ml of heptane was added and cooled the reaction mixture to room temperature. Further cooled the reaction mixture to 5°-10°C and maintained at the same temperature for another 1 hour. The reaction mixture was filtered and washed with heptane. Dry the product obtained under vacuum at 35°C for 2 hour to yield 105g of nitroketone.
  • Buffer solution In 1000 ml water added 1.0 ml of trifluoro acetic acid.
  • Mobile Phase Mixed Solution A : Combine 800ml n-Hexane, 200ml tert-Butyl Methyl Ether and 2 ml trifluoro acetic acid in a suitable container and mix well.
  • Final Composition Transfer 960ml of Mixed Solution A to a container and added 40ml of ethanol, mix well. Allow to equilibrate to room temperature.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a process for the preparation of N-[(1S)-3-nitro-2oxo- l-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Nitroketone) of formula I, comprising the steps of, (a) preparing a solution of N- (tertbutoxycarbonyl)-L-phenylalanylimidazole in an organic solvent, having chiral purity of >98%, (b) preparing a solution of potassium salt of nitromethane in tetrahydrofuran, and (c) reacting the solution of step (a) with the solution of step (b) to obtain the desired compound, nitroketone in >89% yield having >99% chiral purity.

Description

PROCESS FOR ENANTIOSELECTIVE PREPARATION OF NITROKETONE, AN INTERMEDIATE OF PROTEASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of N-[(lS)-3-nitro- 2-oxo-l-(phenylmethyl)propyl]carbamic acid, 1 ,1-dimethylethyl ester, hereinafter referred to as Nitroketone, represented by formula I. More particularly, the present invention relates to an improved process for an enantioselective preparation of nitroketone, which is a key intermediate of protease inhibitors, Amprenavir, Fosamprenavir and Darunavir.
BACKGROUND OF THE INVENTION Amprenavir [(35')-tetrahydro-3-furyl-N-[(15',2i?)-3-(4-amino-N-isobutyl- benzenesulfonamido)- 1 -benzyl-2-hydroxypropyl] carbamate] , having the following structure, is a protease inhibitor, which is used in the treatment of HIV (Human Immunodeficiency Virus) infection.
Figure imgf000002_0001
Amprenavir
A prodrug of Amprenavir, namely Fosamprenavir [[[(2i?,35')-l-[N-(2- methylpropyl)(4-aminobenzene)sulfonamido]-3-([[(35')-oxolan-3-yloxy]carbonyl] amino)-4-phenylbutan-2-yl]oxy]phosphonic acid] is made commercially available by GlaxoSmithKline. Fosamprenavir calcium is an active ingredient of Lexiva® and Telzir®, the product currently used in the treatment of HIV infection. Fosamprenavir is structurally represented as follows:
Figure imgf000003_0001
Fosamprenavir
Darunavir, [N-[3-[N-(4-aminophenylsulfonyl)-N-isobutylamino]-l(S)-benzyl- 2(R)-hydroxypropyl]carbamic acid (3i?,3a5',6ai?)-perhydrofuro[2,3-b]furan-3-yl ester] is used in the treatment of HIV infection. Darunavir is an active ingredient of Prezista®, developed by Tibotec. Prezista is an OARAC (Office of AIDS Research Advisory Council) recommended treatment option for treatment-nai've and treatment-experienced adults and adolescents. Darunavir is structurally represented as follows:
Figure imgf000003_0002
Darunavir
N-[(lS)-3-nitro-2-oxo-l-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Nitroketone) structurally represented as formula I, is a known intermediate of the protease inhibitors, Amprenavir, Fosamprenavir and Darunavir.
Figure imgf000004_0001
Formula I
The process for the preparation of enantiomerically pure nitroketone of formula I is discussed in several prior arts. Generally, the process involves reaction of N- (tert-butoxycarbonyl)-L-phenylalanine of formula II with nitromethane in the presence of an activating agent and an anhydrous base to obtain the enantiomerically pure nitroketone.
Figure imgf000004_0002
Formula II
However, the prior art processes for the preparation of nitroketone of formula I are disadvantageous, in terms of the long reaction time involved, large volumes of solvents used and that the product, nitroketone, is not obtained in desired yield and chiral purity.
The journal reference, Synthesis 1978, page no. 478-479 describes a general process for the preparation of a-nitroketone (alpha-nitroketone). The general process described in said journal reference is depicted as below:
Figure imgf000005_0001
Substituted imidazole alkali salt of nitromethane Desired alpha-Nitroketone where, R = substituted phenyl group and M = Na or K The process disclosed therein comprises the steps of: (i) addition of an appropriate carboxylic acid with Ι,Γ-carbonyldiimidazole (CDI) in the presence of dry tetrahydrofuran (THF) as a solvent, (ii) the resulting reaction mixture was then refluxed for 1 hour to obtain a solution containing crude substituted imidazole,
(iii) this crude substituted imidazole solution can be used directly in the next condensation step or it can be alternatively isolated as a crystalline solid, (iv) to a preformed solution of either potassium tert-butoxide or sodium hydride in 15 volume of dry tetrahydrofuran, nitromethane was added to obtain an alkali salt of nitromethane and then charged the substituted imidazole obtained in step (iii) dropwise with stirring, (v) the resultant solution was refluxed for -16 hours and then cooled to room temperature, (vi) further work-up of the reaction mixture to obtain the product, desired a-nitroketone and typical purification of the resulting product yields desired a-nitroketone.
The process described in said journal reference does not disclose the yield and chiral purity of the substituted imidazole salt or the desired a-nitroketone. Also, the process suggests use of 15 volumes of the reaction solvent which is dry tetrahydrofuran used for the preparation of potassium salt of nitromethane, which incurs high cost in commercial manufacture of nitroketone. Moreover, in the step
(iv) of the above process, the reaction mixture was refluxed for -16 hours, which may not be viable commercially.
In Synthetic Communication, 1998, vol. no. 28, issue no. 3, page no. 395-401, a process for the preparation of nitroketone of formula I from N-(tert- butoxycarbonyl)-L-phenylalanine of formula II is reported. The process comprises the steps of: (i) addition of a preformed solution of 1,1 '- carbonyldiimidazole in dry tetrahydrofuran to N-(tert-butoxycarbonyl)-L- phenylalanine at room temperature and followed by stirring for 2 hours to obtain a solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III, (ii) in another reactor a solution of nitromethane in dry tetrahydrofuran is prepared and cooled to 0°C, to this solution then dropwise charged preformed solution of potassium tert-butoxide in 8 volume of dry tetrahydrofuran, (iii) subsequently the solution obtained in step (i) was added to the solution of potassium salt of nitromethane in tetrahydrofuran and the reaction mixture was stirred for 15 hours at room temperature, (iv) the reaction mixture was then treated with 7% aqueous hydrochloric acid and extracted with ethyl acetate, the solvent was evaporated to obtain the crude nitroketone, which was then recrystallized from ethylacetate/n- hexane to yield 85% nitroketone. This journal reference also does not disclose the chiral purity of nitroketone as well as the compound of formula III, N-(tert- butoxycarbonyl)-L-phenylalanylimidazole. Also, the step (iii) of the above process involves stirring for 15 hours at room temperature for the reaction to take place, which is certainly a drawback of the process for the industrial application of the process.
Moreover, the inventors of the present invention tried out the process for the preparation of nitroketone of formula I from N-(tert-butoxycarbonyl)-L- phenylalanine of formula II as per the method described in Synthetic Communication, 1998, vol. no. 28, issue no. 3, page no. 395-401, they found that the N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III was obtained with 88% chiral purity and further conversion of said compound i.e. the compound of formula III prepared as per said prior art method to the nitroketone (formula I) yielded said nitroketone in 77% yield having 70.5% chiral purity. A typical example of said process carried out by the inventors of the present invention is provided in the experimental section. US Patent No. 5,599,994 describes a process for the preparation of nitroketone of formula I from N-(tert-butoxycarbonyl)-L-phenylalanine of formula II, wherein the process comprising the steps of: (i) reaction of a preformed solution of 1,1 '- carbonyldiimidazole in dry tetrahydrofuran with N-(tert-butoxycarbonyl)-L- phenylalanine under anhydrous conditions to obtain a solution of N-(tert- butoxycarbonyl)-L-phenylalanylimidazole of formula III, (ii) this solution was then refluxed for 1 hour and subsequently cooled to 30°C, (iii) in another reactor, to a pre-cooled solution of potassium tert-butoxide in 15 L of tetrahydrofuran, 96% of nitromethane was added dropwise to form a pale yellow solution, (iv) to this solution of step (iii) then was added the N-(tert-butoxycarbonyl)-L- phenylalanylimidazole solution, obtained in step (i), and concurrently cooled in an ice bath, (v) the reaction mixture was then allowed to stand at room temperature for 12 hours and subsequently refluxed for 3 hours to obtain the nitroketone solution in tetrahydrofuran, (vi) to this solution of nitroketone in tetrahydrofuran then was added sulfuric acid and potassium hydroxide and the two layers formed were then separated, (vii) the organic layer was concentrated to form a paste and the aqueous layer was extracted with ethyl acetate, (viii) the ethyl acetate layer and the organic layer paste were combined and washed with solution of potassium hydrogen sulfate (KHSO4) to yield crude nitroketone, which was then recrystallized with ethyl acetate/hexane as a solvent to obtain the desired nitroketone as an analytical specimen, as is indicated in said US Patent.
In the above described process, said US patent does not disclose the yield and the chiral purity of the nitroketone of formula I as well as the compound of formula III, N-(tert-butoxycarbonyl)-L-phenylalanylimidazole. In the above described process, an anhydrous solution of a base that is, the solution of potassium tert-butoxide in tetrahydrofuran was prepared using 55 volumes of tetrahydrofuran with respect to the base, which certainly renders the process for the manufacture of nitroketone costly.
Moreover, the inventors of the present invention tried out the method described in the afore mentioned US Patent No. 5,599,994 for the preparation of nitroketone of formula I from N-(tert-butoxycarbonyl)-L-phenylalanine of formula II. The inventors found that by following the procedure as described in aforesaid reference, the N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III was obtained with 51% chiral purity and further conversion of said compound i.e. the compound of formula III to the nitroketone (formula I) yielded said nitroketone in 92% yield having only 50% chiral purity. A typical example of said process carried out by the inventors of the present invention is provided in the experimental section.
The process of producing nitroketone of formula I, a key intermediate of protease inhibitors, Amprenavir, Fosamprenavir and Darunavir, can be improved particularly in terms of cost, by providing an enantioselective synthesis that would result in substantially enantiomerically pure nitroketone with good yield. The processes for the preparation of nitroketone described in the cited prior art documents mostly yields the product, N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III with almost 50% racemization. In view of this, it is highly unlikely to obtain the nitroketone having the desired chiral purity from the compound of formula III with almost 50% racemization. Also, such prior art processes require large volume of solvents, longer reaction time and results in low yield and poor chiral purity of the desired enantiomer of nitroketone.
The inventors of the present invention have now found that nitroketone of formula I can be obtained in good yield and substantial enantiomeric purity from N-(tert- butoxycarbonyl)-L-phenylalanine of formula II through an improved process, which although involves use of an activating agent, Ι, -carbonyldiimidazole and alkali nitromethane salt, avoids racemization of nitroketone. Thus, the present invention provides a simple, cost-effective and industrially viable process for the preparation of nitroketone, a key intermediate of Amprenavir, Fosamprenavir and Darunavir, the protease inhibitors useful in the treatment of HIV infection.
OBJECTS OF THE INVENTION An object of the present invention is to provide a process for the enantioselective preparation of N-[(lS)-3-nitro-2-oxo-l-(phenylmethyl)propyl]carbamic acid, 1,1- dimethylethyl ester (Nitroketone) of formula I from N-(tert-butoxycarbonyl)-L- phenylalanine of formula II.
Another object of the present invention is to provide a process for the preparation of substantially enantiomerically pure nitroketone of formula I which utilizes a simple purification method.
Yet another object of the present invention is to provide a process for the enantioselective preparation of nitroketone of formula I having > 89% yield and > 99% chiral purity.
Further object of the present invention is to provide a process for the preparation of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III having chiral purity of > 98%.
Yet further object of the present invention is to provide a simple, cost-effective and industrially applicable process for the enantioselective preparation of nitroketone of formula I. Yet further object of the present invention is to provide a process for the enantioselective preparation of nitroketone of formula I substantially free of the undesired (1R) enantiomer and the reactant, N-(tert-butoxycarbonyl)-L- phenylalanine of formula II and the unreacted, N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III.
STATEMENT OF THE INVENTION
In accordance with the present invention, there is provided a process for the enantioselective preparation of N-[(lS)-3-nitro-2-oxo-l- (phenylmethyl)propyl]carbamic acid, 1 , 1 -dimethylethyl ester (Nitroketone) of formula I, comprising the steps of: (a) reacting N-(tert-butoxycarbonyl)-L-phenylalanine of formula II,
Figure imgf000010_0001
Formula II with an activating agent, Ι, -carbonyldiimidazole in the presence of an organic solvent at a temperature ranging from -10°C to 0°C to obtain a solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III in an organic solvent, having chiral purity of > 98%,
Figure imgf000010_0002
Formula III
(b) reacting a solution of nitromethane in methylene dichloride with a solution of potassium tert-butoxide in tetrahydrofuran at a temperature of 5°C to 10°C to obtain a solution of potassium salt of nitromethane in tetrahydrofuran,
(c) adding the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III in an organic solvent, obtained in step (a) to the solution of potassium salt of nitromethane in tetrahydrofuran, obtained in step (b) at a temperature of 25 °C to obtain the nitroketone of formula I.
The process of the present invention is depicted in the following scheme: Step (a)
Figure imgf000011_0001
Formula II Formula III
Step (b)
Potassium
CH3N02 tert-butoxide KCH2N02
Tetrahydrofuran
Nitromethane Potassium salt of nitomethane
Step (c)
Figure imgf000011_0002
Formula III Formula I
(Nitroketone)
In accordance with another aspect of the present invention, there is provided a process for the purification of nitroketone of formula I to improve the enantiomeric purity of nitroketone.
In accordance with yet another aspect of the present invention, the desired (IS) enantiomer of nitroketone of formula I is obtained in substantially pure form i.e. having a chiral purity of > 99% and with yield of > 89%.
In accordance with yet another aspect of the present invention, there is provided a process for the preparation of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III having chiral purity of > 98%. Moreover, in the compound of formula III, obtained by the process of the present invention, the unreacted reactant, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is present in < 0.20% only.
In accordance with yet another aspect of the present invention, the process for the preparation of nitroketone of formula I provides the desired (IS) enantiomer of nitroketone with good chiral purity and good yield without involving use of lengthy and tedious methods and elaborate work-up procedures, thereby making the process for the preparation of nitroketone simple, cost-effective and industrially viable.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the enantioselective preparation of N- [(1 S)-3-nitro-2-oxo- 1 -(phenylmethyl)propyl]carbamic acid, 1 , 1 -dimethylethyl ester (Nitroketone) of formula I
Figure imgf000012_0001
Formula I
comprising the steps of,
(a) reacting N-(tert-butoxycarbonyl)-L-phenylalanine of formula II,
Figure imgf000012_0002
Formula II with an activating agent, Ι,Γ -carbonyldumidazole in the presence of an organic solvent at a temperature ranging from -10°C to 0°C to obtain a solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III in an organic solvent, having chiral purity of > 98%,
Figure imgf000013_0001
Formula III
(b) reacting a solution of nitromethane in methylene dichloride with a solution of potassium tert-butoxide in tetrahydrofuran at a temperature of 5°C to 10°C to obtain a solution of potassium salt of nitromethane in tetrahydrofuran,
(c) adding the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III in an organic solvent, obtained in step (a) to the solution of potassium salt of nitromethane in tetrahydrofuran, obtained in step (b) at a temperature of 25 °C to obtain the nitroketone of formula I.
In an embodiment of the present invention, the step (a) of the process involves reaction of N-(tert-butoxycarbonyl)-L-phenylalanine of formula II with an activating agent, Ι, -carbonyldiimidazole in the presence of an organic solvent to activate said compound of formula II. The activating agent displaces the hydroxy group, part of the carboxyl group of the compound of formula II with a radical suitable to make the carbonyl carbon of said carboxyl group more susceptible to the nucleophilic addition.
In accordance with the present invention Ι, -carbonyldiimidazole is used as an activating agent , wherein the hydroxy group, part of the carboxyl group, of the compound of formula II is replaced with the imidazole group to obtain the N- (tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III. In accordance with the present invention, the reaction of Ι,Γ-carbonyldiimidazole with N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is carried out in the presence of an organic solvent such as methylene dichloride.
In accordance with the present invention, the N-(tert-butoxycarbonyl)-L- phenylalanine of formula II and 1,1' -carbonyldiimidazole is used in a molar ratio of 1 : 1.2. In accordance with the present invention, the step (a) of the process involving reaction of N-(tert-butoxycarbonyl)-L-phenylalanine of formula II with 1,1 '- carbonyldiimidazole is preferably carried out at a temperature ranging from -7°C to -3°C. In another embodiment of the present invention, the step (b) of the process involves reaction of the preformed solution of nitromethane in methylene dichloride with the preformed solution of potassium tert-butoxide in tetrahydrofuran at a temperature ranging from 5°C to 10°C to obtain a solution of potassium salt of nitromethane in tetrahydrofuran.
In accordance with the present invention, the step (b) of the process involving preparation of potassium salt of nitromethane is carried out using 5 volumes of tetrahydrofuran with respect to the weight of the potassium tert-butoxide. In yet another embodiment of the present invention, the step (c) of the process involves reaction of the solution of N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III in methylene dichloride with the solution of potassium salt of nitromethane in tetrahydrofuran at a temperature of 25 °C to obtain the nitroketone of formula I. In further embodiment of the present invention, there is provided a process for the purification of nitroketone of formula I. The purification of nitroketone results in further improvement of the chiral purity of the desired enantiomer of nitroketone. In accordance with the present invention, the purification of nitroketone of formula I is carried out using an organic solvent selected from methyl tert-butyl ether, ethyl acetate or a mixture thereof. The purification of nitroketone is preferably carried out using methyl tert-butyl ether alone or a mixture of ethyl acetate and methyl tert-butyl ether. The mixture of ethyl acetate and methyl tert- butyl ether is used in the ratio of 1 : 3 wt/vol with respect to the nitroketone of formula I.
In accordance with the present invention, a 'substantially enantiomerically pure' or 'substantially pure' nitroketone of formula I corresponds to the nitroketone having chiral purity of > 99%.
Moreover, the nitroketone of formula I obtained using the process of the present invention contains < 1 % of the undesired (1R) enantiomer of nitroketone and said product is substantially free of the unreacted reactant, N-(tert-butoxycarbonyl)-L- phenylalanine of formula II and unreacted N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III. Thus, the process is advantageous as it would further aid in providing the final product i.e. Amprenavir, Fosamprenavir or Darunavir, the protease inhibitors, in higher purity starting from the substantially pure nitroketone.
In accordance with the present invention, the enantiomeric ratio of desired (IS) enantiomer of nitroketone of formula I and undesired (1R) enantiomer of nitroketone is monitored using the chiral high performance liquid chromatography (HPLC) method of analysis. Further, the percentage of unreacted N-(tert- butoxycarbonyl)-L-phenylalanine of formula II and N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III and the percentage of product formation i.e. mixture of (IS) and (1R) enantiomers of nitroketone is monitored using the achiral HPLC method of analysis.
In accordance with the present invention, in the step (a) of the process the starting material, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is dissolved in an organic solvent such as methylene dichloride to obtain a solution of N-(tert-butoxycarbonyl)-L-phenylalanine in methylene dichloride. In another flask, a solution of Ι,Γ-carbonyldiimidazole in methylene dichloride is prepared. The reagent, Ι,Γ-carbonyldiimidazole acts as an activating agent, which displaces the hydroxy group, which constitutes part of the carboxyl group of N-(tert- butoxycarbonyl)-L-phenylalanine, with an imidazolyl group making the carbonyl carbon of the carboxyl group more susceptible to the nucleophilic addition. To this solution of Ι,Γ-carbonyldiimidazole in methylene dichloride, the solution of N-(tert-butoxycarbonyl)-L-phenylalanine in methylene dichloride is charged over a period of 1 hour at a temperature ranging from -7°C to -3°C to obtain a clear solution. Further the clear solution is maintained at a temperature of -7°C to -3°C for another 1 hour to obtain a solution of N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III in methylene dichloride. At this stage the reaction mixture is monitored using chiral HPLC method of analysis, the product formed i.e., N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III having chiral purity of > 98% and the achiral HPLC method of analysis indicates the unreacted reactant, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II, present in the reaction mixture is only < 0.20%. In the step (b) of the process, the solution of potassium tert-butoxide in tetrahydrofuran is prepared and cooled to 5°-10°C. In a separate flask a solution of nitromethane in methylene dichloride is prepared. To the solution of potassium tert-butoxide in tetrahydrofuran, the solution of nitromethane in methylene dichloride is added drop wise at a temperature of 0° to 10°C, as the formation of nitromethane anion is typically an exothermic reaction. After completion of the addition of the solution of nitromethane in methylene dichloride, the reaction mixture is stirred at 5°-10°C for another 30 minutes and then the reaction mixture is allowed to warm to 25 °C, and the reaction mixture is further maintained at the same temperature for 10 minutes to obtain the solution of potassium salt of nitromethane in tetrahydrofuran.
In the step (c) of the process, to the reactor containing the solution of potassium salt of nitromethane in tetrahydrofuran, the solution of N-(tert-butoxycarbonyl)-L- phenylalanylimidazole of formula III in methylene dichloride is added through cannula over a period of 1 hour at a temperature of 25 °C and stirred for another 10 minutes. Then the reaction mixture is heated to 35°-40°C and further the reaction mixture is maintained at this temperature for another 1 hour. At this stage the reaction mixture is monitored using achiral HPLC method of analysis, which indicates formation of nitroketone of formula I as > 90%, the unreacted, N-(tert- butoxycarbonyl)-L-phenylalanylimidazole of formula III as < 7% and the unreacted reactant, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II as < 3%.
Further, the reaction mixture is cooled to 20°C. The reaction mixture is then acidified using a suitable acid to lower the pH of the reaction mixture to a sufficiently low value to prevent significant enolate formation and to avoid cleavage of the protecting group, for example tert-butoxycarbonyl (BOC). In a preferred embodiment, potassium hydrogen sulphate solution is used to acidify the reaction mixture. In another round bottom flask, a solution of potassium hydrogen sulphate in water is prepared and cooled to a temperature of 0°-5°C. The above reaction mixture is slowly added to the previously cooled solution of potassium hydrogen sulphate by maintaining the temperature of the reaction mixture < 5°C. Then the reaction mixture is filtered through hyflo and the two layers formed, namely the aqueous layer and the organic layer are separated using separating funnel. The aqueous layer is extracted twice with methylene dichloride and all the methylene dichloride layers are washed with 2.5% potassium hydrogen sulphate solution followed by washing with water at 5°-10°C and with 20% brine solution. The resulting methylene dichloride layer is kept at room temperature for 12 hours.
The methylene dichloride layer as obtained above is transferred into a distillation assembly and the methylene dichloride layer is distilled under vacuum at 35°C till the concentrate level is 1 volume. To this concentrate, first lot of heptane is added and distillation is continued, followed by addition of second lot of heptane and the distillation is continued further, finally third lot of heptane is added and the resulting reaction mixture is cooled to room temperature. Further, the reaction mixture is cooled to 5°-10°C and maintained for 1 hour to obtain the product, nitroketone of formula I. The product obtained is filtered under vacuum and then washed with heptane and dried under vacuum at 35 °C for 2 hours. The chiral HPLC method of analysis indicates that the chiral purity of nitroketone is > 95%, and the undesired (1R) enantiomer is < 5%. The achiral HPLC method of analysis indicates that the achiral purity of nitroketone is > 99%.
The nitroketone of formula I as obtained above is sufficiently pure to use it as such in the next step, but if the (IS) enantiomer of nitroketone having a chiral purity > 99% is desired then it may be required to include an additional step of purification to obtain the desired (IS) enantiomer of nitroketone having the desired chiral purity. The resulting nitroketone is dissolved in an organic solvent such as methyl tert-butyl ether or a mixture of ethyl acetate and methyl tert-butyl ether under heating at a temperature of 50°C to obtain a clear solution. This clear solution is then concentrated to obtain a suspension. The resulting suspension is then stirred at room temperature for 1 hour and then filtered to obtain the nitroketone having chiral purity of > 99% and only < 1% of the undesired (1R) enantiomer is obtained.
It is thus possible by the way of the present invention to achieve the much desired synthesis for the preparation of nitroketone of formula I enriched in its desired (IS) enantiomer. The starting material of the process, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is a known compound and can be prepared by a known method or by using the process developed by the present inventors. The process developed by the present inventors involves preparing a clear solution of sodium hydroxide (NaOH) by dissolving flakes of NaOH in water. This clear solution is cooled to 25°-30°C and then L-phenylalanine is added to it. To the resulting reaction mixture, a phase transfer catalyst (PTC) such as tetrabutyl ammonium bromide (TBAB) is added, followed by stirring for 5 minutes and subsequently the reaction mixture is cooled to 0°-5°C. Then, first lot of tert-butoxycarbonyl anhydride i.e. BOC anhydride is added to the reaction mixture and the temperature of the reaction mixture is raised to 25°-30°C and further the reaction mixture is maintained at the same temperature for 4 hours. Then, the second lot of BOC anhydride is charged at 25°-30°C and the reaction mixture is maintained at the same temperature for another 12 hours. The reaction mixture is then treated twice with heptane and the two layers formed, namely the aqueous layer and the organic layer are separated. The aqueous layer is cooled to 0°-5°C and then ethyl acetate is added to it, followed by addition of aqueous solution of potassium hydrogen sulphate to form an organic layer and an aqueous layer. Further, the aqueous layer is separated from the organic layer and is extracted three times with ethyl acetate. Subsequently all the ethyl acetate layers are combined and washed with 20% brine solution. The ethyl acetate layer is distilled under vacuum at 35°- 40°C to yield N-(tert-butoxycarbonyl)-L-phenylalanine of formula II, having chiral purity of > 99%.
As previously discussed, the compound of formula I, N-[(lS)-3-nitro-2-oxo-l- (phenylmethyl)propyl]carbamic acid, 1 ,1-dimethylethyl ester (Nitroketone), the product of the process of the present invention, is a key intermediate of protease inhibitors and antiretroviral drugs, Amprenavir [(S^-tetrahydro-S-furyl-N- [(15',2i?)-3-(4-amino-N-isobutylbenzenesulfonamido)-l-benzyl-2- hydroxypropyl]carbamate], Fosamprenavir [[(2i?,35')-l-[N-(2-methylpropyl)(4- aminobenzene)sulfonamido]-3-([[(35')-oxolan-3-yloxy]carbonyl]amino)-4- phenylbutan-2-yl]oxy]phosphonic acid], and Darunavir [N-[3-[N-(4- aminophenylsulfonyl)-N-isobutylamino] - 1 (S )-benzyl-2(R)-hydroxypropyl] carbamic acid (3i?,3a5',6ai?)-perhydrofuro[2,3-b]furan-3-yl ester]. Accordingly, the nitroketone of formula I may be used to obtain any one of the specified protease inhibitors by a process known in the art which may involve conversion of the nitroketone to the nitroalcohol, as represented below:
Figure imgf000020_0001
Formula I Nitroalcohol
(Nitroketone) The nitroalcohol, which is obtained from the nitroketone, may be subsequently converted to protease inhibitors, Amprenavir, Fosamprenavir or Darunavir by following one or more processes known in the prior art. The nitroketone can be converted to the nitroalcohol by the process described in our pending Indian Patent Application No. 1415/MUM/2009 incorporated herein by reference. Accordingly, the nitroketone obtained by the process of the present invention may be converted to the corresponding nitroalcohol using a reducing agent such as sodium borohydride in the presence of a mixture of methanol and methylene dichloride. The nitroalcohol may be subsequently converted to Amprenavir by following the process described in the prior art, Chinese Patent Application No. 1891698. Mainly the nitroalcohol may be treated with a reducing agent, followed by reaction with isobutyl chloride and 4-nitrobenzenesulfonyl chloride to obtain an intermediate namely, N-[(lS,2R)-2-hydroxy-3-[(2-methylpropyl)[(4- nitrophenyl)sulfonyl] amino] - 1 -(phenylmethyl)propyl]carbamic acid, 1,1- dimethylethyl ester, which on treatment with (S)-3-hydroxytetrahydrofuran and catalytic reduction of the resulting compound, may yield Amprenavir. Further, the nitroketone of formula I obtained by the process of the present invention may be converted to nitroalcohol as discussed above, which is subsequently converted to another protease inhibitor, Darunavir by following one or more processes known in the prior art. For instance, the process for the preparation of Darunavir may involve the steps of : (i) reducing the nitroalcohol of formula I to the corresponding aminoalcohol using an appropriate reducing agent e.g , palladium on charcoal, palladium hydroxide or Raney Nickel, (ii) the resulting aminoalcohol may then be treated with isopropyl amine to obtain 3S- [N-(t-butoxycarbonyl)amino]-l-(2-methylpropyl)amino-4-phenylbutan-2R-ol, as per the method described in US Patent No. 6372778; and (iii) the resulting compound may then be condensed with p-methoxybenzenesulfonyl chloride in the presence of sodium bicarbonate and dichloromethane to yield an intermediate, which may be further condensed with (3R,3aS,6a/?)-3- hydroxyhexahydrofuro[2,3-b]furanyl succinimidyl carbonate using 30% trifluoroacetic acid in dichloromethane solution to obtain Darunavir, as per the method described in the published International Patent Application No. WO 2008/133734.
The following examples which fully illustrate the practice of the preferred embodiment of the present invention are intended to be for illustrative purpose only and should not be considered in anyway to limit the scope of the present invention.
Reference Example 1:
The inventors of the present invention carried out the process for the preparation of nitroketone of formula I from N-(tert-butoxycarbonyl)-L-phenylalanine of formula II as per the method described in Synthetic Communication, 1998, vol. no. 28, issue 3, and page no. 395- 401. The process of said prior art as practiced by the present inventors is referred to herein as a reference example. Said process carried out by the inventors of the present invention is illustrated below: (3S)-3-tert-butoxycarbonylamino- 1 -nitro-2-oxo-4-phenylbutane (4) (as per reference Synthetic Communication, 1998, vol. no. 28, issue 3, page no. 395- 401): The compound (4) corresponds to nitroketone of formula I of the present invention.
To a stirred solution of Ι,Γ-carbonyldimidazole (71.8g, 0.43mol) in dry tetrahydrofuran (THF) (200ml) was added N-tert-butoxycarbonyl-L- phenylalanine (lOOg, 0.42mol) at room temperature for 2 hours to form a carbonyldiimidazole BOC-phenylalanine solution. (At this stage the reaction mixture is monitored using chiral HPLC method of analysis, the chiral purity of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III is 88% and the unreacted N-(tert-butoxycarbonyl)-L-phenylalanine is 12%). A solution of nitromethane (21.5g, 0.35mol) in dry THF (40ml) was cooled to 0°C and was added dropwise to potassium tert-butoxide (35.9g, 0.32mol) in dry THF (360ml), with stirring for 1 hour, and followed by adding the solution of carbonyldiimidazole BOC-phenylalanine dropwise to the resulting reaction mixture. After completion of addition, the reaction mixture was stirred for 15 hours at room temperature. The solution was then washed with 7% aqueous hydrochloric acid (HCl), extracted with ethyl acetate (EtOAc) (330ml), washed with brine, and dried with magnesium sulphate (MgS04). The solvent was evaporated and the crude solid was recrystallized from ethyl acetate/n-hexane to obtain nitroketone (90g, 77%).
Chiral purity = 70.5%
Undesired (1R) enantiomer = 29.5%.
Achiral Purity = 68.19%
Reference Example 2:
The inventors of the present invention carried out the process for the preparation of nitroketone of formula I from N-(tert-butoxycarbonyl)-L-phenylalanine of formula II as per the method described in US Patent No. 5,599,994. The process of said prior art as practiced by the present inventors is referred to herein as a reference example. Said process carried out by the inventors of the present invention is illustrated below:
3-N-BOC-amino-3-benzyl-2-oxo-l-nitropropane (as per US Patent No. 5,599,994): The compound, 3-N-BOC-amino-3-benzyl-2-oxo-l-nitropropane corresponds to nitroketone of formula I of the present invention.
In an argon atmosphere and under anhydrous conditions, 19.6g of 1,1'- carbonyldiimdazole (CD I) and 150ml of dry tetrahydrofuran (THF) were mixed in a reactor. 25g of BOC-phenylalanine was then added in five portions to the reactor to form a carbonyldiimidazole BOC-phenylalanine solution. Vigorous gas evolution was observed from the reaction. The mixture was refluxed for one hour and subsequently cooled to about 30°C. (At this stage the reaction mixture is monitored using chiral HPLC method of analysis, the chiral purity of N-(tert- butoxycarbonyl)-L-phenylalanylimidazole of formula III is 51% and the unreacted N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is 49%).
In a second reactor, 13.6g of potassium tert-butoxide and 746ml of THF were mixed and then cooled in an ice bath. 7.5g of 96% nitromethane was added dropwise to the ice-cooled potassium tert-butoxide solution to form a pale yellow solution.
The carbonyldiimidazole BOC-phenylalanine solution was then added dropwise to said pale yellow solution, which was concurrently cooled in an ice bath, to form a reaction mixture. After completion of the addition, the reaction mixture was allowed to stand at room temperature for 12 hours and then was refluxed for an additional 3 hours to form 3-N-BOC-amino-3-benzyl-2-oxo-l- nitropropane in solution of THF. After refluxing, the product solution was mixed with a 125ml of aqueous solution (pH<l) containing 46.3g sulfuric acid (H2SO4) and 26.4g potassium hydroxide (KOH) to form an organic and an aqueous phase. The organic phase was concentrated to a paste, while the aqueous phase was extracted with ethyl acetate. The extracted ethyl acetate and the paste of organic phase were then combined and washed twice with aqueous potassium hydrogen sulphate (KHSO4) (final pH of the aqueous layer was 3) and then dried over anhydrous magnesium sulphate (MgS04), followed by evaporation of the filtered ethyl acetate, to obtain 92.4% of 3-N-BOC-amino-3-benzyl-2-oxo-l-nitropropane (nitroketone) as a yellow solid.
Chiral purity = 50%
Undesired (1R) enantiomer = 50%.
Achiral Purity = 76.49%
Example 3: Preparation of N-(tert-butoxycarbonyl)-L-phenylalanine
To a round bottom flask charged 1400ml of water and 61.2g of sodium hydroxide (NaOH) flakes and dissolved it to get a clear solution. The clear solution was cooled to 25°-30°C and then 200g of L-phenylalanine was added to the reaction mixture, followed by adding 7.8g of tetrabutyl ammonium bromide (TBAB) to it. The resulting reaction mixture was stirred for 5 minutes and subsequently cooled to 0°-5°C. Then the first lot of tert-butoxycarbonyl anhydride was added to the reaction mixture and the temperature of the resulting reaction mixture was raised to 25°-30°C and the reaction mixture was further maintained at the same temperature for 4 hours. Then the second lot of tert-butoxycarbonyl anhydride at 25°-30°C was added and the reaction mixture was maintained at the same temperature for another 12 hours. The reaction mixture was then treated twice with heptane to form an organic layer and aqueous layer. The aqueous layer was separated from the reaction mixture and was cooled to 0°-5°C. To the aqueous layer was then added ethyl acetate, followed by aqueous solution of potassium hydrogen sulphate to form an organic layer and aqueous layer. Again the aqueous layer formed was separated and extracted three times with ethyl acetate. All the ethyl acetate layers were combined and washed with 20% brine solution. The ethyl acetate layer was distilled under vacuum at 35°-40°C to yield 95% of N- (tert-butoxycarbonyl)-L-phenylalanine having chiral purity of 99.88%. Example 4: Preparation of Nitroketone
(i) Preparation of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole
To a 2L round bottom flask charged 235g of Ι,Γ-carbonyldiimidazole and 320ml of methylene dichloride and stirred under nitrogen atmosphere. To this reaction mixture a separately prepared solution of 320g of N-(tert-butoxycarbonyl)-L- phenylalanine in 640ml of methylene dichloride was added in lots maintaining the temperature of the reaction mixture to -5°C. Then the temperature of the reaction mixture was maintained at -7°C to -3°C for another 1 hour to yield a solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole in methylene dichloride.
Chiral Purity = 99%
Unreacted N-(tert-butoxycarbonyl)-L-phenylalanine = 0.20%
(ii) Preparation of potassium salt of nitromethane
To a 3L round bottom flask, charged 870ml of tetrahydrofuran and 163g of potassium tert-butoxide under nitrogen atmosphere and cool it to 5°-10°C. To this reaction mixture a separately prepared solution of 103.2g of nitromethane in 100ml of methylene dichloride was added drop wise maintaining the temperature of the reaction mixture at 0° to 10°C. The reaction mixture was then stirred at 5°- 10°C for another 30 minutes and was allowed to warm to 25 °C. The reaction mixture was further maintained at 25 °C for 10 minutes to obtain the solution of potassium salt of nitromethane in tetrahydrofuran.
(iii) Preparation of Nitroketone
To a reactor containing the solution of potassium salt of nitromethane in tetrahydrofuran, the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole (obtained in step (i)) was added through cannula at 25°C and stirred for 30 minutes. The reaction mixture was then heated to 35°-40°C and maintained at this temperature for another 1 hour. The reaction mixture was then cooled to 20°C. (At this stage the reaction mixture was monitored using achiral HPLC method of analysis, the product formation, nitroketone of formula I is 92%, the unreacted N- (tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III is 6.23% and the unreacted reactant, N-(tertbutoxycarbonyl)-L-phenylalanine of formula II is 1.81%).
In another flask, 577g of potassium hydrogen sulphate was dissolved in 4180ml of water and cooled it to 0°-5°C. To this solution of potassium hydrogen sulphate, the reaction mixture (obtained as above) was slowly added maintaining the temperature of the reaction mixture < 5°C and stirred for another 10 minutes. The resulting reaction mixture was then filtered through hyflo bed and washed with methylene dichloride. The filtrate was transferred into separating funnel and the two layers formed were separated. The methylene dichloride layer was washed with 2.5% potassium hydrogen sulphate solution and water at 5°-10°C, followed by washed with 20% brine solution. The methylene dichloride layer was then maintained at room temperature for another 12 hours.
The methylene dichloride layer (obtained as above) was then distilled off under vacuum at 35°C till the concentrate level was 1 volume. Then 2 x 320ml of heptane was added to the distilled methylene dichloride layer and distillation continued, followed by the second lot of 640ml of heptane was added and cooled the reaction mixture to room temperature. Further cooled the reaction mixture to 5°-10°C and maintained at the same temperature for another 1 hour. The reaction mixture was filtered and washed with heptane. Dry the product obtained under vacuum at 35°C for 2 hour to yield nitroketone.
Yield = 89.17%
Chiral Purity = 95%
Undesired (1R) enantiomer = 4.7%
Achiral Purity = 99.54%
Example 5: Preparation of Nitroketone
(i) Preparation of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole
To a 1L round bottom flask charged 73.4g of Ι,Γ-carbonyldiimidazole and 100ml of methylene dichloride and stirred under nitrogen atmosphere. To this reaction mixture a separately prepared solution of lOOg of N-(tert-butoxycarbonyl)-L- phenylalanine in 200ml of methylene dichloride was added in lots maintaining the temperature of the reaction mixture to -5°C. Then the temperature of the reaction mixture was maintained at -7°C to -3°C for another 1 hour to yield a solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole in methylene dichloride.
Chiral Purity = 98.5%
Unreacted N-(tert-butoxycarbonyl)-L-phenylalanine = 0.18%
(ii) Preparation of potassium salt of nitromethane
To a 1L round bottom flask, charged 203ml of tetrahydrofuran and 51g of potassium tert-butoxide under nitrogen atmosphere and cool it to 5°-10°C. To this reaction mixture a separately prepared solution of 32g of nitromethane in 32ml of methylene dichloride was added dropwise maintaining the temperature of the reaction mixture at 0° to 10°C. The reaction mixture was then stirred at 5°-10°C for another 30 minutes and was allowed to warm to 25°C. The reaction mixture was further maintained at 25 °C for lOminutes to obtain the solution of potassium salt of nitromethane in tetrahydrofuran.
(iii) Preparation of Nitroketone
To a reactor containing the solution of potassium salt of nitromethane in tetrahydrofuran, the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole (obtained in step (i)) was added through cannula at 25°C and stirred for 30 minutes. The reaction mixture was then heated to 35°-40°C and maintained at this temperature for another 1 hour. The reaction mixture was then cooled to 20°C. (At this stage the reaction mixture was monitored using achiral HPLC method of analysis, the product formation, nitroketone of formula I is 98%, the unreacted N- (tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III is 2.24% and the unreacted reactant, N-(tert-butoxycarbonyl)-L-phenylalanine of formula II is 2.5%). In another flask, 180g of potassium hydrogen sulphate was dissolved in 875ml of water and cooled it to 0°-5°C. To this solution of potassium hydrogen sulphate, the reaction mixture (obtained as above) was slowly added maintaining the temperature of the reaction mixture < 5°C and stirred for another 10 minutes. The resulting reaction mixture was then filtered through hyflo bed and washed with methylene dichloride. The filtrate was transferred into separating funnel and the two layers formed were separated. The methylene dichloride layer was washed with 2.5% potassium hydrogen sulphate solution and water at 5°-10°C, followed by washed with 20% brine solution. The methylene dichloride layer was then maintained at room temperature for another 12 hours.
The methylene dichloride layer (obtained as above) was then distilled off under vacuum at 35°C till the concentrate level was 1 volume. Then 2 x 100ml of heptane was added to the distilled methylene dichloride layer and distillation continued, followed by the second lot of 200ml of heptane was added and cooled the reaction mixture to room temperature. Further cooled the reaction mixture to 5°-10°C and maintained at the same temperature for another 1 hour. The reaction mixture was filtered and washed with heptane. Dry the product obtained under vacuum at 35°C for 2 hour to yield 105g of nitroketone.
Yield = 89.7%
Chiral Purity = 95.6%
Undesired (1R) enantiomer = 4%
Achiral Purity = 99.64%
Example 6: Purification of Nitroketone
To a round bottom flask charged l lOg of nitroketone (having chiral purity 96%) and 1320ml of methyl tert-butyl ether and the resulting reaction mixture was then heated under stirring to obtain a clear solution. This clear solution was then concentrated to obtain a suspension. The suspension was then cooled to room temperature and stirred for another 1 hour to obtain the pure nitroketone. The obtained nitroketone was filtered and washed with chilled methyl tert-butyl ether. Yield = 90% Chiral Purity = 99.82%
Undesired (1R) enantiomer
Example 7: Purification of Nitroketone
To a round bottom flask charged 5 g of nitroketone (having chiral purity 88%), 7ml of ethyl acetate and 21ml of methyl tert-butyl ether and the resulting reaction mixture was then heated under stirring to obtain a clear solution. The clear solution was then cooled to 5°C and stirred further for 1 hour. The reaction mixture was then filtered to obtain pure nitroketone.
Yield = 80%
Chiral Purity = 100%
ANALYTICAL METHOD FOR ANALYSIS
Achiral HPLC method of analysis
Column Eclipse XDB C18, (150mm x 4.6mm, 5μπι)
Make: Agilent (Part No.- 993967-902)
Mobile Phase A: Buffer
B: Acetonitrile (Gradient grade)
Buffer solution In 1000 ml water added 1.0 ml of trifluoro acetic acid.
Detector UV, 215nm
Flow 1.2 ml / minutes
Temperature Ambient
Run Time 28 minutes
Injection Volume ΙΟμΙ
Diluent Water: acetonitrile (3:7)
Chiral HPLC method of analysis
Column : Chiralcel OD-H, 250mm x 4.6mm, 5um
Make: Diecel Chemical Industries.
Mobile Phase : Mixed Solution A : Combine 800ml n-Hexane, 200ml tert-Butyl Methyl Ether and 2 ml trifluoro acetic acid in a suitable container and mix well.
Final Composition : Transfer 960ml of Mixed Solution A to a container and added 40ml of ethanol, mix well. Allow to equilibrate to room temperature.
Detector : UV, 215nm
Flow : 0.5 ml/minutes
Temperature : Ambient
Run Time : 30 minutes
Injection Volume : 20μ1
Diluent : Mobile Phase.

Claims

WE CLAIM,
1. A process for the preparation of N-[(lS)-3-nitro-2-oxo-l- (phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Nitroketone) of formula I,
Figure imgf000031_0001
Formula I
comprising the steps of,
(a) reacting N-(tert-butoxycarbonyl)-L-phenylalanine of formula II,
Figure imgf000031_0002
Formula II
with an activating agent, Ι, -carbonyldiimidazole in the presence of an organic solvent at a temperature ranging from -10°C to 0°C to obtain a solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III in an organic solvent, having chiral purity of > 98%,
Figure imgf000031_0003
Formula III
(b) reacting a solution of nitromethane in methylene dichloride with a solution of potassium tert-butoxide in tetrahydrofuran at a temperature of 5°C to 10°C to obtain a solution of potassium salt of nitromethane in tetrahydrofuran,
(c) adding the solution of N-(tert-butoxycarbonyl)-L-phenylalanylimidazole of formula III in an organic solvent, obtained in step (a) to the solution of potassium salt of nitromethane in tetrahydrofuran, obtained in step (b) at a temperature of 25 °C to obtain the nitroketone of formula I.
2. The process as claimed in claim 1 further comprising purification of nitroketone using an organic solvent to obtain substantially pure nitroketone of formula I.
3. The process as claimed in claim 1, wherein in the step (a) the organic solvent used is methylene dichloride.
4. The process as claimed in claim 1, wherein in the step (a) the molar ratio of said N-(tert-butoxycarbonyl)-L-phenylalanine of formula II to said 1,1 '- carbonyldiimidazole is 1 : 1.2.
5. The process as claimed in claim 1, wherein the step (a) involving reaction of N-(tert-butoxycarbonyl)-L-phenylalanine of formula II with 1,1 '- carbonyldiimidazole is carried out at a temperature ranging from -7°C to - 3°C.
6. The process as claimed in claim 1, wherein in the step (b) tetrahydrofuran solvent is used in 5 volume with respect to the weight of potassium tert- butoxide.
7. The process as claimed in claim 2, wherein said organic solvent used for purification of nitroketone of formula I is selected from methyl tert-butyl ether, ethyl acetate or a mixture thereof. The process as claimed in claim 7, wherein said organic solvent is methyl tert-butyl ether.
The process as claimed in claim 7, wherein said organic solvent is a mixture of ethyl acetate and methyl tert-butyl ether.
The process as claimed in claim 9, wherein said ethyl acetate and said methyl tert-butyl ether is used in the ratio of 1 : 3 wt/vol with respect to the nitroketone of formula I.
A process for the preparation of N-[(lS)-3-nitro-2-oxo-l- (phenylmethyl)propyl] carbamic acid, 1 , 1 -dimethylethyl ester (Nitroketone) as herein described with reference to Examples 3 to 7.
PCT/IB2010/055184 2009-11-18 2010-11-16 Process for enantioselective preparation of nitroketone, an intermediate of protease inhibitors Ceased WO2011061675A1 (en)

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