[go: up one dir, main page]

WO2011061675A1 - Procédé d'élaboration énantiosélective de la nitrocétone qui est un intermédiaire des inhibiteurs des protéases - Google Patents

Procédé d'élaboration énantiosélective de la nitrocétone qui est un intermédiaire des inhibiteurs des protéases Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
nitroketone
formula
tert
solution
butoxycarbonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2010/055184
Other languages
English (en)
Inventor
Abhay Atmaram Upare
Sushil Kumar Mishra
Santosh Crasta
Karuna Wankhede
Sandesh Vishwasrao
Hariharan Sivaramakrishnan
Mita Roy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Piramal Enterprises Ltd
Original Assignee
Piramal Healthcare Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Piramal Healthcare Ltd filed Critical Piramal Healthcare Ltd
Publication of WO2011061675A1 publication Critical patent/WO2011061675A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé d'élaboration de nitrocétone représentée par la formule (I), à savoir le 1,1-diméthyléthyl-ester de l'acide N-[(1S)-3-nitro-2oxo-1-(phénylméthyl)propyl]carbamique. Ce procédé comporte les étapes suivantes: (a) préparation d'une solution de N-(tertbutoxycarbonyl)-L-phénylalanylimidazole dans un solvant organique, solution dont la pureté chirale est supérieure à 98%; (b) préparation d'une solution de sel de potassium de nitrométhane dans du tétrahydrofurane; et (c) réaction de la solution issue de (a) avec la solution issue de (b) de façon à obtenir le composé attendu, la nitrocétone, avec un rendement supérieur à 89%, pour une pureté chirale supérieure à 99%.
PCT/IB2010/055184 2009-11-18 2010-11-16 Procédé d'élaboration énantiosélective de la nitrocétone qui est un intermédiaire des inhibiteurs des protéases Ceased WO2011061675A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2666MU2009 2009-11-18
IN2666/MUM/2009 2009-11-18

Publications (1)

Publication Number Publication Date
WO2011061675A1 true WO2011061675A1 (fr) 2011-05-26

Family

ID=44059263

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/055184 Ceased WO2011061675A1 (fr) 2009-11-18 2010-11-16 Procédé d'élaboration énantiosélective de la nitrocétone qui est un intermédiaire des inhibiteurs des protéases

Country Status (1)

Country Link
WO (1) WO2011061675A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103524470A (zh) * 2013-10-15 2014-01-22 北京师范大学 2-氨基-1-(-6-氟-2-色满基)乙醇的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0449622A (ja) * 1990-06-19 1992-02-19 Nec Corp 抵抗線形成方法及び装置
WO1996001788A2 (fr) * 1994-07-07 1996-01-25 Pharm-Eco Laboratories, Incorporated Diaminopropanols derives d'un amino-acide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0449622A (ja) * 1990-06-19 1992-02-19 Nec Corp 抵抗線形成方法及び装置
WO1996001788A2 (fr) * 1994-07-07 1996-01-25 Pharm-Eco Laboratories, Incorporated Diaminopropanols derives d'un amino-acide

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BAKER ET AL.: "C-Acylation of nitrometane. A synthetic route to a-nitroketones", SYNTHESIS, 1978, pages 478 - 479, XP002222754, DOI: doi:10.1055/s-1978-24791 *
DATABASE CAS Database accession no. 174302-72-8 *
PATENT ABSTRACTS OF JAPAN *
YUASA ET AL.: "A facile synthesis of (2R,3S)-1-amino-3-tert-butoxycarbonylamino-2- hydroxy-4-phenylbutane; A useful component block of HIV protease inhibitor", SYNTHETIC COMMUNICATIONS, vol. 28, no. 3, 1998, pages 395 - 401, XP008011186, DOI: doi:10.1080/00397919808005092 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103524470A (zh) * 2013-10-15 2014-01-22 北京师范大学 2-氨基-1-(-6-氟-2-色满基)乙醇的合成方法

Similar Documents

Publication Publication Date Title
US11370739B2 (en) Sacubitril intermediate and preparation method thereof
CZ20014285A3 (cs) Mono- a disubstituované kyseliny 3-propyl gamma-aminomáselné
TW200817308A (en) A process for the preparation of optically active intermediates
AU2012601A (en) Novel esters derived from (rr,ss)-2-hydroxybenzoate of 3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenyl
US20100267988A1 (en) Processes for preparing intermediate compounds useful for the preparation of cinacalcet
EP2551259A1 (fr) Composés intermédiaires de la sitagliptine, leurs procédés de préparation et utilisations
Medina et al. Enantioselective Syntheses of Conformationally Rigid, Highly Lipophilic Mesityl‐Substituted Amino Acids
EP2397141A1 (fr) Procédé pour la synthèse d'acides aminés beta et leurs dérivés
Tozawa et al. Enantioselective synthesis of 3, 4-dihydropyran-2-ones by chiral quaternary ammonium phenoxide-catalyzed tandem Michael addition and lactonization
KR20190103933A (ko) 입체 선택성이 우수한 이 작용성 유기 키랄 촉매 화합물, 이의 제조 방법 및 이를 이용한 나이트로 화합물로부터의 비천연 감마-아미노산의 제조 방법
WO2011061675A1 (fr) Procédé d'élaboration énantiosélective de la nitrocétone qui est un intermédiaire des inhibiteurs des protéases
Li et al. An efficient enantioselective synthesis of florfenicol via a vanadium-catalyzed asymmetric epoxidation
WO2012165607A1 (fr) Procédé de fabrication d'un composé proline
US20240083889A1 (en) Scalable process for the preparation of a GlyT-1 Inhibitor
JP3999028B2 (ja) 光学活性２−アシル化１，２−ジオール化合物誘導体の製造方法
JP2009073739A (ja) 医薬品中間体として許容しうる高純度な光学活性１−アリール−１，３−プロパンジオールの製造方法
KR20010000196A (ko) 아지리딘으로부터 페닐알라닌 및 호모페닐알라닌을포함하는 알파아미노산 및 그 유도체의 제조방법
JP4540197B2 (ja) （ｅ）−３−メチル−２−シクロペンタデセノンの製造法
US6872840B1 (en) Synthesis of 8-membered carbocyclic compound having diexomethylene groups
JP4189500B2 (ja) ディールス・アルダー反応触媒及び不斉環化付加生成物の製造方法
CN113968807B (zh) 制备拉坦前列烯布诺德的方法和其中间物以及包含其的组合物
JP5023443B2 (ja) ４−フルオロプロリン誘導体の製造方法
KR101085170B1 (ko) (ｓ)-리바스티그민의 제조방법
WO2011031764A2 (fr) Composés et procédés d'utilisation s'y rapportant
JP4529419B2 (ja) 光学活性含フッ素化合物類、及びこれらの製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10831239

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10831239

Country of ref document: EP

Kind code of ref document: A1