WO2013189978A1 - Procédé de préparation de dérivés d'acides ss-amino et utilisation dudit procédé pour la préparation de télaprévir - Google Patents

Procédé de préparation de dérivés d'acides ss-amino et utilisation dudit procédé pour la préparation de télaprévir Download PDF

Info

Publication number
WO2013189978A1
WO2013189978A1 PCT/EP2013/062732 EP2013062732W WO2013189978A1 WO 2013189978 A1 WO2013189978 A1 WO 2013189978A1 EP 2013062732 W EP2013062732 W EP 2013062732W WO 2013189978 A1 WO2013189978 A1 WO 2013189978A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
group
defined above
hydrogen
Prior art date
Application number
PCT/EP2013/062732
Other languages
English (en)
Inventor
Kathrin HOEFERL-PRANTZ
Wolfgang Felzmann
Original Assignee
Sandoz Ag
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 Sandoz Ag filed Critical Sandoz Ag
Publication of WO2013189978A1 publication Critical patent/WO2013189978A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to a process for preparing ⁇ -amino acid derivatives.
  • the process can be used for the preparation of telaprevir or a pharmaceutically acceptable salt or solvate thereof, wherein the process includes an organocatalytic epoxidation reaction which avoids the use of titanium catalysts and thus avoids contamination of the final product with titanium as present in known products.
  • Another embodiment refers to telaprevir a pharmaceutically acceptable salt or solvate thereof as well as to an intermediate product for preparation of the same, wherein the afore-mentioned products are obtained by the process described herein.
  • Telaprevir is a protease inhibitor that can be used as antiviral drug.
  • telaprevir inhibits the hepatitis C virus NS3-4A serine protease.
  • telaprevir requires the preparation of an 3-amino-2-hydroxyhexanamide as an intermediate.
  • EP2039689 A1 refers to the preparation of optically-active 3-amino-2-hydroxypropionic cyclopropylamide derivatives.
  • X halogen
  • the document describes the use of Noyori's catalyst (Ru + BINAP) for the generation of this optically-active 2-halo-3-hydroxypropionic acid derivative.
  • WO2007109023 A1 discloses a process for the preparation of protease inhibitors, the process comprises a step of converting an unsaturated compound into an epoxide by using known methods such as oxidation with peroxides.
  • WO2008029267 A2 discloses a process for preparing 3-amino-2-hydroxycarboxylic acid amines, which comprises the epoxidation of a trans- ⁇ - ⁇ unsaturated carboxylic acid or alcohol. Said epoxidation is conducted by using a Sharpless asymmetric epoxidation of an allyl alcohol based on a standard protocol using Ti(OiPr) 4 , DET (diethyltartrate) and tBuOOH. A further epoxidation process is described by J0rgensen (Journal of the American Chemical Society 2005, 127, 6964) for ⁇ , ⁇ -unsaturated aldehydes. This epoxidation process uses a sterically-hindered pyrrolidine derivative as catalyst:
  • a further epoxidation process is disclosed by Bondzic et al. (Org. Lett., Vol. No. 23, 2010, 5434- 5437). According to this document, a-substituted acroleins can be oxidized by using diphenylprolinol diphenylmethylsilyl ether as catalyst. It is reported that bulky silyl groups on the tertiary alcohol give good results with a-substituted acroleins.
  • WO2009152474 A2 describes a process for the preparation of 3-amino-N-cyclopropyl-2- hydroxyalkane amide derivatives as key intermediates in the production of HCV inhibitors.
  • the synthesis route comprises a step of reacting an aminoaldehyde with a cyclopropyl isocyanide to obtain an 3-amino-2-hydroxycarboxylic acid amide.
  • Harbeson et al. J. Med. Chem. 1994, 37, 2918-2929 also describe the synthesis of 3-amino-2- hydroxycarboxylic acid amides by cyanide addition to an a-amino aldehyde, followed by hydrolysis of the cyanohydrin and amidation.
  • telaprevir intermediates are based on the use of organometallic catalysts for performing epoxidation reactions.
  • the use of such catalysts results in the presence of metal impurities in the final compound.
  • (S)-2- (diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine can advantageously be used for the stereoselective epoxidation of ⁇ , ⁇ -unsaturated aldehydes.
  • the process described herein may improve the synthesis of telaprevir.
  • the process described herein may for example allow avoiding the use of organometallic catalysts.
  • the process described herein can be used instead of a Sharpless epoxidation reaction that is commonly applied. Compared to the Sharpless epoxidation, the process described herein may require a less rigid temperature control, less toxic oxidants and avoids titanium waste. Moreover, the intermediate which is an epoxy acid can be converted into an ⁇ -amino acid in a "one pot" reaction, thus reducing process steps.
  • the present invention thus relates to a process for preparing telaprevir as defined in the claims. It also relates to processes for preparing intermediates of telaprevir and related compounds as defined in the claims. Furthermore, it relates to telaprevir/telaprevir dosage forms and an intermediate of telaprevir as defined in the claims.
  • Figure 1 Shows an example of a reaction scheme for the synthesis of an intermediate according to Formula 5a for the preparation of telaprevir.
  • Figure 2 Shows examples of reaction schemes for preparing compounds according to
  • Figure 3 Shows examples of reaction schemes for preparing compounds according to
  • the invention relates to a process for the preparation of telaprevir of Formula 1
  • telaprevir of formula 1 is prepared via the compounds of Formulas 2a, 4a, 4'a, 5a, 6, and 7.
  • Figure 1 shows an example of the process for preparing the intermediate compound according to Formula 5a.
  • Pharmaceutically acceptable salts may for example be selected from the group consisting of hydrochloride, hydrobromide, acetate, citrate, maleate, succinate, and lactate, benzoate.
  • Pharmaceutically acceptable salts can be obtained by standard methods, for example by addition of the respective acid to telaprevir as free base.
  • step (i) a compound of Formula 2a is provided:
  • R-i is a propyl group
  • R 2 is a hydrogen atom
  • step (i) includes dissolving the compound of Formula 2a in a solvent or mixture of solvents.
  • Suitable solvents can be chosen by a person skilled in the art of common practice.
  • inert solvents are used.
  • inert solvent refers to any solvents that do not react with the compounds described herein. Inert solvents suitable in this respect are commonly known.
  • the solvent(s) used in step (i)/(ii), (iii) and/or step (iv) is/are selected from the group consisting of ethylacetate, dichloromethane, N,N- dimethylacetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone, acetonitrile, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene and dimethylformamide, hydrocarbon solvents, for example hexane and heptane, alcohols, for example methanol and ethanol, and water; preferably, dichloromethane and water are used in step (i)/(ii), (iii) and/or step (iv).
  • solvents or mixtures thereof may also be used in other steps of the process described herein, where applicable.
  • Azidation reactions (in step iv) are preferably carried out in water.
  • a skilled person can choose a suitable way of bringing the compounds into contact with each other. This can for example be done by dissolving said compounds either separately or as a mixture of compounds or by dissolving one of the compounds and adding to this solution the respective other compound.
  • the order of combining the compounds can be chosen by a person skilled in the art.
  • the compound of Formula 2a is commercially available and can also be prepared by applying standard synthesis methods. It is preferably used with a purity of at least 97%.
  • step (ii) the compound of Formula 2a is brought into contact with a compound of Formula 3
  • R 5 is methyl or ethyl, preferably methyl (see Example 2).
  • the compound of Formula 3 is commercially available and can also be prepared by applying standard synthesis methods. It is preferably used with a purity of at least 97%.
  • the compound of Formula 3 is preferably used in stereochemical ⁇ pure form.
  • the enantiomeric purity of the compound of Formula 3 is >99%ee.
  • a comparison of the optical rotation is suitable.
  • stereochemical purity/enantiomeric purity can for example be determined by chiral high performance liquid chromatography (HPLC) as known in the art.
  • Step (ii) is performed in the presence of an oxidant, for example hydrogen peroxide, tBuOOH, cumene hydroperoxide, urea-hydrogen peroxide, preferably hydrogen peroxide, wherein step (ii) yields a compound of Formula 4a, when the compound of Formula 2a is oxidized:
  • an oxidant for example hydrogen peroxide, tBuOOH, cumene hydroperoxide, urea-hydrogen peroxide, preferably hydrogen peroxide
  • Ri can be selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof, preferably R-i has 1 -12 carbon atoms, in particular is a linear, branched, or cyclic aliphatic C r Ci 2 or C C 6 group, in addition R-i is preferably a saturated group.
  • R 2 can be selected from the group consisting of a hydrogen; alkoxy group; linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof; preferably R 2 is a hydrogen atom or linear, branched, or cyclic aliphatic C Ci 2 or Ci-C 6 group, in addition R 2 is preferably a saturated group; preferably, R 2 is hydrogen, an Ci- 6 aliphatic group or an d -6 alkoxy group; in particular R 2 is hydrogen. In the compound of Formula 4' R 2 is a hydroxyl group.
  • R 2 can be selected from the group consisting of a hydroxyl; alkoxy group; linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof; preferably R 2 is a linear, branched, or cyclic aliphatic Ci-C 12 or C C 6 group, in addition R 2 is preferably a saturated group, in particular, R 2 is an hydroxyl group in the compounds of Formulas 9a, 10a and 10'a.
  • R 4 can be selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof, preferably R 4 has 1-12 carbon atoms, in particular R 4 is a linear, branched, or cyclic aliphatic C-i-C 12 or an C 1-6 group, preferably, R 4 is saturated; for example R 4 is cyclopropyl.
  • Epoxidation of a compound of Formula 2 results in the formation of a compound of Formula 4. This is described in more detail below.
  • step (ii) the compound of Formula 3 can for example be used in an amount of 0.01-0.5, in particular 0.02-0.1 , equivalents based on the total amount of the compound of Formula 2/2a.
  • the reaction can be carried out at ambient temperature/room temperature.
  • Step (ii) can for example be carried out for at least 6 hours, preferably for up to 16 hours, at room temperature.
  • the oxidant for example hydrogen peroxide
  • the oxidant can for example be used in an amount of 1.0-1.5 equivalents based on the total amount of the compound of Formula 2/2a.
  • the compound of Formula 4/4a can be isolated and purified, for example it can be purified by filtration over a silicagel plug, for example by using a pentane/diethyl ether mixture.
  • the reaction products described herein can be isolated after each reaction step. Suitable methods for isolating compounds are known in the art and comprise for example the washing of the organic layer with an aqueous salt solution (e.g. brine), separation of the organic layer, drying of said organic layer and removal of the organic solvent in vacuo.
  • the work-up may further include acid and/or base washes.
  • the compounds may be purified by using chromatography techniques.
  • step (iii) R 2 in the compound of Formula 4a of step (ii) is oxidized, thereby obtaining a compound of Formula 4'a
  • Step (iii) can also be carried out with a compound of Formula 4 as described below.
  • the oxidizing agent in step (iii) can for example be selected from the group consisting of pyridinium chlorochromate (PCC), CrCVI-kSCVacetone (Jones reagent), RuCI 3 .2H 2 0/Nal0 4 , sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO); preferably, the oxidizing agent is sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO).
  • PCC pyridinium chlorochromate
  • CrCVI-kSCVacetone Jones reagent
  • RuCI 3 .2H 2 0/Nal0 4 sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO)
  • TEMPO 2,2,6,6- tetramethylpiperidinyloxy free radical
  • Step (iii) can for example be carried out for a time period of 10 minutes to 10 hours at a temperature of 15°C or below, preferably between 0° and 15°C.
  • the oxidizing agent can for example be used in catalytic amounts in the presence of stoichiometric co-oxidants.
  • a phase transfer catalyst preferably a quaternary ammonium salt, especially preferred is aliquate 336 (mixture of C8 (octyl) and C10 (decyl) chains (tricaprylylmethylammonium chloride trioctylmethylammonium chloride) with C8 predominating) can additionally be used.
  • aliquate 336 mixture of C8 (octyl) and C10 (decyl) chains (tricaprylylmethylammonium chloride trioctylmethylammonium chloride) with C8 predominating
  • step (iii) the compound of Formula 4'a/4' can be isolated, for example by extraction from the reaction mixture with an organic solvent.
  • step (iv) the compound of Formula 4'a/4' of step (iii) is subjected to reaction steps comprising (1 ) an azidation of the epoxide group;
  • step (3) performing an amide coupling reaction with cyclopropylamine in the presence of one or more coupling agents, either before or after said azidation/reduction step, wherein if the amine of step (2) is used for coupling with cyclopropylamine, said amine is protected with a protective group before the coupling reaction;
  • the above reaction step (3) can be carried out either before or after the azidation step and either before or after the reduction of the azide group (see Figure 3).
  • Azidation of the above ester and amide is described in WO2008029267 A2 and WO2007109023 A1.
  • step (iv) the compound of Formula 5a can be isolated, for example by extraction from the reaction mixture with an organic solvent.
  • the compound of Formula 5a can be purified by methods known in the art.
  • the azidation can for example be conducted by using NaN 3 in an amount of 1 to 2 equivalents based on the amount of the compound of Formula 4'a/4'.
  • the azidation can for example be conducted in the presence of 0.02 to 0.2 equivalents, preferably 0.1 equivalents Cu(N0 3 ) 2 .
  • Water can for example be used as solvent for the azidation.
  • Suitable conditions for carrying out azidation reactions are known in the art.
  • the azidation can be carried out at temperature of about 50°C-80°C for a period of 0.5 to 3 hours.
  • the azide group can be reduced in order to obtain an amine.
  • This reduction can for example be carried out by using hydrogen in the presence of palladium on charcoal and water or by using NaBH 4 in the presence of water. Suitable conditions for reducing azide groups are known in the art.
  • the reduction can be carried out by using hydrogen and Pd/C at room temperature for a period of 0.5 to 3 hours.
  • the amine coupling reaction in step (iv) and/or step (v) can for example be carried in the presence of a base and one or more coupling agents selected from the group consisting of dicyclohexylcarbodiimide (DCC), diispropylcarbodiimide (DIC), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1-hydroxy-benzotriazole (HOBt) or 1- hydroxy-7-aza-benzotriazole (HOAt), 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium- hexafluoro-phosphate (HBTU), 0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 0-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'
  • a preferred coupling agent used in step (v) is a substituted 1 ,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide, preferably a compound of Formula 8 R 3. O °
  • R 3 is a saturated or unsaturated, branched, cyclic or linear, substituted or unsubstituted C- o hydrocarbon compound, preferably, R 3 is n-propyl or phenyl.
  • preferred coupling agents are 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) and 2,4,6- triphenyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide. If a compound of Formula 8 is used as coupling agent, it is preferred to use it as the only coupling agent.
  • Also preferred coupling agents are carbodiimides such as diispropylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride and N,N'-dicyclohexylcarbodiimide.
  • Carbodiimides are known in the art. However, it is also possible to use other coupling agents known in the art such as uranium coupling agents.
  • uranium coupling agents For an overview of possible coupling reagents, reference is made to Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447-2467.
  • the amine coupling in step (iv) and/or step (v) can for example be carried by using an amount of 1 to 2 equivalents of cyclopropylamine based on the amount of the compound of Formula 5a and wherein the solvent is dichloromethane or dimethylformamide.
  • Suitable conditions for coupling reactions are known in the art. Reference is also made to the patent application EP12159923.7.
  • the reaction can be started at a temperature of about 0°C by adding all components and reaction is then completed at room temperature for a period of several hours such as 10-24 hours.
  • the total amount of coupling agent(s) that can be used in the processes described herein can for example be from 0.8 to 6 equivalents, preferably from 0.9 to 4 equivalents, further preferred from 1 to 2 equivalents, based on the total amount of the compound that is to be reacted with the amine compound (e.g. compound according to Formula 4'a, 9a, 10'). If more than one coupling agent is used, the different types of coupling agents can be used in the same or different amounts. For example, they can be used in an amount of more than 1 equivalent based on the amount of the compound that is to be reacted with the amine compound. Further preferred, each coupling agent is used in an amount of 1 to 2 equivalents.
  • step (iv) can for example be conducted in the following order (option a): (1 ) firstly conducting the azidation of the epoxide group of the compound of Formula 4'a step (iii), for example by conducting the azidation as described herein, thereby obtaining compound of Formula 9a
  • R-i is a propyl group
  • R 2 is a hydroxyl group
  • Ri is a propyl group
  • R 2 is a hydroxyl group
  • R 3 is a hydrogen atom
  • R 3 is a protective group, preferably a carbamate group, preferably a Boc group
  • Ri is a propyl group
  • R 3 is a protective group, preferably a carbamate group, preferably a Boc group
  • R 4 is cyclopropyl
  • protecting groups for the purpose of the invention are for example described in T. W. Greene & P.G.M Wuts, "Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons, Inc. (2006).
  • the deprotecting agent and conditions for carrying out the deprotection reaction can be chosen of common knowledge depending on the protective group that is used (see e.g. the afore-mentioned reference: T. W. Greene & P.G.M Wuts, "Protective Groups in Organic Synthesis”).
  • the reaction sequence is carried out without isolating the compound of Formula 9a, which is directly reduced with hydrogen in the presence of palladium on charcoal and the resulting compound of Formula 10a, wherein R 3 is hydrogen, is then brought into contact with Boc 2 0 either with diisopropylethylamine (DIPEAytetrahydrofurane (THF)/H 2 0 or NaOH/H 2 0/dioxane to provide the compound of Formula 10'a, wherein R 3 is Boc.
  • DIPEAytetrahydrofurane (THF)/H 2 0 or NaOH/H 2 0/dioxane to provide the compound of Formula 10'a, wherein R 3 is Boc.
  • step (iv) can for example be conducted in the following order (option b):
  • R 2 is a hydroxyl group
  • R-i is as defined above; and R 4 is cyclopropyl;
  • R 4 are defined above; and R 3 is hydrogen.
  • step (iv) can for example be conducted in the following order (option c): (1 ) subjecting the compound of Formula 4'a of step (iii) to said amine coupling reaction with cyclopropylamine in the presence of one or more coupling agents, thereby obtaining a compound of Formula 12a
  • Ft is as defined above; and R 4 is cyclopropyl;
  • Ri is as defined above; and R 4 is cyclopropyl;
  • R 4 are as defined above; and R 3 is hydrogen.
  • the solvent(s) used in steps (i)/(ii), (iii) and/or (iv) can for example be selected from the group consisting of ethylacetate, dichloromethane, ⁇ , ⁇ -dimethylacetamide, dimethyl sulfoxide, N- methylpyrrolidone, acetonitrile, methyl tert-butyl ether, methyltetrahydrofuran, tetrahydrofuran, toluene, dimethylformamide, hydrocarbon solvents, for example hexane and heptane, alcohols, for example methanol and ethanol, and water.
  • dichloromethane and water are used in step (ii) and (iii).
  • water is used in the azidation and reduction in step (iv) and DCM or DMF for the amidation of the free acid.
  • Suitable amount(s) of solvent(s) can be chosen by a person skilled in the art. The use of lower amounts of solvents leading to higher concentrations may provide for a faster reaction rate.
  • step (v) the compound of Formula 5a is brought into contact with a compound of Formula 6
  • the compound of Formula 6 can for example be prepared as described in the patent application EP12159923.7. It is also possible to prepare the compound of Formula 6 by applying the methods described in WO2010/126881. Regarding the methods and conditions for coupling the compounds of Formula 5a and 6 in order to obtain a compound of Formula 7, reference is also made to EP12159923.7 and WO2010/126881.
  • the compound of Formula 5a can be added in the form of a suspension (for example in dichloromethane) to a reaction mixture comprising the compound of Formula 6 and optionally the coupling agent(s).
  • said suspension can comprise an organic base, such as tertiary amine bases like diisopropylethylamine, N-methylmorpholine, and triethylamine, or an inorganic base such as potassium carbonate, sodium carbonate or sodium bicarbonate.
  • organic base such as tertiary amine bases like diisopropylethylamine, N-methylmorpholine, and triethylamine
  • inorganic base such as potassium carbonate, sodium carbonate or sodium bicarbonate.
  • a suitable reaction temperature for step (v) can be chosen by a person skilled in the art.
  • the step of combining the compound of Formula 5a with the other compounds can be carried out at 0°C to room temperature (for example for a time of 1 minute to 1 hour) and the reaction can then be completed at 0°C to 50°C (for example for a time of 1 hour to 12 hours).
  • the reaction mixture is quenched by addition of water followed by acidification.
  • the compound of Formula 7 is then isolated by using the same or a similar method as described above. Preferred coupling agents and amounts of coupling agents are described above.
  • the solvent(s) used in step (v)/(vi) is/are selected from the group consisting of ethylacetate, dichloromethane, ⁇ , ⁇ -dimethylacetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene and N,N- dimethylformamide, preferably toluene, N-methylpyrrolidone, ⁇ , ⁇ -dimethylacetamide, N,N- dimethylformamide, methyl tert-butyl ether, 2-methyltetrahydrofuran or dichloromethane, and most preferably N,N-dimethylacetamide, ⁇ , ⁇ -dimethylformamide, and dichloromethane, and most preferably N,N-dimethylformamide.
  • DMSO dimethyl sulfoxide
  • step (vi) the compound of Formula 7 is oxidized, thereby obtaining telaprevir of Formula 1 , or a pharmaceutically acceptable salt or solvate thereof.
  • telaprevir of Formula 1 or a pharmaceutically acceptable salt or solvate thereof.
  • the oxidizing agent in step (vi) is known to someone skilled in the art, preferably it is selected from the group of hypervalent iodine oxidants, comprising the Dess-Martin periodinane (1 ,1 ,1- Tris(acetyloxy)-1 ,1-dihydro-1 ,2-benziodoxol-3-(1 H)-one) or IBX (2-iodoxybenzoic acid), or sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO), preferably, the oxidizing agent sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO).
  • TEMPO 2,2,6,6- tetramethylpiperidinyloxy free radical
  • Suitable amounts of oxidizing agent(s) can be chosen by a person skilled in the art of common practice.
  • the oxidizing agent can be used in an amount of 0.9-2 equivalents, preferably, from 0.9 to 1.2 equivalents, based on the total amount of the compound of Formula 7.
  • TEMPO can be used in catalytic amounts. Particular suitable is a combination of a catalytic amount of TEMPO with KBr, NaHC0 3 , and NaOCI in dichloromethane. Process steps (v) and (vi) can be carried out as described in EP12159923.7 and WO2010/126881.
  • Step (vi) can additionally comprise adding compounds such as acids to the reaction mixture to provide pharmaceutically acceptable salts of telaprevir.
  • step (vi) comprises a further step of isolating telaprevir or a pharmaceutically acceptable salt or solvate thereof.
  • the obtained telaprevir or its pharmaceutically acceptable salt or solvate is precipitated and for example filtered off, washed with solvent and dried.
  • a flash chromatography may be applied for purification. It is also preferred to isolate telaprevir, or a pharmaceutically acceptable salt or solvate thereof by crystallization.
  • telaprevir of Formula 1 a pharmaceutically acceptable salt or solvate thereof is obtained in amorphous form, crystalline form or as cocrystals.
  • the present invention also refers to a process for the preparation of a compound of Formula 4
  • F ⁇ is as defined above, for example Ri is a propyl group; and R 2 is as defined above, for example R 2 is a hydrogen atom;
  • Step (ii) can be carried out as described in relation to the compound of Formula 2a herein.
  • the invention also related to a process for the preparation of a compound of Formula 9 or 10
  • Step (a) includes providing a compound of Formula 4
  • Ri and R 2 are as defined above, by applying any methods for preparing a compound of Formula 4 as described herein. If R 2 is hydrogen in the compound of Formula 4, the compound of Formula 4 is oxidized to provide Formula 4' wherein R 2 is hydroxyl.
  • Step (b) includes subjecting the compound of Formula 4/4' to reaction steps of:
  • step (b) in the afore-mentioned process can be carried out by
  • R 3 is hydrogen
  • the invention also relates to a process for the preparation of a compound of Formula 5
  • R 4 is as defined above, for example R 4 is cyclopropyl
  • R 2 is as defined above, for example R 2 is a hydroxyl group; wherein the compound of Formula 9 can be prepared by using the methods described herein;
  • R 2 is as defined above; for example is a propyl group; R 2 is as defined above, for example R 2 is a hydroxyl group; and R 3 is hydrogen, by applying the process as described herein;
  • R 3 is a protective group, preferably a carbamate group, preferably a Boc group
  • R 4 is as defined above, for example cyclopropyl and R 3 is a protective group
  • the invention also refers to a process for the preparation of a pharmaceutical composition or pharmaceutical dosage form comprising telaprevir of Formula 1 , or a pharmaceutically acceptable salt or solvate thereof, comprising the process steps as described herein, and further comprising formulating the obtained telaprevir of Formula 1 , or a pharmaceutically acceptable salt or solvate thereof into a pharmaceutical composition or pharmaceutical dosage form.
  • the preparation comprises the process steps as described above and further comprises formulating the obtained telaprevir of Formula 1 or a pharmaceutically acceptable salt or solvate thereof (the aforementioned compounds may also be referred to as active pharmaceutically compounds, API) into a pharmaceutical composition or pharmaceutical dosage form.
  • the step of formulating the API into a dosage form may be carried out by applying techniques known in the art.
  • the API can be formulated into tablets by using direct compression, dry or wet granulation processes, spray-coating processes or the like.
  • the API may be formulated as an acid solution or as a solid.
  • the invention also refers to a compound of Formula 5a or a composition comprising a compound of Formula 5a
  • R 3 is hydrogen; and R 4 is cyclopropyl; obtainable or obtained by the process described herein, wherein the compound of Formula 5 or the composition comprising a compound of Formula 5a has a metal content such as titanium or ruthenium content of less than 20 ppm.
  • the invention also refers to telaprevir of Formula 1 or a composition comprising telaprevir of Formula 1
  • Telaprevir of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, which is prepared by using the process described herein has an epimeric impurity which is the same as 6/depends on the purity of 6.
  • a further aspect relates to telaprevir of Formula 1 , a pharmaceutically acceptable salt or solvate thereof, obtainable or obtained by the process described herein.
  • 3-amino-2-hydroxyhexanoic acid (compound of Formula 10a) was dissolved in 1 M NaOH (10mL) and a solution of Boc 2 0 (1.7g, 8mmol) in dioxane (10mL) was added. After 3.5h at rt, water was added and the aqueous layer extracted with Et 2 0. The pH of the aqueous layer was adjusted to pH 2 with 2M HCI and extracted with Et 2 0. The combined ethereal layers were dried over Na 2 S0 4 and the solvent was removed under reduced pressure.
  • Bondzic et al. "Asymmetric epoxidation of a-substituted acroleins catalyzed by diphenylprolinol silyl ether" (Org. Lett., Vol. No. 23, 2010, 5434-5437);

Abstract

L'invention concerne un procédé de préparation de dérivés d'acides ß-amino, lequel procédé peut être utilisé pour la préparation de télaprévir ou d'un sel ou solvate pharmaceutiquement acceptable de celui-ci, le procédé mettant en jeu une réaction d'époxydation organocatalytique qui évite l'utilisation de catalyseurs de titane et, par conséquent, évite la contamination du produit final par du titane tel que présent dans des produits connus. Un autre mode de réalisation concerne le télaprévir, un sel ou solvate pharmaceutiquement acceptable de celui-ci, ainsi qu'un produit intermédiaire pour sa préparation, les produits mentionnés ci-dessus étant obtenus par le procédé décrit dans la présente invention.
PCT/EP2013/062732 2012-06-20 2013-06-19 Procédé de préparation de dérivés d'acides ss-amino et utilisation dudit procédé pour la préparation de télaprévir WO2013189978A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12172776 2012-06-20
EP12172776.2 2012-06-20

Publications (1)

Publication Number Publication Date
WO2013189978A1 true WO2013189978A1 (fr) 2013-12-27

Family

ID=48652092

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/062732 WO2013189978A1 (fr) 2012-06-20 2013-06-19 Procédé de préparation de dérivés d'acides ss-amino et utilisation dudit procédé pour la préparation de télaprévir

Country Status (1)

Country Link
WO (1) WO2013189978A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022459A2 (fr) 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Procedes et intermediaires
WO2007109023A1 (fr) 2006-03-16 2007-09-27 Vertex Pharmaceuticals Incorporated Procédés et intermédiaires pour la synthèse de composés stériques
WO2008029267A2 (fr) 2006-09-06 2008-03-13 Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnik Hydrochlorures de 3-amino-2-hydroxycarboxamides
EP2039689A1 (fr) 2006-05-26 2009-03-25 Kaneka Corporation Procédé de production de dérivés optiquement actifs de cyclopropylamide d'acide 3-amino-2-hydroxypropionique et de leurs sels
WO2009152474A2 (fr) 2008-06-13 2009-12-17 Virobay, Inc. Procédé de préparation de dérivés de (3s)-3-amino-n-cyclopropyl-2-hydroxyalcanamide
WO2010126881A1 (fr) 2009-04-27 2010-11-04 Vertex Pharmaceuticals Incorporated Procédés et intermédiaires

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022459A2 (fr) 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Procedes et intermediaires
WO2007109023A1 (fr) 2006-03-16 2007-09-27 Vertex Pharmaceuticals Incorporated Procédés et intermédiaires pour la synthèse de composés stériques
EP2039689A1 (fr) 2006-05-26 2009-03-25 Kaneka Corporation Procédé de production de dérivés optiquement actifs de cyclopropylamide d'acide 3-amino-2-hydroxypropionique et de leurs sels
WO2008029267A2 (fr) 2006-09-06 2008-03-13 Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnik Hydrochlorures de 3-amino-2-hydroxycarboxamides
WO2009152474A2 (fr) 2008-06-13 2009-12-17 Virobay, Inc. Procédé de préparation de dérivés de (3s)-3-amino-n-cyclopropyl-2-hydroxyalcanamide
WO2010126881A1 (fr) 2009-04-27 2010-11-04 Vertex Pharmaceuticals Incorporated Procédés et intermédiaires

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
AVOLIO ET AL., BIOORG. MED. CHEM. LETT, vol. 19, 2009, pages 2295 - 2298
BONDZIC ET AL., ORG. LETT., vol. 23, 2010, pages 5434 - 5437
BONDZIC ET AL.: "Asymmetric epoxidation of a-substituted acroleins catalyzed by diphenylprolinol silyl ether", ORG. LETT., vol. 23, 2010, pages 5434 - 5437
FRANCESCO FRINGUELLI ET AL: "First One - Pot Copper-Catalyzed Synthesis of [alpha]-Hydroxy-[beta]-Amino Acids in Water. A New Protocol for Preparation of Optically Active Norstatines", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 68, no. 18, 1 September 2003 (2003-09-01), pages 7041 - 7045, XP055065783, ISSN: 0022-3263, DOI: 10.1021/jo034752y *
FRANCOIS MALTAIS ET AL: "In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats", JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 24, 24 December 2009 (2009-12-24), pages 7993 - 8001, XP055054210, ISSN: 0022-2623, DOI: 10.1021/jm901023f *
FRINGUELLI: "First Efficient Regio- and Stereoselective Metal-Catalyzed Azidolysis of 2,3-Epoxycarboxylic Acids in Water", SYNLETT, vol. 2000, no. 03, 1 January 2000 (2000-01-01), pages 311 - 314, XP055077517, ISSN: 0936-5214, DOI: 10.1055/s-2000-6541 *
GUI-LING ZHAO ET AL: "Amine-Catalyzed Asymmetric Epoxidation of [alpha],[beta]-Unsaturated Aldehydes", ADVANCED SYNTHESIS & CATALYSIS, vol. 349, no. 7, 7 May 2007 (2007-05-07), pages 1210 - 1224, XP055077494, ISSN: 1615-4150, DOI: 10.1002/adsc.200600529 *
HAN, S.-Y.; KIM, Y.-A., TETRAHEDRON, vol. 60, 2004, pages 2447 - 2467
HARBESON ET AL., J. MED. CHEM., vol. 37, 1994, pages 2918 - 2929
HARBESON ET AL.: "Stereospecific synthesis of peptidyl a-keto amides as inhibitors of calpain", J. MED. CHEM., vol. 37, 1994, pages 2918 - 2929
JØRGENSEN, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 127, 2005, pages 6964
JØRGENSEN: "Asymmetric organocatalytic epoxidation of a,fi-unsaturated aldehydes with hydrogen peroxide", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 127, 2005, pages 6964
SUNDEN H ET AL: "Direct organocatalytic asymmetric epoxidation of alpha,beta-unsaturated aldehydes", TETRAHEDRON LETTERS, PERGAMON, vol. 47, no. 1, 2 January 2006 (2006-01-02), pages 99 - 103, XP025005006, ISSN: 0040-4039, [retrieved on 20060102], DOI: 10.1016/J.TETLET.2005.10.128 *
T. W. GREENE; P.G.M WUTS: "Protective Groups in Organic Synthesis 4th Edition,", 2006, JOHN WILEY & SONS, INC.
T. W. GREENE; P.G.M WUTS: "Protective Groups in Organic Synthesis", 2006, JOHN WILEY & SONS, INC., pages: 701 - 802

Similar Documents

Publication Publication Date Title
US8367847B2 (en) Production of monatin enantiomers
EP3297678B1 (fr) Procédé perfectionné de préparation de carfilzomib ou de sels pharmaceutiquement acceptables de celui-ci
JP5593342B2 (ja) ドセタキセルの製造方法
EP2382198B1 (fr) Procédés et intermédiaires pour préparer un inhibiteur macrocyclique de protéase du vhc
WO2019043724A1 (fr) Procédés pour la préparation de l'acide (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tétrahydroisoquinoléine-6-carboxamido)-3-(3-(méthylsulfonyl)phényl)propanoïque et de polymorphes de celui-ci
CN103687489A (zh) 制备5-氮杂螺[2.4]庚烷-6-甲酸及其衍生物的方法
US8431733B2 (en) Process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyalkanamide derivatives
WO2009074020A1 (fr) Amides n-substitués par alpha-amino, composition pharmaceutique les contenant et leurs utilisations
CN111018901B (zh) 扎那米韦和拉那米韦的中间体及其合成方法
WO2007099843A1 (fr) DÉRIVÉ α,β-INSATURÉ DE CYCLOHEXANONE, PROCÉDÉ DE SYNTHÈSE DUDIT DÉRIVÉ ET PROCÉDÉ DE SYNTHÈSE D'UN INTERMÉDIAIRE DE LADITE SYNTHÈSE
CN106278928B (zh) 一种磷酸奥司他韦异构体杂质的合成方法
WO2013189978A1 (fr) Procédé de préparation de dérivés d'acides ss-amino et utilisation dudit procédé pour la préparation de télaprévir
US8143448B2 (en) Process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyalkanamide derivatives
EP2801566A1 (fr) Procédé pour la préparation d'un inhibiteur de la protéase virale et ses intermédiaires
AU2003256861B2 (en) Methods and compositions for converting taxane amides to paclitaxel or other taxanes
WO2013189980A1 (fr) Synthèse de télaprévir et de bocéprévir, ou de sels ou de solvates pharmaceutiquement acceptables de ceux-ci et produits intermédiaires correspondants, notamment des acides ss-aminés, préparés par addition aldolique de mukaiyama
WO2016020403A1 (fr) Préparation d'un dérivé d'acide benzoïque et son utilisation pour la préparation de suvorexant
US20170298093A1 (en) Process for the Preparation of (S)-4-Methyl-N-((S)-1-(((S)-4-Methyl-1-((R)-2-Methyloxiran-2-YL)-1-OXO Pentan-2-YL) Amino)-1-OXO-3-Phenylpropan-2-YL)-2-((S)-2-(2-Morpholinoacetamido)-4-Phenylbutanamido) Pentanamide
JP5704763B2 (ja) トランス−４−アミノシクロペンタ−２−エン−１−カルボン酸誘導体の製造
KR102152445B1 (ko) 의약품 합성용 중간체 화합물의 제조 방법
AU711057B2 (en) 2-azabicyclo(2,2,1)heptane derivatives, their preparation and their application
WO2023137007A1 (fr) Procédés de préparation d'acide 4,6,7-trifluoro-1h-indole-2-carboxylique
JP6205530B2 (ja) パクリタキセル及びドセタキセルの側鎖前駆体の製造方法
WO2019066578A1 (fr) Procédé de préparation d'un composé intermédiaire pour une synthèse pharmaceutique
RU2588132C2 (ru) Способы и промежуточные соединения для получения макроциклического ингибитора протеазы вируса гепатита с

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: 13729737

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: 13729737

Country of ref document: EP

Kind code of ref document: A1