WO2013177713A1 - Procédé de préparation d'un agent antifolate - Google Patents

Procédé de préparation d'un agent antifolate Download PDF

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Publication number
WO2013177713A1
WO2013177713A1 PCT/CA2013/050419 CA2013050419W WO2013177713A1 WO 2013177713 A1 WO2013177713 A1 WO 2013177713A1 CA 2013050419 W CA2013050419 W CA 2013050419W WO 2013177713 A1 WO2013177713 A1 WO 2013177713A1
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Prior art keywords
compound
process according
formula
hydrocarbon
organic solvent
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PCT/CA2013/050419
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English (en)
Inventor
Walter Giust
Ryan BURTON
Boris Gorin
Joshua Clayton
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Alphora Research Inc.
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Publication of WO2013177713A1 publication Critical patent/WO2013177713A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

Definitions

  • the specification relates to a process for preparation of an antifolate agent, and intermediates useful therein.
  • 10-Propargyl-lO-deazaaminopterin (10-propargyl-lOdAM) has been disclosed as an antifolate designed to accumulate preferentially in cancer cells, blocking or slowing critical enzymes involved in DNA synthesis and subsequently causing cell death.
  • 10-propargyl-lOdAM was disclosed by Degraw et al., "Synthesis and Antitumour Activity of 10-Propargyl-lOdeazaaminopterin", J. Medical Chem., 36 : 2228-2231 (1993) (incorporated herein by reference), to act as an inhibitor of growth in the murine L1210 cell line and to a lesser extent on the enzyme dihydrofolate reductase.
  • 10-propargyl-lOdAM is also known as pralatrexate, and has been commercially marketed as FolotynTM, as an anti-cancer therapeutic.
  • the IUPAC name disclosed for pralatrexate is /V-(4- ⁇ l-[(2,4-diaminopteridin-6-yl)methyl]but- 3-yn-l-yl ⁇ benzoyl)-L-glutamic acid, having the chemical structure shown below.
  • Figure 1 shows high performance liquid chromatography (HPLC) analysis of the compound of formula 9b;
  • Figure 2 shows high performance liquid chromatography (HPLC) analysis of the compound of formula 7b;
  • Figure 3 shows high performance liquid chromatography (HPLC) analysis of the compound of formula 6a
  • Figure 4 shows high performance liquid chromatography (HPLC) analysis of the compound of formula 5a;
  • Figure 5 shows high performance liquid chromatography (HPLC) analysis of the compound of formula 4a
  • Figure 6 shows high performance liquid chromatography (HPLC) analysis of the compound of formula 2a
  • the specification discloses a process for preparation of the compound of formula 7, the process containing the steps of:
  • the specification discloses a process for preparation of the compound of formula 6, the process containing the steps of:
  • the specification relates to a process for preparation of the compound of formula 4, the process including the steps of:
  • R, R 1 and LG are as disclosed herein.
  • the specification relates to a process for preparation of the compound of formula 9, the process including the steps as disclosed herein.
  • the specification discloses a process for preparation of the compound of formula 7, the process containing the steps of:
  • Y and Z each independently is N or CR 3 , wherein R 3 is H or Ci -3 hydrocarbon;
  • R is OH, OM, or a functional group replaceable by N in the compound of formula 8, where M is an alkali or alkali earth metal;
  • R 1 is H or a Ci -6 hydrocarbon
  • each R 2 is OH or XR 4 , where X is 0, NH or S and R 4 is H or Ci-io hydrocarbon, optionally substituted with one or more heteroatoms.
  • the step of coupling the compound of formula 6 with the compound of formula 8 is not particularly limited.
  • the coupling step is performed using a coupling agent, and can include coupling agents used for peptide coupling reactions.
  • the coupling agent used in the coupling reaction is, for example and without limitation, benzotriazol-l-yl-oxytripyrrolidinophosphonium
  • the coupling reaction can be carried out by having an R group in the compound of formula 6 that can be replaced by the N in the compound of formula 8.
  • the method for performing such a coupling reaction is also not particularly limited.
  • the R group along with the carbonyl functionality in the compound of formula 6 forms an activated ester, which can react with the compound of formula 8 to form the compound of formula 7.
  • alkali and alkali earth metal as used herein is not particularly limited and should be known to a skilled worker.
  • Alkali metals excluding hydrogen (H), make-up the group 1 elements of the periodic table, and can include lithium (Li), sodium (Na), potassium (K), rubidium (Rb), caesium (Cs), and francium (Fr).
  • the alkali metal used in accordance with the description is lithium (Li), sodium (Na) or potassium (K).
  • Alkali earth metals make-up the group 2 elements of the periodic table, and can include beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), and radium (Ra).
  • Be beryllium
  • Mg magnesium
  • Ca calcium
  • Sr strontium
  • Ba barium
  • Ra radium
  • the alkali earth metal used in accordance with the description is magnesium (Mg) or calcium (Ca).
  • the reaction can be quenched in an aqueous medium to precipitate the compound of formula 7.
  • the organic solvent used for the coupling reaction can be miscible with the aqueous medium .
  • organic solvents miscible with water can include, dimethylformamide (DMF), tetrahydrofuran (THF), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), acetone or acetonitrile.
  • the solvent used for the coupling reaction is, for example and without limitation, dimethylformamide (DMF).
  • aqueous medium for precipitating the compound of formula 7 is not particularly limited, and should be known to a skilled worker.
  • Aqueous medium includes a solvent system that contains predominantly water.
  • the aqueous medium is water. It has been found that compound of formula 7 having high purity can be obtained upon analysis by HPLC ( Figure 2).
  • the step of separating the compound of formula 7 is also not particularly limited and should be known to a skilled worker, or can be determined. In one embodiment, for example and without limitation, the step of separating the compound of formula 7 is performed by filtering the compound of formula 7.
  • hydrocarbon refers to a group that contains hydrogen and carbon, linked generally via a carbon backbone, but can optionally include heteroatoms.
  • Hydrocarbyl groups include, but are not limited to alkyl, aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this specification.
  • alkyl as used herein is not particularly limited and should be known to a person of skill in the art; and refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.
  • the alkyl group is a Ci -6 alkyl.
  • Ci -6 hydrocarbon may be, for example, and without limitation, any straight or branched Ci -6 alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 1,2-dimethylpropyl, 2-methylbutyl, 1,2-dimethylbutyl, 1- ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethyl
  • the C 2- 6 hydrocarbon can include an alkenyl or alkynyl group.
  • alkenyl and alkynyl groups should be known to a skilled worker.
  • R 1 is an alkynyl group, and is propargyl (HCCCH 2 -).
  • aryl as used herein is not particularly limited, and should be known to a person of skill in the art.
  • the aryl group is a C 6- i 4 aryl.
  • aryl includes 5-, 6-, and 7-membered substituted or unsubstituted single-ring aromatic groups that can have one or more
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • aryl include, for example and without limitation, benzene, pyridine, naphthalene, phenanthrene, phenol, aniline, anthracene, and phenanthrene.
  • heteroatom is not particularly limited and should be understood by a skilled worker.
  • the term means an atom of any element other than carbon or hydrogen.
  • heteroatoms include nitrogen, oxygen, and sulfur.
  • the coupling reaction as noted above can be carried out in the presence of a base.
  • the type of base used is not particularly limited, and can be selected so that the base can be separated from the compound of formula 7.
  • the base used is pyridine, imidazole, benzimidazole or a tertiary amine.
  • Tertiary amine bases should be known to a skilled worker and are not particularly limited.
  • the tertiary base is triethylamine (Et 3 N).
  • the base used can be separated during the precipitation process, by selecting a base that remains dissolved in reaction mixture, while the compound of formula 7
  • the specification relates to a process for preparation of the compound of formula 6, the process containing the steps of
  • Y and Z each independently is N or CR 3 , wherein R 3 is H or Ci -3
  • R is OH, OM or OR 5 , where M is an alkali or alkali earth metal and R 5 is Ci-14 hydrocarbon, optionally substituted with one or more heteroatoms; and
  • R 1 is H or a Ci -6 hydrocarbon.
  • the step of decarboxylating the compound of formula 5 is not particularly limited and should be known to a skilled worker on can be determined.
  • the decarboxylation is carried out at elevated temperatures.
  • the elevated temperature is not particularly limited and can include temperatures from 100 to 150°C, and values in between.
  • decarboxylation is carried out from 110 to 140°C or 120 to 130°C, or any values in between.
  • decarboxylation is carried out at a temperature of about 120°C.
  • the term "about” as used herein, relates to ⁇ 10% of the value noted.
  • the temperature selected should avoid or minimize decomposition of the reaction product.
  • decarboxylation at temperatures as low as 25°C and as high as 200°C have been used with good results.
  • the solvent used for carrying out the decarboxylation reaction is not particularly limited, so long as the solvent is miscible with an aqueous medium and can allow precipitation of the compound of formula 6 upon quenching the decarboxylation reaction with the aqueous medium . Therefore, in one embodiment, for example and without limitation the decarboxylation reaction is carried out in an organic solvent miscible with an aqueous medium .
  • the organic solvent is, for example and without limitation, dimethylformamide (DMF), dimethylsulfoxide (DMSO), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), pyridine, pyrimidine or N-methyl-2-pyrrolidone (NMP).
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • NMP N-methyl-2-pyrrolidone
  • the method of quenching the reaction is not particularly limited. In one embodiment, for example and without limitation, it can involve diluting the decarboxylation reaction with an aqueous medium, where the term "aqueous medium" is as described herein above.
  • the decarboxylation reaction is quenched in an aqueous basic medium as described herein, and can also include , for example and without limitation, aqueous sodium hydroxide or aqueous potassium hydroxide.
  • the product obtained can then be recrystallized to obtain the purified product.
  • the solvent used for recrystallization is not particularly limited. In one embodiment, for example and without limitation, the solvent used for
  • recrystallization is aqueous methanol, aqueous ethanol, aqueous propanol, aqueous isopropanol (IPA), or mixtures thereof.
  • the solvent used for recrystallization is isopropanol ( Figure 3).
  • pH adjustment of the mixture can be carried out prior to filtration of the compound of formula 6.
  • the pH is adjusted with an acid prior to filtering the precipitate.
  • the pH adjustment with an acidic medium is not particularly limited, so long as decomposition of the product can be avoided or can be
  • the pH is adjusted to a range from 4.0 to 6.0 and values in between.
  • the pH is adjusted to about 5.5.
  • the acid used herein is not particularly limited and should be known to a skilled worker.
  • An acid can be considered as a substance that can act as a proton donor (Bronsted-Lowry acid).
  • the acid used in the process disclosed herein is, for example and without limitation, hydrochloric acid (HCI), hydrobromic acid (HBr), acetic acid (CH 3 C0 2 H), sulfuric acid (H 2 S0 4 ) or p- toluenesulfonic acid (p-TSA).
  • the acid is acetic acid.
  • further pH adjustment/treatment following the treatment with acid, can be carried out on the precipitate in an aqueous medium .
  • the filtered precipitate can be treated in an aqueous basic solution.
  • the pH of the basic solution is not particularly limited, so long as decomposition of the product can be avoided or can be minimized.
  • the pH is adjusted to a range from 9.0 to 11.0 and values in between.
  • the base used is not particularly limited and should be known to a skilled worker.
  • a base can be considered as a substance that can accept hydrogen ions (protons) or donate an electron pair.
  • the base used in the process disclosed herein is an inorganic base and can include, for example and without limitation, sodium hydroxide (NaOH), potassium hydroxide (KOH) or lithium hydroxide (LiOH).
  • the suspension can be filtered and the precipitate obtained can be treated with an aqueous acidic solution, similar to the method described above. It has been found that the precipitation and pH adjustments/treatment of the precipitate, as described above, can provide a product having high purity, based on HPLC analysis. In one embodiment, for example and without limitation, the purity of the compound of formula 6 is >99%, >99.0%, >99.5% or >99.9% as determined by HPLC. [0043] In a further aspect, as noted above, the specification relates to a process for preparation of the compound of formula 4, the process including the steps of:
  • Y and Z each independently is N or CR 3 , wherein R 3 is H or Ci -3 hydrocarbon;
  • R is OR 5 , where R 5 is d-i 4 hydrocarbon, optionally substituted with one or more heteroatoms;
  • R 1 is H or a Ci -6 hydrocarbon
  • LG is a leaving group
  • the coupling reaction of the compound of formula 2 with the compound of formula 3, to form the compound of formula 4, is not particularly limited.
  • the coupling reaction is carried out in an organic solvent miscible with water in the presence of a base.
  • the organic solvent used can include the organic solvents which are noted herein.
  • the base is not particularly limited and should be known to a skilled worker or can be determined.
  • the base used for the coupling reaction should be strong enough to allow deprotonation of the compound of formula 2.
  • suitable bases can include, for example and without limitation, lithium
  • LDA diisopropylamide
  • NaHMDS sodium bis(trimethylsilyl)amide
  • KHMDS potassium bis(trimethylsilyl)amide
  • NaH sodium hydride
  • a leaving group (abbreviation used within this application : LG) as disclosed herein is a molecular fragment or stable species that can be detached from a molecule in a bond-breaking step.
  • the leaving group in accordance with the specification, is not particularly limited and should be known to a person of skill in the art or can be determined .
  • the ability of a leaving group to depart is correlated with the pK a of the conjugate acid, with lower pK a being associated with better leaving group ability.
  • Examples of leaving group include, without lim itation, halide or a sulfonate.
  • Halides can include, for example, CI, Br or I.
  • sulfonates can include, without limitation, nonaflate, triflate, fluorosulfonate, tosylate, mesylate or besylate.
  • the leaving group is bromide.
  • R is OR 5 , where R 5 is d-i 4 hydrocarbon, optionally substituted with one or more heteroatoms;
  • R 1 is a Ci-6 hydrocarbon
  • LG is a leaving group
  • the coupling of the compound of formula 1 with LG-R 1 can be carried out in a non-alcoholic organic solvent.
  • the compound of formula 1 is deprotonated using a base, followed by reaction with LG-R 1 .
  • the nonalcoholic organic solvent is not particularly limited and should be known to a skilled worker.
  • a non-alcoholic organic solvent can include, for example and without limitation, dimethylformamide (DMF), tetrahydrofuran (THF), l,3-dimethyl-3, 4,5,6- tetrahydro-2(lH)-pyrimidinone (DMPU), acetone or acetonitrile.
  • the selected nonalcoholic solvent can also be a solvent that does not form a hazardous combination with the base, such as the combination of dimethylformamide (DMF) with sodium hydride (NaH) as disclosed in prior processes for preparation of pralatrexate.
  • the base used is not particularly limited and should be known to a skilled worker or can be determined.
  • the base used for the coupling reaction should be strong enough to allow deprotonation of the compound of formula 1.
  • suitable bases can include, for example and without limitation, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS) or sodium hydride (NaH).
  • the reaction can be quenched using, for example and without limitation, an acid.
  • the type of acid used is not particularly limited, and can include the acids noted herein above.
  • the reaction mixture can be concentrated to remove substantially all of the non-alcoholic organic solvent and replaced with an alcoholic solvent. Additional processing steps, such as, for example and without limitation, extraction and filtration can be carried out during the process.
  • alcoholic solvent is not particularly limited and should be understood by a skilled worker.
  • An alcohol can be considered as an organic compound having a hydroxyl (-OH) functional group attached to a carbon atom.
  • alcoholic solvents can include, for example and without limitation, methanol, ethanol, propanol, isopropanol, butanol, isobutanol or sec-butanol. In one embodiment, the alcoholic solvent is isopropanol.
  • Homoterepthalic acid dimethyl ester (la) is deprotonated with potassium hexamethyldisilazide (KHMDS) followed by reaction with propargyl bromide.
  • KHMDS potassium hexamethyldisilazide
  • the reaction can be carried out in tetrahydrofuran (THF) under conditions that avoid use of the hazardous combination of sodium hydride (NaH)
  • Compound 2a is deprotonated followed by coupling with the compound of formula 3a.
  • the coupling reaction can be carried out in an organic solvent that is miscible with an aqueous medium, such as water. Upon completion of the reaction, the reaction is quenched with the aqueous medium.
  • the amount of aqueous medium can vary and should be sufficient to allow precipitation of the compound of formula 4a. In one embodiment, the amount of aqueous medium is from about 1 to about 10 times, and values in between, such as, 2, 3, 4, 5, 6, 7, 8 or 9, to the volume of the organic solvent used to carry out the reaction.
  • the precipitate can be separated and washed to provide compound of formula 4a having high purity ( Figure 5).
  • IPA isopropanol
  • Compound of formula 6a is coupled with the compound of formula 8a to form the compound of formula 7b.
  • the reaction can be carried out in an organic solvent using a coupling agent.
  • the reaction is quenched/diluted with an aqueous medium, under conditions similar to those described above to obtain a precipitate (compound of formula 7b).
  • the compound of formula 7b is isolated and washed to provide compound 7b in high purity ( Figure 2).
  • Treatment of the compound of formula 7b with a basic solution, followed by separation and pH adjustment to an acidic medium yields the compound of formula 9b in high purity ( Figure 1).
  • Determination of purity by HPLC [0061] Determination of the purity of the compounds as disclosed herein can be determined by High Pressure Liquid Chromatography (HPLC) as known in the art.
  • HPLC High Pressure Liquid Chromatography
  • the substance of interest is dissolved in a suitable solvent, for example in an organic solvent such as ethanol and subjected to HPLC.
  • the elution profile of the substance of interest and of any potential impurities or degradation products is recorded.
  • the percentage of purity of the substance of interest for example can then be calculated by determining the area below the peak of the substance of interest and separately the area below the peaks of all other substances eluted from the HPLC column.
  • EXAMPLE 6 COMPOUND 7b [0075] Compound 6a (16g), compound 8a (8.9g) and recrystallized benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (27g) was dissolved in dimethyl formamide (DMF) (160ml). To the solution at room temperature (rt) was added dropwise triethylamine (Et 3 N) (8.7g) over 10 mins. The reaction mixture was stirred 4-8 hrs at rt until compound 6a was consumed. The reaction mixture was charged dropwise into water (800m l) over 1 hr at which time a yellow precipitate forms. This solid was collected by vacuum filtration and re- slurried in water yielding Compound 7b (21g) with a purity of about 99% as indicated by HPLC analysis.
  • DMF dimethyl formamide
  • Et 3 N triethylamine
  • Y and Z each independently is N or CR 3 , wherein R 3 is H or Ci -3 hydrocarbon;
  • R is OH, OM, or a functional group replaceable by N in the compound of formula 8, where M is an alkali or alkali earth metal;
  • R 1 is H or a Ci -6 hydrocarbon; and [0086] each R 2 is OH or XR 4 , where X is 0, N H or S and R 4 is H or Ci-io hydrocarbon, optionally substituted with one or more heteroatoms.
  • BOP hexafluorophosphate
  • each R 2 is XR 4 , where X is 0, NH or S and R 4 is H or Ci-io hydrocarbon, optionally substituted with one or more heteroatoms, the process further containing the step of hydrolyzing the compound to form the compound of formula 7 where R 2 is OH .
  • Y and Z each independently is N or CR 3 , wherein R 3 is H or Ci -3 hydrocarbon;
  • R is OH, OM or OR 5 , where M is an alkali or alkali earth metal and R 5 is Ci-14 hydrocarbon, optionally substituted with one or more heteroatoms; and
  • R 1 is H or a Ci -6 hydrocarbon.
  • [00112] 20 The process according to embodiment 19, wherein the decarboxylation reaction is carried out in an organic solvent miscible with water.
  • the organic solvent is dimethylformamide (DM F), dimethylsulfoxide (DMSO), 1,3-dimethyl- 3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DM PU), pyridine, pyrimidine or N-methyl- 2-pyrrolidone (N M P).
  • DM F dimethylformamide
  • DMSO dimethylsulfoxide
  • DM PU 1,3-dimethyl- 3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • N M P N-methyl- 2-pyrrolidone
  • [00130] 33 The process according to any one of embodiments 26 to 32, wherein the pH adjustment to an acidic range is carried out using an acid, and wherein the acid is hydrochloric acid, sulfuric acid, acetic acid or formic acid.
  • aqueous basic medium is aqueous sodium hydroxide, aqueous potassium hydroxide or aqueous lithium hydroxide.
  • Y and Z each independently is N or CR 3 , wherein R 3 is H or Ci -3 hydrocarbon; [00151] R is OR 5 , where R 5 is d-i 4 hydrocarbon, optionally substituted with one or more heteroatoms;
  • R 1 is H or a Ci -6 hydrocarbon; and [00153] LG is a leaving group.
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • acetone acetonitrile
  • DMSO dimethylsulfoxide
  • DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • NMP N-methyl-2-pyrrolidone
  • R is OR 5 , where R 5 is d-i 4 hydrocarbon, optionally substituted with one or more heteroatoms;
  • R 1 is a Ci -6 hydrocarbon
  • LG is a leaving group.
  • [00173] 59 The process according to embodiment 58, wherein the coupling reaction is quenched with an acid, followed by extracting the organic solvent with an aqueous medium .
  • Y and Z each independently is N or CR 3 , wherein R 3 is H or Ci -3 hydrocarbon;
  • R 1 is H or a Ci -6 hydrocarbon.
  • Y and Z each independently is N or CR 3 , wherein R 3 is H or Ci -3
  • R is OH, OM or OR 5 , where M is an alkali or alkali earth metal and R 5 is Ci-14 hydrocarbon, optionally substituted with one or more heteroatoms; and
  • R 1 is H or a Ci -6 hydrocarbon.

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Abstract

La présente invention concerne un procédé de préparation d'un composé antifolate selon la formule 7, tel que le Pralatrexate. La présente invention concerne également des intermédiaires et des procédés de préparation d'intermédiaires utiles dans la préparation du composé antifolate. Les substituants Y, Z, R, R1 et R2 sont tels que décrits dans la présente invention. Les procédés et intermédiaires peuvent fournir une voie alternative à la synthèse du composé antifolate. En outre, les procédés peuvent permettre d'éviter une distillation ou une évaporation de solvants à haut point d'ébullition, une purification par chromatographie et l'utilisation de combinaisons dangereuses de solvants ; et peuvent également fournir un produit de pureté élevée, tout ceci étant souhaitable pour une synthèse à grande échelle.
PCT/CA2013/050419 2012-05-31 2013-05-31 Procédé de préparation d'un agent antifolate WO2013177713A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014068599A3 (fr) * 2012-11-02 2015-03-19 Hetero Research Foundation Procédé pour le pralatrexate
CN107488178A (zh) * 2016-06-10 2017-12-19 山东新时代药业有限公司 一种高纯度普拉曲沙中间体的制备方法
CN107488112A (zh) * 2016-06-10 2017-12-19 山东新时代药业有限公司 一种普拉曲沙中间体的制备方法
CN108069971A (zh) * 2016-11-18 2018-05-25 鲁南制药集团股份有限公司 一种普拉曲沙中间体的精制方法
CN108069970A (zh) * 2016-11-18 2018-05-25 鲁南制药集团股份有限公司 一种普拉曲沙的制备方法

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CN107488112B (zh) * 2016-06-10 2021-06-04 山东新时代药业有限公司 一种普拉曲沙中间体的制备方法
CN108069971A (zh) * 2016-11-18 2018-05-25 鲁南制药集团股份有限公司 一种普拉曲沙中间体的精制方法
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CN108069970B (zh) * 2016-11-18 2020-06-02 鲁南制药集团股份有限公司 一种普拉曲沙的制备方法
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