WO2014141181A1 - Procédés de préparation d'inhibiteurs de la peptide déformylase - Google Patents

Procédés de préparation d'inhibiteurs de la peptide déformylase Download PDF

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Publication number
WO2014141181A1
WO2014141181A1 PCT/IB2014/059810 IB2014059810W WO2014141181A1 WO 2014141181 A1 WO2014141181 A1 WO 2014141181A1 IB 2014059810 W IB2014059810 W IB 2014059810W WO 2014141181 A1 WO2014141181 A1 WO 2014141181A1
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fluoro
compound
cyclopentylmethyl
benzyloxy
oxazin
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PCT/IB2014/059810
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English (en)
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Kae Miyake BULLOCK
Nicole DESCHAMPS
Vassil Elitzin
Russell Fitzgerald
William Hawthorne GRADDY
Richard Tadao Matsuoka
Robert Rahn Mckeown
Mark Bryan Mitchell
Matthew Jude Sharp
Peter W. SUTTON
Elie Amine TABET
Xiaoming Zhou
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Glaxosmithkline Intellectual Property No 2 Limited
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Publication of WO2014141181A1 publication Critical patent/WO2014141181A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel processes for preparing peptide deformylase inhibitor compounds and corresponding intermediates, where aforementioned compounds are useful in the inhibition of bacterial peptide
  • PDF deformylase
  • the present invention relates to novel processes for preparing ⁇ 2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl ⁇ hydroxyformamide compounds of Formula (I) or pharmaceutically acceptable salts and intermediates thereof.
  • the present invention relates a novel process for preparing (2R)-2- (Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)-hexahydropyrazino[2, 1 -c][1 ,4]oxazin- 8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3-oxopropyl]hydroxyformamide or pharmaceutically acceptable salts thereof.
  • the present invention also relates to novel compound intermediates and corresponding novel preparation methods thereof.
  • Peptide deformylase PDF is a metalloenzyme that removes the N-formyl group of the polypeptides as they emerge from the ribosome during the elongation process [Adams, J.M. (1968) J.
  • MAP methionine amino peptidase
  • f-Met-tRNA — 3 / ⁇ . f-Met-pp ⁇ Met-pp
  • tRNA j (aa-tRNA e ) n (tRNA e ) n PDF is ubiquitous in bacteria, with at least one pdf gene present in all bacterial genomes sequenced to date.
  • PDF does not play a role in eukaryotic cytoplasmic protein synthesis which does not involve N-formylation, but nuclear-encoded PDF proteins, containing a chloroplast/mitochondria localization signal, have been identified in parasites, plants and mammals, including humans.
  • PDF is essential in plant and parasite organelles since their genomes encode for a number of proteins which require deformylation for activity, but there is evidence to suggest that this is not the case in animals.
  • characterization of human mitochondrial PDF has shown that it is much less active than its bacterial counterpart.
  • PDF inhibitors represent a promising new class of antibacterial agents with a novel mode of action covering a broad-spectrum of pathogens.
  • WO '879 Appln. teaches that a pharmaceutically acceptable salt, and/or novel crystalline form of ⁇ 2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]- 3-oxopropyl ⁇ hydroxyformamide compounds of the present invention, such as [(2R)-2- (Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)-hexahydropyrazino[2, 1 -c] [1 ,4]oxazin- 8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3-oxopropyl]hydroxyformamide, with greater aqueous solubility, chemical stability, etc. would offer many potential benefits for provision of medicinal products, especially for inhibition of bacterial peptide deformylase (PDF) activity and in treatment methods for bacterial infections.
  • PDF bacterial peptide deformylase
  • novel pharmaceutically acceptable salts of ⁇ 2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]-3- oxopropyl ⁇ hydroxyformamide compounds such as [(2f?)-2-(Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)-hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl]-2-methyl-4- pyrimidinyl ⁇ hydrazino)-3-oxopropyl]hydroxyformamide, can be isolated as pure, crystalline solids, which exhibit much higher aqueous solubility than the corresponding free base.
  • Such novel crystalline forms also improve aqueous solubility and stability in solution of [(2 )-2-(Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide or pharmaceutically acceptable salts thereof, in respective salt forms or in pharmaceutical compositions or formulations.
  • primary aims during chemical process development are to ensure that processes are safe, increase yields and throughput and to make the process scaleable, robust and reproducible, such as with shorter routes, while minimizing costs associated with each process.
  • additional process development considerations include: ensuring control of active drug principal ingredient purity, eliminating need for chiral auxiliaries, protecting groups, expensive or toxic reagents and solvents (which provide additional concerns for scale-up), avoiding chromatography and minimizing waste, especially by eliminating use of metal reagents, optimizing final product isolation by developing conditions to produce crystalline material or if needed, isolation via salt formation.
  • compounds ⁇ 2-(alkyl)-3-[2-(5-fluoro-4- pyrimidinyl)hydrazino]-3-oxopropyl ⁇ hydroxyformamide compounds of Formula (I) or pharmaceutically acceptable salts thereof which may include, but are not limited to [(2 )-2-(Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)-hexahydropyrazino[2, 1 - c][1 ,4]oxazin-8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide or pharmaceutically acceptable salts thereof, may also be prepared efficiently using the novel processes of the present invention, which use novel intermediates and reaction conditions in high yield and high purity, where such alternate processes may be useful and adaptable for commercial manufacture.
  • the present invention relates to novel processes for preparing peptide deformylase inhibitor compounds and corresponding intermediates, where aforementioned compounds are useful in the inhibition of bacterial peptide deformylase (PDF) activity and in treatment methods for bacterial infections.
  • PDF bacterial peptide deformylase
  • the present invention relates to novel processes for preparing ⁇ 2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl ⁇ hydroxyformamide compounds of Formula (I) or pharmaceutically acceptable salts and intermediates thereof.
  • the present invention relates a novel process for preparing (2R)-2- (Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)-hexahydropyrazino[2, 1 -c][1 ,4]oxazin- 8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3-oxopropyl]hydroxyformamide or pharmaceutically acceptable salts thereof.
  • the present invention also relates to novel compound intermediates and corresponding novel preparation methods thereof.
  • the present invention relates to novel processes for preparing peptide deformylase inhibitor compounds and corresponding intermediates, where aforementioned compounds are useful in the inhibition of bacterial peptide deformylase (PDF) activity and in treatment methods for bacterial infections.
  • PDF bacterial peptide deformylase
  • R1 is selected from the group consisting of C2-C7 alkyl and -(CH2)n-C3-C6 cycloalkyl;
  • R2 is selected from the group consisting of C1-C3 alkyl; cyclopropyl; C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 sulfanyl; 5-membered heteroaryl; 5-membered heterocycloalkyi; halo; hydroxymethyl; and -NRaRb;
  • R3 is selected from the group consisting of -NR4R5; halo; phenyl, optionally substituted by one to three R6 groups; and heteroaryl, optionally substituted by one to three R6 groups;
  • R4 is selected from the group consisting of H; C1-C6 alkyl, optionally substituted with one or two R7 groups; C1-C6 alkoxy; C3-C6 cycloalkyl, optionally substituted with one to three R6 groups; heterocycloalkyi, optionally substituted by one to three R6 groups; heteroaryl, optionally substituted by one to three R6 groups; and phenyl, optionally substituted by one to three R6 groups;
  • R5 is selected from H; C1-C6 alkyl, optionally substituted with one or two R7 groups; C1-C6 alkoxy; C3-C6 cycloalkyl, optionally substituted with one to three R6 groups; heterocycloalkyi, optionally substituted by one to three
  • R6 groups heteroaryl, optionally substituted by one to three R6 groups; and phenyl, optionally substituted by one to three R6 groups; or
  • R4 and R5 are joined together with the N-atom to which they are attached, forming a heterocycloalkyi group optionally substituted with one to three R6 groups; each R6 is independently selected from the group consisting of C1-C6 alkyl, optionally substituted with one to three R7 groups, hydroxy; C1-C3 alkoxy; -C(0)NRaRb; -C(0)Rc; -C(0)ORc; heterocycloalkyi; C3-C6 cycloalkyi optionally substituted with one -NRaRb or pyrrolidinyl; oxo; cyano; -NRaRb; phenyl; heteroaryl; and halo; each R7 is independently selected from the group consisting of hydroxy; C1-C3 alkoxy; halo; phenyl; cyano; -NRaRb; -C(0)NRaRb; -C(0)Rc; C3-C6 cycloalkyi, optionally substitute
  • each Rc is independently selected from the group consisting of C1-C3 alkyl optionally substituted with one methoxy group; phenyl; heterocycloalkyi; and heteroaryl; and
  • n is an integer from 0 to 2;
  • the present invention relates to a process, where the compound of Formula (I) is a free base form.
  • the present invention relates to a process, where the compound of Formula (I) is a pharmaceutically acceptable salt. In one aspect, the present invention relates to a process, where the
  • pharmaceutically acceptable salt is selected from sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ - hydroxybutyrates, glycollates, tartrates mandelates
  • xylenesulfonates methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates or naphthalene-2-sulfonates.
  • the present invention relates to a process, where the
  • pharmaceutically acceptable salt of a compound of Formula (I) is an acid addition salt formed from acids selected from hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, malonate, lactate, tartrate, citrate, formate, gluconate, succinate, piruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, methanesulphonic, ethanesulphonic, p-toluenesulphonic or isothionate.
  • acids selected from hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate
  • the present invention relates to a process, where the compound of Formula (I) is a pharmaceutically acceptable salt selected from methanesuphonate salt, dimethanesuphonate salt or camphorsulfonate salt.
  • the present invention relates to a process, where the
  • the present invention relates to a novel process for preparing a compound of Form
  • R1 is C2-C7 alkyl or -(CH 2 ) n -C3-C6 cycloalkyl
  • R2 is C1-C3 alkyl, cyclopropyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 sulfanyl, 5-membered heteroaryl, 5-membered heterocycloalkyi, halo, hydroxymethyl, or - NRaRb;
  • R3 is -NR4R5, halo, phenyl, optionally substituted by one to three R6 groups; and heteroaryl, optionally substituted by one to three R6 groups;
  • R4 is H; C1-C6 alkyl, optionally substituted with one or two R7 groups; C1- C6 alkoxy; C3-C6 cycloalkyl, optionally substituted with one to three R6 groups;
  • heterocycloalkyi optionally substituted by one to three R6 groups
  • heteroaryl optionally substituted by one to three R6 groups
  • phenyl optionally substituted by one to three R6 groups
  • R5 is H; C1-C6 alkyl, optionally substituted with one or two R7 groups; C1- C6 alkoxy; C3-C6 cycloalkyl, optionally substituted with one to three R6 groups;
  • heterocycloalkyi optionally substituted by one to three R6 groups; heteroaryl, optionally substituted by one to three R6 groups; or phenyl, optionally substituted by one to three R6 groups; or
  • R4 and R5 are joined together with the N-atom to which they are attached, forming a heterocycloalkyi group optionally substituted with one to three R6 groups;
  • each R6 is C1-C6 alkyl, optionally substituted with one to three R7 groups; hydroxy; C1-C3 alkoxy; -C(0)NRaRb; -C(0)Rc; -C(0)ORc;
  • heterocycloalkyi C3-C6 cycloalkyl optionally substituted with one -NRaRb or pyrrolidinyl; oxo; cyano; -NRaRb; phenyl; heteroaryl; or halo;
  • each R7 is hydroxy; C1-C3 alkoxy; halo; phenyl; cyano;
  • each Ra as defined above is H or C1-C3 alkyl optionally substituted with one hydroxy, methoxy, or dimethylamine;
  • each Rb as defined above is H or C1-C3 alkyl
  • each Rc as defined above is C1-C3 alkyl optionally substituted with one methoxy group; phenyl; heterocycloalkyl; or heteroaryl;
  • n is an integer from 0 to 2;
  • R 2 and R 3 are as defined above;
  • Ri is as defined above; to which is added a base selected from sodium tert-pentoxide (CH 3 CH 2 C(CH 3 )20 " Na + ), potassium carbonate (K 2 C0 3 ), sodium hydroxide (NaOH), lithium tertbutoxide (LiOtBu), sodium tertbutoxide (NaOtBu), potassium tertbutoxide (KOtBu), Lithium
  • KHMDS Sodium bis(trimethylsilyl)amide ((CH 3 ) 3 Si) 2 NNa, “NaHMDS”), sodium hydride (NaH) in an organic solvent or organic solvent mixtures, which may include, but are not limited to organic solvent(s) selected from tetrahydrofuran (THF), ethanol (EtOH), Dimethyl sulfoxide (DMSO), Dimethylacetamide (DMAC), 1 ,3-Dimethyl-3, 4,5,6- tetrahydro-2(1 H)-pyrimidinone (DMPU), N-Methyl-2-pyrrolidone (NMP) or
  • DM F Dimethylformamide
  • organic solvent mixtures selected from DMSO/toluene, 1 ,3-Dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU)/toluene and the like, suitably at a temperature from about 20°C to about 60°C, thanmore suitably at a temperature below 30°C to form ( )-3-((benzyloxy)amino)-2-(R1)-N'-(5-fluoro-6-(R 3 )-2- R 2 -pyrimidin-4-yl) propanehydrazide:
  • a formylating agent selected from, but not limited to: trimethyl orthoformate and mixed anhydrides, which may include, but are not limited to acetic formic anhydride (HC0 2 COMe), formic pivalic anhydride (HC0 2 CO-t-Bu) or mixtures thereof and the like,
  • organic solvents selected from alcohols selected from methanol, isopropyl alcohols and the like or ethers selected from te/f-butyl methyl ether (MBTE) and the like, at a suitable temperature range from about 35°C to about 50°C, or more suitably at a temperature of about 40°C to form intermediate N-(benzyloxy)-N-(( )-2-(R 1 )-3-(2-(5- fluoro-6-( R 3 )-2-R 2 -pyrimidin-4- l h drazin l -3-oxo ro l formamide:
  • Ri is -(CH2)n-C3-C 6 cycloalkyl.
  • Ri is -(CH 2 ) n — C 3 -C 6 cycloalkyl wherein n is 1.
  • Ri is -CH 2 -cyclopentyl.
  • R 2 is C C 3 alkyl; C C 3 alkoxy; C C 3 haloalkyl; C C 3 sulfanyl; or halo.
  • R 2 is methyl; ethyl; thiomethyl; thioethyl; fluoromethyl; difluoromethyl;
  • R 2 is methyl; ethyl;
  • R 3 is -N R 4R 5 ; d-C 6 alkoxy; or heteroaryl, optionally substituted by one to three R 6 groups.
  • R 3 is -NR 4 R 5 wherein R 4 is C C 6 alkyl, optionally substituted with one or two R 7 groups; or C3-C6 cycloalkyl, optionally substituted by one to three R 6 groups; and R 5 is H, C C 6 alkyl, or C C 6 alkoxy.
  • R4 is cyclopropyl; cyclobutyl; cyclopentyl; tetrahydro-2H-pyranyl;
  • R4 is methyl; ethyl optionally substituted with one substituent selected from the group consisting of: hydroxyl, methoxy and -NRaRb; propyl; isopropyl; cyclopropyl; cyclobutyl; and cyclopentyl.
  • R5 is selected from the group consisting of H; C1-C6 alkyl; C1- C6 alkoxy; and C3-C6 cycloalkyl.
  • R5 is H; methyl; or methoxy.
  • R5 is H; C1-C3 alkyl; cyclopropyl; or piperazinyl optionally substituted with one R6 group.
  • R3 is -NR4R5 wherein R4 and R5 are joined together with the N-atom to which they are attached to form a heterocycloalkyl group optionally substituted with one to three R6 groups, where heterocycloalkyl groups may include, but are not limited to monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems.
  • R3 is -NR4R5 wherein R4 and R5 are joined together with the N- atom to which they are attached forming azetidinyl; pyrrolidinyl; piperazinyl;
  • R3 is -NR4R5 wherein R4 and R5 are joined together with the N-atom to which they are attached forming 1-piperidinyl; 4-thiomorpholinyl; 1- pyrazolidinyl; tetrahydro-5H-[1 ,3]dioxolo[4,5-c]pyrrolyl; tetrahydro-1 H-furo[3,4- c]pyrrol-(3H)-yl; hexahydropyrrolo[3,4-c]pyrrol-(1 H)-yl; hexahydropyrrolo[3,4-c]pyrrol-(1 H)-yl; hexahydropyrrolo[1 ,2- a]pyrazin-(1 H)-yl; hexahydropyrazino[2, 1-c][1 ,4]oxazin-(1 H)-yl; hexahydrofuro[3,4-
  • R3 is -NR4R5 wherein R4 and R5 are joined together with the N- atom to which they are attached forming azetidinyl optionally substituted with one or two R6 groups each independently selected from the group consisting of methyl; ethyl; fluoro; methoxy; hydroxyl; hydroxymethyl; cyclopropyl; dimethylamino;
  • R3 is -NR4R5 wherein R4 and R5 are joined together with the N- atom to which they are attached forming pyrrolidinyl optionally substituted with one to three R6 groups each independently selected from the group consisting of methyl; methoxy; -CH2-methoxy; hydroxyl; hydroxymethyl; hydroxyethyl;
  • R3 is -NR4R5 wherein R4 and R5 are joined together with the N- atom to which they are attached forming piperazinyl optionally subsituted with one to three R6 groups each indepdendently selected from the group consisting of methyl; ethyl; isopropyl; hydroxymethyl; hydroxyethyl; -CH2-O-CH3; and -COOCH3.
  • R3 is -NR4R5 wherein R4 and R5 are joined together with the N- atom to which they are attached forming (9aS)-octahydropyrazino[2, 1- c] [1 ,4]oxazinyl.
  • R6 is C1-C3 alkyl, optionally substituted with one to three R7 groups; hydroxy; C1-C3 alkoxy; -C(0)NRaRb; or -NRaRb.
  • R6 is methyl; ethyl; isopropyl; methoxy; hydroxyl; diethylamino; or A/./V-dimethylacetamido.
  • R6 is heteroaryl.
  • R6 is a 6-membered heteroaryl.
  • R6 is pyridinyl.
  • R7 is C1-C3 alkoxy; hydroxyl; or - NRaRb.
  • R7 is methoxy.
  • R7 is heterocycloalkyi.
  • R7 is a 6-membered heterocycloalkyi.
  • R7 is morpholinyl.
  • R7 is heteroaryl.
  • R7 is pyridinyl; 1 ,3-thiazolyl; thienyl; furanyl; imidazolyl; 1 H-benzamidazolyl; 3H- [1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl; or 3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl.
  • Ra and Rb are both methyl.
  • Rc is heterocycloalkyi.
  • Rc is pyrrolidinyl.
  • the present invention relates to a process for preparing a compound according to Formula (II):
  • R1 is C2-C7 alkyl or -(CH 2 ) n -C3-C6 cycloalkyi;
  • R2 is C1-C3 alkyl; cyclopropyl; C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 sulfanyl; 5-membered heteroaryl; 5-membered heterocycloalkyi; halo;
  • R3 is selected from the group consisting of -NR4R5; halo; phenyl, optionally substituted by one to three R6 groups; and heteroaryl, optionally substituted by one to three R6 groups;
  • R4 is selected from the group consisting of H; C1-C6 alkyl, optionally substituted with one or two R7 groups; C1-C6 alkoxy; C3-C6 cycloalkyi, optionally substituted with one to three R6 groups; heterocycloalkyi, optionally substituted by one to three R6 groups; heteroaryl, optionally substituted by one to three R6 groups; and phenyl, optionally substituted by one to three R6 groups;
  • R5 is selected from the group consisting of H; C1-C6 alkyl, optionally substituted with one or two R7 groups; C1-C6 alkoxy; C3-C6 cycloalkyi, optionally substituted with one to three R6 groups; heterocycloalkyi, optionally substituted by one to three R6 groups; heteroaryl, optionally substituted by one to three R6 groups; and phenyl, optionally substituted by one to three R6 groups; or
  • R4 and R5 are joined together with the N-atom to which they are attached, forming a heterocycloalkyi group optionally substituted with one to three R6 groups;
  • each R6 is independently selected from the group consisting of C1- C6 alkyl, optionally substituted with one to three R7 groups; hydroxy; C1-C3 alkoxy; -C(0)NRaRb; -C(0)Rc; heterocycloalkyi; C3-C6 cycloalkyl; oxo;
  • each R7 is independently selected from the group consisting of hydroxy; C1-C3 alkoxy; halo; phenyl; cyano; -NRaRb; - C(0)NRaRb; -C(0)Rc; C3-C6 cycloalkyl, optionally substituted with one hydroxy, heterocycloalkyi or -NRaRb group; heterocycloalkyi; and heteroaryl;
  • each Ra as defined above is independently selected from the group consisting of H and C1-C3 alkyl
  • each Rb as defined above is independently selected from the group consisting of H and C1-C3 alkyl
  • each Rc as defined above is independently selected from the group consisting of C1-C3 alkyl; phenyl; heterocycloalkyi; and heteroaryl; and
  • n is an integer from 0 to 2;
  • R 2 and R 3 are as defined above;
  • a base selected from sodium tert-pentoxide (CH 3 CH 2 C(CH 3 ) 2 0 " Na + ), potassium carbonate (K 2 C0 3 ), sodium hydroxide (NaOH), lithium tertbutoxide (LiOtBu), sodium tertbutoxide (NaOtBu), potassium tertbutoxide (KOtBu), Lithium
  • diisopropylamide ((CH 3 ) 2 CH] 2 NLi; "LDA”), Lithium bis(trimethylsilyl)amide ((CH 3 ) 3 Si] 2 N Li. "LiHMDS”), Potassium bis(trimethylsilyl)amide (((CH 3 ) 3 Si) 2 NK, "KHMDS”), Sodium bis(trimethylsilyl)amide ((CH 3 ) 3 Si) 2 NNa, "NaHMDS”), sodium hydride (NaH) in an organic solvent or organic solvent mixtures, which may include, but are not limited to organic solvent(s) selected from tetrahydrofuran (THF), ethanol (EtOH), Dimethyl sulfoxide (DMSO), Dimethylacetamide (DMAC), 1 ,3-Dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone (DMPU), N-Methyl-2-pyrrolidone (NMP) or Dimethylformamide (DM
  • a formylating agent selected from, but not limited to trimethyl orthoformate and mixed anhydrides, which may include, but are not limited to acetic formic anhydride (HC0 2 COMe), formic pivalic anhydride (HC0 2 CO-t-Bu) or mixtures thereof and the like, formic acid (HC0 2 H), organic solvents selected from alcohols selected from methanol, isopropyl alcohols and the like or ethers selected from te/f-butyl methyl ether (MBTE) and the like at a suitable temperature range from about 35°C to about 50°C, or more suitably at a temperature of about 40°C to form intermediate N-(benzyloxy)-N-((R)-2- (Ri)-3-(2-(5-fluoro-6-( R 3 )-2-R 2 -pyrimidin-4-yl)hydrazinyl)-3-oxopropyl)formamide:
  • the present invention relates to a process for preparing a compound accordin
  • R1 is C2-C7 alkyl or -(CH 2 ) n -C3-C6 cycloalkyl
  • R2 is C1-C3 alkyl; cyclopropyl; C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 sulfanyl; 5-membered heteroaryl; 5-membered heterocycloalkyl; halo;
  • R3 is -NR4R5 wherein R4 and R5 are joined together with the N-atom to which they are attached forming (9aS)-octahydropyrazino[2,1-c][1 ,4]oxazinyl;
  • R4 is selected from the group consisting of H; C1-C6 alkyl, optionally substituted with one or two R7 groups; C1-C6 alkoxy; C3-C6 cycloalkyi, optionally substituted with one to three R6 groups; heterocycloalkyi, optionally substituted by one to three R6 groups; heteroaryl, optionally substituted by one to three R6 groups; and phenyl, optionally substituted by one to three R6 groups;
  • R5 is selected from the group consisting of H; C1-C6 alkyl, optionally substituted with one or two R7 groups; C1-C6 alkoxy; C3-C6 cycloalkyi, optionally substituted with one to three R6 groups; heterocycloalkyi, optionally substituted by one to three R6 groups; heteroaryl, optionally substituted by one to three R6 groups; and phenyl, optionally substituted by one to three R6 groups; or
  • each R6 as defined above is independently selected from the group consisting of C1-C6 alkyl, optionally substituted with one to three R7 groups;
  • each R7 as defined above is independently selected from the group consisting of hydroxy; C1-C3 alkoxy; halo; phenyl; cyano; -NRaRb; - C(0)NRaRb; -C(0)Rc; C3-C6 cycloalkyi, optionally substituted with one hydroxy, heterocycloalkyi or -NRaRb group; heterocycloalkyi; and heteroaryl;
  • each Ra as defined above is independently selected from the group consisting of H and C1-C3 alkyl
  • each Rb as defined above is independently selected from the group consisting of H and C1-C3 alkyl
  • each Rc as defined above is independently selected from the group consisting of C1-C3 alkyl; phenyl; heterocycloalkyi; and heteroaryl; and
  • n is an integer from 0 to 2;
  • a base selected from sodium tert-pentoxide (CH 3 CH 2 C(CH 3 ) 2 0 " Na + ), potassium carbonate (K 2 C0 3 ), sodium hydroxide (NaOH), lithium tertbutoxide (LiOtBu), sodium tertbutoxide (NaOtBu), potassium tertbutoxide (KOtBu), Lithium
  • diisopropylamide ((CH 3 ) 2 CH] 2 NLi; "LDA”), Lithium bis(trimethylsilyl)amide ((CH 3 ) 3 Si] 2 N Li. "LiHMDS”), Potassium bis(trimethylsilyl)amide (((CH 3 ) 3 Si) 2 NK, "KHMDS”), Sodium bis(trimethylsilyl)amide ((CH 3 ) 3 Si) 2 NNa, "NaHMDS”), sodium hydride (NaH) in an organic solvent or organic solvent mixtures, which may include, but are not limited to organic solvent(s) selected from tetrahydrofuran (THF), ethanol (EtOH), Dimethyl sulfoxide (DMSO), Dimethylacetamide (DMAC), 1 ,3-Dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone (DMPU), N-Methyl-2-pyrrolidone (NMP) or Dimethylformamide (DM
  • a formylating agent selected from, but not limited to trimethyl orthoformate and mixed anhydrides, which may include, but are not limited to acetic formic anhydride (HC0 2 COMe), formic pivalic anhydride (HC0 2 CO-t-Bu) or mixtures thereof and the like, formic acid (HC0 2 H), organic solvents selected from alcohols selected from methanol, isopropyl alcohols and the like or ethers selected from te/f-butyl methyl ether (MBTE) and the like at a suitable temperature range from about 35°C to about 50°C, or more suitably at a temperature of about 40°C to form intermediate N-(benzyloxy)-N-((R)-2- (Ri)-3-(2-(5-fluoro-6-( R 3 )-2-R 2 -pyrimidin-4-yl)hydrazinyl)-3-oxopropyl)formamide:
  • the present invention relates to a process for preparation of a compound of Formula (III):
  • R1 is selected from the group consisting of C2-C7 alkyl and -(CH2)n-C3-C6 cycloalkyl;
  • R2 is selected from the group consisting of C1-C3 alkyl; cyclopropyl; C1-C3 alkoxy; C1-C3 haloalkyi; C1-C3 sulfanyl; 5-membered heteroaryl; 5-membered heterocycloalkyl; halo; hydroxymethyl; and -NRaRb;
  • each Ra is each independently selected from the group consisting of H and C1-C3 alkyl optionally substituted with one hydroxy, methoxy, or dimethylamine;
  • each Rb is independently selected from the group consisting of H and
  • n is an integer from 0 to 2;
  • R 2 is as defined above; with a base to form a organic solvent aqueous reaction solution;
  • the present invention relates to a process, where the compound N-(( )-2-(R 1 )-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-R 2 - pyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-Nhydroxyformamide is a free base form.
  • the present invention relates to a process, where the compound N-(( )-2-(R 1 )-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-R 2 - pyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-Nhydroxyformamide is a pharmaceutically acceptable salt.
  • the present invention relates to a process, where the
  • pharmaceutically acceptable salt is selected from sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ - hydroxybutyrates, glycollates, tartrates mandelates
  • xylenesulfonates methanesulfonates, propanesulfonates, naphthalene-1-sulfonates or naphthalene-2-sulfonates.
  • the present invention relates to a process, where the
  • pharmaceutically acceptable salt of a compound of Formula (I) is an acid addition salt formed from acids selected from hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, malonate, lactate, tartrate, citrate, formate, gluconate, succinate, piruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, methanesulphonic, ethanesulphonic, p-toluenesulphonic or isothionate.
  • acids selected from hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate
  • the present invention relates to a process, where the compound of Formula (I) is a pharmaceutically acceptable salt selected from methanesuphonate salt, dimethanesuphonate salt or camphorsulfonate salt.
  • the present invention relates to a process, where the
  • the present invention relates to a process for preparation of a compound of Formula (I).
  • R1 is selected from the group consisting of C2-C7 alkyl and -(CH2)n-C3-C6 cycloalkyl;
  • R2 is selected from the group consisting of C1-C3 alkyl; cyclopropyl; C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 sulfanyl; 5-membered heteroaryl; 5-membered heterocycloalkyl; halo; hydroxymethyl; and -NRaRb;
  • each Ra is each independently selected from the group consisting of H and C1-C3 alkyl optionally substituted with one hydroxy, methoxy, or dimethylamine;
  • each Rb is independently selected from the group consisting of H and C1-C3 alkyl
  • n is an integer from 0 to 2; which comprises steps of:
  • a first base which may be selected from, but not limited to carbonate salts, bicarbonate salts, phosphate salts, hydroxide salts, respectively, which may include, but are not limited to potassium carbonate (K 2 C0 3 ), sodium carbonate (Na 2 C0 3 ), sodium bicarbonate (NaHC0 3 ), potassium phosphate (K 3 P0 4 ), triethylamine (TEA) or pyridine to form a organic solvent aqueous reaction solution, where organic solvents, may include, but are not limited to tetrahydrofuran, 2-methyltetrahydrofuran (2-Me- THF), dichloromethane, acetonitlrile, methyl or tert-butyl ether (MTBE); and by successively adding to the reaction solution:
  • an acylating agent which may include, but is not limited to chloroacetyl chloride, bromoacetyl chloride or chloroacetic acid anhydride and then cooling down the reaction solution to a temperature range not to exceed 15°C, after which the reaction is stirred at 25°C;
  • an acid which may be selected from, but is not limited to hydrochloric acid, sulphuric acid or phosphoric acid;
  • a reducing agent which may be selected from, but not limited to:
  • borane complexes which may be selected from, but are not limited to borane-THF, borane-DMS, diethylaniline borane, isoamylsulfide borane, borane-ammonia);
  • o borohydride reagents which may be selected from, but are not limited to: sodium borohydride (NaBH 4 ), lithium borohydride (LiBH 4 ), in the presence of an additive agent, which may be selected from, but are not limitations to iodine, bromine, chlorotrimethylsilane, sulphuric acid, boron trifluoride or trimethyl borate; or o aluminium hydride reagents, which may be selected from, but are not limited to lithium aluminium hydride (LAH) or sodium bis(2- methoxyethoxy)aluminumhydride (Red-AI); and
  • a second base which may be selected from, but not limited to to carbonate salts, bicarbonate salts, phosphate salts, hydroxide salts, respectively, which may include, but are not limited to potassium carbonate (K 2 C0 3 ), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium carbonate (Na 2 C0 3 ), sodium bicarbonate (NaHC0 3 ), potassium phosphate (K 3 P0 4 ), triethylamine (TEA) or pyridine and the like to form a compound (S)-8-(6-chloro-5-fluoro-2-R2-pyrimidin-4- yl)octahy 4]oxazine:
  • Ri is as defined above; and by adding a third base selected sodium tert-pentoxide (CH 3 CH 2 C(CH 3 ) 2 0 " Na + ), potassium carbonate (K 2 C0 3 ), sodium hydroxide (NaOH), lithium tertbutoxide (LiOtBu), sodium tertbutoxide (NaOtBu), potassium tertbutoxide (KOtBu), Lithium
  • KHMDS Sodium bis(trimethylsilyl)amide ((CH 3 ) 3 Si) 2 NNa, “NaHMDS”), sodium
  • organic solvent or organic solvent mixtures, which may include, but are not limited to organic solvent(s) selected from tetrahydrofuran (THF), ethanol
  • step [3] reacting the compound (f?)-3-((benzyloxy)amino)-2-(Ri)-N'-(5-fluoro-6-((S)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-R 2 -pyrimidin-4-yl)propanehydrazide formed in step [2] with a formylating agent selected from, but not limited to trimethyl orthoformate and mixed anhydrides, which may include, but are not limited to acetic formic anhydride (HC0 2 COMe), formic pivalic anhydride (HC0 2 CO-t-Bu) or mixtures thereof and the like, formic acid (HC0 2 H), organic solvents selected from alcohols selected from methanol, isopropyl alcohols and the like or ethers selected from tert- butyl methyl ether (MBTE) and the like at a suitable temperature range from about 35°C to about
  • the present invention relates to a process, where the compound N-(( )-2-(R 1 )-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1-c][1 ,4]oxazin- 8(1 H)-yl)-2-R 2 -pyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N-hydroxyformamide is a free base form.
  • the present invention relates to a process, where the compound N-(( )-2-(Ri)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1-c][1 ,4] oxazin- 8(1 H)-yl)-2-R 2 -pyrimidin-4-yl) hydrazinyl)-3-oxopropyl)-Nhydroxyformamide is a pharmaceutically acceptable salt.
  • the present invention relates to the process, where the pharmaceutically acceptable salt is selected from sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ - hydroxybuty
  • xylenesulfonates methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates and naphthalene-2-sulfonates.
  • the present invention relates to the process, where the pharmaceutically acceptable salt is an acid addition salt formed from acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, malonate, lactate, tartrate, citrate, formate, gluconate, succinate, piruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate,
  • acids which form non-toxic salts examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, malonate, lactate, tartrate, citrate, formate, gluconate, succinate, piruvate, oxalate, oxaloacetate,
  • methanesulphonate ethanesulphonate, benzenesulphonate, p-toluenesulphonate, methanesulphonic, ethanesulphonic, p-toluenesulphonic, and isothionate.
  • the present invention relates to the process, where the pharmaceutically acceptable salt is a methanesuphonate salt, dimethanesuphonate salt or camphorsulfonate salt.
  • the present invention relates to the process, where the pharmaceutically acceptable salt is a methanesulphonate salt.
  • the present invention relates to a process for preparing compound which is N-((f?)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-
  • the present invention relates to a process for preparation of a compound which is N-((f?)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3- oxopro
  • a first base which may be selected from, but not limited to carbonate salts, bicarbonate salts, phosphate salts, hydroxide salts, respectively, which may include, but are not limited to potassium carbonate (K 2 C0 3 ), sodium carbonate (Na 2 C0 3 ), sodium bicarbonate (NaHC0 3 ), potassium phosphate (K 3 P0 4 ), triethylamine (TEA) or pyridine to form a organic solvent aqueous reaction solution, where organic solvents, may include, but are not limited to tetrahydrofuran, 2-methyltetrahydrofuran (2-Me- THF), dichloromethane, acetonitlrile, methyl or tert-butyl ether (MTBE); and by successively adding to the organic solvent aqueous reaction solution:
  • an acylating agent which may include, but is not limited to chloroacetyl
  • an acid which may be selected from, but is not limited to hydrochloric acid, sulphuric acid or phosphoric acid;
  • a reducing agent which may be selected from, but not limited to:
  • o borane complexes which may be selected from, but are not limited to
  • borane-THF borane-DMS, diethylaniline borane, isoamylsulfide borane, borane-ammonia);
  • o borohydride reagents which may be selected from, but are not limited
  • sodium borohydride NaBH 4
  • lithium borohydride LiBH 4
  • an additive agent which may be selected from, but are not limitationss to iodine, bromine, chlorotrimethylsilane, sulphuric acid, boron trifluoride or trimethyl borate; or
  • o aluminium hydride reagents which may be selected from, but are not limited to lithium aluminium hydride (LAH) or sodium bis(2- methoxyethoxy)aluminumhydride (Red-AI); and a second base, which may be selected from, but not limited to to carbonate salts, bicarbonate salts, phosphate salts, hydroxide salts, respectively, which may include, but are not limited to potassium carbonate (K 2 C0 3 ), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium carbonate (Na 2 C0 3 ), sodium bicarbonate (NaHC0 3 ), potassium phosphate (K 3 P0 4 ), triethylamine (TEA) or pyridine and the like to form a compound (S)-8-(6-chloro-5-fluoro-2-methylpyrimidin-4- yl)octahy 4]oxazine:
  • LAH lithium aluminium hydride
  • Red-AI sodium bis(
  • LiOtBu sodium tertbutoxide
  • NaOtBu sodium tertbutoxide
  • KtBu potassium tertbutoxide
  • organic solvent or organic solvent mixtures which may include, but are not limited to organic solvent(s) selected from tetrahydrofuran (THF), ethanol (EtOH), Dimethyl sulfoxide (DMSO), Dimethylacetamide (DMAC), 1 ,3-Dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone (DMPU), N-Methyl-2-pyrrolidone (NMP) or Dimethylformamide (DMF) and organic solvent mixtures selected from DMSO/toluene, 1 ,3-Dimethyl-3,4,5,6-tetrahydro- 2(1 H)-pyrimidinone (DMPU)/toluene and the like, suitably at a temperature from about 20°C to about 60°C, more suitably at a temperature below 30°C to form ⁇ R)-2>- ((benzyloxy)amino)-2-(cyclopentylmethyl)-N'-(5-fluoro-6-(
  • step [3] reacting the compound form (f?)-3-((benzyloxy)amino)-2-(cyclopentylmethyl)-N'- (5-fluoro-6-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4- yl)propanehydrazide formed in step [2] with a formylating agent selected from, but not limited to trimethyl orthoformate and mixed anhydrides, which may include, but are not limited to acetic formic anhydride (HC0 2 COMe), formic pivalic anhydride (HC0 2 CO-t- Bu) or mixtures thereof and the like, formic acid (HC0 2 H), organic solvents selected from alcohols selected from methanol, isopropyl alcohols and the like or ethers selected from terf-butyl methyl ether (MBTE) and the like at a suitable temperature range from about 35°C
  • step [4] reacting the intermediate intermediate N-(benzyloxy)-N-((f?)-2- (cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)- 2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)formamide:from step [3] with a hydrogenating agent under pressure from about 30 pounds per square inch (psi) to about 90 pounds per square inch (psi) and heated to a suitable temperature range of about 40 °C to at least about 50 °C or more suitable at a temperature of about 40°C to form the compound N-(( )-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)- hexahydropyrazino[2 -c][1 ,4]oxazin-8(1 H)-y
  • the present invention relates to a process, which further comprises an additional step of:
  • the present invention relates to a process, where the compound N-((R)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2,1- c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)- Nhydroxyformamide is a free base form.
  • the present invention relates to a process, where the compound N-((R)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2,1- c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N- hydroxyformamide is a free base Form I.
  • the present invention relates to a process, where the compound N-((R)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2,1- c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N- hydroxyformamide is a free base Form II.
  • the present invention relates to a process, where the compound N-((R)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2,1- c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N- hydroxyformamide is a free base Form III.
  • the present invention relates to a process, where the compound N-((R)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2,1- c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)- Nhydroxyformamide is a pharmaceutically acceptable salt.
  • the present invention relates to a process, which further comprises further seeding the organic solution of step [5] with crystalline N-((f?)-2- (cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)- 2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N-hydroxyformamide methanesulfonate to form:
  • polymorphic Form 1 N-(( )-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)- hexahydro pyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4- yl)hydrazinyl)-3-oxopropyl)-N-hydroxyformamide methanesulfonate; polymorphic Form 2 N-(( )-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)- hexahydro pyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4- yl)hydrazinyl)-3-oxopropyl)-N-hydroxyformamide methanesulfonate; or or a mixture thereof.
  • the present invention relates to a process, where N-((f?)-2- (cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)- 2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N-hydroxyformamide methanesulfonate is polymorphic Form 1 , N-((f?)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydro pyrazino[2 -c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropy hydroxyformamide methanesulfonate.
  • the present invention relates to a process, where N-((f?)-2- (cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1 -c][1 ,4]oxazin-8(1 H)-yl)- 2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N-hydroxyformamide methanesulfonate is polymorphic Form 2, N-((f?)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydro pyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N- hydroxyformamide methanesulfonate.
  • the present invention relates to a process, where N-((f?)-2- (cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2, 1 -c][1 ,4]oxazin-8(1 H)-yl)- 2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N-hydroxyformamide methanesulfonate is polymorphic Form 3, N-((f?)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydro pyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N- hydroxyformamide methanesulfonate.
  • the present invention also relates to novel compound intermediates and corresponding novel preparation methods thereof.
  • the present invention relates to novel proceses for making intermediates , which may include, but are not limited to
  • the present invention relates to a compound which is (S)-4-(6- chloro-5-fluoro-2-methylpyrimidin- -yl)piperazine-2-carboxylic acid:
  • the present invention relates to a compound which is ⁇ R)-3- ((benzyloxy)amino)-2-(cyclopentylmethyl) propanehydrazide:
  • the present invention relates to a process for preparation of a compound which is (S)-4-(6-chloro-5-fluoro-2-methylpyrimidin-4-yl) piperazine-2- carboxylic acid:
  • the present invention relates to a process for preparation of a compound which is (S)-4-(6-chloro-5-fluoro-2-methylpyrimidin-4-yl) piperazine-2- carboxylic acid:
  • a base selected from, but is not limited to:
  • a carbonate which may be selected from, but is not limited to sodium carbonate or potassium carbonate,
  • an amine which may be selected from, but is not limited to pyridine, tertiary amines, which may be selected from, but are not limited to N,N-
  • DIPEA Diisopropylethyiamine
  • TSA triethylamine
  • hydroxides which may be selected from, but are not limited to sodium hydroxide or potassium hydroxide;
  • an organic solvent which may be selected from, but is not limited to acetonitrile (ACN), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (Me-THF), N - Methyl-2-pyrrolidone (NMP), dichloromethane, Dimethylacetamide (CH 3 C(0)N(CH 3 )2 or DMAc), dimethylsulfoxide (DMSO), dimethylformamide (DMF), toluene or the like, heated at a suitable temperature range from about 20°C to about 60°C, more suitable at a temperature of about 40°C to forming a reaction solution; and
  • ACN acetonitrile
  • IPA isopropyl alcohol
  • THF tetrahydrofuran
  • Me-THF 2-methyl-tetrahydrofuran
  • NMP N - Methyl-2-pyrrolidone
  • dichloromethane Dimethylacetamide (CH 3
  • step [2] reacting the reaction solution of step [1] with 4,6-dichloro-5-fluoro-2- methylpyrimidine: to form the compound which is (S)-4-(6-chloro-5-fluoro-2-methylpyrimidin-4-yl) piperazine-2-carboxylic acid.
  • the present invention relates to a process for preparation of a compound which is (f?)-3-((benzyloxy)amino)- 2-(cyclopentylmethyl) propanehydrazide: which comprises steps of:
  • the present invention relates to a process for preparation of a compound which is (f?)-3-((benzyloxy)amino)- 2-(cyclopentylmethyl) propanehydrazide:
  • the present inventon relates to a process for preparation of a compound which is (f?)-3-((benzyloxy)amino)- 2-(cyclopentylmethyl)
  • formaldehyde a base
  • formaldehyde a base
  • KOH potassium hydroxide
  • TAA triethylamine
  • Na 2 C0 3 sodium carbonate
  • K 2 C0 3 postassium carbonate
  • organic solvent which may be selected from, but not limited to tert-butyl methyl ether, Dichloromethane, toluene, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF) and water to form an intermediate formaldehyde O-benzyl oxime:
  • a silylating agent which may be selected from, but is not limited to trimethylchlorosilane or trimethylsilyl trifluoromethanesulfonate or at a temperature of about 15°C to 25°C and a sodium halide selected from sodium iodide in an organic solvent, which may be selected from, but is not limited to acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (Me-THF), Toluene, to which was added an amine, which may be selected from triethylamine (TEA), N, N- Diisopropylethylamine (DIPEA), or the like to form 3-((benzyloxy)amino)-2- (cyclopentylmethyl)propanoic acid:
  • a silylating agent which may be selected from, but is not limited to trimethylchlorosilane or trimethylsilyl trifluoromethan
  • chiral resolving agent may be selected from, but is not limited to a (R)-1 ,2,3,4-tetrahydro naphthalen-1-amine, [(R)-(-)-1-amino- indane, (R)-2-phenylglycinal, (R)-(-)-methoxy-4-methylbenzylamine or the like
  • an organic solvent which may be selected from, but is not limited to isopropyl acetate, ethyl acetate, isopropyl acetate, toluene, n-propanol, 2-propanol and the like to form (f?)-1 ,2,3,4-tetrahydronaphthalen-1-aminium (f?)-3-cyclopentyl-2- ((phenoxyamino)methyl) propanoate:
  • step [4] reacting the (f?)-1 ,2,3,4-tetrahydronaphthalen-1-aminium (f?)-3-cyclopentyl-2- ((phenoxyamino)methyl)propanoate formed in step [3] with: an acid, which may be selected from a mineral acid, which may include, but are not limited to citric acid, hydrochloric acid and the like;
  • a coupling agent which may be selected from, but not limited to 2(1 h- benzotriazol-1-yl)-1 , 1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU), 0-(7- azabenzotriazol-1-yl)-A/,A/,A/ A/'-tetramethyluronium hexafluorophosphate (HATU), 2-(1 h-benzotriazol-1-yl)-1 , 1 ,3,3-tetramethyluronium
  • hexafluorophosphate hbtu
  • BOP Benzotriazole-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate
  • the present invention relates to an alternate process for preparation of a compound which is (f?)-3-((benzyloxy)amino)- 2-(cyclopentylmethyl) propanehydrazide:
  • step [2] converting the racemic mixture of step [1] with a chiral resolution agent and a base to obtain R- 3-((benzyloxy)amino)-2-(cyclopentylmethyl)propanoic acid:
  • the present invention relates to an alternate process for preparation of a compound which is (f?)-3-((benzyloxy)amino)- 2-(cyclopentylmethyl) propanehydrazide:
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • TMSI trimethylsilyliodide
  • TMSCI trimethylsilyliodide
  • chiral resolution agent may be selected from, but is not limited to Subtilisin, Subtilisin Carlsberg and Bacillus sp.; Protease TypeVII, Bacterial; SubtilisinA Bacillus Licheniforms; Proteinase TypeXXIV, Bacterial; Novozymes protease, alkaline;
  • subtilisin is a proteolytic enzyme produced by the bacterium Bacillus suhtllis, used as an chiral resolution agent.
  • Alcalase ® 2.4 L FG solution and Alcalase 2.4L, respectively are commercially available solutions of an enzyme called Protease (Subtilisin) (i.e., as available from from such commercial vendors as Novozymes North America, where such enzyme solution was used for the selective hydrolysis of the desired enantiomer of racemate R and S forms of 3-((benzyloxy)amino)-2-(cyclopentylmethyl)propanoic acid to produce enantioenriched obtain R- 3-((benzyloxy)amino)-2- (cyclopentylmethyl)propanoic acid.
  • Protease Subtilisin
  • AlkyI refers to a monovalent saturated hydrocarbon chain having the specified number of member carbon atoms.
  • C1-C7 alkyl refers to an alkyl group having from 1 to 7 member carbon atoms.
  • Alkyl groups may be optionally substituted with one or more substituents as defined herein.
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • Alkenyl refers to an unsaturated hydrocarbon chain having the specified number of member carbon atoms and having one or more carbon-carbon double bonds within the chain.
  • C2-C6 alkenyl refers to an alkenyl group having from 2 to 6 member carbon atoms.
  • alkenyl groups have one carbon- carbon double bond within the chain.
  • alkenyl groups have more than one carbon-carbon double bond within the chain.
  • Alkenyl groups may be optionally substituted with one or more substituents as defined herein.
  • Alkenyl groups may be straight or branched. Representative branched alkenyl groups have one, two, or three branches.
  • Alkenyl includes ethylenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • Alkoxy refers to an alkyl moiety attached through an oxygen bridge (i.e. a -0-C1- C6 alkyl group wherein C1-C6 is defined herein). Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • Alkynyl refers to an unsaturated hydrocarbon chain having the specified number of member carbon atoms and having one or more carbon-carbon triple bonds within the chain.
  • C2-C6 alkynyl refers to an alkynyl group having from 2 to 6 member atoms.
  • alkynyl groups have one carbon-carbon triple bond within the chain.
  • alkynyl groups have more than one carbon-carbon triple bond within the chain.
  • unsaturated hydrocarbon chains having one or more carbon-carbon triple bond within the chain and one or more carbon-carbon double bond within the chain are referred to as alkynyl groups.
  • Alkynyl groups may be optionally substituted with one or more substituents as defined herein.
  • alkynyl groups have one, two, or three branches.
  • Alkynyl includes ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • Aryl refers to an aromatic hydrocarbon ring system.
  • Aryl groups are monocyclic ring systems or bicyclic ring systems.
  • Monocyclic aryl ring refers to phenyl.
  • Bicyclic aryl rings refer to napthyl and to rings wherein phenyl is fused to a cycloalkyl or cycloalkenyl ring having 5, 6, or 7 member carbon atoms.
  • Aryl groups may be optionally substituted with one or more substituents as defined herein.
  • Chiral resolution in stereochemistry is a process for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active drugs. Derivatization of racemic compounds is possible with optically pure reagents forming pairs of diastereomers which can be separated by conventional techniques in physical chemistry.
  • Chiral resolution agent is a chiral auxiliary or agent, which can convert a mixture of enantiomers into a single diastereomer(s), which may be useful to analyse the quantities of each enantiomer present within the mix.
  • Chiral resolution agents suitable for use in the present invention may be selected from, but is not limited to Subtilisin, Subtilisin Carlsberg and Bacillus sp.; Protease TypeVII, Bacterial;
  • SubtilisinA Bacillus Licheniforms; Proteinase TypeXXIV, Bacterial; Novozymes protease, alkaline; Novozymes lipase, Rhizomucor miehei and Thermomyces lanuginosus, mutant ; Esterase, Mucor Miehei; Acylase I, Porcine Kidney and the like.
  • subtilisin is a proteolytic enzyme produced by the bacterium Bacillus subtiiis, used as an chiral resolution agent.
  • Alcalase ® 2.4 L FG solution is a commercially available solution of an enzyme called Protease (Subtilisin) (from such vendors as Novozymes North America, where such enzyme solution was used for the selective hydrolysis of the desired enantiomer of racemate R and S forms of 3-((benzyloxy)amino)-2-(cyclopentylmethyl)propanoic acid to produce enantioenriched obtain R- 3-((benzyloxy)amino)-2- (cyclopentylmethyl)propanoic acid.
  • Protease Subtilisin
  • Cycloalkyl refers to a saturated hydrocarbon ring having the specified number of member carbon atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Cycloalkenyl refers to an unsaturated hydrocarbon ring having the specified number of member carbon atoms and having a carbon-carbon double bond within the ring.
  • C3-C6 cycloalkenyl refers to a cycloalkenyl group having from 3 to 6 member carbon atoms.
  • cycloalkenyl groups have one carbon-carbon double bond within the ring. In other embodiments, cycloalkenyl groups have more than one carbon-carbon double bonds within the ring.
  • Cycloalkenyl rings are not aromatic. Cycloalkenyl groups are monocyclic ring systems. Cycloalkenyl groups may be optionally substituted with one or more substituents as defined herein. Cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.
  • Enantiomeric excess or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, or greater than 90% ee.
  • Enantiomerically pure refers to products whose enantiomeric excess is 99% ee or greater.
  • Halo refers to the halogen radicals fluoro, chloro, bromo, and iodo.
  • HaloalkyI refers to an alkyl group wherein at least one hydrogen atom attached to a member atom within the alkyl group is replaced with halo.
  • the number of halo substituents include but are not limited to 1 , 2, 3, 4, 5, or 6 substituents.
  • Haloalkyl includes monofluoromethyl, difluoroethyl, and trifluoromethyl.
  • Heteroaryl refers to an aromatic ring containing from 1 to 5, suitably 1 to 4, more suitably 1 or 2 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Heteroaryl groups are monocyclic ring systems, or are fused bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 6 member atoms. Bicyclic heteroaryl rings have from 8 to 10 member atoms.
  • Bicyclic heteroaryl rings include those rings wherein the primary heteroaryl and the secondary monocyclic cycloalkyi, cycloalkenyl, heterocycloalkyl, aryl or heteroaryl ring are attached, forming a fused bicyclic ring system.
  • Heteroaryl includes, among others, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzisoxazolyl, benzofurany
  • Heteroatom refers to a nitrogen, sulfur, or oxygen atom.
  • Heterocycloalkyl refers to a saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Heterocycloalkyl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heterocycloalkyl rings have from 4 to 7 member atoms. Bicyclic heterocycloalkyl rings have from 7 to 11 member atoms.
  • heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated, but not aromatic. Heterocycloalkyl includes, among others, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1- pyrazolidinyl, azepinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-dithianyl, azetidinyl, isoxazolidinyl, 3-azabicyclo[3.1.0]
  • Member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
  • Optionally substituted indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituents as defined herein.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Substituted in reference to a group indicates that one or more hydrogen atoms attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term
  • substituted includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by hydrolysis, rearrangement, cyclization, or elimination, and that is sufficiently robust to survive isolation from a reaction mixture).
  • a group may contain one or more substituents, one or more (as appropriate) member atom within the group may be substituted.
  • a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
  • Sulfanyl refers to an alkyl moiety attached through a sulphur bridge (i.e -S-C1-C6 alkyl group wherein C1-C6 alkyl is as defined herein).
  • sulfanyl groups include thiomethyl and thioethyl.
  • the compounds according to Formula (I) or a pharmaceutically acceptable salt thereof or any of the other compounds of the present invention defined herein may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • a substituent such as an alkyl group.
  • novel process of the present invention related to compounds according to Formula (I) or pharmaceutically acceptable salts thereof, or any of the other compounds of the present invention defined herein, containing one or more chiral centers may be used as racemic mixtures, diastereomeric mixtures, enantiomerically enriched mixtures, diastereomerically enriched mixtures, or as enantiomerically and diastereomerically pure individual stereoisomers.
  • the compound or salt including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof.
  • the compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms).
  • free base and/or salt forms of the present invention may exhibit characteristic polymorphism.
  • polymorphism is defined as an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
  • a polymorph is defined as a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
  • Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds. Such compounds may differ in packing, geometrical arrangement of respective crystalline lattices, etc.
  • polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the
  • Solvates and/or hydrates of crystalline salt forms of the present invention also may be formed when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process.
  • solvate forms of the present invention may incorporate nonaqueous solvents such as methanol and the like as described herein below. Hydrate forms are solvate forms, which incorporate water as a solvent into a crystalline lattice.
  • Anhydrous with respect to solid state polymorphism refers to a crystalline structure that does not contain a repeating, crystalline solvent in the lattice.
  • crystalline materials can be porous and may exhibit reversible surface adsorption of water.
  • the present invention relates to a process for preparing polymorphic forms of free base of [(2R)-2-(Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide, which may exist as a crystalline anhydrate or crystalline anhydrous form, a hydrate, or a mixture thereof.
  • the present invention relates to a process for preparing polymorphic Form 1 of [(2R)-2-(Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide, which may exist as a crystalline anhydrate or crystalline anhydrous form, a hydrate, or a mixture thereof.
  • the present invention relates to a process for preparing polymorphic Form 2 of [(2R)-2-(Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide, which may exist as a crystalline anhydrate or crystalline anhydrous form, a hydrate, or a mixture thereof.
  • the present invention relates to a process for preparing polymorphic Form 3 of [(2R)-2-(Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide, which may exist as a crystalline anhydrate or crystalline anhydrous form, a hydrate, or a mixture thereof.
  • novel salt compounds of the present invention may exist as crystalline anhydrous forms or crystalline anhydrates, hydrated forms (i.e., hydrate forms are solvate forms, which incorporate water as a solvent into a crystalline lattice) or mixtures thereof.
  • the present invention relates to a process for preparing polymorphic forms of the compound (Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1/-/)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide methanesulphonate, which may exist as a crystalline anhydrate or crystalline anhydrous form, a hydrate, or a mixture thereof.
  • the present invention relates to a process for preparing the compound (Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)-hexahydropyrazino[2, 1- c][1 ,4]oxazin-8(1 /-/)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide methanesulphonate Form 1 , which may exist as a crystalline anhydrate or crystalline anhydrous form, a hydrate, or a mixture thereof.
  • the present invention relates to a process for preparing the compound (Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)-hexahydropyrazino[2, 1- c][1 ,4]oxazin-8(1 /-/)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide methanesulphonate Form 2, which may exist as a crystalline anhydrate or crystalline anhydrous form, a hydrate, or a mixture thereof.
  • Polymorphs therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
  • the compounds according to Formula (I) or a pharmaceutically acceptable salt thereof or any of the other compounds of the present invention defined herein may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form.
  • invention includes all such polymorphs.
  • Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties.
  • the various forms i.e., which may include, but are not limited to polymorphic, salt, solvate, anhydrate, hydrate, crystalline, forms etc.
  • [(2R)-2-(Cyclopentylmethyl)-3-(2- ⁇ 5-fluoro-6-[(9aS)-hexahydropyrazino[2, 1- c][1 ,4]oxazin-8(1 H)-yl]-2-methyl-4-pyrimidinyl ⁇ hydrazino)-3- oxopropyl]hydroxyformamide i.e. which include salts and/or solvates thereof
  • Such techniques include solid state 3 C Nuclear Magnetic Resonance (NMR), 3 P Nuclear Magnetic Resonance (NMR), Infrared (IR), Raman, X-ray powder diffraction, etc. and/or other techniques, such as Differential Scanning Calorimetry (DSC) (i.e., which measures the amount of energy (heat) absorbed or released by a sample as it is heated, cooled or held at constant temperature).
  • DSC Differential Scanning Calorimetry
  • Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may spontaneously convert to another polymorph under certain conditions.
  • the crystalline state of a compound can be described by several crystallographic parameters: unit cell dimensions, space groups, and atomic position of the atoms in the compound relative to the origin of its unit cell. These parameters are experimentally determined by crystal X-ray analysis. It is possible for a compound to form more than one type of crystal. These different crystalline forms are called polymorphs.
  • Characteristic powder X-ray diffraction pattern peak positions are reported for polymorphs in terms of the angular positions (two theta) with an allowable variability, generally of about 0.1 +/- °2-theta or 0.1 +/- °3-theta. The entire pattern, or most of the pattern peaks may also shift by about 0.1 +/- ° due to difference in calibration, setting, and other variations from instrument to instrument and from operator to operator.
  • compounds according to Formula I or a pharmaceutically acceptable salt thereof or any of the other compounds of the present invention defined herein may contain an acidic functional group.
  • compounds according to Formula I or pharmaceutically acceptable salt thereof, or any of the other compounds of the present invention defined herein may contain a basic functional group.
  • salts of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, salts of the compounds according to Formula I may be preferred over the respective free base or free acid because, for example, such salts may impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form.
  • salts of the compounds of Formulas (I) are suitably pharmaceutically acceptable salts.
  • compositions include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19.
  • a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, which may include, but is not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, but is not limited to acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-tolu
  • an inorganic acid which may include, but is not limited to acids such as hydroch
  • Examples of pharmaceutically acceptable salts may include, but is not limited to acids such asclude sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates,
  • methylbenzoates dinitrobenzoates, hydroxy benzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ - hydroxybutyrates, glycollates, tartrates mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates or naphthalene-2-sulfonates and the like.
  • Base salts may include, but are not limited to ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, N-methyl-D-glucamine and the like.
  • an inventive basic compound is isolated as a salt
  • the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • Acid salts are formed from acids, may include, but are not limited, which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, malonate, lactate, tartrate, citrate, formate, gluconate, succinate, piruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, methanesulphonic, ethanesulphonic, p-toluenesulphonic, isethionate and the like.
  • Certain of the compounds of this invention may form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety).
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as ethylene diamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as glycine and arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as ethylene diamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • pharmaceutically acceptable salts may be prepared by treating these compounds with an alkaline reagent or an acid reagent, respectively. Accordingly, this invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of this invention, e.g., a hydrochloride salt, into another pharmaceutically acceptable salt of a compound of this invention, e.g., a sodium salt.
  • a pharmaceutically acceptable salt of a compound of this invention e.g., a hydrochloride salt
  • another pharmaceutically acceptable salt of a compound of this invention e.g., a sodium salt.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • the term "compounds of the invention” means both the compounds according to Formula I and salts thereof, including pharmaceutically acceptable salts.
  • the term "a compound of the invention” also appears herein and refers to both a compound according to Formula I and its salts, including
  • the compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Hydrates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates. SOLVATES
  • solvates of the compounds of the invention, or salts thereof, that are in crystalline form may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Hydrates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • the invention also includes various deuterated forms of the compounds of Formulas (I) or pharmaceutically acceptable salts thereof.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom.
  • a person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formulas(l) to (II) of the present invention.
  • deuterated materials such as alkyl groups may be prepared by conventional techniques (see for example: methyl-d 3 -amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).
  • ISOTOPES ISOTOPES
  • the subject invention also includes isotopically-labeled compounds which are identical to those recited in Formulas (I) and (II) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 3 H, 11 C, 14 C, 18 F, 123 l or 125 l.
  • Isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 4 C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, ie. 3 H, and carbon-14, ie. 4 C, isotopes are particularly preferred for their ease of preparation and detectability. C and 8 F isotopes are particularly useful in PET (positron emission tomography).
  • the compounds of the present invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical
  • the present invention also relates to processes for making compounds of Formula (I), or pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the present invention also relates to processes for making compounds of Formulas (I) or pharmaceutically acceptable salts thereof.
  • the compounds according to Formulas (I) to (II), respectively, or pharmaceutically acceptable salts thereof, are prepared using conventional organic syntheses.
  • the compounds of the present invention may be obtained by using synthetic procedures illustrated in Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • Scheme 1 represents a general scheme for the preparation of compounds according to Compounds (3), (4) and (5) as shown above, where Ri is attached to the oxygen atom via a carbon atom, and R 2 is an alkyl group.
  • Compounds (1) depicted as starting material are commercially available.
  • Compounds (2) are readily prepared by the condensation of formaldehyde and the corresponding O- alkyl hydroxylamine. Reaction conditions are as described above in the scheme; however, the skilled artisan will appreciate that certain modifications in the reaction conditions and/or reagents used are possible.
  • Scheme 3 represents a general scheme for the preparation of compounds according to Compounds (12) and (13) as shown above, where Ri is attached to the oxygen atom via a carbon atom, and Xi and X 2 are acidic compounds used for the preparation of the corresponding salt.
  • Coupling of 6 and 7 in the presence of base produces 8.
  • Treatment of 8 with chloroacetyl chloride, followed by global carbonyl reduction with borane and treatment with base gives 9 which can be isolated as either the free base or a salt (for example, p-toluenesulfonate, p-toluenesulfonic acid).
  • Formylation of 10 produces 11.
  • ⁇ _ microliters
  • psi pounds per square inch
  • ⁇ micromolar
  • nM nanomolar
  • pM picomolar
  • nm nanometer
  • Tr retention time
  • RP reverse phase
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • TFAA trifluoroacetic anhydride
  • THF tetrahydrofuran
  • DCE dichloroethane
  • DMF A/,A/-dimethylformamide
  • DMPU ⁇ /, ⁇ /'-dimethylpropyleneurea
  • CDI 1-carbonyldiimidazole
  • IBCF isobutyl chloroformate
  • AcOH acetic acid
  • THP tetrahydropyran
  • NMM N-methylmorpholine
  • HOBT 1-hydroxybenzotriazole
  • mCPBA metal-chloroperbenzoic acid
  • DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);
  • TIPS triisopropylsilyl
  • TBS f-butyldimethylsilyl
  • DMAP 4-dimethylaminopyridine
  • BSA bovine serum albumin
  • NAD nicotinamide adenine dinucleotide
  • BOP bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • TBAF tetra-n-butylammonium fluoride
  • HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);
  • DPPA diphenylphosphoryl azide
  • LAH Lithium aluminum hydride
  • fHN0 3 finite HN0 3
  • NaOMe sodium methoxide
  • EDTA ethylenediaminetetraacetic acid
  • TMEDA N,N,N',N'-tetramethyl-1 ,2-ethanediamine
  • NBS N-bromosuccinimide
  • DIPEA diisopropylethylamine
  • dppf 1, 1 '-bis(diphenylphosphino)ferrocene
  • NIS N-iodsuccinimide
  • Acetonitrile (6.5L) was added to the reactor. The solution was concentrated to ⁇ 5 L. A sample was obtained for w/w assay analysis. 3.576 kg of formaldehyde O-benzyl oxime (BRL-8514IN) was obtained based on w/w assay (94% yield).
  • the suspension was cooled to 32°C over at least 30 min, stirred for 2h, cooled to 27°C over 45min, and stirred overnight.
  • the contents were cooled to 4°C over 1 h 40min and stirred for 2h.
  • the mixture was filtered.
  • the cake was washed with iso-propyl acetate (2x8.6kg).
  • the wet cake was charged back to the reactor.
  • the reactor was charged with iso- propyl acetate (30.34kg).
  • the contents were warmed to 50°C and stirred for 1 h.
  • the contents were stirred at 45°C-40°C for 2h and cooled to 18°C over 60min.
  • the mixture was stirred for 2h and filtered.
  • the cake was washed with iso-propyl acetate (2x5L) and dried under vacuum at room temperature to give 3.03 kg product. Yield 40% with 93% ee by chiral HPLC.
  • the organic layer was then transferred into a clean vessel, and the hydrazine reactor was rinsed with methyl t-butyl ether (0.5 L, 0.2 vol) and added to the crystallization vessel.
  • the solution was concentrated down under vacuum to about 2.5 vol, and isopropyl acetate (7.6 L, 3.0 vol) was charged.
  • the solution was concentrated down under vacuum again to about 2.5 vol, and isopropyl acetate (3.8 L, 1.5 vol) was charged, followed by heptane (20.2 L, 8.0 vol).
  • the slurry was heated to
  • the resulting biphasic slurry was cooled to about 5°C and then treated at that temperature with chloroacetyl chloride (1.16 kg, 10.3 mol).
  • the rate of the chloroacetyl chloride addition was such that the reaction temperature never exceeded 15°C; the addition took about 20 minutes to complete. After stirring the reaction mixture for about
  • reaction mixture was stirred at 40-45°C for 3 h and then cooled to 37°C.
  • the reaction mixture was then carefully treated with acetone (4.30L, 58.6 mol).
  • the rate of the acetone addition was such that the reaction temperature never exceeded 40°C; the addition took about 30 minutes to complete.
  • the reaction mixture was cooled to ambient temperature and left to stir overnight. In the morning, the reaction mixture was treated at ambient temperature with isopropanol (6.69 L) and then carefully with aqueous 5N NaOH solution (12.0 L, 60.0 mol). The rate of the aqueous NaOH solution addition was such that the reaction temperature never exceeded 30°C; the addition took about 15 minutes to complete.
  • the reaction mixture was heated to about 40°C and stirred at about 40 C for about 4h.
  • the reaction mixture was cooled to about 25°C and the layers were allowed to settle and separate.
  • the aqueous layer was removed.
  • the organic layer was treated with water (10.0 L) and then
  • the concentrated reaction mixture containing (S)-8-(6-chloro-5-fluoro-2-methylpyrimidin-4-yl)octahydropyrazino[2, 1- c][1 ,4]oxazine was treated with heptane (8.00 L) and then heated to about 60°C.
  • the heated reaction mixture was treated with a solution of p-toluenesulfonic acid monohydrate (1.32 kg, 6.92 mol) previously dissolved in isopropanol (4.00 L).
  • the resulting solution was cooled to about 55 °C and seeded with (S)-8-(6-chloro-5-fluoro- 2-methylpyrimidin-4-yl)octahydropyrazino[2, 1-c][1 ,4]oxazine p-toluenesulfonate (1.67 g, 3.64 mmol).
  • the resulting suspension was stirred at 55°C for about 2 h, cooled to 0°C over a 100 minute period, and stirred at 0°C for 1 h.
  • the resulting thick slurry was filtered and the wet cake was washed with chilled heptane (2.00 L).
  • the wet cake was transferred back into the 50-L reactor and treated with 1-propanol (10.0 L).
  • the reaction mixture was heated with stirring to about 60°C in order to dissolve all of the solids.
  • the reaction mixture was cooled to 47°C.
  • the solution was seeded with (S)- 8-(6-chloro-5-fluoro-2-methylpyrimidin-4-yl)octahydropyrazino[2, 1-c][1 ,4]oxazine p- toluenesulfonate (1.67 g, 3.64 mmol).
  • the resulting suspension was stirred at 47°C for about 2h, cooled to 0°C over a 100 minute period, and stirred at 0°C for 1 h.
  • the toluene solution was placed into a clean reactor and DMSO (300 ml_) was added.
  • the solution was distilled at 50 mbar until the volume was 3.2-3.5 vol.
  • the jacket was set at 85 °C toward the end of the distillation and when the contents reached 80 °C, the solution was held under vacuum for an additional 30 min to ensure removal of toluene to an acceptable level.
  • the DMSO solution was cooled to 35 °C and (R)-3-((benzyloxy)amino)-2- (cyclopentylmethyl)propanehydrazide (69.8 g, 240 mmol) was added. The mixture was stirred until dissolution was observed.
  • the solution was cooled I to 25 °C and sodium tert-pentoxide (24 g, 218 mmol) was added portion-wise over 1.5 h maintaining the temperature below 30 °C.
  • the reaction was stirred at 30 °C for 5 h and sampled for HPLC.
  • the dark solution was cooled to 25 °C and formic acid (9.78 mL, 255 mmol) was added over -20 min.
  • n-Butyl acetate (600 mL) and water (300 mL) were added.
  • the biphasic mixture was stirred for 15 min while heating to 45 °C and then the layers were settled for >8 h.
  • the aqueous layer was removed and water (300 mL) was added.
  • the mixture was stirred for 10-15 min at 45 °C and then the layers were settled. The aqueous layer was removed. The volume of the solution was reduced under vacuum (60 mbar) to -400 mL and iso-octane (200 mL) was added. The solution was heated to 80 °C to ensure dissolution and then cooled to 68°C.
  • Formic acid (41.2 g, 895 mmol) was added over 5 minutes during which time, the temperature of the contents increased to 24.3°C and solids dissolved into a golden brown solution.
  • the contents of the reactor were then heated to 40C at a rate of 0.5°C/min and the clear golden colored solution was stirred at 40C for 3 hrs and then sampled for HPLC.
  • the solution was then cooled to 25°C and NaOH (25wt% in water, 40.5 g) was added.
  • the mixture was stirred at 25°C for 1 hr and then sampled for HPLC.
  • the reactor was purged three times with nitrogen (3.5 bar), once with hydrogen (2.5 bar), and twice with hydrogen (3.5 bar).
  • the contents was pressurized to 3.5 bar (2.5barg) and the contents was heated to 40°C and then stirred for 2.5 hrs at 40°C.
  • the vessel was vented and then purged three times with nitrogen (2.5 bar).
  • the catalyst was removed by filtering the contents through a 0.45 urn polytetrafluoroethylene (PTFE) filter. MeOH (161 ml_) was added to rinse the reactor and the filter. The filter was blown dry with nitrogen. The solution was transferred back to the reactor and passed through another 0.45 urn PTFE filter. A sample of the filtrate was taken for HPLC analysis.
  • PTFE polytetrafluoroethylene
  • the solvent was distilled at reduced pressure (350torr) with a jacket temperature of 70°C down to a total volume of 800mL.
  • the mixture was heated to dissolution and a sample was taken for GC analysis to determine the ratio of methanol to 2-propanol.
  • the mixture was cooled to 60°C and was seeded with N-(( )-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)- hexahydropyrazino[2, 1-c][1 ,4]oxazin-8(1 H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3- oxopropyl)-N-hydroxyformamide Form 3 (0.2 g).
  • the slurry was stirred at 60°C for 3 hrs then was cooled to 10°C at a rate of 0.1 °C/min.
  • the solids were isolated by filtration and were washed twice with cold 2-propanol.
  • the wet cake was placed in a vacuum oven at 60C, 25inHg vac and was dried overnight.
  • the solution was filtered through a 0.45 urn filter and transferred to a 150 mL JLR.
  • the 50 mL JLR was rinsed with 0.5 volumes (2.0 mL) of n-butanol, which was then transferred through a 0.45 urn filter into the 150 mL JLR.
  • the 150 mL JLR was reheated to 88°C. Dissolution was again observed.
  • the slurry was aged at 50°C for 300 minutes while 10 volumes (53 mL) of isooctane were added at a constant rate of 0.176 mL/min.
  • the slurry was cooled to 0°C at 0.25°C/min.
  • the slurry was aged at 0°C overnight.
  • the solids were isolated by filtration.
  • the filter cake was rinsed with 5 volumes (25 mL) of isooctane.
  • the filter cake was dried under vacuum at 60°C.
  • the slurry was aged for 2 hours at 20°C.
  • the slurry was cooled to 0°C at a linear rate of 0.1 °C/min and aged overnight.
  • the slurry was filtered under nitrogen and the cake was washed with chilled n-propanol (100 mL). The resulting wet cake was blown with nitrogen. The wet cake was then dried under vacuum at 50°C.
  • Seeds (0.5 g) were added (pot temp 47-50 °C) and the mixture was cooled to 45 °C. Seeds (0.5 g) were added again (pot temp -45 °C) and the mixture was cooled to 40 0 C. The mixture was cooled to 20 °C over 30 minutes. Heptane (4.05 kg) was added and the mixture was stirred for -3.5 hours. The suspension was filtered and the cake was washed with heptanes (2.4 L). The solid was dried under vacuum at -37 °C. After drying, 2382 g (94.6% yield) was obtained.
  • reaction pH was adjusted to 6.5 ⁇ 0.5 using 30 % w/w aqueous citric acid solution ( ⁇ 260ml).
  • Methyl tert-butyl butyl ether (MTBE) (4.9L, 7 vols) was added to the reactor. The mixture was stirred for 20 min and settled for 30min. The aqueous layer was back-extracted with MTBE (4.9L, 7vol). The organic layers were combined. To the combined organic solution were added water (3.5L, 5vol) and 2N NaOH (0.875L, 1.25vol). The contents were stirred for 30min and settled for 30min.
  • the aqueous layer was washed with MTBE (2vol) and adjusted pH to 5.5 + 0.5 with 2M hydrochloric acid.
  • MTBE (3.5L, 5vol) was added to the reactor, and the contents were stirred at 35 °C for 10min. The layers were settled for 30min. The aqueous layer was back-extracted with MTBE (2.1 L, 3vol). The organic layers were combined (4.1 kg). A sample was obtained for w/w assay. (40% yield). 91 % ee by chiral HPLC. A sample was obtained for H-NMR (remove all MTBE).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des procédés de préparation de composés de {2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}- hydroxyformamide de Formule (I), ou de sels pharmaceutiquement acceptables de ceux-ci et d'intermédiaires leur correspondant, lesdits composés étant utiles pour inhiber l'activité de la peptide déformylase (PDF) bactérienne et dans des méthodes destinées à traiter les infections bactériennes.
PCT/IB2014/059810 2013-03-15 2014-03-14 Procédés de préparation d'inhibiteurs de la peptide déformylase WO2014141181A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101442A1 (fr) 2002-05-31 2003-12-11 Smithkline Beecham Corporation Inhibiteurs de peptide deformylase
WO2006055663A2 (fr) 2004-11-17 2006-05-26 Smithkline Beecham Corporation Nouvelle utilisation
WO2009061879A1 (fr) 2007-11-09 2009-05-14 Smithkline Beecham Corporation Inhibiteurs de la peptide déformylase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101442A1 (fr) 2002-05-31 2003-12-11 Smithkline Beecham Corporation Inhibiteurs de peptide deformylase
US7919528B2 (en) 2002-05-31 2011-04-05 Glaxosmithkline Llc Peptide deformylase inhibitors
WO2006055663A2 (fr) 2004-11-17 2006-05-26 Smithkline Beecham Corporation Nouvelle utilisation
WO2009061879A1 (fr) 2007-11-09 2009-05-14 Smithkline Beecham Corporation Inhibiteurs de la peptide déformylase
US7893056B2 (en) 2007-11-09 2011-02-22 Glaxosmithkline Llc Peptide deformylase inhibitors

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ADAMS, J.M., J. MOL. BIOL., vol. 33, 1968, pages 571 - 589
BALL, L.A.; KAESBERG, P., J. MOL. BIOL., vol. 79, 1973, pages 531 - 537
BERGE; BIGHLEY; MONKHOUSE, J.PHARM.SCI, vol. 66, 1977, pages 1 - 19
JOYCE A. SUTCLIFFE: "Antibiotics in development targeting protein synthesis", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 1241, no. 1, 22 December 2011 (2011-12-22), pages 122 - 152, XP055120873, ISSN: 0077-8923, DOI: 10.1111/j.1749-6632.2011.06323.x *
LIVINGSTON, D.M.; LEDER, P., BIOCHEMISTRY, vol. 8, 1969, pages 435 - 443
NGUYEN, K.T.; HU, X.; COLTON, C.; CHAKRABARTI, R.; ZHU, M.X.; PEI, D., BIOCHEMISTRY, vol. 42, 2003, pages 9952 - 9958
T. GREENE; P. WUTS: "Protecting Groups in Chemical Synthesis", 1999, JOHN WILEY & SONS

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