WO2002018319A1 - Process for making n-aryl-anthranilic acids and their derivatives - Google Patents
Process for making n-aryl-anthranilic acids and their derivatives Download PDFInfo
- Publication number
- WO2002018319A1 WO2002018319A1 PCT/US2001/022948 US0122948W WO0218319A1 WO 2002018319 A1 WO2002018319 A1 WO 2002018319A1 US 0122948 W US0122948 W US 0122948W WO 0218319 A1 WO0218319 A1 WO 0218319A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- alkyl
- hydrogen
- process according
- Prior art date
Links
- 0 *c(cc1)cc(*)c1Nc(c(F)c1F)c(*)cc1F Chemical compound *c(cc1)cc(*)c1Nc(c(F)c1F)c(*)cc1F 0.000 description 9
- OOXDZFNAHQNAIC-UHFFFAOYSA-N CCCCCC1=C(C)C(C)=C(C)C(C)C1C Chemical compound CCCCCC1=C(C)C(C)=C(C)C(C)C1C OOXDZFNAHQNAIC-UHFFFAOYSA-N 0.000 description 1
- LMNJTASMCPEESC-UHFFFAOYSA-N O=C(C(C=CC(C1F)F)=C1Nc(c(Cl)c1)ccc1I)NOCC1CC1 Chemical compound O=C(C(C=CC(C1F)F)=C1Nc(c(Cl)c1)ccc1I)NOCC1CC1 LMNJTASMCPEESC-UHFFFAOYSA-N 0.000 description 1
- XCNBGWKQXRQKSA-UHFFFAOYSA-N OC(c(ccc(F)c1F)c1Nc(c(Cl)c1)ccc1I)=O Chemical compound OC(c(ccc(F)c1F)c1Nc(c(Cl)c1)ccc1I)=O XCNBGWKQXRQKSA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Definitions
- the present invention relates to a process for the preparation of N-aryl anthranilic acids, which are useful pharmaceutical agents and, for example, are known anti-inflammatory agents.
- N-aryl-anthranilic acids can serve as intermediates in the preparation of N-aryl anthranilic amides, N-aryl-anthranilic hydroxamic acids, and N-aryl anthranilic hydroxamic acid esters.
- Certain N-aryl anthranilic hydroxamic acids and N-aryl anthranilic hydroxamic acid esters inhibit certain dual specificity kinase enzymes involved in proliferative diseases such as cancer and restenosis.
- Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Cancer, for example, is commonly caused by a series of defects in these signaling proteins, resulting from a change either in their intrinsic activity or in their cellular concentrations. For example, a cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or over expression of intracellular signaling proteins such as Ras can lead to spurious mitogenic signals within a cell. Some of the most common mutations occur in genes encoding for Ras, which is a G-protein that is in an activated state when it is bound to GTP, and in an inactivated state when it is bound to GDP. Activation and inactivation of Ras is regulated in normal cells.
- MAP kinase mitogen-activated protein kinase
- ERK extracellular signal-regulated kinase
- MEK MAP/ERK kinase
- MAP kinase Activation of MAP kinase by mitogens appears to be essential for proliferation, and constitutive activation of this kinase is thought to be sufficient to induce cellular transformation.
- Blockade of downstream Ras signaling for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants.
- Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases. This participation most likely occurs through a phosphorylation mechanism.
- Raf and other kinases are known to phosphorylate MEK on two closely adjacent serine residues, namely S ⁇ 1 -* and S ⁇ 2 j n the case of MEK-1, which is a prerequisite for activation of MEK as a kinase.
- Phosphorylated MEK in turn phosphorylates MAP kinase on tyrosine, Y ⁇ -5, and threonine, T ⁇ 3
- This double phosphorylation activates MAP kinase at least 100-fold, and leads to the activated MAP kinase catalyzing the phosphorylation f a large number of proteins, including several transcription factors and other kinases.
- Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, whether the target protein is another kinase, a transcription factor, or other cellular protein.
- MEK is also activated by several kinases other than Raf-1, including MEK itself, which appears to be a signal integrating kinase.
- MEK is highly specific for the phosphorylation of MAP kinase.
- no substrate for MEK other than MAP kinase has been demonstrated to date, and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase.
- MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Accordingly, it is thought that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be valuable.
- This invention provides processes for making compounds that are highly specific inhibitors of the kinase activity of MEK. Both in enzyme assays and in whole cells, the compounds made by the processes of this invention inhibit the phosphorylation of MAP kinase by MEK, thus preventing the activation of MAP kinase in cells in which the Ras cascade has been activated.
- One result of this enzyme inhibition is a reversal of transformed phenotype of some cells types, as measured both by the ability of the transformed cells to grow in an anchorage- independent manner and by the ability of some transformed cell lines to proliferate independently of external mitogens.
- the present invention unexpectedly provides high-yielding processes for preparing N-aryl anthranilic acids and derivatives thereof comprising coupling about 1 mole equivalent of an aniline with about 1 mole equivalent of an ortho- halobenzoic acid.
- the yield of product provided by the present process is unexpectedly higher than the yield of product provided by a process that employs 2 mol equivalents of the aniline.
- the invention process allows successful commercial scale production of the N-aryl anthranilic acids and derivatives thereof.
- One embodiment of the present invention is a process, hereinafter referred to as Process Embodiment 1, of synthesizing a compound of Formula I
- Ri is hydrogen, alkyl, alkoxy, or aryl
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro, CN,
- RIO that are bonded to contiguous ring carbon atoms may be taken together with the contiguous ring carbon atoms themselves, to form an aryl, heteroaryl, a heterocyclic group, or cycloalkyl of from 4 to 7 total ring atoms, or Rl and R ⁇ may be taken together with the nitrogen atom to which Rl is attached, the carbon atom to which R ⁇ is attached, and the carbon atom contiguous to said nitrogen atom to which R* is attached and said carbon atom to which R ⁇ is attached, to form a 5-membered or 6-membered, aromatic or dihydro-aromatic ring having carbon atoms and 1 or 2 nitrogen atoms; R 11 is hydrogen, hydroxy, -CO2H, orN(R 12 )R 13 ,
- R i2 and R ⁇ 3 are each independently hydrogen or alkyl, or R l2 and R* 3 are taken together with the nitrogen atom to which they are attached to form a 3 - to
- 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, andNR 14 , wherein l4 is hydrogen or alkyl; m is an integer of 0 or 1; n is an integer selected from 0, 1, 2, 3, 4; and
- Z is COOH, COOM, COOR 15 , -C(O)R 15 , -C(O)N(R 16 )R 17 , -C(O)N(R 18 )OR 1 9, NO 2 , or CN, wherein M is a Group I metal cation or a hemi Group II metal cation, R15 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group, and l , R l7 , R l8 , and R ⁇ are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or Rl6 and i7 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and ⁇ , wherein R l4 is hydrogen or alkyl; comprising reacting a compound of Formula (A)
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the base is selected from: lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, and potassium tert- butoxide.
- the base is selected from: lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, and potassium tert- butoxide.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the base is selected from lithium hydride, sodium hydride, and potassium hydride.
- Another embodiment of the present invention is a process of Process
- Embodiment 1 wherein the base is lithium hydride.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the base is selected from lithium amide, sodium amide, and potassium amide.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the base is lithium amide.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the base is lithium diisopropylamide.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the base is selected from sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein from 1 to 5 mol equivalents of base are employed initially, and optionally from 0.5 to 4 additional mol equivalents of base are added to the reaction after a time, wherein said 0.5 to 4 additional mol equivalents of base are added in one portion or are added sequentially in unequal or equal portions at unequal or equal time intervals.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein said 0.5 to 4 additional mol equivalents of base are added sequentially to the reaction in unequal portions of decreasing size.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein said 0.5 to 4 additional mol equivalents of base are added sequentially to the reaction in unequal portions of decreasing size.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein said 0.5 to 4 additional mol equivalents of base are added sequentially to the reaction in unequal portions of decreasing size.
- Embodiment 1 wherein in the compound of formula (B), Z is COOH and 2 mol equivalents of base are employed initially or Z is COOM and 1 mol equivalent of base is employed initially, and said 0.5 to 4 additional mol equivalents of base are added sequentially to the reaction in unequal portions of decreasing size as follows: about 0.5 mol equivalents, followed by about 0.25 mol equivalents, followed by about 0.13 mol equivalents, followed by about 0.06 mol equivalents, optionally followed by about 0.03 mol equivalents, followed by about 0.015 mol equivalents.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein R* is hydrogen.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein X is fluoro.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein X is O-LG, wherein LG is SO 2 CF3 or
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein X is O-LG, wherein LG is SO CF3 or
- Embodiment 1 wherein R 2 , R 3 , R 4 , and R ⁇ are each independently selected from hydrogen, alkoxy, fluoro, chloro, bro o, and iodo.
- Another embodiment of the present invention is a process of Process
- Embodiment 1 wherem R ⁇ , B7, R 8 , R 9 , and R ⁇ 0 are each independently selected from hydrogen, alkyl, fluoro, chloro, bromo, and iodo.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein Z is COOH or COOM.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein Z is COOH or COOM.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein Z is COOH or COOM.
- Embodiment 1 wherein R is hydrogen, X is fluoro, R 2 , R 3 , R 4 , and R ⁇ are each independently selected from hydrogen, alkoxy, fluoro, chloro, bromo, and iodo, R6 R 7 , R 8 , R 9 , andRlO are each independently selected from hydrogen, methyl, fluoro, chloro, bromo, and iodo, and Z is COOH or COOM.
- Another embodiment of the present invention is a process of Process
- Embodiment 1 wherein a solvent is present and the solvent comprises acetonitrile, tetrahydrofuran, 1,2-diethoxyethane, 2,2-dimethoxypropane, 1,2-dimethoxypropane, diethylether, dioxane, or methyl tert-butylether.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein a solvent is present and the solvent comprises tetrahydrofuran or acetonitrile.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein a solvent is present and the solvent comprises a mixture of from about 1 part by volume of acetonitrile and about 1 part by volume of tetrahydrofuran to about 5 parts by volume of acetonitrile and about 1 part by volume of tetrahydrofuran.
- a solvent is present and the solvent comprises a mixture of from about 1 part by volume of acetonitrile and about 1 part by volume of tetrahydrofuran to about 5 parts by volume of acetonitrile and about 1 part by volume of tetrahydrofuran.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein when the base is added, the reaction mixture is at a temperature of from -78°C to 150°C.
- Another embodiment of the present invention is a process of Process Embodiment 1, or any one of the other above embodiments of a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of Formula la or a pharmaceutically acceptable salt thereof, wherein R ⁇ is halo or methyl, R 8 is bromo or iodo, and Z is COOH, COOM,
- R 1 ⁇ is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group
- Ri6 - r ⁇ R18 ? an£ j g l9 are eacn independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or R*6 and R l7 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR* 4 wherein
- R 14 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of Formula lb
- R ⁇ is halo or methyl
- R 8 is bromo or iodo
- Z is COOH, COOM
- R l( > and R 17 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from 0, S, and NR 4 wherein Rl4 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process
- Embodiment 1 wherein the compound of Formula I is a compound of Formula
- R ⁇ is halo or methyl
- R 8 is bromo or iodo
- Z is COOH, COOM
- R 1 ⁇ and R 17 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 4 , wherein
- R 14 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of Formula Ic2 or a pharmaceutically acceptable salt thereof, wherein R ⁇ is halo or methyl, R 8 is bromo or iodo, and Z is COOH, COOM,
- R 16 , R 17 R 18 and R 19 are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or R 1 ⁇ and R 17 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 4 wherein
- R 14 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of Formula Id
- R ⁇ is halo or methyl
- R 8 is bromo or iodo
- Z is COOH, COOM
- R ⁇ , R 17 , R 1 , and R 19 are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or
- R ⁇ and R 17 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 , wherein R 4 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1, wherein the compound of Formula I is a compound of formula
- Process Embodiment 1A Another embodiment of the present invention is a process, hereinafter referred to as Process Embodiment 1A, of synthesizing a compound of Formula I
- R 1 is hydrogen, alkyl, alkoxy, or aryl
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro,
- n, and R 1 are as defined below, or any two substituents selected from R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 , R 8 ,
- R 9 , and R 1 ⁇ that are bonded to contiguous ring carbon atoms may be taken together with the contiguous ring carbon atoms themselves, to form an aryl, heteroaryl, a heterocyclic group, or cycloalkyl of from 4 to 7 total ring atoms, or R and R° may be taken together with the nitrogen atom to which R is attached, the carbon atom to which R ⁇ is attached, and the carbon atom contiguous to said nitrogen atom to which R 1 is attached and said carbon atom to which R is attached, to form a 5-membered or 6- membered, aromatic or dihydro-aromatic ring having carbon atoms and 1 or 2 nitrogen atoms;
- R 11 is hydrogen, hydroxy, -CO 2 H, orN(R 12 )R 13
- R 12 and R 3 are each independently hydrogen or alkyl, or R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, andNR 4 , wherein R 4 is hydrogen or alkyl; m is an integer of 0 or 1; n is an integer selected from 0, 1, 2, 3, 4; and
- Z is COOH, COOM, COOR 15 , -C(O)R 15 , -C(O)N(R 16 )R 17
- R 15 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group
- R ⁇ R 1 3 Rl 8 3 and R 9 are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or ⁇ and R 7 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 4 wherein R 14 is hydrogen or alkyl; comprising reacting a compound of Formula (A)
- Another embodiment of the present invention is a process of Process Embodiment 1 A, wherein the base is lithium bis(trimethylsilyl)amide.
- Another embodiment of the present invention is a process of Process Embodiment 1A, wherein from 1 to 5 mol equivalents of base are employed initially, and optionally from 0.5 to 4 additional mol equivalents of base are added to the reaction after a time, wherein said 0.5 to 4 additional mol equivalents of base are added in one portion or are added sequentially in unequal or equal portions at unequal or equal time intervals.
- Another embodiment of the present invention is a process of Process Embodiment 1A, wherein said 0.5 to 4 additional mol equivalents of base are added sequentially to the reaction in unequal portions of decreasing size.
- Another embodiment of the present invention is a process of Process
- Embodiment 1 A wherein R 1 is hydrogen.
- Another embodiment of the present invention is a process of Process Embodiment 1 A, wherein X is fluoro.
- Another embodiment of the present invention is a process of Process
- Embodiment 1A wherein X is O-LG, wherein LG is SO 2 CF3 or
- R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, alkoxy, fluoro, chloro, bromo, and iodo.
- Another embodiment of the present invention is a process of Process Embodiment 1A, wherein ⁇ , R 7 , R 8 , R 9 , and R 1 ⁇ are each independently selected from hydrogen, alkyl, fluoro, chloro, bromo, and iodo.
- Embodiment 1A wherein Z is -C(O)N(R 18 )OR 19 , wherein R 18 and R 19 are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl.
- R 18 and R 19 are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl.
- Embodiment 1 A wherein R 1 is hydrogen, X is fluoro, R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, alkoxy, fluoro, chloro, bromo, and iodo, R6, R 7 , R 8 , R 9 , and R 1 ⁇ are each independently selected from hydrogen, methyl, fluoro, chloro, bromo, and iodo, and Z is -C(O)N(R )OR 19 , wherein R 18 and R 19 are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl.
- Another embodiment of the present invention is a process of Process Embodiment 1 A, wherein a solvent is present and the solvent comprises acetonitrile, tetrahydrofuran, 1,2-diethoxyethane, 2,2-dimethoxypropane, 1,2-dimethoxypropane, diethylether, dioxane, or methyl fert-butylether.
- a solvent is present and the solvent comprises tetrahydrofuran or acetonitrile.
- Another embodiment of the present invention is a process of Process Embodiment 1 A, wherein a solvent is present and the solvent comprises a mixture of from about 1 part by volume of acetonitrile and about 1 part by volume of tetrahydrofuran to about 5 parts by volume of acetonitrile and about 1 part by volume of tetrahydrofuran.
- Another embodiment of the present invention is a process of Process Embodiment 1 A, wherein when the base is added, the reaction mixture is at a temperature offrom -78°C to 150°C.
- Another embodiment of the present invention is a process of Process Embodiment 1A, or any one of the other above embodiments of a process of Process Embodiment 1A, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1A, wherein the compound of Formula I is a compound of Formula la or a pharmaceutically acceptable salt thereof, wherein R ⁇ is halo or methyl, R 8 is bromo or iodo, and Z is COOH, COOM,
- R 1 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group
- R 14 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1A, wherein the compound of Formula I is a compound of Formula lb
- R ⁇ is halo or methyl
- R 8 is bromo or iodo
- Z is COOH, COOM
- R 5 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group, and R16 3 R17 5 18 ? an( j R19 are eacn independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or
- R 1 ⁇ and R 7 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 , wherein
- R 14 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1A, wherein the compound of Formula I is a compound of Formula Icl
- R ⁇ is halo or methyl
- R 8 is bromo or iodo
- Z is COOH, COOM
- R 15 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group
- R18 ⁇ an( j R19 are eacn independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or R 1 ⁇ and R 17 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 , wherein
- R 14 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1A, wherein the compound of Formula I is a compound of Formula Ic2
- R ⁇ is halo or methyl
- R 8 is bromo or iodo
- Z is COOH, COOM
- anc j R19 are eacn independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or R 1 ⁇ and R 17 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, andNR 14 wherein
- R 4 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1A, wherein the compound of Formula I is a compound of Formula Idl
- R ⁇ is halo or methyl
- R 8 is bromo or iodo
- Z is COOH, COOM
- R 14 is hydrogen or alkyl.
- Another embodiment of the present invention is a process of Process Embodiment 1 A, further comprising hydrolyzing the compound of Formula I wherein Z is COOR 15 , wherein R 5 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group, to provide the compound of Formula Id2
- R is hydrogen, alkyl, alkoxy, or aryl
- R 2 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro, CN,
- R 1 ⁇ may be taken together with the contiguous ring carbon atoms themselves, to form an aryl, heteroaryl, a heterocyclic group, or cycloalkyl of from 4 to 7 total ring atoms, or R 1 and R ⁇ may be taken together with the nitrogen atom to which R 1 is attached, the carbon atom to which R ⁇ is attached, and the carbon atom contiguous to said nitrogen atom to which R 1 is attached and said carbon atom to which R ⁇ is attached, to form a 5-membered or 6- membered, aromatic or dihydro-aromatic ring having carbon atoms and 1 or 2 nitrogen atoms;
- R 11 is hydrogen, hydroxy, -CO 2 H, orN(R 12 )R 13 ,
- R 12 and R 3 are each independently hydrogen or alkyl, or R 12 and R 3
- R 3 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 wherein R 14 is hydrogen or alkyl; m is an integer of 0 or 1; and n is an integer selected from 0, 1, 2, 3, 4. This is hereinafter referred to as Process Embodiment 1A1.
- Another embodiment of the present invention is a process of Process Embodiment 1A, or any one of the other above embodiments of a process of Process Embodiment 1 A, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1A1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1A1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1A1, wherein the compound of Formula I is a compound of formula or a pharmaceutically acceptable salt thereof.
- Another embodiment of the present invention is a process of Process Embodiment 1 Al, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1A1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1A1, wherem the compound of Formula I is a compound of formula
- Embodiment 1 Al wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1A1, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 1A1, wherein the compound of Formula I is a compound of formula or a pharmaceutically acceptable salt thereof.
- Process Embodiment 2 Another embodiment of the present invention is a process, hereinafter referred to as Process Embodiment 2, of synthesizing a compound of Formula le
- R 1 is hydrogen, alkyl, alkoxy, or aryl
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 , R 9 and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro,
- R 9 , and R 1 ⁇ that are bonded to contiguous ring carbon atoms may be taken together with the contiguous ring carbon atoms themselves, to form an aryl, heteroaryl, a heterocyclic group, or cycloalkyl of from 4 to 7 total ring atoms, or R 1 and R ⁇ may be taken together with the nitrogen atom to which R 1 is attached, the carbon atom to which R ⁇ is attached, and the carbon atom contiguous to said nitrogen atom to which R 1 is attached and said carbon atom to which R ⁇ is attached, to form a 5-membered or 6-membered, aromatic or dihydro-aromatic ring having carbon atoms and 1 or 2 nitrogen atoms;
- R 11 is hydrogen, hydroxy, -CO H, orN(R 12 )R 13 , R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, andNR 4 , wherein R 14 is hydrogen or alkyl; m is an integer of 0 or 1 ; n is an integer selected from 0, 1, 2, 3, 4; and
- Z is COOR 15 , -C(O)N(R 16 )R 17 , or -C(O)N(R 18 )OR 19 wherein R 15 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group, and R16 ⁇ R17 ⁇ R18 ⁇ arjd R!9 are eacn independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or
- R 1 ⁇ and R 17 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 , wherein R 14 is hydrogen or alkyl; comprising coupling a compound of Formula If wherein Z is COOH or COOM, wherein M is a Group I metal cation or a hemi
- R l ⁇ are as defined above, or when Z is COOM, R is optionally a Group I metal cation or a hemi Group II metal cation, with a compound of Formula II
- Embodiment 2 wherein R 8 is hydrogen and R 19 is selected from methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, 2-methyl-prop-l-yl, 1,1-dimethylethyl, 1-buten-l-yl, l-buten-2-yl, l-buten-3-yl, l-buten-4-yl, 2-buten-l-yl, 2-buten-2-yl, 1-methylcyclopropyl, 2-methylcyclopropyl, 1-methylcyclobutyl,
- Embodiment 2 wherein R 18 is hydrogen and R 19 is cyclopropylmethyl.
- Another embodiment of the present invention is a process of Process Embodiment 2, or any one of the other above embodiments of a process of Process Embodiment 2, wherein the compound of Formula I is a compound of formula
- Another embodiment of the present invention is a process of Process Embodiment 2, wherein R ⁇ is hydrogen and R 17 is cyclopropylmethyl,
- Another embodiment of the present invention is a process of Process Embodiment 2, which hereinafter is referred to as a PROCESS OF
- R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro,
- R 9 , and R 1 ⁇ that are bonded to contiguous ring carbon atoms may be taken together with the contiguous ring carbon atoms themselves, to form an aryl, heteroaryl, a heterocyclic group, or cycloalkyl of from 4 to 7 total ring atoms;
- R 11 is hydrogen, hydroxy, -CO H, orN(R 12 )R 13 ,
- R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and
- R 13 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O,
- R 14 is hydrogen or alkyl
- m is an integer of 0 or 1
- n is an integer selected from 0, 1, ,2, 3, 4
- R 15 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group, 1 ⁇ , R 17 , R 8 , and R 19 are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or
- R 1 ⁇ and R 7 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 , wherein
- R 14 is hydrogen or alkyl comprising reacting an acid selected from trifluoroacetic acid, trichloroacetic acid, a mineral acid, an alkylsulfonic acid, and an arylsulfonic acid with a compound of Formula Ij
- R 2 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are as defined above,
- M and M a are each independently a Group I metal cation or a hemi Group II metal cation; adding a carboxylic acid activating reagent to the mixture of Step (a), and reacting for a time, and at a temperature, sufficient to form a corresponding activated carboxylic acid intermediate; and adding, optionally in the presence of up to 10 mol equivalents of a tertiary organic amine, a reactant which is selected from: a compound of Formula II HOR 15 II or a pharmaceutically acceptable salt thereof, wherein R is as defined above, or a compound of Formula III
- Embodiment 2a wherein M a is selected from lithium cation, sodium cation, and potassium cation.
- Another embodiment of the present invention is a process of Process Embodiment 2a, wherein M a is lithium cation.
- Another embodiment of the present invention is a process of Process Embodiment 2a, wherein in Step (a), the acid employed is trifluoroacetic acid, trichloroacetic acid, a mineral acid selected fromHCl, HBr, or H2SO4, an alkylsulfonic acid selected from CH3SO3H and CF3SO3H, or an arylsulfonic acid selected from phenyl-SO3H and / ? r ⁇ -toluenesulfonic acid.
- Step (a) the acid employed is CH3SO3H.
- Another embodiment of the present invention is a process of Process Embodiment 2a, wherein the carboxylic acid activating reagent employed in Step (b) is S(O)Cl 2 .
- Another embodiment of the present invention is a process of Process Embodiment 2a, or any one of the other above embodiments of the process of
- step (c) wherein the reactant added in step (c) is O-cyclopropylmethyl-hydroxylamine, or a pharmaceutically acceptable acid addition salt thereof.
- Another embodiment of the present invention is a process of Process Embodiment 2a, or any one of the other above embodiments of the process of
- Process Embodiment 3 of synthesizing a compound of Formula Ik
- R is hydrogen, alkyl, alkoxy, or aryl
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 , R 9 , and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro,
- m, n, andR 11 are as defined below, or any two substituents selected from R 2 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R ⁇ that are bonded to contiguous ring carbon atoms, may be taken together with the contiguous ring carbon atoms themselves, to form an aryl, heteroaryl, a heterocyclic group, or cycloalkyl of from 4 to 7 total ring atoms, or
- R 1 and R ⁇ may be taken together with the nitrogen atom to which R 1 is attached, the carbon atom to which R ⁇ is attached, and the carbon ato contiguous to said nitrogen atom to which R 1 is attached and said carbon atom to which R ⁇ is attached, to form a 5-membered or 6-membered, aromatic or dihydro-aromatic ring having carbon atoms and 1 or 2 nitrogen atoms;
- R 11 is hydrogen, hydroxy, -CO 2 H, or N(R 12 )R 13 ,
- R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and R 13 are each independently hydrogen or alkyl, or R 12 and
- R 3 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O,
- R 4 is hydrogen or alkyl
- m is an integer of 0 or 1
- n is an integer selected from 0, 1, 2, 3, 4
- Z is COOR 15 wherein R 15 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group; comprising coupling a compound of Formula If
- Z is COOH or COOM, wherein M is a Group I metal cation or a hemi
- R 1( ⁇ are as defined above, or when Z is COOM, R 1 is optionally a Group I metal cation or a hemi Group II metal cation, with a compound of Formula II
- Process Embodiment 4 for synthesizing a compound of Formula I
- R 1 is hydrogen, alkyl, alkoxy, or aryl
- R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro,
- R 1 and R ⁇ may be taken together with the nitrogen atom to which R 1 is attached, the carbon atom to which R ⁇ is attached, and the carbon atom contiguous to said nitrogen atom to which R 1 is attached and said carbon atom to which R ⁇ is attached, to form a 5-membered or 6-membered, aromatic or dihydro-aromatic ring having carbon atoms and 1 or 2 nitrogen atoms;
- R 1 1 is hydrogen, hydroxy, -CO 2 H, or N(R 12 )R 13 ,
- R 2 andR 13 are each independently hydrogen or alkyl, orR 12 and
- R 13 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 wherein R 14 is hydrogen or alkyl; m is an integer of 0 or 1; n is an integer selected from 0, 1, 2, 3, 4; and
- Z is COOH, COOM, COOR 15 , -C(O)R 15 , -C(O)N(R 16 )R 17
- R 15 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group
- R ⁇ , R 17 R 18 , and R 19 are each independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or
- R ⁇ and R 17 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 , wherein
- R 14 is hydrogen or alkyl; comprising: (a) a step for reacting a compound of Formula (A) wherein R 1 , R ⁇ , R 7 , R 8 , R 9 , and R 1 ⁇ are as defined above, with a compound of Formula (B)
- Process Embodiment 5 Another embodiment of the present invention is a process, hereinafter referred to as Process Embodiment 5, for synthesizing a compound of Formula I
- R 1 is hydrogen, alkyl, alkoxy, or aryl
- R 2 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro, CN, -(0 m - CH 2 )n-R- n , o ⁇
- R 1 ⁇ that are bonded to contiguous ring carbon atoms may be taken together with the contiguous ring carbon atoms themselves, to form an aryl, heteroaryl, a heterocyclic group, or cycloalkyl of from 4 to
- R 1 and R ⁇ may be taken together with the nitrogen atom to which R 1 is attached, the carbon atom to which R ⁇ is attached, and the carbon atom contiguous to said nitrogen atom to which R 1 is attached and said carbon atom to which R ⁇ is attached, to form a 5-membered or 6-membered, aromatic or dihydro-aromatic ring having carbon atoms and 1 or 2 nitrogen atoms;
- R 11 is hydrogen, hydroxy, -CO 2 H, orN(R 12 )R 13 ,
- R 2 and R 13 are each independently hydrogen or alkyl, or R 12 and R 1 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O,
- R 14 is hydrogen or alkyl
- m is an integer of 0 or 1
- n is an integer selected from 0, 1, 2, 3, 4;
- Z is COOR 15 , -C(O)R 15 , -C(O)N(R 16 )R 17 -C(O)N(R 18 )OR 19 NO 2 , or CN, wherein R 15 is alkyl, alkenyl, alkynyl, aryl, or a heterocyclic group, and 16 3 17 ? 18 ⁇ an( j R19 are eacn independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or
- R ⁇ and R 1 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 , wherein
- R 14 is hydrogen or alkyl; comprising:
- R 1 is alkyl, alkoxy, or aryl
- R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from: hydrogen, halo, alkyl, aryl, a heterocyclic group, haloalkyl, alkoxy, nitro, CN,
- R 9 , and R 1 ⁇ that are bonded to contiguous ring carbon atoms may be taken together with the contiguous ring carbon atoms themselves, to form an aryl, heteroaryl, a heterocyclic group, or cycloalkyl of from 4 to 7 total ring atoms, or R 1 and R ⁇ may be taken together with the nitrogen atom to which R 1 is attached, the carbon atom to which R ⁇ is attached, and the carbon atom contiguous to said nitrogen atom to which R 1 is attached and said carbon atom to which R° is attached, to form a 5-membered or 6- membered, aromatic or dihydro-aromatic ring having carbon atoms and 1 or 2 nitrogen atoms;
- R 11 is hydrogen, hydroxy, -CO 2 H, orN(R 12 )R 13 , R 12 and R 3 are each independently hydrogen or alkyl, or R 12 and
- R 13 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclic group having carbon atoms and one, two, or three heteroatoms selected from O, S, and NR 14 , wherein R 14 is hydrogen or alkyl; m is an integer of 0 or 1; n is an integer selected from 0, 1, 2, 3, 4; and
- Z is COOH or COOM; comprising reacting a compound of Formula (A)
- R , R 6 , R 7 R 8 , R 9 and R 1 ⁇ are as defined above, with a compound of Formula (B)
- the base is a Group I metal cation bis(trialkylsilyl)amide or a Group 2 metal cation bis(trialkylsilyl)amide, including lithium bis(trimethylsilyi
- Process Embodiment 7 Another embodiment of the present invention is a process, hereinafter referred to as Process Embodiment 7, wherein the process is a process of any one of Process Embodiments 1, 1A, 2, 3, 4, 5, or 6 that is carried out on a commercial scale.
- the present invention is methods of synthesizing a compound of Formula I
- R 7 R 8 , R 9 , R ⁇ , and Z are as defined above.
- alkyl means (i) a straight chain or branched chain hydrocarbon group having from 1 to 20 carbon atoms, (ii) a cyclic hydrocarbon group having from 3 to 20 carbon atoms, which is also known as a
- cycloalkyl group (iii) a cyclic hydrocarbon group bonded through a straight chain or branched chain hydrocarbon group, which is also known as a "cycloalkyl-alkylene” group, wherein the total number of carbon atoms is from 4 to 20 and wherein alkylene is as defined below, or (iv) an alkyl group bonded through a cyclic alkylene, which is also known as an "alkyl-cycloalkylene” group, wherein the total number of carbon atoms is from 4 to 20 and wherein cycloalkylene is as defined below.
- Alkyl groups may be unsubstituted or substituted with from 1 to 4 substituents as described below.
- Preferred straight chain or branched chain alkyl groups have from 1 to 8 carbon atoms.
- Preferred cycloalkyl groups have from 3 to 8 carbon atoms.
- Other preferred alkyl groups have from 4 to 8 carbon atoms.
- C ⁇ -Cg alkyl means a straight chain or branched chain hydrocarbon group having from 1 to 6 carbon atoms.
- C3-C6 cycloalkyl means a cyclic hydrocarbon group having from 3 to 6 carbon atoms.
- Typical examples of straight chain or branched chain unsubstituted alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl,
- 2-pentyl 2,2-dimethylpropyl, 1-hexyl, 1-heptyl, 4-heptyl, 2-octyl, 2-methyl-hept- 2-yl, 1-nonyl, 1-decyl, 1-undecyl, 1-dodecyl, 2-dodecyl, 2,4-dimethyl-2-decyl, 2-(l-methylethyl)-l-nonyl, 2-hexadecyl, and 1-tetradecyl.
- Illustrative examples of unsubstituted cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclohexadecyl, and cyclotetradecyl.
- Illustrative examples of cycloalkyl-alkylene groups include cyclopropylmethyl, 3-cyclopentyl-hexyl, and 2-cyclopentyl-decyl.
- alkyl-cycloalkylene groups include 1-methyl-cyclopropyl, 3- hexyl-cyclopentyl, and 2-(dec-3-yl)-cyclopentyl. Substituted alkyl is described and illustrated below.
- alkenyl means a straight chain or branched chain mono- or di-unsaturated hydrocarbon group having from 2 to 20 carbon atoms, or a cyclic mono-unsaturated hydrocarbon group having from 3 to 20 carbon atoms, which is also known as a "cycloalkenyl” group. Alkenyl groups may be unsubstituted or substituted with from 1 to 4 substituents as described below.
- Preferred straight chain or branched chain alkenyl groups have from 2 to 8 carbon atoms.
- Preferred cycloalkenyl groups have from 5 to 8 carbon atoms.
- C(H) C(H)-, and 2,4-dimethyl-2-decen-l-yl.
- unsubstituted cycloalkenyl groups are 1-cyclopropenyl, 2-cyclobutenyl, 2-cyclopentenyl, 4-cyclohexenyl, 1-cycloheptenyl, 5-cyclooctenyl, 5-cyclononenyl, and 6-cyclotetradecenyl. Substituted alkenyl is described and illustrated below.
- alkynyl means a straight chain or branched chain mono- or di- unsaturated hydrocarbon group having from 2 to 20 carbon atoms, or a cyclic mono-unsaturated hydrocarbon group having from 12 to 20 carbon atoms, which is also known as a "cycloalkynyl” group.
- Alkynyl groups may be unsubstituted or substituted with from 1 to 4 substituents as described below.
- Preferred straight chain or branched chain alkynyl groups have from 2 to 8 carbon atoms.
- Preferred cycloalkynyl groups have from 12 to 14 carbon atoms.
- Typical examples of straight chain or branched chain unsubstituted alkynyl groups include ethynyl, 1-propyn-l-yl, l-propyn-3-yl, 2-propyn-l-yl, l-butyn-3-yl, 1-butadiynyl, 2-pentyn-5-yl, l-hexyn-6-yl, l-heptyn-3-yl, 3-heptyn-l-yl, 2-octyn-6-yl, hept- 2-yn-4-yl, and 4,4-dimethyl-2-decyn-l-yl.
- Illustrative examples of unsubstituted cycloalkynyl groups are 6-cyclotetradecynyl. Substituted alkynyl is described and illustrated below.
- alkoxy means an alkyl group bonded through an oxygen atom, which is alkyl-O-, wherein alkyl is as defined above.
- unsubstituted alkoxy include methoxy, isopropoxy, 2-hexyloxy, cyclopropyloxy, cyclopentyloxy, and cyclohexyloxy.
- substituted alkoxy are provided below.
- acyl means R r -C(O), wherein R r is hydrogen, alkyl, alkenyl, alkynyl, all as defined above, or aryl (including heteroaryl) as defined below.
- R r is hydrogen, alkyl, alkenyl, alkynyl, all as defined above, or aryl (including heteroaryl) as defined below.
- Illustrative examples of acyl include acetyl, benzoyl, 2-thienylcarbonyl, and cyclopentylcarbonyl.
- substituted acyl include hydroxyacetyl, 3,5-dichloro-4nitrobenzoyl, (2-methylphenyl)propylcarbonyl, and 3-hydroxycyclopentylcarbonyl.
- acyloxy means R r -C(O)-O, wherein R r is hydrogen, alkyl, alkenyl, alkynyl, all as defined above, or aryl (including heteroaryl) as defined below.
- R r is hydrogen, alkyl, alkenyl, alkynyl, all as defined above, or aryl (including heteroaryl) as defined below.
- Illustrative examples of acyloxy include acetyloxy, benzoyloxy,
- substituted acyloxy include hydroxyacetyloxy, trifluoroacetyloxy, 3,5-dichloro-
- haloalkyl means a halo bonded through an alkylene, which is a halo-alkylene group, wherein halo and alkylene are as defined below.
- halo and halogen may be used interchangeably, and mean fluoro, chloro, bromo, or iodo.
- alkylene means a divalent, straight chain or branched chain, hydrocarbon group having from 1 to 20 carbon atoms, or a divalent cyclic hydrocarbon group having from 3 to 20 carbon atoms, each of which may be unsubstituted or substituted with from 1 to 4 substituents.
- Illustrative examples of an unsubstituted alkylene group include -CH 2 -, -CH 2 CH -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -C(CH 3 ) 2 -CH 2 -C(H)CH 3 -(CH 2 ) 12 -, -CH(CH 3 )CH 2 CH 2 -,
- 1,4-cyclobutylene, 1,3-cyclohexylene, and 1,2-cycloheptadecylene are provided below.
- alkylsulfonic acid means an alkyl group bonded to a SO3H group, which is also known as an alkyl-SO3H group, wherein alkyl is unsubstituted alkyl as defined above, or is a fluoro-substituted alkyl.
- unsubstituted alkylsulfonic acids include CH3SO3H, ethanesulfonic acid, fert-butylsulfonic acid, and cyclohexylsulfonic acid.
- fluoro-substituted alkylsulfonic acid include CH FSO3H, CF 2 HSO3H,
- arylsulfonic acid means an aryl group bonded to a SO3H group, which is also known as an aryl-SO3H group, wherein aryl is unsubstituted aryl or is aryl substituted with halo or unsubstituted alkyl, wherein halo and unsubstituted alkyl are as defined above.
- alkylsulfonyloxy means an alkyl group bonded to a SO3 group, which is also known as an alkyl- SO3 group, wherein alkyl is unsubstituted alkyl as defined above, or is a fluoro-substituted alkyl.
- unsubstituted alkylsulfonic acids include CH3SO3, ethanesulfonyloxy, tert-butylsulfonyloxy, and cyclohexylsulfonyloxy.
- fluoro-substituted alkylsulfonyloxy examples include CH 2 FSO3, CF 2 HSO3, CF3SO3, and CH 3 CF 2 SO 3 .
- arylsulfonyloxy means an aryl group bonded to a SO3 group, which is also known as an aryl-SO3 group, wherein aryl is unsubstituted aryl or is aryl substituted with halo or unsubstituted alkyl, wherein halo and unsubstituted alkyl are as defined above.
- alkyl, alkenyl, alkynyl, alkylene, alkoxy, and acyl may be substituted with from 1 to 4 substituents.
- the substituents are independently selected from: phenyl, phenyl substituted with from 1 to 3 substituents selected from C -C6 alkyl, halo, OH, O-Ci-Cg alkyl, 1,2-methylenedioxy, CN, NO 2 , N ,
- heteroaryl wherein heteroaryl is as defined below, heterocyclic group, wherein heterocyclic group is as defined below, oxo, O-R z , wherein R z is hydrogen, C ⁇ -C6 alkyl, C3-C6 cycloalkyl, phenyl, or benzyl, wherein phenyl and benzyl may be substituted with from 1 to 3 substituents as described below, S-R z , wherein R z is hydrogen, C ⁇ -Cg alkyl, C3-C6 cycloalkyl, phenyl, or benzyl, wherein phenyl and benzyl may be substituted with from 1 to 4 substituents as described below, C(O)-R z , wherein R z is hydrogen, C ⁇ -Cg alkyl, C3-C6 cycloalkyl, phenyl, or benzyl,
- R z is hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, phenyl, or benzyl, wherein phenyl and benzyl may be substituted with from 1 to 4 substituents as described below, C(O)-N(R z )Ry, wherein R z and Ry are independently hydrogen,
- (Z) is as defined above, N(R z )-C(O)-Ry, wherein R z and Ry are independently hydrogen,
- substituted straight chain or branched chain alkyl groups include CH 2 OH, CF 2 OH, CH 2 C(CH 3 ) 2 CO 2 CH 3 , CF 3 , C(O)CF 3 , C(O)-
- substituted cycloalkyl groups include 1-hydroxy- cyclopropyl, cyclobutanon-3-yl, 3-(3-phenyl-ureido)-cyclopent-l-yl, 4-carboxy- cyclohexyl, and 9-trifluromethyl-cyclododecanyl.
- substituted cycloalkyl-alkylene groups include cyclopropyl-difluoro-methyl, 2-cyclopropyl-l, 1-difluoroethyl, cyclopropyl(methyl)methyl, 3-cyclopentyl- 2-oxo-hexyl, and 2-cyclopentyl-l,l,l-trifluorodecyl.
- substituted alkyl-cycloalkylene groups include 1-trifluoromethyl-cyclopropyl,
- substituted cycloalkenyl groups include 1-hydroxy-cyclopropenyl, 3-oxo-cyclobuten-l-yl, and 9-trifluromethyl- cyclododecen- 1 -yl.
- substituted straight chain or branched chain alkynyl groups include C ⁇ CCH 2 OH, C ⁇ CF, CH 2 C ⁇ C-(CH 2 ) 2 CF 2 OH,
- substituted cycloalkynyl groups include 4-trifluromethyl-cyclododecyn-4-yl.
- substituted alkoxy examples include trifluoromethoxy, 2-carboxy-isopropoxy, 3 -oxo-2-hexyloxy, ( ⁇ )-2-methyl-cyclopropyloxy, ( ⁇ )-3-amino-cyclopentyloxy, and 1-cyano-cyclohexyloxy.
- substituted alkylene examples include hydroxymethylene, 2-dimethylaminobutylene, 2-fluoro-2-hexyl-propylene, and 2,4-cyclobutanone- diyl.
- aryl means phenyl, substituted phenyl, 1 -naphthyl, substituted 1 -naphthyl, 2-napthyl, substituted 2-napthyl, or heteroaryl, wherein heteroaryl is as defined below.
- Substituted phenyl, substituted 1 -naphthyl, and substituted 2-naphthyl groups are substituted with from 1 to 4 substituents as described below.
- Illustrative examples of substituted phenyl, substituted 1 -naphthyl, and substituted 2-naphthyl are provided below.
- heteroaryl means a 5-membered, monocyclic heteroaryl, a 6-membered, monocyclic heteroaryl, or a 9- or 10-membered, fused-bicyclic heteroaryl, which are as defined below, each of which may be unsubstituted or substituted as described below.
- 5-membered, monocyclic heteroaryl means an unsubstituted or substituted, 5-membered, monocyclic, aromatic ring group having carbon atoms and from 1 to 4 heteroatoms selected fromN, O, and S, with the proviso that not more than 1 heteroatom atom which is O or S is present.
- Illustrative examples of an unsubstituted 5-membered, monocyclic heteroaryl include thiophen-2-yl, furan-2-yl, pyrrol-3-yl, pyrrol-1-yl, imidazol-4-yl, isoxazol-3-yl, oxazol-2-yl, thiazol-4-yl, tetrazol-1-yl, l,2,4-oxadiazol-3-yl, 1,2,4-triazol-l-yl, and pyrazol-3-yl.
- Substituted 5-membered, monocyclic heteroaryl is described below.
- 6-membered, monocyclic heteroaryl means an unsubstituted or substituted, 6-membered, monocyclic, aromatic ring group having carbon atoms and 1 or 2 nitrogen atoms.
- unsubstituted 6-membered, monocyclic heteroaryl include pyridin-2-yl, pyridin-4-yl, pyrimidin-
- 9- or 10-membered, fused-bicyclic heteroaryl means an unsubstituted or substituted, 9-membered or 10-membered, fused-bicyclic, aromatic ring group having carbon atoms and from 1 to 4 heteroatoms selected from N, O, and S, with the proviso that not more than 2 heteroatoms which are oxygen atoms or sulfur atoms are present, and further that when 2 heteroatoms which are O and/or S are present, the O and/or S atoms are not bonded to each other.
- Illustrative examples of an unsubstituted 9- or 10-membered, fused-bicyclic heteroaryl include indol-2-yl, indol-6-yl, iso-indol-2-yl, benzimidazol-2-yl, benzimidazol-1-yl, benztriazol-1-yl, benztriazol-5-yl, quinolin-2-yl, isoquinolin- 7-yl, benzopyrimidin-2-yl, benzoxazol-2-yl, benzothiophen-5-yl, and benzofuran- 3-yl.
- Substituted 9- or 10-membered, bicyclic heteroaryl is described below.
- substituted 5-membered, monocyclic heteroaryl means a 5-membered, monocyclic, aromatic ring group having carbon atoms and from 1 to 4 heteroatoms selected fromN, O, and S, which is substituted with 1 or 2 substituents as defined below, with the proviso that not more than 1 heteroatom atom which is O or S is present, and further that each substituent is not bonded to an oxygen atom or a sulfur atom.
- substituents Illustrative examples of a substituted, 5-membered, monocyclic heteroaryl are provided below.
- substituted 6-membered, monocyclic heteroaryl means a 6-membered, monocyclic, aromatic ring group having carbon atoms and 1 or 2 nitrogen atoms, which is substituted with 1 or 2 substituents as defined below, with the proviso that each substituent is not bonded to a nitrogen atom.
- substituents as defined below, with the proviso that each substituent is not bonded to a nitrogen atom.
- Illustrative examples of a substituted, 6-membered, monocyclic heteroaryl are provided below.
- substituted 9- or 10-membered, fused-bicyclic heteroaryl means a 9-membered or 10-membered, fused-bicyclic, aromatic ring group having carbon atoms and from 1 to 4 heteroatoms selected from N, O, and S, which is substituted with from 1 to 3 substituents as defined below, with the proviso that not more than 2 heteroatoms which are O and/or S are present, and further that when 2 heteroatoms which are O and/or S atoms are present, the O and/or S atoms are not bonded to each other, and further that each substituent is not bonded to an oxygen atom or a sulfur atom.
- Illustrative examples of a substituted 9- or 10-membered, fused-bicyclic heteroaryl are provided below.
- heterocyclic group means, except where otherwise noted, a heteroaryl, wherein heteroaryl is as defined above, or saturated or partially unsaturated 3- to 14-membered, monocyclic, bicyclic, or tricyclic ring having carbon atoms and from 1 to 5 heteroatoms selected from N, O, and S, which ring may be unsubstituted or substituted as defined below.
- the ring nitrogen atom(s) may be unprotected or protected with suitable nitrogen protecting groups.
- Preferred is a 5-membered, monocyclic heterocycloalkyl, a 6-membered, monocyclic heterocycloalkyl, or a 9- or 10-membered, fused-bicyclic heterocycloalkyl, which may be unsubstituted or substituted and are as defined below.
- heterocyclic groups included unsubstituted or substituted acridinyl, aziridinyl, benzathiaolinyl, benzimidazolyl, benzofuranyl, imidazolyl, lH-indolyl, lH-indazolyl, isoindolyl, isoquinolinyl, isothiazolyl, N-methyl-piperazinyl, morpholinyl, oxazolyl, 1,2,4-oxadiazolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperidinyl, piperazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinalinyl,
- 5-membered, monocyclic heterocycloalkyl means a 5-membered, monocyclic nonaromatic ring group having carbon atoms and from 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally 1 double bond, and optionally substituted with 1 or 2 substituents as defined below, with the proviso that not more than 2 heteroatoms which are O and/or S atoms are present, and further when 2 heteroatoms which are O and/or S atoms are present, the O and/or S atoms are not bonded to each other.
- Preferred 5-membered, monocyclic heterocycloalkyl groups have no double bonds.
- unsubstituted 5-membered, monocyclic heterocycloalkyl examples include 2,3-dihydrofuran-2-yl, tetrahydrofuran-3-yl, and tetrahydroimidazol-1-yl. Substituted 5-membered, monocyclic heterocycloalkyl are described and illustrated below.
- 6-membered, monocyclic heterocycloalkyl means a 6-membered, monocyclic, nonaromatic ring group having carbon atoms and from
- heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally 1 or
- 6-membered, monocyclic heterocycloalkyl groups have no double bonds.
- Illustrative examples of unsubstituted 6-membered, monocyclic heterocycloalkyl include l,2,5,6-tetrahydropyridin-2-yl, piperidin-4-yl, piperazin-1-yl, morpholin- 1-yl, and thiomorpholin-2-yl.
- the phrase "9- or 10-membered, fused-bicyclic heterocycloalkyl" means a
- 6-membered nonaromatic ring having carbon atoms and 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and wherein the first ring and second ring are fused by sharing 1 double bond, (ie, the second ring is a dihydroaromatic ring), and optionally substituted with from 1 to 3 substituents as defined below, with the proviso that not more than 3 heteroatoms which are O and/or S atoms are present, and further that when 2 or 3 heteroatoms which are O and/or S atoms are present, the O and/or S atoms are not bonded to each other.
- Preferred 9- or 10-membered, fused-bicyclic heterocycloalkyl groups have a 6-membered ring fused to a 5-membered ring.
- Illustrative examples of unsubstituted 9- or 10-membered, fused-bicyclic heterocycloalkyl include 2,3-dihydro-benzofuran- 2-yl and 2,3-dihydro-indol-5-yl.
- substituted aryl which as shown above means substituted phenyl, substituted 1 -naphthyl, substituted 2-naphthyl, substituted heteroaryl, which as shown above means a substituted 5-membered, monocyclic heteroaryl, a substituted 6-membered, monocyclic heteroaryl, or a substituted 9- or 10-membered, fused-bicyclic heteroaryl, or substituted heterocycloalkyl, which as shown above means substituted 5-membered, monocyclic heterocycloalkyl, substituted 6-membered, monocyclic heterocycloalkyl, or substituted 9- or
- 10-membered, fused-bicyclic heterocycloalkyl are independently selected from: C ⁇ -C 6 alkyl,
- R z is hydrogen, C ⁇ -Cg alkyl, phenyl, or benzyl
- R z is hydrogen, Ci -C ⁇ alkyl, phenyl, or benzyl
- R z is hydrogen, Ci -Cg alkyl, phenyl, or benzyl
- Ci -Cg alkyl, phenyl, or benzyl, or R z and Ry are taken together with the nitrogen atom to which they are attached to form a 5-membered, saturated heterocyclic ring having 1 nitrogen atom and 4 carbon atoms or a 6-membered, saturated heterocyclic ring of formula (Z), wherein (Z) is as defined above, C(H)F-OH,
- R z is hydrogen, Ci-Cg alkyl, phenyl, or benzyl
- Ci -Cg alkyl, phenyl, or benzyl, or R z and Ry are taken together with the nitrogen atom to which they are attached to form a
- Ci -Cg alkyl, phenyl, or benzyl, orR z and R y are taken together with the nitrogen atom to which they are attached to form a 5-membered, saturated heterocyclic ring having 1 nitrogen atom and 4 carbon atoms or a 6-membered, saturated heterocyclic ring of formula (Z), wherein (Z) is as defined above, NO 2 ,
- R z and R y are independently hydrogen, Ci -Cg alkyl, phenyl, or benzyl, or R z and Ry are taken together with the nitrogen atom to which they are attached to form a 5-membered, saturated heterocyclic ring having 1 nitrogen atom and 4 carbon atoms or a 6-membered, saturated heterocyclic ring of formula (Z), wherein (Z) is as defined above, and R x is hydrogen, hydroxy, methoxy, or CN,
- Ci-Cg alkyl, phenyl, or benzyl, orR z and Ry are taken together with the nitrogen atom to which they are attached to form a 5-membered, saturated heterocyclic ring having 1 nitrogen atom and 4 carbon atoms or a 6-membered, saturated heterocyclic ring of formula (Z), wherein (Z) is as defined above, and
- Preferred substituents for substituted aryl, and preferred substituents at carbon atoms for substituted 5-membered, monocyclic heteroaryl, substituted 6-membered, monocyclic heteroaryl, substituted 9- or 10-membered, fused- bicyclic heteroaryl, substituted 5-membered, monocyclic heterocycloalkyl, substituted 6-membered, monocyclic heterocycloalkyl, and substituted 9- or 10-membered, fused-bicyclic heterocycloalkyl are Cj-Cg alkyl, halo, OH,
- substituted 5-membered, monocyclic heteroaryl, substituted 9- or 10-membered, fused-bicyclic heteroaryl substituted 5-membered, monocyclic heterocycloalkyl, substituted 6-membered, monocyclic heterocycloalkyl, and substituted 9- or 10-membered, fused-bicyclic heterocycloalkyl may optionally be substituted at a nitrogen atom, instead of a carbon atom, with 1 of certain substituents of said 1 or 2 substituents. Substitution at a nitrogen atom is possible when a ring -N(H)- is present.
- the substituent replaces the hydrogen atom in the diradical -N(H)- and is selected from:
- substituted aryl means substituted phenyl, substituted
- substituted phenyl include 4-methoxyphenyl, 2,6-difluorophenyl, 3-hydroxy-4-methylphenyl, 2-hydroxymethyl-3,4-dichloro-phenyl, l,3-benzoxazol-5-yl, and 2-methoxy-4-nitrophenyl;
- substituted l-naphthyl include 5-trifluoromethanesulfonylaminonaphth-
- substituted 2-naphthyl includes 5-trifluoromethanesulfonylaminonaphth- 2-yl and l-(N-hydroxy-carboxamido)-naphth-2-yl.
- substituted heteroaryl means substituted, 5-membered, monocyclic heteroaryl, substituted 6-membered, monocyclic heteroaryl, or substituted, 9- or 10-membered, fused-bicyclic heteroaryl.
- substituted 5-membered, monocyclic heteroaryl include 3-chloro-thiophen- 2-yl, 5-hexyl-furan-2-yl, l-methyl-pyrrol-3-yl, 2-carboxy-pyrrol-l-yl, l,2-dimethyl-imidazol-4-yl, 5-(4-carboethoxy-7-fluoro-heptyl)-isoxazol- 3-yl, 4-trifluoromethyl-oxazol-2-yl, 2-hydroxy-thiazol-4-yl,
- substituted 6-membered, monocyclic heteroaryl include 4,6-difluoro- pyridin-2-yl, 2-methyl-pyridin-4-yl, 4-azido-pyrimidin-2-yl, 6-ureido- pyridazin-4-yl, and 5-methylthio-pyrazin-2-yl; and
- (iii) 9- or 10-membered, bicyclic heteroaryl include 6,7-dimethoxy-indol-2-yl, l-propyl-indol-6-yl, 7-nitro-isoindol-2-yl, l-benzyl-benzimidazol-2-yl, 4-chloro-benzimidazol- 1 -yl, 7-(2-propyl)-benztriazol- 1 -yl, l-(2-hydroxyethyl)-benztriazol-5-yl, 4-iodo-quinolin-2-yl, 1-nitro- isoquinolin-7-yl, 4-cyano-benzopyrimidin-2-yl, 4,5,6-trifiuoro- benzoxazol-2-yl, 2-carboxy-benzothiophen-5-yl, and 4-methylsulfinyl- benzofuran-3-yl.
- substituted heterocycloalkyl means substituted, 5-membered, monocyclic heterocycloalkyl, substituted 6-membered, monocyclic heterocycloalkyl, or substituted, 9- or 10-membered, fused-bicyclic heterocycloalkyl.
- substituted heterocycloalkyl means substituted, 5-membered, monocyclic heterocycloalkyl, substituted 6-membered, monocyclic heterocycloalkyl, or substituted, 9- or 10-membered, fused-bicyclic heterocycloalkyl.
- substituted 5-membered, monocyclic heterocycloalkyl include 5-chloro- 2,3-dihydrofuran-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, l-(3,4-dichloro- phenyl)-2,5-dihydro-lH-pyrrole-3,4-diyl (e.g., a 1 -substituted, 2,5- dihydro-pyrrole benzo-fused at the 3 ,4-positions) and 2-oxo- tetrahydroimidazol- 1 -yl;
- substituted 6-membered, monocyclic heterocycloalkyl include 4-acetyl- l,2,5,6-tetrahydropyridin-2-yl, l-methyl-piperidin-4-yl, 4-benzyl- piperazin-1-yl, 3-fluoro-morpholin-l-yl, and 2-methyl-thiomorph
- amino means NH .
- Group I metal cation means Li + , Na + , K + , Rb + , Cs + , or Fr + .
- Group II metal cation means Be “2 , Mg +2 , Ca +2 , Sr +2 ,
- Group I metal cation amide means a base which comprises
- Group II metal cation amide means a base which comprises NH 2 " and a cation which is Be +2 Mg +2 , Ca +2 , Sr+ 2 Ba +2 , or Ra +2 .
- Group I metal cation dialkylamide means a base which comprises two independent alkyl groups each bonded to a N ⁇ group, which is an
- alkyl-N(")-alkyl group wherein alkyl is unsubstituted alkyl as defined above, and a cation which is Li + , Na + , K + , Rb + , Cs + , or Fr + .
- a Group I metal cation dialkylamide includes lithium diisopropylamide ("LDA").
- Group II metal cation dialkylamide means a base which comprises two independent alkyl groups each bonded to a N ⁇ group, which is an
- alkyl-N(")-alkyl group wherein alkyl is unsubstituted alkyl as defined above, and a cation which is Be +2 , Mg +2 , Ca +2 , Sr +2 , Ba +2 or Ra +2 .
- a Group II metal cation dialkylamide includes magnesium bis(diisopropylamide) .
- Group I metal cation bis(trialkylsilyl)amide means a base which comprises two independent trialkylsilyl groups each bonded to a N" group, which is an (alkyl) 3 Si-N(")-Si(alkyl) 3 group, wherein each alkyl is independently
- Illustrative examples of a Group I metal cation bis(trialkylsilyl)amide includes lithium bis(trimethylsilyl)amide ("LiHDMS” or “lithium hexamethyldisilazane”).
- Group II metal cation bis(trialkylsilyl)amide means a base which comprises two independent trialkylsilyl groups each bonded to a N " group,
- Illustrative examples of a Group II metal cation bis(trialkylsilyl)amide includes magnesium di[bis(trimethylsilyl)amide].
- Group I metal cation alkoxide means a base which comprises an alkyl bonded to a O" group, which is an alkyl-O ⁇ group, wherein alkyl is unsubstituted alkyl as defined above, and a cation which is Li + , Na + , K + , Rb + , Cs + , or Fr + .
- Illustrative examples of a Group I metal cation alkoxide includes lithium methoxide, sodium ethoxide, and potassium tert-butoxide.
- Group LI metal cation alkoxide means a base which comprises an alkyl bonded to a O ⁇ group, which is an alkyl-O " group, wherein alkyl is unsubstituted alkyl as defined above, and a cation which is Be +2 , Mg +2 , Ca +2 , Sr +2 , Ba +2 , or Ra +2 .
- Illustrative examples of a Group II metal cation alkoxide includes magnesium bismethoxide and calcium bisethoxide.
- bases which comprise a salt of a Group I metal cation. More preferred are bases which comprise a salt of Li + , Na + , K + . Still more preferred are bases which comprise a salt of Li + .
- any base whereof the conjugate acid has a pKa > 16 will work in the invention process.
- Preferred carboxylic acid activating reagents are selected from: (COCl) 2 ,
- organopalladium catalyst means a catalyst comprising palladium and an organic ligand.
- organopalladium catalysts include palladium acetate, palladium tetrakis(triphenylphosphine), and palladium dichloride [bis(diphenylphosphino)ferrocene].
- Other organopalladium catalysts are known, and may be found in Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc, New York, 1989.
- reactive functional group means a group that is expected to react with certain solvents, reagents, catalysts, reaction starting materials, reaction intermediates, or reaction products under the particular reaction conditions employed.
- non-nucleophilic base means a base that is slow to act as a nucleophile in a substitution reaction such as, for example, a nucleophilic aromatic substitution reaction.
- non-nucleophilic bases include tertiary organic amines, which are defined below, Group I metal cation hydrides, Group II metal cation hydrides, Group I metal cation dialkylamides, Group II metal cation dialkylamides, Group I metal cation bis(trialkylsilyl)amides, Group LT metal cation bis(trialkylsilyl)amides, Group I metal cation fertz ⁇ ry-alkoxides, and Group II metal cation tert/ ' ry-alkoxides.
- tertiary organic amines which are defined below, Group I metal cation hydrides, Group II metal cation dialkylamides, Group II metal cation dialkylamides, Group I metal cation bis(trialkylsilyl)amides, Group LT metal cation bis(trialkylsilyl)amides, Group I metal cation fertz ⁇ ry-alkoxide
- acid catalyst means a Br ⁇ nsted acid or Lewis acid which may be present in catalytic, stochiometric, or greater than stochiometric amounts.
- aprotic solvent means a solvent that does not yield a proton
- aprotic solvent ie, acts as a Br ⁇ nsted acid
- pKa relative to water or, optionally, DMSO
- Typical aprotic solvents with high pKa's include diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, hexane, heptane, dimethylformamide, toluene, and benzene.
- Typical aprotic solvents with lower pKa's include ethyl acetate, acetone, and acetonitrile.
- Solvents with pKa's less than 19 such as, for example, tert-butyl alcohol, usually are not aprotic, although nitromethane is an aprotic solvent.
- Solvents that contain a functional group selected from OH, NH, and SH are typically not aprotic.
- the phrases "protic solvent” or "protic contaminant” mean a solvent or contaminant, respectively, that does yield a proton under the particular conditions employed.
- tertiary organic amine means a trisubstituted nitrogen group wherein the three substituents are independently selected from C ⁇ -C ⁇ 2 alkyl,
- tertiary organic amine examples include triethylamine, diisopropylethylamine, benzyldiethylamine, dicyclohexyl-methyl-amine, l,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”), l,4-diazabicyclo[2.2.2]octane (“TED”), and l,5-diazabicyclo[4.3.0]non-5-ene.
- DBU diisopropylethylamine
- benzyldiethylamine dicyclohexyl-methyl-amine
- TED l,4-diazabicyclo[2.2.2]octane
- l,5-diazabicyclo[4.3.0]non-5-ene examples include triethylamine, diisopropylethylamine, benzyldiethylamine, dicyclohexyl-methyl-amine, l,
- purifying means separating a desired compound from undesired components of a mixture which contains both by methods which include distillation, chromatography, including column chromatography, thin layer chromatography, normal phase chromatography, reverse phase chromatography, gas phase chromatography, and ion exchange chromatography, precipitation, extraction, rotary evaporation, chemical-based trapping by reaction with an incompatible functional group, including quenching with polymer-bound quenching reagents, filtration, centrifugation, physical separation, and fractional crystallization.
- the phrase "carried out on a commercial scale” means a process which employs more than 1 kilogram of a compound of formula (A) or a compound of formula (B), wherein a compound of formula (A) and a compound of formula (B) are as defined above.
- Some of the compounds prepared according to a process of the present invention are capable of further forming pharmaceutically acceptable salts, including, but not limited to, acid addition and/or base salts.
- the acid addition salts are formed from basic compounds, whereas the base addition salts are formed from acidic compounds. All of these forms are within the scope of the compounds prepared by a process of the present invention.
- Pharmaceutically acceptable acid addition salts of the basic compounds prepared according to a process of the present invention include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
- inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like
- organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids
- Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like.
- salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts,” J. ofPharma. Sci.,
- An acid addition salt of a basic compound prepared according to a process of the present invention is prepared by contacting the free base form of the compound with a sufficient amount of a desired acid to produce a nontoxic salt in the conventional manner.
- the free base form of the compound may be regenerated by contacting the acid addition salt so formed with a base, and isolating the free base form of the compound in the conventional manner.
- the free base forms of compounds prepared according to a process of the present invention differ from their respective acid addition salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise free base forms of the compounds and their respective acid addition salt forms are equivalent for purposes of the present invention.
- a pharmaceutically acceptable base addition salt of an acidic compound prepared according to a process of the present invention may be prepared by contacting the free acid form of the compound with a nontoxic metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine.
- a nontoxic metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine.
- suitable metal cations include sodium cation ( a + ), potassium cation (K + ), magnesium cation (Mg +2 ), calcium cation (Ca +2 ), and the like.
- a base addition salt of an acidic compound prepared according to a process of the present invention may be prepared by contacting the free acid form of the compound with a sufficient amount of a desired base to produce the salt in the conventional manner.
- the free acid form of the compound may be regenerated by contacting the salt form so formed with an acid, and isolating the free acid of the compound in the conventional manner.
- the free acid forms of the compounds prepared according to a process of the present invention differ from their respective salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
- Certain of the compounds prepared according to a process of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
- Certain of the compounds prepared according to a process of the present invention possess one or more chiral centers, and each center may exist in the R or S configuration.
- a process of the present invention prepares all diastereomeric, enantiomeric, and epimeric forms of the compounds as well as mixtures thereof. Additionally, certain compounds prepared according to a process of the present invention may exist as geometric isomers such as the Seven (E) and sixteen (Z) isomers of alkenyl groups. A process of the present invention prepares all cis, trans, syn, anti, and Seven (E), and sixteen (Z) isomers as well as mixtures thereof.
- Certain compounds prepared according to a process of the present invention can exist as two or more tautomeric forms. Tautomeric forms of the compounds may interchange, for example, via enolization/de-enolization and the like.
- a process of the present invention prepares all tautomeric forms of the compounds of Formula I.
- Preparations of the compounds of the present invention may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above.
- Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for example, The Aldrich Chemical Company, and other subsidiaries of Sigma- Aldrich Corporation, St. Louis, Missouri, BACHEM, BACHEM A.G.,
- Syntheses of some compounds of the present invention may utilize starting materials, intermediates, or reaction products that contain a reactive functional group.
- a reactive functional group may be protected using protecting groups that render the reactive group substantially inert to the reaction conditions employed.
- a protecting group is introduced onto a starting material prior to carrying out the reaction step for which a protecting group is needed. Once the protecting group is no longer needed, the protecting group can be removed. It is well within the ordinary skill in the art to introduce protecting groups during a synthesis of a compound of Formula I, and then later remove them.
- protecting groups such as the following may be utilized to protect amino, hydroxyl, and other groups: carboxylic acyl groups such as, for example, formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as, for example, ethoxycarbonyl, tert- butoxycarbonyl (BOC), ⁇ , ⁇ , ⁇ -trichloroethoxycarbonyl (TCEC), and ⁇ -iodoethoxycarbonyl; aralkyloxycarbonyl groups such as, for example, benzyloxycarbonyl (CBZ), tfra-methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (FMOC); trialkylsilyl groups such as, for example, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); and other groups such as, for example, triphenylmethyl (trityl), t
- Examples of procedures for removal of protecting groups include hydrogenolysis of CBZ groups using, for example, hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10% palladium on carbon, acidolysis of BOC groups using, for example, hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane, and the like, reaction of silyl groups with fluoride ions, and reductive cleavage of TCEC groups with zinc metal.
- a hydrogenation catalyst such as 10% palladium on carbon
- R 1 to R ⁇ , X, and Z are as defined above, is outlined below in Scheme 1.
- the number of mole-equivalents ("mol eq.") of base used in the process of the present invention compared to the smaller of the number of moles of a compound of Formula (A) or a compound of Formula (B) used in the present invention is preferably greater than about 2, more preferably greater than about 2.5, still more preferably greater than about 2.75, and most preferably between 3 and 3.5. Reducing the number of equivalents below 3 decreases the yield except in cases wherein a compound of Formula (B), wherein Z is COOM, wherein M is Group I metal cation or a hemi Group U metal cation, is used as a starting material. In these cases, the preferable amount is between 2 and
- a reaction of the present invention is accomplished by mixing a compound of Formula (A) with a compound of Formula (B), preferably in an aprotic solvent, which solvent is preferably tetrahydrofuran or acetonitrile, along with a base.
- a reaction is generally carried out at a temperature of about -78°C to about 150°C (preferably about -70°C to about 120°C), and normally is complete within about 2 hours to about 4 days.
- a compound of Formula I produced by a process of the present invention can be isolated by removing the solvent, for example, by rotary evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization or distillation. Other standard purification methods are recited above.
- the base employed in the process of the present invention can be added to the reaction in several ways. Four methods, namely Methods A-D, are described below.
- Method A The base can be added in a "two-pot procedure," wherein a first flask, base is added to a solution or suspension of a compound of Formula (B) ( ⁇ 1 mol eq.); in a second flask, base is added to a solution or suspension of a compound of Formula (A) ( ⁇ 1 mol eq.). The contents can be combined, and the resulting mixture warmed, if necessary or desired, to react.
- Method B The base can be added in a "one-pot procedure," where both compounds of Formulas (A) and (B) are dissolved or suspended, in solvent and cooled. The base is added, and the mixture is warmed, if necessary or desired, to react.
- Method C The base can be added in an alternate "two-pot procedure," where in a first flask is a solution or suspension of a compound of Formula (B) ( ⁇ 1 mol eq.); in a second flask, the base and a compound of Formula A ( ⁇ 1 eq.) are mixed. The contents from the first flask are transferred into the second flask, or, optionally, the contents from the second flask are transferred into the first flask, and the resulting is mixture warmed, if necessary or desired, to react.
- Method D A solution or suspension of a compound of Formula (B) ( ⁇ 1 eq.); and a compound of Formula (A) ( ⁇ 1 eq.) is made, and the contents transferred into a flask containing the base or, optionally, the contents of the flask containing the base are transferred into the flask containing compounds of Formulas (A) and (B). The resulting mixture is warmed, if necessary or desired, to react.
- a compound of Formula I can be reacted with an alcohol (optionally in the presence of a coupling agent) to produce an ester.
- a compound of Formula I can be reacted with NH 3 , a primary or secondary amine, hydroxylamine, or an O-substituted hydroxylamine to form an amide, hydroxamic acid, or a hydroxamic ester.
- Step (a) of Scheme 2 1 mol eq. of an acid such as MeSO 3 H is added at a temperature and for a time sufficient to monoprotonate a compound of Formula I, to give a carboxylate salt intermediate.
- the temperature is about -78°C to about 0°C (preferably about -20°C), and the reaction is complete within about 30 minutes.
- Step (b) the carboxylate salt intermediate is converted to the corresponding acid chloride intermediate with a reagent such as thionyl chloride (SOCl 2 ). Subsequently, the acid chloride intermediate is reacted with an alcohol, amine, or a hydroxylamine derivative to obtain an ester, amide, or hydroxamic acid or hydroxamic ester, wherein Z is as defined immediately above.
- a reagent such as thionyl chloride (SOCl 2 ).
- SOCl 2 thionyl chloride
- higher yields of a compound of Formula I, obtained by reaction of a compound of Formula (A) with a compound of Formula (B), may be achieved by employing sequential addition of said base.
- the procedure comprises (a) dissolving or suspending a compound of formula (A) and a compound of formula (B) in a solvent, preferably an aprotic solvent;
- Step (b) adding a base to the mixture of Step (a), which mixture is preferably at a temperature of from about -70°C to about 30°C, and allowing the compound of formula (A) and the compound of formula (B) to react for a time sufficient to increase the amount of a compound of Formula I;
- Step (c) optionally, heating the reaction mixture of Step (b) for a time sufficient to increase the amount of a compound of Formula I or decrease the time required to produce an amount of a compound of Formula I;
- Step (d) adding a base to the mixture of Step (b), which mixture is preferably at a temperature of from about -70°C to about 30°C and allowing to react for a time sufficient to increase the amount of a compound of Formula I; or cooling the mixture of step (c) to a temperature of from about -70°C to about 30°C, adding a base to the cooled mixture, and allowing to react for a time sufficient to increase the amount of a compound of Formula I; (e) optionally, heating the reaction mixture of step (d) for a time sufficient to increase the amount of a compound of Formula I; and (f) optionally repeating steps (d) and (e).
- the number of times that Step (d) or Steps (d) and (e) are repeated according to Step (f) is preferably less than 10, and is most preferably from 0 to 7 times.
- the amount of base added in Step (b) is preferably about 2 mol equivalents, except in cases where a compound of Formula (B), wherein Z is
- COOM wherein M is as defined above, is employed. Then the amount of base is preferably about 1 mol equivalent.
- the amount of base added in Step (d) is preferably about 0.5 mol equivalents. As Step (d) is repeated, the number of mol equivalents of base should be decreased by about 50% compared to the number of mol eq. used previously.
- the base used in Steps (b) and (d) above can be the same or different.
- Suitable bases include lithium diisopropylamide (LDA), lithium hydride, lithium amide, lithium diethylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide.
- LDA is preferably used in a process of the present invention in the commercial (ie, large-scale) setting, but more preferred bases are LiHMDS, LiH, or LiNH 2 .
- the reaction was then cooled to about -20°C, and 50 mL of 1.5 M LDA solution in hexane/THF was added. The reaction was then allowed to warm to room temperature and stirred for at least 1 hour. The reaction was then cooled to about -20°C, and 25 mL of 1.5 MLDA solution in hexane/THF was added. The reaction was then allowed to warm to room temperature and stirred for at least 1 hour. The reaction was then cooled to about -20°C, and 12 mL of 1.5 M LDA solution in hexane/THF was added. The reaction was then allowed to warm to room temperature and stirred for at least 1 hour.
- the reaction was then cooled to about -20° C, and 6 mL of 1.5 M LDA solution in hexane/THF was added. The reaction was then allowed to warm to room temperature and stirred for at least 1 hour. The reaction was then cooled to about -40°C, and 600 mL of 4 M aqueous HC1 was added. The reaction was then allowed to warm to room temperature and stirred for at least 10 minutes and the phases allowed to separate for at least 1 hour. The lower layer was then discarded and the upper layer concentrated by vacuum distillation to a slurry. The slurry was dissolved in hot acetone and the solution diluted with water and cooled to crystallize. The product was isolated by filtration and dried in a vacuum oven resulting in 96 g (78%) of 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid as an off-white solid.
- Table 1 below presents the in-process high performance liquid chromatography ("HPLC") results obtained during the preparation described in Example 1.
- HPLC high performance liquid chromatography
- EXAMPLE 14 Lithium hydride coupling procedure to make 2-(2-chloro-4- iodophenyIamino)-3,4-difluorohenzoic acid using the sodium salt of 2,3,4-trifluorobenzoic acid
- the organic layer was washed with water at 40°C to 45°C (2 x 250 mL). After distilling off about 400 mL solvent, the organic layer was allowed to crystallize overnight. The slurry was cooled in an ice/acetone bath for about 2 hours, and then vacuum filtered. The cake was washed with toluene (2 x 100 mL) and water (100 mL) and dried in a vacuum oven. 71.3 g of white solid remained (87% yield, 99.8% pure by HPLC area %).
- Step (a) In an inerted three-neck round-bottomed flask equipped with a thermometer and powder addition funnel were dissolved 2,3,4,5- tetrafluorobenzoic acid (30.00 g, 154.6 mmol, 1 eq.) and 4-iodo-2-methyl aniline
- Step (b) To an inerted three-necked, round-bottomed flask, containing a solution of 2-(4-iodo-2-methylphenylamino)-3,4,5-trifluorobenzoic acid (30.00 g,
- indoline 5 g, 42.0 mmol
- 2-fluorobenzoic acid 6.2 g, 44.1 mmol
- THF 140 mL
- lithium amide 2.0 g, 88.2 mmol
- This mixture was heated to 50°C under nitrogen for about 4 hours, then cooled to room temperature.
- the reaction was quenched with water (25 mL), concentrated HCl (10 mL), and tBuOMe (25 mL). The aqueous layer was removed, and the organic layer was washed with water (25 mL).
- Method Al Three further embodiments of Method A, Method B, or Method C, namely Method Al, Methods BI and B2, and Method CI, respectively, were used in the preparation of Examples 25-39 and Preparations 3-8.
- Method Al a "two-pot procedure", in a first flask, a base (1 mol equivalent) was added to a solution of a compound of formula (B), wherein Z is COOH (1 mol equivalent), in an aprotic solvent such as, for example, tetrahydrofuran (“THF”) at about -78°C.
- THF tetrahydrofuran
- base (2 mol equivalents) was added to a solution of a compound of formula (A) (1 mol equivalent) in an aprotic solvent such as, for example, THF at about -
- Method CI which is also a two-pot procedure, in a first flask, a solution of a compound of formula (B), wherein Z is COOH (1 mol equivalent), in an aprotic solvent such as, for example, THF at about -78 °C was made.
- base 3 mol equivalents
- base was added to a solution of a compound of formula (A) (1 mol equivalent) in an aprotic solvent such as, for example, THF at about -
- N-methylaniline 3.75g, 35.0 mmol
- 2- fluorobenzoic acid 5.1g, 36.8 mmol
- THF 115 mL
- lithium amide 1.7g, 73.5 mmol
- This mixture was heated to 50°C under nitrogen for about 3.5 hours, then cooled to room temperature.
- the reaction was quenched with water (25 mL), cone. HCl (10 mL), and MTBE (25 mL). The aqueous layer was removed, and the organic layer was washed with water (25 mL).
- 1 part THF and about 1 part acetonitrile provides the desired ort ⁇ o-substituted product without contamination by the corresponding ra-substituted regioisomer.
- Group I metal cation hydride and Group I metal cation amide bases are preferred over Group I metal cation and Group II metal cation bis(trialkylsilyl) amides for the preparation of a compound of Formula I, wherein the compound of Formula I is as defined above except Z is COOH or COOM, wherein M is a Group I metal cation or hemi Group II metal cation.
- Bases such as lithium hexamethyldisilazide must be preformed for best results, as the bases degrade slowly over time, and the commercially available materials are usually impure. More importantly, bases such as lithium hexamethyldisilazide should be added sequentially to avoid formation of a reactive benzyne intermediate.
- Group I metal cation hydride and Group I metal cation amide bases are solids, which can be added to the reaction all at once while still providing best results. Since the bases are solids, the amount of base in contact with reactants is controlled by the rate of dissolution of the base and/or limited surface area contact of the reactants with the solid particles of the base. Further, the Group I metal cation hydrides and the Group I metal cation amides do not have to be preformed before use.
- Another advantage of the process of the instant invention lies in the discovery of superior carboxylic acid activating reagents for the coupling of a compound of Formula I as defined above except wherein Z is COOH or COOM, wherein M is a Group I metal cation or hemi Group II metal cation, with a compound of formula II, III, or IV, each as defined above, to give a product which is a compound of Formula I, wherein Z is COOR 15 , -C(O)N(R 16 )R 17 , or -C(O)N(R 18 )OR 19 , wherein R 15 , R 16 , R 17 , R 18 , and R 19 are as defined above.
- the present invention process employs carboxylic acid activating reagents such as thionyl chloride, DPPC1, or EDC, in particular. These reagents provide product in higher yields. Further, the products are easier to purify typically. Still further, the cost of the carboxylic acid activating reagents used in the instant invention is usually lower than the cost of PyBOP. These advantages are important for commercial scale production.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Indole Compounds (AREA)
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL36069901A PL360699A1 (en) | 2000-08-25 | 2001-07-20 | Process for making n-aryl-anthranilic acids and their derivatives |
CA002420003A CA2420003A1 (en) | 2000-08-25 | 2001-07-20 | Process for making n-aryl-anthranilic acids and their derivatives |
US10/344,294 US20040039208A1 (en) | 2001-07-20 | 2001-07-20 | Process for making n-aryl-anthranilic acids and their derivatives |
IL15450701A IL154507A0 (en) | 2000-08-25 | 2001-07-20 | Process for making n-aryl-anthranilic acids and their derivatives |
HU0300828A HUP0300828A2 (hu) | 2000-08-25 | 2001-07-20 | Eljárás N-aril-antranilsavak és e vegyületek származékainak elżállítására |
KR10-2003-7002675A KR20030059115A (ko) | 2000-08-25 | 2001-07-20 | N-아릴-안트라닐산 및 그의 유도체의 제조 방법 |
EP01954824A EP1313694A1 (en) | 2000-08-25 | 2001-07-20 | Process for making n-aryl-anthranilic acids and their derivatives |
MXPA03001654A MXPA03001654A (es) | 2000-08-25 | 2001-07-20 | Proceso para la elaboracion del acido n-aril-antranilico y sus derivados. |
JP2002523437A JP2004507518A (ja) | 2000-08-25 | 2001-07-20 | N−アリール−アントラニル酸及びその誘導体の製造法 |
APAP/P/2001/002249A AP2001002249A0 (en) | 2000-08-25 | 2001-07-20 | Process for making N-ARYL-ANTHRANILIC acids and their derivatives. |
BR0113520-1A BR0113520A (pt) | 2000-08-25 | 2001-07-20 | Processo de preparação de ácidos n-aril-antranìlicos e seus derivados |
AU2001277044A AU2001277044A1 (en) | 2000-08-25 | 2001-07-20 | Process for making N-aryl-anthranilic acids and their derivatives |
EA200300187A EA200300187A1 (ru) | 2000-08-25 | 2001-07-20 | Способ получения n-арилантраниловых кислот и их производных |
SK207-2003A SK2072003A3 (en) | 2000-08-25 | 2001-07-20 | Process for making N-aryl-anthranilic acids and their derivatives |
IS6724A IS6724A (is) | 2000-08-25 | 2003-02-20 | Aðferð til framleiðslu á N-arýl-anþranilískum sýrum og afleiðum þeirra |
NO20030844A NO20030844L (no) | 2000-08-25 | 2003-02-24 | Fremgangsmåte for fremstilling av N-aryl-antranilinsyrer og derivater derav |
BG107635A BG107635A (bg) | 2000-08-25 | 2003-03-13 | Метод за получаване на n-арил-антранилови киселини и техни производни |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US22820600P | 2000-08-25 | 2000-08-25 | |
US60/228,206 | 2000-08-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002018319A1 true WO2002018319A1 (en) | 2002-03-07 |
Family
ID=22856235
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/022948 WO2002018319A1 (en) | 2000-08-25 | 2001-07-20 | Process for making n-aryl-anthranilic acids and their derivatives |
Country Status (31)
Country | Link |
---|---|
EP (1) | EP1313694A1 (zh) |
JP (1) | JP2004507518A (zh) |
KR (1) | KR20030059115A (zh) |
CN (1) | CN1458921A (zh) |
AP (1) | AP2001002249A0 (zh) |
AR (1) | AR032175A1 (zh) |
AU (1) | AU2001277044A1 (zh) |
BG (1) | BG107635A (zh) |
BR (1) | BR0113520A (zh) |
CA (1) | CA2420003A1 (zh) |
CZ (1) | CZ2003477A3 (zh) |
DO (1) | DOP2001000238A (zh) |
EA (1) | EA200300187A1 (zh) |
GT (1) | GT200100174A (zh) |
HN (1) | HN2001000216A (zh) |
HU (1) | HUP0300828A2 (zh) |
IL (1) | IL154507A0 (zh) |
IS (1) | IS6724A (zh) |
MA (1) | MA26949A1 (zh) |
MX (1) | MXPA03001654A (zh) |
NO (1) | NO20030844L (zh) |
PA (1) | PA8526501A1 (zh) |
PE (1) | PE20020393A1 (zh) |
PL (1) | PL360699A1 (zh) |
SK (1) | SK2072003A3 (zh) |
SV (1) | SV2002000601A (zh) |
TN (1) | TNSN01127A1 (zh) |
UY (1) | UY26908A1 (zh) |
WO (1) | WO2002018319A1 (zh) |
YU (1) | YU14303A (zh) |
ZA (1) | ZA200301182B (zh) |
Cited By (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005054179A3 (en) * | 2003-12-03 | 2005-08-04 | Leo Pharma As | Hydroxamic acid esters and pharmaceutical use thereof |
US7060856B2 (en) | 2003-10-21 | 2006-06-13 | Warner-Lambert Company | Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide |
US7230099B2 (en) | 2003-09-03 | 2007-06-12 | Array Biopharma, Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US7235537B2 (en) | 2002-03-13 | 2007-06-26 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US7425637B2 (en) | 2002-03-13 | 2008-09-16 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US7485643B2 (en) | 2003-11-19 | 2009-02-03 | Array Biopharma Inc. | Bicyclic inhibitors of MEK and methods of use thereof |
US7517994B2 (en) | 2003-11-19 | 2009-04-14 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US7538120B2 (en) | 2003-09-03 | 2009-05-26 | Array Biopharma Inc. | Method of treating inflammatory diseases |
US7700625B2 (en) | 2005-04-13 | 2010-04-20 | Astex Therapeutics Ltd. | Hydroxybenzamide derivatives and their use as inhibitors of Hsp90 |
US7732616B2 (en) | 2003-11-19 | 2010-06-08 | Array Biopharma Inc. | Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof |
US7754725B2 (en) | 2006-03-01 | 2010-07-13 | Astex Therapeutics Ltd. | Dihydroxyphenyl isoindolymethanones |
US8003651B2 (en) | 2006-07-06 | 2011-08-23 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8063050B2 (en) | 2006-07-06 | 2011-11-22 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8277807B2 (en) | 2006-10-12 | 2012-10-02 | Astex Therapeutics Limited | Pharmaceutical combinations |
US8299076B2 (en) | 2005-05-18 | 2012-10-30 | Array Biopharma Inc. | Crystalline forms of 2-(2-flouro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide |
US8329701B2 (en) | 2006-07-06 | 2012-12-11 | Array Biopharma Inc. | Dihydrofuro pyrimidines as AKT protein kinase inhibitors |
US8377937B2 (en) | 2007-07-05 | 2013-02-19 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8383619B2 (en) | 2008-04-11 | 2013-02-26 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8618097B2 (en) | 2007-07-05 | 2013-12-31 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8653084B2 (en) | 2006-10-12 | 2014-02-18 | Astex Therapeutics Ltd. | Hydrobenzamide derivatives as inhibitors of Hsp90 |
US8680114B2 (en) | 2003-11-21 | 2014-03-25 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
US8779132B2 (en) | 2006-10-12 | 2014-07-15 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8835434B2 (en) | 2008-01-09 | 2014-09-16 | Array Biopharma, Inc. | Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors |
US8846683B2 (en) | 2007-07-05 | 2014-09-30 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as Akt protein kinase inhibitors |
US8853216B2 (en) | 2008-01-09 | 2014-10-07 | Array Biopharma, Inc. | Hydroxylated pyrimidyl cyclopentane as AKT protein kinase inhibitor |
US8883790B2 (en) | 2006-10-12 | 2014-11-11 | Astex Therapeutics Limited | Pharmaceutical combinations |
US8916552B2 (en) | 2006-10-12 | 2014-12-23 | Astex Therapeutics Limited | Pharmaceutical combinations |
US9150548B2 (en) | 2011-04-01 | 2015-10-06 | Genentech, Inc. | Combinations of AKT inhibitor compounds and vemurafenib, and methods of use |
US9303040B2 (en) | 2006-07-06 | 2016-04-05 | Array Biopharma Inc. | Substituted piperazines as AKT inhibitors |
US9409886B2 (en) | 2007-07-05 | 2016-08-09 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US9682082B2 (en) | 2011-04-01 | 2017-06-20 | Genentech, Inc. | Combinations of AKT and MEK inhibitor compounds, and methods of use |
US9730912B2 (en) | 2006-10-12 | 2017-08-15 | Astex Therapeutics Limited | Pharmaceutical compounds |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101985428B (zh) * | 2009-07-29 | 2014-02-12 | 杭州民生药业有限公司 | 邻苯胺基苯甲酸衍生物或其药学上可接受的盐、其制备方法及其用途 |
CA2789361A1 (en) * | 2010-02-19 | 2011-08-25 | Jacques Mortier | Method for preparing chemical compounds of interest by aromatic nucleophilic substitution |
EP2536682A1 (fr) * | 2010-02-19 | 2012-12-26 | Centre National De La Recherche Scientifique | Procede de preparation de composes chimiques d'interet par substitution nucleophile aromatique de derives d'acides carboxyliques aromatiques portant au moins un groupement electroattracteur |
GEP201706690B (en) * | 2012-10-12 | 2017-06-26 | Exelixis Inc | Novel process for making compounds for use in treatment of cancer |
CN112745237B (zh) * | 2019-10-29 | 2023-06-20 | 中国科学院上海药物研究所 | 2-芳基胺类化合物及其制备方法和应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB935405A (en) * | 1960-06-23 | 1963-08-28 | Parke Davis & Co | Anthranilic acid derivatives and methods for producing same |
WO1998037881A1 (en) * | 1997-02-28 | 1998-09-03 | Warner Lambert Company | Method of treating or preventing septic shock by administering a mek inhibitor |
WO1999001426A1 (en) * | 1997-07-01 | 1999-01-14 | Warner-Lambert Company | 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as mek inhibitors |
WO1999001421A1 (en) * | 1997-07-01 | 1999-01-14 | Warner-Lambert Company | 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as mek inhibitors |
WO2000041994A1 (en) * | 1999-01-13 | 2000-07-20 | Warner-Lambert Company | 4-arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective mek inhibitors |
WO2000064856A1 (en) * | 1999-04-21 | 2000-11-02 | Warner-Lambert Company | Method for making 2-(n-phenylamino)benzoic acids |
-
2001
- 2001-07-20 YU YU14303A patent/YU14303A/sh unknown
- 2001-07-20 AP APAP/P/2001/002249A patent/AP2001002249A0/en unknown
- 2001-07-20 HU HU0300828A patent/HUP0300828A2/hu unknown
- 2001-07-20 SK SK207-2003A patent/SK2072003A3/sk unknown
- 2001-07-20 JP JP2002523437A patent/JP2004507518A/ja active Pending
- 2001-07-20 MX MXPA03001654A patent/MXPA03001654A/es unknown
- 2001-07-20 CA CA002420003A patent/CA2420003A1/en not_active Abandoned
- 2001-07-20 PL PL36069901A patent/PL360699A1/xx unknown
- 2001-07-20 CZ CZ2003477A patent/CZ2003477A3/cs unknown
- 2001-07-20 CN CN01815869A patent/CN1458921A/zh active Pending
- 2001-07-20 AU AU2001277044A patent/AU2001277044A1/en not_active Abandoned
- 2001-07-20 BR BR0113520-1A patent/BR0113520A/pt not_active Application Discontinuation
- 2001-07-20 WO PCT/US2001/022948 patent/WO2002018319A1/en not_active Application Discontinuation
- 2001-07-20 EA EA200300187A patent/EA200300187A1/ru unknown
- 2001-07-20 KR KR10-2003-7002675A patent/KR20030059115A/ko not_active Application Discontinuation
- 2001-07-20 IL IL15450701A patent/IL154507A0/xx unknown
- 2001-07-20 EP EP01954824A patent/EP1313694A1/en not_active Withdrawn
- 2001-08-15 SV SV2001000601A patent/SV2002000601A/es not_active Application Discontinuation
- 2001-08-22 TN TNTNSN01127A patent/TNSN01127A1/en unknown
- 2001-08-23 PA PA20018526501A patent/PA8526501A1/es unknown
- 2001-08-24 GT GT200100174A patent/GT200100174A/es unknown
- 2001-08-24 PE PE2001000853A patent/PE20020393A1/es not_active Application Discontinuation
- 2001-08-24 DO DO2001000238A patent/DOP2001000238A/es unknown
- 2001-08-24 UY UY26908A patent/UY26908A1/es not_active Application Discontinuation
- 2001-08-24 AR ARP010104047A patent/AR032175A1/es unknown
- 2001-09-26 HN HN2001000216A patent/HN2001000216A/es unknown
-
2003
- 2003-02-12 ZA ZA200301182A patent/ZA200301182B/en unknown
- 2003-02-20 IS IS6724A patent/IS6724A/is unknown
- 2003-02-24 NO NO20030844A patent/NO20030844L/no not_active Application Discontinuation
- 2003-03-13 BG BG107635A patent/BG107635A/bg unknown
- 2003-03-14 MA MA27069A patent/MA26949A1/fr unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB935405A (en) * | 1960-06-23 | 1963-08-28 | Parke Davis & Co | Anthranilic acid derivatives and methods for producing same |
WO1998037881A1 (en) * | 1997-02-28 | 1998-09-03 | Warner Lambert Company | Method of treating or preventing septic shock by administering a mek inhibitor |
WO1999001426A1 (en) * | 1997-07-01 | 1999-01-14 | Warner-Lambert Company | 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as mek inhibitors |
WO1999001421A1 (en) * | 1997-07-01 | 1999-01-14 | Warner-Lambert Company | 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as mek inhibitors |
WO2000041994A1 (en) * | 1999-01-13 | 2000-07-20 | Warner-Lambert Company | 4-arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective mek inhibitors |
WO2000064856A1 (en) * | 1999-04-21 | 2000-11-02 | Warner-Lambert Company | Method for making 2-(n-phenylamino)benzoic acids |
Cited By (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7973170B2 (en) | 2002-03-13 | 2011-07-05 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US7425637B2 (en) | 2002-03-13 | 2008-09-16 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US8513293B2 (en) | 2002-03-13 | 2013-08-20 | Array Biopharma Inc. | Methods of treating a hyperproliferative disorder or inhibiting cell growth in a mammal |
US7235537B2 (en) | 2002-03-13 | 2007-06-26 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US8193230B2 (en) | 2002-03-13 | 2012-06-05 | Array Biopharma Inc. | Compositions comprising N3 alkylated benzimidazole derivatives as MEK inhibitors and methods of use thereof |
US8193229B2 (en) | 2002-03-13 | 2012-06-05 | Array Biopharma Inc. | Method of treatment using N3 alkylated benzimidazole derivatives as MEK inhibitors |
US8193231B2 (en) | 2002-03-13 | 2012-06-05 | Array Biopharma Inc. | Compositions comprising N3 alkylated benzimidazole derivatives as MEK inhibitors and methods of use thereof |
US8178693B2 (en) | 2002-03-13 | 2012-05-15 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US8003805B2 (en) | 2002-03-13 | 2011-08-23 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US7230099B2 (en) | 2003-09-03 | 2007-06-12 | Array Biopharma, Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US7538120B2 (en) | 2003-09-03 | 2009-05-26 | Array Biopharma Inc. | Method of treating inflammatory diseases |
US7060856B2 (en) | 2003-10-21 | 2006-06-13 | Warner-Lambert Company | Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide |
US7598383B2 (en) | 2003-11-19 | 2009-10-06 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US7732616B2 (en) | 2003-11-19 | 2010-06-08 | Array Biopharma Inc. | Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof |
US7485643B2 (en) | 2003-11-19 | 2009-02-03 | Array Biopharma Inc. | Bicyclic inhibitors of MEK and methods of use thereof |
US7517994B2 (en) | 2003-11-19 | 2009-04-14 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US7772234B2 (en) | 2003-11-19 | 2010-08-10 | Array Biopharma Inc. | Bicyclic inhibitors of MEK and methods of use thereof |
US8268852B2 (en) | 2003-11-19 | 2012-09-18 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US8211920B2 (en) | 2003-11-19 | 2012-07-03 | Array Biopharma Inc. | 6-oxo-1,6-dihydropyridine derivatives as inhibitors of MEK and methods of use thereof |
US7576072B2 (en) | 2003-11-19 | 2009-08-18 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US8101611B2 (en) | 2003-11-19 | 2012-01-24 | Array Biopharma Inc. | Substituted pyridazines inhibitors of MEK |
US8431574B2 (en) | 2003-11-19 | 2013-04-30 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US8680114B2 (en) | 2003-11-21 | 2014-03-25 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
WO2005054179A3 (en) * | 2003-12-03 | 2005-08-04 | Leo Pharma As | Hydroxamic acid esters and pharmaceutical use thereof |
US8034811B2 (en) | 2003-12-03 | 2011-10-11 | Leo Pharma A/S | Hydroxamic acid esters and pharmaceutical use thereof |
US8101648B2 (en) | 2005-04-13 | 2012-01-24 | Astex Therapeutics, Ltd. | Hydroxybenzamide derivatives and their use as inhibitors of HSP90 |
US8816087B2 (en) | 2005-04-13 | 2014-08-26 | Astex Therapeutics Limited | Hydroxybenzamide derivatives and their use as inhibitors of Hsp90 |
US9914719B2 (en) | 2005-04-13 | 2018-03-13 | Astex Therapeutics Ltd. | Hydroxybenzamide derivatives and their use as inhibitors of HSP90 |
US7700625B2 (en) | 2005-04-13 | 2010-04-20 | Astex Therapeutics Ltd. | Hydroxybenzamide derivatives and their use as inhibitors of Hsp90 |
US8530469B2 (en) | 2005-04-13 | 2013-09-10 | Astex Therapeutics Ltd. | Therapeutic combinations of hydroxybenzamide derivatives as inhibitors of HSP90 |
US8299076B2 (en) | 2005-05-18 | 2012-10-30 | Array Biopharma Inc. | Crystalline forms of 2-(2-flouro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide |
US8106057B2 (en) | 2006-03-01 | 2012-01-31 | Astex Therapeutics, Ltd. | Dihydroxyphenyl isoindolylmethanones |
US7754725B2 (en) | 2006-03-01 | 2010-07-13 | Astex Therapeutics Ltd. | Dihydroxyphenyl isoindolymethanones |
US8329701B2 (en) | 2006-07-06 | 2012-12-11 | Array Biopharma Inc. | Dihydrofuro pyrimidines as AKT protein kinase inhibitors |
US8063050B2 (en) | 2006-07-06 | 2011-11-22 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8003651B2 (en) | 2006-07-06 | 2011-08-23 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US9359340B2 (en) | 2006-07-06 | 2016-06-07 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as Akt protein kinase inhibitors |
US9303040B2 (en) | 2006-07-06 | 2016-04-05 | Array Biopharma Inc. | Substituted piperazines as AKT inhibitors |
US8853199B2 (en) | 2006-07-06 | 2014-10-07 | Array Biopharma, Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8846681B2 (en) | 2006-07-06 | 2014-09-30 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8916552B2 (en) | 2006-10-12 | 2014-12-23 | Astex Therapeutics Limited | Pharmaceutical combinations |
US8653084B2 (en) | 2006-10-12 | 2014-02-18 | Astex Therapeutics Ltd. | Hydrobenzamide derivatives as inhibitors of Hsp90 |
US8277807B2 (en) | 2006-10-12 | 2012-10-02 | Astex Therapeutics Limited | Pharmaceutical combinations |
US9730912B2 (en) | 2006-10-12 | 2017-08-15 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8779132B2 (en) | 2006-10-12 | 2014-07-15 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8883790B2 (en) | 2006-10-12 | 2014-11-11 | Astex Therapeutics Limited | Pharmaceutical combinations |
US9428439B2 (en) | 2006-10-12 | 2016-08-30 | Astex Therapeutics Ltd. | Hydrobenzamide derivatives as inhibitors of Hsp90 |
US8377937B2 (en) | 2007-07-05 | 2013-02-19 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8846683B2 (en) | 2007-07-05 | 2014-09-30 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as Akt protein kinase inhibitors |
US9409886B2 (en) | 2007-07-05 | 2016-08-09 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8618097B2 (en) | 2007-07-05 | 2013-12-31 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8853216B2 (en) | 2008-01-09 | 2014-10-07 | Array Biopharma, Inc. | Hydroxylated pyrimidyl cyclopentane as AKT protein kinase inhibitor |
US8835434B2 (en) | 2008-01-09 | 2014-09-16 | Array Biopharma, Inc. | Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors |
US8383619B2 (en) | 2008-04-11 | 2013-02-26 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8664218B2 (en) | 2008-04-11 | 2014-03-04 | Astex Therapeutics Ltd. | Pharmaceutical compounds |
US9346789B2 (en) | 2011-04-01 | 2016-05-24 | Genentech, Inc. | Combinations of AKT inhibitor compounds and abiraterone, and methods of use |
US9150549B2 (en) | 2011-04-01 | 2015-10-06 | Genentech, Inc. | Combinations of AKT inhibitor compounds and erlotinib, and methods of use |
US9150548B2 (en) | 2011-04-01 | 2015-10-06 | Genentech, Inc. | Combinations of AKT inhibitor compounds and vemurafenib, and methods of use |
US9610289B2 (en) | 2011-04-01 | 2017-04-04 | Genentech, Inc. | Combinations of AKT inhibitor compounds and erlotinib, and methods of use |
US9682082B2 (en) | 2011-04-01 | 2017-06-20 | Genentech, Inc. | Combinations of AKT and MEK inhibitor compounds, and methods of use |
US9717730B2 (en) | 2011-04-01 | 2017-08-01 | Genentech, Inc. | Combinations of AKT inhibitor compounds and chemotherapeutic agents, and methods of use |
US10092567B2 (en) | 2011-04-01 | 2018-10-09 | Genentech, Inc. | Combinations of AKT inhibitor compounds and chemotherapeutic agents, and methods of use |
Also Published As
Publication number | Publication date |
---|---|
PL360699A1 (en) | 2004-09-20 |
SV2002000601A (es) | 2002-04-03 |
GT200100174A (es) | 2002-07-18 |
BR0113520A (pt) | 2003-06-24 |
CZ2003477A3 (cs) | 2003-10-15 |
AP2001002249A0 (en) | 2001-09-30 |
HUP0300828A2 (hu) | 2003-09-29 |
EP1313694A1 (en) | 2003-05-28 |
TNSN01127A1 (en) | 2005-11-10 |
UY26908A1 (es) | 2001-11-30 |
MA26949A1 (fr) | 2004-12-20 |
SK2072003A3 (en) | 2004-01-08 |
KR20030059115A (ko) | 2003-07-07 |
PE20020393A1 (es) | 2002-05-09 |
HN2001000216A (es) | 2002-05-22 |
NO20030844D0 (no) | 2003-02-24 |
IS6724A (is) | 2003-02-20 |
ZA200301182B (en) | 2004-05-12 |
PA8526501A1 (es) | 2002-07-30 |
JP2004507518A (ja) | 2004-03-11 |
CN1458921A (zh) | 2003-11-26 |
IL154507A0 (en) | 2003-09-17 |
CA2420003A1 (en) | 2002-03-07 |
BG107635A (bg) | 2004-09-30 |
EA200300187A1 (ru) | 2003-08-28 |
DOP2001000238A (es) | 2003-01-31 |
MXPA03001654A (es) | 2004-09-10 |
YU14303A (sh) | 2006-08-17 |
AR032175A1 (es) | 2003-10-29 |
AU2001277044A1 (en) | 2002-03-13 |
NO20030844L (no) | 2003-02-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2002018319A1 (en) | Process for making n-aryl-anthranilic acids and their derivatives | |
JP6966590B2 (ja) | オメカムチブメカルビルの塩及び塩を調製するプロセス | |
EP2185510B1 (en) | New salts of bazedoxifene | |
US10323003B2 (en) | Process for the preparation of a PDE4 inhibitor | |
US20040039208A1 (en) | Process for making n-aryl-anthranilic acids and their derivatives | |
TW201311629A (zh) | 用於製備前列腺素醯胺之新穎方法 | |
JP6185021B2 (ja) | 塩酸リトドリンの調製方法 | |
JP4568398B2 (ja) | ヘキサヒドロイソインドリン・酸付加塩およびその使用方法 | |
CN112384493B (zh) | 稠合三环γ-氨基酸衍生物的制备方法及中间体 | |
EP1907377A1 (en) | A process for the preparation of almotriptan | |
EP3097082B1 (en) | Processes for the synthesis of substituted urea compounds | |
CA3214107A1 (en) | New process for the synthesis of 5-{5-chloro-2-[(3s)-3- [(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1h)- carbonyl]phenyl}-1,2-dimethyl-1h-pyrrole-3-carboxylic acid derivatives and its application for the production of pharmaceutical compounds | |
CN110494417B (zh) | N-取代的芳族羟胺的生产 | |
RU2176639C2 (ru) | Новые гетероарилоксиэтиламины, способ их получения, содержащая их фармацевтическая композиция, обладающая сродством к 5нт1a рецепторам, промежуточные соединения | |
KR101493530B1 (ko) | N-히드록시-3-[4-[[[2-(2-메틸-1h-인돌-3-일)에틸]아미노]메틸]페닐]-2e-2-프로펜아미드 및 이의 출발 물질의 제조 방법 | |
AU720483B2 (en) | New derivatives of phenoxyethylamine, a process for their preparation, their use as medicaments and pharmaceutical compositions containing them | |
JP2022540142A (ja) | 置換ピラゾール誘導体の調製方法 | |
US20040181070A1 (en) | Process and intermediates for the preparation of 4-aryl piperidines | |
JP2002053552A (ja) | 4,6−ジメチルインドール及びその誘導体の製造方法 | |
WO2013002253A1 (ja) | ベンゾフェノン誘導体の製造法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: P-143/03 Country of ref document: YU |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 10344294 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003/01182 Country of ref document: ZA Ref document number: 200301182 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 154507 Country of ref document: IL Ref document number: 236/MUMNP/2003 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV2003-477 Country of ref document: CZ Ref document number: 2420003 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001954824 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2072003 Country of ref document: SK |
|
WWE | Wipo information: entry into national phase |
Ref document number: 03015327 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2003/001654 Country of ref document: MX Ref document number: 1020037002675 Country of ref document: KR Ref document number: 2002523437 Country of ref document: JP |
|
ENP | Entry into the national phase |
Ref document number: 20030222 Country of ref document: UZ Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001277044 Country of ref document: AU Ref document number: 200300187 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 524528 Country of ref document: NZ |
|
ENP | Entry into the national phase |
Ref document number: 10763501 Country of ref document: BG Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 018158692 Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: P20030221A Country of ref document: HR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1200300280 Country of ref document: VN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 5115 Country of ref document: GE |
|
WWP | Wipo information: published in national office |
Ref document number: 2001954824 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020037002675 Country of ref document: KR |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: PV2003-477 Country of ref document: CZ |
|
WWR | Wipo information: refused in national office |
Ref document number: PV2003-477 Country of ref document: CZ |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2001954824 Country of ref document: EP |