Development of the Commercial Manufacturing Process for Ipatasertib.

Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.

Amides of gold(I) diphosphines prepared from N-heterocyclic sources and their in vitro and in vivo screening for anticancer activity.

A series of new neutral mononuclear or dinuclear gold(I) complexes and a cyclic cationic tetranuclear amidogold(I) complex comprising of the phosphines 1,2-bis(dimethylphosphino)ethane (dmpe), µ-1,2-bis(diphenylphosphino)ethane (dppe), µ-1,3-bis(diphenylphosphino)propane (dppp), µ-1,5-bis(diphenylphosphino)pentane (dpppe), µ-1,6-bis(diphenylphosphino)hexane (dpph) or trimethylphosphine, and several N-heterocyclic ring systems (imidazolate, pyrazolate, 1,2,3-triazolate, 1,2,4-triazolate, pyrrolate, 9H-purine-9-ate or 9H-purine-6-amine-9-ate) as ligands, reveal intermolecular aurophilic interactions and 2D channels available for solvent molecules in some of their crystal structures. The antitumour activity of the acyclic gold(I) compounds is highly dependent on the substituents on the phosphorus atoms being highest for phenyl groups and lower for methyl groups. The activity of these compounds against selected cell lines is linked to the length of the carbon bridge between the two phosphorus atoms being highest with a bridge consisting of 5 or 6 carbons. Two compounds with the highest tumour specifities that contain dpppe and pyrazolate (a lipophilic compound) or 1,2,4-triazolate (a hydrophilic compound) induce an apoptotic cell death pathway and a maximum dose to Balb/C mice is tolerated.

Modulation of luminescence by subtle anion-cation and anion-π interactions in a trigonal Au(I)···Cu(I) complex.

The trigonally coordinated [AuCu(PPh(2)py)(3)](BF(4))(2) (1) crystallizes in two polymorphs and a pseudopolymorph, each of which contains a trigonally coordinated cation with short Au(I)-Cu(I) separations of ∼2.7 Å. Under UV illumination, these crystals luminesce different colors ranging from blue to yellow. The structures of these cations are nearly superimposable, and the primary difference resides in the relative placement of the anions and solvate molecules. As confirmed by time-dependent density functional theory calculations, it is these interactions that are responsible for the differential emission properties.

t-Butyl biphenylation of o-dibromoarenes: a route to soluble polycyclic aromatic hydrocarbons.

Large, soluble polycyclic aromatic hydrocarbons (PAHs) have been synthesized using Zr-mediated and Stille-type biphenylation reactions. Both the Zr and Stille methodologies have been adopted to incorporate tert-butyl substituents, permitting the direct synthesis of alkylated PAHs that are much more soluble than their unsubstituted analogues. To demonstrate the utility of these methods and the importance of solubilizing functionality, several large PAHs were synthesized and crystallographically characterized. The scope of the Zr-mediated and Stille methodologies is shown to be complementary. The Stille methodology often gives higher yields but is ineffective for the introduction of strain and failed with some polybrominated arenes. In these difficult cases, the zirconium methodology is effective, albeit in low yields.

[Bis-(4-methyl-1,3-thia-zol-2-yl-κN)methane]-tricarbonyl-dichlorido-tungsten(II).

The title compound, [WCl(2)(C(9)H(10)N(2)S(2))(CO)(3)], is a hepta-coordinate tungsten(II) complex with a capped-octa-hedral coordination sphere in which one CO ligand caps a face formed by a chloro ligand and the two other carbonyls. The chloro ligands are mutually trans positioned at an angle of 156.98 (7)°. The chelating bis-(4-methyl-1,3-thia-zol-2-yl)methane ligand coordinates with the imine N atoms. In the crystal, mol-ecules are linked into chains parallel to [201] by weak C-H⋯O contacts between the CH(2) group of the bis-(4-methyl-thia-zol-2-yl)methane ligand and the O atom of the capping CO group.

Luminescent copper(I) halide adducts of [Au(im(CH2py)2)2]PF6 exhibiting short Au(I)···Cu(I) separations and unusual semibridging NHC ligands.

The picolyl-substituted NHC complex [Au(im(CH(2)py)(2))(2)]PF(6) (1) reacts with two equivalents of copper(I) halides, affording compounds [Au(im(CH(2)py)(2))(2)(CuX)(2)]PF(6) (X = Cl, 2; Br, 3; I, 4). Each complex contains a nearly linearly coordinated [Au(NHC)(2)](+) center where the two picolyl groups on each im(CH(2)py)(2) ligand chelate a single copper atom. The Cu(I) center resides in a distorted tetrahedral environment and is coordinated to two pyridyl groups, a halide ion, and a gold metalloligand. The Au(I)-Cu(I) separations measure 2.7030(5), 2.6688(9), and 2.6786(10) Å for 2-4, respectively. Additionally, each Cu(I) center is further coordinated by a semibridging NHC ligand with short Cu-C separations of ~2.3 Å. In solution, these complexes dissociate the Cu(I) ion. In the solid state, 2-4 are photoluminescent with respective emission maxima of 512, 502, and 507 nm. The reaction of [Au(im(CH(2)py)(2))(2)]PF(6) with four equivalents of CuBr afforded the coordination polymer {[AuCu(2)Br(2)(im(CH(2)py)(2))(2)]Br·3CH(3)CN}(n) (5). This polymeric complex contains [Au(NHC)(2)](+) units interconnected by Cu(2)Br(2) dimers. In 5, the Au-Cu separations are long at 4.23 and 4.79 Å, while the Cu-Cu distance is considerably shorter at 2.9248(14) Å. In the solid state, 5 is photoluminescent with a broad band appearing at 533 nm.

Modulation of metal-metal separations in a series of Ag(I) and intensely blue photoluminescent Cu(I) NHC-bridged triangular clusters.

A series of picolyl-substituted NHC-bridged triangular complexes of Ag(I) and Cu(I) were synthesized upon reaction of the corresponding ligand precursors, [Him(CH(2)py)(2)]BF(4) (1a), [Him(CH(2)py-3,4-(OMe)(2))(2)]BF(4) (1b), [Him(CH(2)py-3,5-Me(2)-4-OMe)(2)]BF(4) (1c), [Him(CH(2)py-6-COOMe)(2)]BF(4) (1d), and [H(S)im(CH(2)py)(2)]BF(4) (1e), with Ag(2)O and Cu(2)O, respectively. Complexes [Cu(3)(im(CH(2)py)(2))(3)](BF(4))(3) (2a), [Cu(3)(im(CH(2)py-3,4-(OMe)(2))(2))(3)](BF(4))(3) (2b), [Cu(3)(im(CH(2)py-3,5-Me(2)-4-OMe)(2))(3)](BF(4))(3), (2c), [Ag(3)(im(CH(2)py-3,4-(OMe)(2))(2))(3)](BF(4))(3), (3b), [Ag(3)(im(CH(2)py-3,5-Me(2)-4-OMe)(2))(3)](BF(4))(3) (3c), [Ag(3)(im(CH(2)py-6-COOMe)(2))(3)](BF(4))(3) (3d), and [Ag(3)((S)im(CH(2)py)(2))(3)](BF(4))(3) (3e) were easily prepared by this method. Complex 2e, [Cu(3)((S)im(CH(2)py)(2))(3)](BF(4))(3), was synthesized by a carbene-transfer reaction of 3e, [Ag(3)((S)im(CH(2)py)(2))(3)](BF(4))(3), with CuCl in acetonitrile. The ligand precursor 1d did not react with Cu(2)O. All complexes were fully characterized by NMR, UV-vis, and luminescence spectroscopies and high-resolution mass spectrometry. Complexes 2a-2c, 2e, and 3b-3e were additionally characterized by single-crystal X-ray diffraction. Each metal complex contains a nearly equilateral triangular M(3) core wrapped by three bridging NHC ligands. In 2a-2c and 2e, the Cu-Cu separations are short and range from 2.4907 to 2.5150 Å. In the corresponding Ag(I) system, the metal-metal separations range from 2.7226 to 2.8624 Å. The Cu(I)-containing species are intensely blue photoluminescent at room temperature both in solution and in the solid state. Upon UV excitation in CH(3)CN, complexes 2a-2c and 2e emit at 459, 427, 429, and 441 nm, whereas in the solid state, these bands move to 433, 429, 432, and 440 nm, respectively. As demonstrated by (1)H NMR spectroscopy, complexes 3b-3e are dynamic in solution and undergo a ligand dissociation process. Complexes 3b-3e are weakly photoemissive in the solid state.

(Acetonitrile-κN)penta-carbonyl-tungsten(0).

The acetonitrile ligand in the title compound, [W(CH(3)CN)(CO)(5)], is coordinated end-on to a penta-carbonyl-tungsten(0) fragment with a W-N bond length of 2.186 (4) Å, completing an octa-hedral coordination environment around the W atom.

2,2'-(Sulfanediyldimethyl-ene)bis-(1,3-benzothia-zole).

In the title compound, C(16)H(12)N(2)S(3), the two benzothia-zole groups are oriented differently with respect to the -CH(2)- groups, one being approximately staggered and one nearly eclipsed. A sulfur-π inter-action of 3.3627 (11) Šis observed between the bridging thio-ether S atom and a thia-zole ring. The crystal packing is further stabilized by inter-molecular C-H⋯N and C-H⋯π inter-actions.

"On-off" Au(I)...Cu(I) interactions in a Au(NHC)2 luminescent vapochromic sensor.

Reaction of the Au(I) N-heterocyclic carbene (NHC) compound [Au(im(CH(2)py)(2))(2)]PF(6) with 2 equiv of [Cu(MeCN)(4)]PF(6) affords the tricationic compound [Au(im(CH(2)py)(2))(2)(Cu(MeCN)(2))(2)](PF(6))(3) (1), which exhibits blue luminescence (lambda(max) = 462 nm). Reaction of 1 with either liquid MeOH or MeOH vapor affords [Au(im(CH(2)py)(2))(2)(Cu(MeOH))(2)](PF(6))(3) (2), which produces green luminescence (lambda(max) = 520 nm) under UV excitation. The molecular structures of 1 x 2MeCN and 2 x 2MeOH.2Et(2)O were determined by single-crystal X-ray diffraction. Compound 1 contains a linearly coordinated [Au(NHC)(2)](+) core in which each picolyl side arm bridges a [Cu(MeCN)(2)](+) center. The Au...Cu separations are long at 4.596 A. Compound 2 exhibits two short Au...Cu interactions of 2.7195(7) A, with the Au(NHC)(2) core acting as an additional ligand toward each copper center to complete its tetrahedral coordination mode. Exposure of 2 to atmosphere produces a partial loss of MeOH accompanied by a luminescence color change to yellow (lambda(max) = 543 nm). The uptake and loss of MeOH vapor is rapid and reversible. Exposure of 2 to vacuum affords complete loss of MeOH, and the luminescence changes to yellow-orange (lambda(max) = 573 nm). Treatment of 2 with MeCN vapor regenerates 1. The interconversion of 1 and 2 was confirmed by powder X-ray diffraction. Compound 1 also reacts with acetone and H(2)O vapors, leading to species that produce yellow-orange (lambda(max) = 591 nm) and green (lambda(max) = 519 nm) emission, respectively. Compounds 1 and 2 are examples of molecular vapochromic materials that exhibit large changes in the emission though ligand substitution reactions between the solid complex and solvent vapors. The dramatic color change likely results from the "on-off" Au...Cu interactions induced by the ligand exchange reaction.

{1,5,9-Tris[(2S)-2-hydroxy-prop-yl]-1,5,9-triaza-cyclo-dodeca-ne}zinc(II) dinitrate monohydrate.

In the title compound, [Zn(C(18)H(39)N(3)O(3))](NO(3))(2)·H(2)O, the coordination geometry around the central Zn(II) atom is distorted octa-hedral. The hydroxyl groups in the macrocyclic ligand and water mol-ecules are engaged in O-H⋯O hydrogen bonding, which forms two-dimensional corrugated sheets comprising 34-membered rings. Neighbouring sheets are connected by C-H⋯O inter-actions.

Bis(1,1,2,2-tetramethyldiphosphane-1,2-dithione-κS,S')gold(I) trifluoro-methane-sulfonate.

In the title compound, [Au(C(4)H(12)P(2)S(2))(2)](CF(3)SO(3)), the gold(I) atom is tightly bonded to two S atoms belonging to different ligand mol-ecules and forms two weaker contacts to the remaining S atoms. The coordination geometry around gold is inter-mediate between linear-dicoordinate and tetra-hedral with an S-Au-S angle of 161.49 (3)°.

Ligating properties of anionic Fischer-type carbene complexes, [(CO)(5)M[double bond, length as m-dash]C(X)Y](-).

With the simplest of anionic Fischer-type carbene complexes acting as ligands, Cp(2)Zr(Cl){OCMe}M(CO)(5) compounds (M = Cr or W) promote alpha-olefin oligomerization and polymerization in the presence of MAO. Attaching an N-heterocyclic ring to the carbene carbon atom in similar precursors, allows a variety of hard metal ions and fragments to be captured by external bidentate coordination. The outcome of the attachment of a phosphorus or sulfur functionality to an alpha-carbon of an O-anionic carbene is formation of a bidentate ligand and then internal four-membered carbene-heteroatom chelate formation. alpha-Deprotonated carbene complexes are also precursors for remote, one-N, six-membered carbene complexes of various metals whereas alpha-C-, alpha-N- or alpha-O-deprotonated as well as beta-deprotonated Fischer-type carbene complexes display unique synthon properties towards Ph(3)PAu(+) and partake in unusual ensuing coordination of liberated group 6 metal carbonyl moieties to form dinuclear products.

Competitive bulk liquid membrane transport and solvent extraction of some metal ions using RC(S)NHP(X)(OiPr)(2) (X = O, S) as ionophores. Formation of the polynuclear complex of [Ag(N[triple bond]C-NP(S)(OiPr)(2))](n).

Competitive transport experiments involving metal ions from an aqueous source phase through a chloroform membrane into an aqueous receiving phase have been carried out using a series of N-(thio)phosphorylated (thio)amide and thiourea ligands as the ionophore present in the organic phase. The source phase contained equimolar concentrations of Co(II), Ni(II), Cu(II), Zn(II), Ag(I), Cd(II) and Pb(II) with the source and receiving phases being buffered at a number of different pHs. Solvent extraction properties of the ligands towards the same metal cations under the same experimental conditions as for the transport were also studied. All ligands demonstrated 100% extraction of Ag(I). Reaction of AgNO(3) with the potassium salt of the N-thiophosphorylated thiourea NH(2)C(S)NHP(S)(OiPr)(2) gave a new supramolecular Ag(I) complex, [AgZ](n) (Z = {N[triple bond]C-NP(S)(OiPr)(2)}(-)) that contains both tri- and tetracoordinated Ag(I). The novel polynuclear Ag(I) complex [AgZ](n) described and structurally characterized by single crystal X-ray diffraction has no precedent.

[(3-Methylphenyl)(triphenylphosphonio)methanide-κC]triphenyl-phospho-rane}(penta-fluoro-phenyl-κC)gold(I) diethyl ether solvate.

The metal atom in the title ylid-gold(I) adduct, [Au(C(6)F(5))(C(26)H(23)P)]·C(4)H(10)O, exists in a linear coordination environment [C-Au-C = 174.1 (2)°]. The mol-ecule has a short intra-molecular contact involving an aromatic H atom (Au⋯H = 2.64 Å); two adjacent mol-ecules are linked by an Au⋯H(ylid) inter-action (Au⋯H = 3.14 Å).

4-Bromo-N-(diisopropoxyphosphor-yl)benzamide.

In the title compound, C(13)H(19)BrNO(4)P, the crystal structure is stabilized by inter-molecular N-H⋯O hydrogen bonds between the phosphoryl O atom and the amide N atom which link the mol-ecules into centrosymmetric dimers. These dimers are further packed into stacks along the c axis by inter-molecular C-H⋯O and C-H⋯π inter-actions.

(m-Phenyl-enedimethyl-ene)bis-(triphenyl-phospho-nium) bis-[chlorido(penta-fluoro-phen-yl)aurate(I)] dichloro-methane disolvate.

The title compound, (C(44)H(38)P(2))[AuCl(C(6)F(5))](2)·2CH(2)Cl(2), crystallizes with a twofold rotation axis through the central benzene ring in the bis-phospho-nium dication. In the crystal, the dications and anions are ordered into columns running parallel to the c axis by contacts of the pro-ylidic CH(2) groups with the Cl atom of one and an ortho-F atom of another anion. The space between the columns is occupied by CH(2)Cl(2) solvent mol-ecules.

Bis(1,3-benzothia-zol-2-amine-κN)silver(I) nitrate acetone solvate.

In the title compound, [Ag(C(7)H(6)N(2)S)(2)]NO(3)·C(3)H(6)O, the Ag(I) ion is coordinated to two benzothia-zol-2-amine ligands via the thia-zole N atoms in an approximately linear arrangement. The dihedral angle between the mean planes of the two 1,3-benzothia-zole groups is 5.9 (3)°. Both amine groups on the ligands are oriented in the same direction and are engaged in N-H⋯O hydrogen bonding with the nitrate counter-anion, forming one-dimensional columns along the b-axis direction. Voids created by inefficient crystal packing are occupied by acetone solvent mol-ecules which are disordered over two sites with occupancies of 0.563 (11) and 0.437 (11).

Bis[µ-1,2-bis-(diphenyl-phosphino)ethane-κP:P']digold(I)(Au-Au) bis-(trifluoro-methane-sulfonate) acetonitrile disolvate.

The title compound, [Au(2)(C(26)H(24)P(2))(2)](CF(3)SO(3))(2)·2CH(3)CN, comprises a cyclic cation with a short intra-molecular aurophilic inter-action of 2.9220 (3) Å. The trifluoro-methane-sulfonate anions and acetonitrile solvent mol-ecules are located in channels formed by the complex cations that run along the crystallographic c axis. Each counter-anion is also engaged in a C-H⋯O contact with one of the methyl-ene H atoms of a 1,2-bis-(diphenyl-phosphino)ethane (dppe) ligand; another C-H⋯O contact involving an aromatic H atom is also observed.

catena-Poly[copper(I)-bis(µ-trifluoro-methane-sulfonato-κO:O')-copper(I)-bis(µ-trimethyl trithio-phosphite)-κP:S;κS:P].

The title compound, [Cu(2)(CF(3)SO(3))(2)(C(3)H(9)PS(3))(2)](n), crystallizes as infinite chains in which two trimethyl trithio-phosphite ligands and two trifluoro-methane-sulfonate anions bridge the essentially tetra-hedrally coordinated Cu(I) ions in an alternating fashion. The P and one S atom of each trimethyl trithio-phosphite ligand are employed for coordination. The mol-ecular structure exhibits the rare motif of copper(I) bridged by two trifluoro-methane-sulfonate anions generating eight-membered rings.