WO2013052839A1 - Efficient processes for large scale preparation of phosphaplatins antitumor agents - Google Patents

Efficient processes for large scale preparation of phosphaplatins antitumor agents Download PDF

Info

Publication number
WO2013052839A1
WO2013052839A1 PCT/US2012/059016 US2012059016W WO2013052839A1 WO 2013052839 A1 WO2013052839 A1 WO 2013052839A1 US 2012059016 W US2012059016 W US 2012059016W WO 2013052839 A1 WO2013052839 A1 WO 2013052839A1
Authority
WO
WIPO (PCT)
Prior art keywords
phosphaplatins
reaction mixture
approximately
pyrophosphate
temperature
Prior art date
Application number
PCT/US2012/059016
Other languages
English (en)
French (fr)
Inventor
Rathindra N. Bose
Shadi MOGHADDAS
Homa DEZVAREH
Original Assignee
Bose Rathindra N
Moghaddas Shadi
Dezvareh Homa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bose Rathindra N, Moghaddas Shadi, Dezvareh Homa filed Critical Bose Rathindra N
Priority to MX2014004181A priority Critical patent/MX357865B/es
Priority to EP12838315.5A priority patent/EP2763537B1/en
Priority to CA2851254A priority patent/CA2851254A1/en
Priority to JP2014534791A priority patent/JP6027619B2/ja
Priority to CN201280059538.9A priority patent/CN104010508B/zh
Publication of WO2013052839A1 publication Critical patent/WO2013052839A1/en
Priority to HK15100298.2A priority patent/HK1199795A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to efficient synthetic and reaction management processes for the production of phosphaplatin antitumor agents that can be applied to large scale industrial production.
  • Phosphaplatms are pyrophosphate coordinated platinum(II) and platinum(IV) complexes containing inert amine ligands (R. J. Mishur, et al., Synthesis and X-ray crystallographic Characterization of Monomeric Platinum(II)- and Platinum(IV)- Pyrophosphato Complexes, Inorg. Chem., 2008, 47, 7972-7982). These compounds show excellent antitumor activities against a variety of human cancers as demonstrated by both in vitro (R. N. Bose, et al., Non-DNA Binding Platinum Anticancer Agents: Remarkable Cytotoxic Activities of Platinum- phosphato Complexes Towards Human Ovarian Cancer Cells, Proc.
  • a process for synthesizing phosphaplatins on a large scale.
  • the process eliminates the need to use large volumes of starting materials by increasing the solubility of those starting materials in a low volume reaction mixture. Furthermore, the process eliminates the need to use concentration procedures during precipitation of the desired phosphaplatins. Finally, the process significantly reduces the reaction time.
  • platinum complex is slowly added to a reaction mixture containing concentrated pyrophosphate at a pH between about 6.0 to 8.5. After stirring, the temperature and pH are lowered to precipitate our desired phosphaplatins.
  • a process for recycling un-reacted platinum complex and pyrophosphate after a first synthesis of phosphaplatins. After the first synthesis, waste product is filtered from the reaction mixture and appropriate starting materials are added to yield further phosphaplatins.
  • Figure 1 Shows the general formula (I) of phosphaplatin antitumor agents
  • Rl and R2 are amine ligands, and R3 and R4 are either amine or other monodentate ligands.
  • Figure 2 Shows examples of cis-, trans- and optical isomers of general formula
  • Figure 3 Shows a schematic representation of large scale production of phosphaplatins.
  • Figure 4 Shows a Phosphorous-31 NMR spectrum of a reaction mixture produced from an embodiment of the present invention.
  • Figure 5 Shows HPLC data for products recovered after performing a process according to an embodiment of the present invention.
  • the present invention describes new processes for making large quantities of phosphaplatins that eliminates both large volumes of starting reaction mixtures and alleviates the concentration process for precipitation, and reduces the reaction time.
  • the phosphaplatins of the present invention can be described by general formula (I) depicted in Figure 1, where Rl and R2 are amine ligands, and R3 and R4 are either amine or other monodentate ligands.
  • Rl and R2 are amine ligands
  • R3 and R4 are either amine or other monodentate ligands.
  • Rl and R2 are amine ligands
  • R3 and R4 are either amine or other monodentate ligands.
  • Of particular interest are also the many chemical variations of these phosphaplatin structures, which include cis-, trans-, racemic and enantio-pure forms where the amine ligands contain chiral centers.
  • platinum reagents of general formula PtA 2 X 2 (where A is an inert monodentate ligand or A 2 is a bidentate ligand, and X is a replaceable ligand) are added to a saturated solution of H n Na 4 _ n P 2 0 7 at a pH of between about 6.0 and 8.5, preferably about 8, and at a temperature of between about 20°C and 60°C, preferably between about 20°C and 50°C, and more preferably about 40°C.
  • the reaction is stirred for approximately 6-15 hours (depending upon the process conditions previously mentioned since reaction time is reduced at higher temperatures).
  • the pH is adjusted with concentrated HN0 3 , and temperature is adjusted to about 0-5°C.
  • the reaction mixture is left on ice for 5 minutes (depending upon conditions) to precipitate out the phosphaplatins, and then the phosphaplatins are filtered out.
  • the temperature of the filtrate is adjusted to about 40°C and then let stand for about two hours, preferably a few minutes, to precipitate out dimers and oligomers, if any.
  • the pH of the filtrate is adjusted to between 6.0 and 8.5, preferably pH 8, appropriate amounts of pyrophosphate and starting platinum reagents are added to meet starting conditions, and the above steps are then repeated to yield further phosphaplatins.
  • a concentrated solution of tetrasodium pyrophosphate (-0.4 g) is prepared in a minimum volume of water at about 40°C by adjusting the pH with concentrated nitric acid. This limiting minimum volume is equal to the solubility of pyrophosphate at about pH 8 and at about 40°C.
  • the starting platinum compound (-0.1 g) is slowly added to the pyrophosphate solution under vigorous stirring until the platinum compound is completely dissolved in the solution.
  • the reaction mixture is then maintained at about 40°C for about 12 hr.
  • this total volume of the reaction mixture in this specific example can be on the order of about 10 mL instead of much larger prior art volumes, such as 250 mL.
  • nitric acid of desired concentration are added to lower the pH to about 2.
  • concentration and volume of nitric acid depend on the desired adjustment of final volume to precipitate the compound.
  • the final volume is calculated based on the solubility of pyrophosphate moiety at about pH 2 and at about 5°C so that the excess of un-reacted pyrophosphate does not precipitate out.
  • the desired phosphaplatin complex precipitates out.
  • the total volume after the pH adjustment can be brought to about 8-10 mL.
  • This improved method and process can be applied to all phosphaplatin compounds.
  • the process can be scaled up by increasing the concentration of reactants and adjusting the volumes accordingly.
  • one kilogram of a phosphaplatin complex can be synthesized in 10 to 20 L volumes, instead of the much larger five thousand liter volumes described in the prior art.
  • Another advantage of the disclosed process is its potential to recycle the mother liquor after collecting the first crop of phosphaplatins, which contains unused starting platinum complex and pyrophosphate along with the product that was not precipitated due to its inherent solubility.
  • the temperature of the mother liquor is increased again to 40 °C and the reaction mixture is let stand for 2 hrs, preferably a few minutes.
  • Undesired products including dimeric/polymeric pyrophosphate complexes (if any), are then filtered out.
  • additional pyrophosphate is added at a concentration necessary to exceed the amount of platinum reactant for the synthesis via a kinetic controlled process. Since up to 25% of the starting pyrophosphate ligand is consumed in the reaction, 75% of the un-reacted starting pyrophosphate can be reused.
  • the first reaction is conducted using ten-fold excess of pyrophosphate ligand.
  • the starting platinum complex needs to be replenished until the mole ratio of platinum:pyrophosphate reaches 1 :4.
  • additional pyrophosphate is added to meet the kinetic criteria and to avoid the formation of dimeric product.
  • a low-volume synthesis of phosphaplatins is obtained by removing the chloride or iodide ligand from the starting platinum complex, thus creating a highly soluble di-aqua-platinum(II) compound, and reacting that compound with the pyrophosphate moiety. Under such conditions, the reaction yields several minor products in addition to the major monomeric phosphaplatin complexes.
  • Platinum (IV) complexes were also synthesized following the low-volume strategy by oxidizing the platinum (II) complexes with hydrogen peroxide at the end of the incubation time at pH 6-8 (see Example 6). Hence, the invention is equally applicable to low- volume synthesis of platinum (II) and platinum (IV) complexes.
  • the disclosed processes lead to the elimination or minimization of the formation of undesired complexes, including dimeric and oligomeric species, by slowly adding the starting platinum substrates.
  • This slow addition of starting platinum reactants ensures a condition of excess pyrophosphate environment that prevents the formation of undesired dimeric and oligomeric platinum complexes.
  • rapid precipitation in the processes disclosed herein can be accomplished by merely lowering the temperature, and does not require the need for concentrating the reaction mixture.
  • the leftover, un-reacted pyrophosphate can be reused for the next batch, which can represent up to 75% of the initial quantity. As a result, the overall cost of the process is significantly decreased.
  • the present invention is useful for the treatment of cancer patients, and other clinical applications. It can also be used in other applications where significant quantities of compounds are desired.
  • Example 1 Low-Volume Synthesis of (trans-1, 2-Cyclohexanediamine) (dihydrogen pyrophosphate) platinum (II) (trans-dach-2) or (1R, 2R-cylohexanediamine) dihydrogen-pyrophosphato-platinum(II) (RR-dach-2).
  • Sodium pyrophosphate decahydrate (0.4 g) was dissolved in 25 mL of distilled water at 60°C and the pH of the solution was adjusted to 8 with 1M HNO 3 .
  • the downfield peak at 1.93 ppm is for the monomeric pyrophosphate complex, and the peak at -5.62 is for the excess un-reacted pyrophosphate ligand.
  • the reaction time can be shortened considerably. In fact, prolonged reaction times beyond 9 hr at 60 C seemed to reduce the product peak.
  • it is possible to reduce the reaction time by increasing the temperature below the decomposition of the pyrophosphate ligand. Following the incubation period, the solution was filtered to remove any un-reacted starting material and was concentrated to 5-7 mL by rotary evaporation under vacuum at 48°C.
  • Example 2 HPLC Characterization.
  • Figure 5(a) shows a high performance liquid chromatogram of the products recovered after the above first reaction cycle recorded immediately after dissolving the product (1 mg) in 600 of 25 mM sodium bicarbonate at pH 7.5. A 50 aliquot of the sample was injected for the separation. Each separation was repeated three times.
  • the high performance liquid chromatography experiments were performed on a Waters HPLC system equipped with a dual gradient programmer and a photodiode array detector (Waters).
  • the HPLC peaks at 3.04 and 4.2 min correspond to the deligated pyrophosphate ligand and the desired monomeric complex (phosphaplatin), respectively. It is understood that the released ligand and the dimeric compound are formed due to dynamic behavior of the compound in acidic solution, which is absent at neutral pH where only the monomeric compound exists in solution.
  • Example 3 Mass Spectrometry Characterization.
  • the mass spectrometric analysis of final product and collected HPLC fractions of the final product were performed on LCQ DECA-XP (Thermo-Finnigans) mass spectrometer by direct infusion using 500 syringe (2.30 mm diameter) at a ⁇ / ⁇ flow rate (infused volume 32 ⁇ ⁇ ).
  • the mass spectrometer was set to positive ion polarity (+MS), dry temperature of 350 °C, capillary voltage 30.22 V, sheath gas flow rate at 49.36 1/min, dry gas 5.00 1/min, and tube lens voltage 15.0 V.
  • the mass to charge ratios were collected from 150 to 2000.
  • the collected fractions were also identified via mass spectrometry.
  • the peak at m/z 486.4 corresponds to the desired monomeric complex (phosphaplatin).
  • the peak at m/z 508.1 corresponds to its sodium adduct.
  • Example 4 NMR Characterization. NMR experiments were performed on a JEOL ECA-500 MHz instrument equipped auto-tune broadband n-15-P31 probe using the JEOL delta operation's software. Proton decoupled P-31 resonances were recorded at 202 MHz and their chemical shifts are reported with respect to 85% phosphoric acid at 0.0 ppm. A pulse of 4.6-microsecond with a repetition time of 0.8 s was used to generate Fourier induction decay. Typically, 52 K data points were collected within 31.72 KHz frequency domain. A line- broadening factor of 1.0 Hz was introduced before Fourier Transformation.
  • the P-31 NMR spectrum displayed a single peak at 2.02 ppm (trans-dach-2).
  • the product exhibited a single P-31 NMR resonance at 2.02 ppm.
  • the P-31 NMR spectrum displayed a single peak at 1.92 ppm (RR-dach-2).
  • Example 5 Recycling the un-reacted materials from leftover mother liquor.
  • Example 2 The mother liquor left over from the isolation of the product in Example 1 above was used for a second cycle of synthesis by replenishing 0.1 g pyrophosphate ligand along with the 0.1 g of the starting platinum complex. The exact same process explained in Example 1 was followed to isolate the product. The yield of the product again was consistent with the first crop as noted above.
  • the HPLC chromatogram, mass spectra, and P-31 NMR of the product isolated in Example 2 resemble that of the product isolated in Example 1.
  • Example 6 Low- Volume Synthesis of (irans-l,2-Cyclohexanediamine)-irans- dihydroxo(dihydrogen pyrophosphate) platinum(IV).
  • Sodium pyrophosphate decahydrate (0.4 g) was dissolved in 25 mL of distilled water at 60°C and the pH of solution was adjusted to 8 with 1M HNO 3 .
  • the solution was left at 60°C for 15 minutes and 0.1 g of the precursor compounds (i.e. cz ' s-dichloro(trans-l,2-cyclohexanediamine) platinum(II) was added in small quantities in a 30 min period.
  • the mixture was incubated at 60°C for 12 hours.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
PCT/US2012/059016 2011-10-05 2012-10-05 Efficient processes for large scale preparation of phosphaplatins antitumor agents WO2013052839A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
MX2014004181A MX357865B (es) 2011-10-05 2012-10-05 Procedimientos eficientes para preparación a gran escala de agentes antitumorales de fosfaplatinos.
EP12838315.5A EP2763537B1 (en) 2011-10-05 2012-10-05 Efficient processes for large scale preparation of phosphaplatins antitumor agents
CA2851254A CA2851254A1 (en) 2011-10-05 2012-10-05 Efficient processes for large scale preparation of phophaplatins antitumor agents
JP2014534791A JP6027619B2 (ja) 2011-10-05 2012-10-05 ホスファプラチン系抗腫瘍剤の大規模調製のための効率的プロセス
CN201280059538.9A CN104010508B (zh) 2011-10-05 2012-10-05 用于大规模制备磷铂类抗肿瘤剂的高效方法
HK15100298.2A HK1199795A1 (zh) 2011-10-05 2015-01-12 大規模製備磷鉑類抗腫瘤劑的高效方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161543540P 2011-10-05 2011-10-05
US61/543,540 2011-10-05
US201213922917A 2012-10-05 2012-10-05
US13922917 2012-10-05

Publications (1)

Publication Number Publication Date
WO2013052839A1 true WO2013052839A1 (en) 2013-04-11

Family

ID=48044196

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/059016 WO2013052839A1 (en) 2011-10-05 2012-10-05 Efficient processes for large scale preparation of phosphaplatins antitumor agents

Country Status (3)

Country Link
CN (1) CN104010508B (zh)
CA (1) CA2851254A1 (zh)
WO (1) WO2013052839A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11154529B2 (en) 2016-04-06 2021-10-26 Phosplatin Therapeutics Inc. Phosphaplatin liquid formulations

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042838A1 (en) 2007-08-06 2009-02-12 Ohio University Phosphaplatins and their use in the treatment of cancers resistant to cisplatin and carboplatin
WO2011053365A1 (en) 2009-10-26 2011-05-05 Celanese International Corporation Processes for making ethanol from acetic acid

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103037859A (zh) * 2010-06-04 2013-04-10 俄亥俄大学 磷铂及其在治疗癌症中的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042838A1 (en) 2007-08-06 2009-02-12 Ohio University Phosphaplatins and their use in the treatment of cancers resistant to cisplatin and carboplatin
WO2009021081A2 (en) 2007-08-06 2009-02-12 Ohio University Phosphaplatins and their use in the treatment of cancers resistant to cisplatin and carboplatin
US7700649B2 (en) 2007-08-06 2010-04-20 Ohio University Phosphaplatins and their use in the treatment of cancers resistant to cisplatin and carboplatin
US20100233293A1 (en) 2007-08-06 2010-09-16 Ohio University Phosphaplatins and their use in the treatment of cancers resistant to cisplatin and carboplatin
US8034964B2 (en) 2007-08-06 2011-10-11 Ohio University Phosphaplatins and their use in the treatment of cancers resistant to cisplatin and carboplatin
WO2011053365A1 (en) 2009-10-26 2011-05-05 Celanese International Corporation Processes for making ethanol from acetic acid

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BOSE ET AL.: "Non-DNA-binding platinum anticancer agents: Cytotoxic activities of platinum-phosphato complexes towards human ovarian cancer cells", PNAS, 25 November 2008 (2008-11-25), XP002661267 *
R. D. CORNELIUS ET AL.: "Phosphorus-31 NMR and kinetic studies of the formation of ortho-, pyro-, and triphosphate complexes of cis-dichlorodiammineplatinum(II", J. AM. CHEM. SOC., vol. 106, no. 11, 1 May 1984 (1984-05-01), pages 3336 - 3343, XP055168566, DOI: doi:10.1021/ja00323a047
R. J. MISHUR ET AL.: "Synthesis and X-ray crystallographic Characterization of Monomeric Platinum(II)- and Platinum(IV)- Pyrophosphate Complexes", INORG. CHEM., vol. 47, 2008, pages 7972 - 7982
R. J. MISHUR ET AL.: "Synthesis and X-ray crystallographic Characterization of Monomeric Platinum(II)- and Platinum(IV)- Pyrophosphato Complexes", INORG. CHEM., vol. 47, 2008, pages 7972 - 7982
R. N. BOSE ET AL.: "Non-DNA Binding Platinum Anticancer Agents: Remarkable Cytotoxic Activities of Platinum-phosphato Complexes Towards Human Ovarian Cancer Cells", PROC. NATL. ACAD. SCI., vol. 105, 2008, pages 18314 - 18419
R. N. BOSE ET AL.: "Synthesis, X-ray Crystallographic, and NMR Characterisations of Platinum(II) and Platinum(IV) pyrophosphate complexes", INORG. CHEM., vol. 47, 2008, pages 7972 - 7982
S. MOGHADDAS ET AL.: "Phosphaplatins, Next Generation Platinum Antitumor Agents: A Paradigm Shift in Designing and Defining Molecular Targets", INORG. CHIM. ACTA., ISBN: 0020-1693
S. MOGHADDAS ET AL.: "Superior Efficacy of Phosphaplatins: Novel Non-DNA-Binding Platinum Drugs for Human Ovarian Cancer", FASEB J., vol. 24, 2010, pages 527

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11154529B2 (en) 2016-04-06 2021-10-26 Phosplatin Therapeutics Inc. Phosphaplatin liquid formulations

Also Published As

Publication number Publication date
CN104010508A (zh) 2014-08-27
CA2851254A1 (en) 2013-04-11
CN104010508B (zh) 2017-03-15

Similar Documents

Publication Publication Date Title
de Frémont et al. Cationic NHC–gold (I) complexes: Synthesis, isolation, and catalytic activity
US9012669B2 (en) Efficient processes for large scale preparation of phosphaplatins antitumor agents
Allen et al. Resolutions with metal complexes. Preparation and resolution of (R, S)-methylphenyl (8-quinolyl) phosphine and its arsenic analog. Crystal and molecular structure of (+) 589-[(R)-dimethyl (1-ethyl-. alpha.-naphthyl) aminato-C2, N][(S)-methylphenyl (8-quinolyl) phosphine] palladium (II) hexafluorophosphate
Oberhausen et al. New tripodal Cu (II) complexes containing imidazole ligands
Provent et al. Solution Equilibria of Enantiopure Helicates: The Role of Concentration, Solvent and Stacking Interactions in Self‐Assembly
Stoppa et al. Mononuclear and dinuclear gold (i) complexes with a caffeine-based di (N-heterocyclic carbene) ligand: synthesis, reactivity and structural DFT analysis
Farrer et al. Platinum (IV) azido complexes undergo copper-free click reactions with alkynes
EP2855496B1 (en) Synthetic and purification methods for phosphaplatin compounds and uses thereof
Butsch et al. Organoplatinum (II) and-palladium (II) complexes of nucleobases and their derivatives
WO2013052839A1 (en) Efficient processes for large scale preparation of phosphaplatins antitumor agents
KR101566568B1 (ko) 백금 착체 화합물 및 그 이용
Lee et al. Stepwise assembly of heterobimetallic complexes: synthesis, structure, and physical properties
Stoccoro et al. Dinuclear platinum (II) complexes with bridging twofold deprotonated 2, 2′: 6′, 2 ″-terpyridine. New molecules with a 3, 5-diplatinated-pyridyl inner core:[Pt2 (terpy-2H)(Me) 2 (L) 2],[Pt2 (terpy-2H)(X) 2 (L) 2] and [Pt2 (terpy-2H)(H) 2 (L) 2](L= neutral ligand; X= halide)–Crystal and molecular structure of [Pt2 (terpy-2H)(Cl) 2 (PPh3) 2]
Duan et al. Synthesis, Crystal Structure and Fluorescent Property of Cis-bis [N, N-diethyl-N'-(p-nitrobenzoyl) thiourea-kS, O] Platinum (II) Complex
Backes-Dahmann et al. Preparation, characterization, and electrochemistry of novel, air-stable nitrosyl complexes of molybdenum and tungsten of the type {M-NO} 6, 5, 4 containing the ligand N, N', N"-trimethyl-1, 4, 7-triazacyclononane
Margiotta et al. Cationic intermediates in oxidative addition reactions of Cl 2 to [PtCl 2 (cis-1, 4-DACH)]
Szüčová et al. Preparation and cis-to-trans transformation study of square-planar [Pt (Ln) 2Cl2] complexes bearing cytokinins derived from 6-benzylaminopurine (Ln) by view of NMR spectroscopy and X-ray crystallography
Kirchner et al. Reactions of tertiary phosphines, phosphites, and arsines with [Ru (. eta. 5-C5H5)(. eta. 4-C5H4O)]+ derivatives: x-ray structures of [Ru (. eta. 5-C5H4PCy3)(. eta. 5-C5H4OH)]+,[Ru (. eta. 5-C5H5)(. eta. 4-C5H4O)(P (OPh) 3]+, and [Ru (. eta. 5-C5H5)(. eta. 4-C5H3O-2-PPh3)(MeCN) 2+
Garci et al. Electrochemical synthesis and crystal structures of bis {4-methyl-N-(2-pyridin-2-yl-ethyl) benzenesulfonamide} copper (II) and bis {4-methyl-N-(2-pyridin-2-yl-ethyl) benzenesulfonamide} nickel (II)
Yoo et al. Synthesis of stable platinum complexes containing carborane in a carrier group for potential BNCT agents
CN103224533B (zh) 含硝酸酯基团的烷基羧酸根为配体的抗肿瘤铂(ii)配合物
Ertl et al. Sweetness and light: Sugar-functionalized CˆN and NˆN ligands in [Ir (CˆN) 2 (NˆN)] Cl complexes
Margiotta et al. Synthesis and characterization of new platinum (II) complexes with cyclic iminoether-type ligands having the azomethine group out of cycle
Matrosov et al. N-(1, 5-dimethyl-3-oxo-2-phenyl-1, 2-dihydropyrazol-4-yl)-P, P-diphenylamidophosphinate and its complexes with neodymium (III), erbium (III), thorium (IV), and uranyl nitrates: Synthesis and crystal and molecular structure
Arena et al. Half-sandwich ruthenium (II) and rhodium (III) complexes bearing chiral amino-phosphoramidite ligands: Synthesis, characterization and application in asymmetric transfer hydrogenation of acetophenone

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12838315

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2014534791

Country of ref document: JP

Kind code of ref document: A

Ref document number: 2851254

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/A/2014/004181

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2012838315

Country of ref document: EP