尼达尼布 ニンテダニブ NINTEDANIB

NINTEDANIB, BBIF 1120, Intedanib
Boehringer Ingelheim Corp

As a potential treatment for a range of different solid tumour types

CAS 656247-17-5

1377321-64-6 (nintedanib bisethanesulfonate)

3(Z)-[1-[4-[N-Methyl-N-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenylamino]-1-phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester

launched 2014….Idiopathic pulmonary fibrosis
尼达尼布    ニンテダニブ

NMR, HPLC, MS http://www.medkoo.com/uploads/product/Nintedanib/qc/QC-Nintedanib-TZC50128Web.pdf
http://file.selleckchem.com/downloads/nmr/S101002-BIBF1120-NMR-Selleck.pdf
http://jocpr.com/vol7-iss8-2015/JCPR-2015-7-8-774-782.pdf

Synthesis
http://newdrugapprovals.org/2014/12/10/%E5%B0%BC%E8%BE%BE%E5%B0%BC%E5%B8%83-%E3%83%8B%E3%83%B3%E3%83%86%E3%83%80%E3%83%8B%E3%83%96-nintedanib-for-idiopathic-pulmonary-fibrosis/

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COSY PREDICT

 1H NMR PREDICT

 13C NMR PREDICT

Nintedanib (formerly BIBF 1120) is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR) being developed by Boehringer Ingelheim as an anti-angiogenesis anti-cancer agent under the trade name Vargatef, and recently approved for treatment of idiopathic pulmonary fibrosis as Ofev

see

http://www.google.com/patents/US20110201812


EXAMPLE 7Synthesis of the “anilino” (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone)

Method 1
A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (10.0 g; 0.032 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (8.6 g; 0.032 mol) in a mixture of methanol (72 ml) and N,N-dimethylformamide (18 ml) is heated to reflux. After 7 h of refluxing the suspension is cooled down to 0° C. and stirring is maintained for additional 2 h. The solid is filtered, washed with methanol (40 ml) and dried to afford 15.4 g (88.1%) of the “anilino” compound as yellow crystals.

¹H-NMR (500 MHz, DMSO-d₆) δ: 11.00 (s, 1H, 23-H); 12.23 (s, 19-H); 7.61 (t; J=7.1 Hz, 1H, 33-H); 7.57 (t, J=7.5 Hz, 2H, 32-H+34-H); 7.50 (d, J=7.7 Hz, 2H, 31-H+35-H); 7.43 (d, J=1.6 Hz, 1H, 29-H); 7.20 (dd, J=8.3; 1.6 Hz, 1H, 27-H); 7.13 (d, J=8.3 Hz, 2H, 14-H+18-H); 6.89 (d, 8.3 Hz, 2H, 15-H+17-H); 5.84 (d, J=8.3 Hz, 1H, 26-H); 3.77 (s, 3H, 40-H₃); 3.06 (m, 3H, 12-H₃); 2.70 (m, 2 H, 8-H₂); 2.19 (m, 8H, 2-H₂, 3-H₂, 5-H₂, 6-H₂); 2.11 (s, 3H, 7-H₃).


¹³C-NMR (126 MHz, DMSO-d₆) δ: 54.5 (C-2+C-6); 52.2 (C-3+C-5); 45.6 (C-7); 59.1 (C-8); 168.5 (C-9); 36.6 (C-12); 140.1 (C-13); 127.6 (C-14+C-18); 123.8 (C-17+C-15); 137.0 (C-16); 158.3 (C-20); 97.5 (C-21); 170.1 (C-22); 136.2 (C-24); 128.9 (C-25); 117.2 (C-26); 121.4 (C-27); 124.0 (C-28); 109.4 (C-29); 131.9 (C-30); 128.4 (C-31+C-35); 129.4 (C-32+C-34); 130.4 (C-33); 166.3 (C-37); 51.7 (C-40).

MS (m/z): 540 (M+H)⁺.

Anal. calcd. for C₃₁H₃₃N₅O₄: C, 69.00; H, 6.16; N, 12.98. Found: C, 68.05; H, 6.21; N, 12.81.
Method 2
A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (20.0 g; 0.064 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (17.1 g; 0.065 mol) in methanol (180 ml) is heated to reflux for 7.5 h. The resulting suspension is cooled down to 10° C. within 1 h and stirring is maintained for 1 h. After filtration, the solid is washed with ice cold methanol (80 ml) and dried to afford 31.0 g (89.0%) of the “anilino” compound as yellow crystals.


EXAMPLE 8
Synthesis of the 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, monoethanesulfonate

A suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone (30.0 g; 0.055 mol) in methanol (200 ml) and water (2.4 ml) is heated to 60° C. Aqueous ethanesulfonic acid (70% (w/w); 8.75 g; 0.056 mol) is added to the reaction mixture. The resulting solution is cooled to 50° C., seeded and then diluted with isopropanol (200 ml). The mixture is further cooled to 0° C. and stirred for 2 h at this temperature. The precipitate is isolated, washed with isopropanol (120 ml) and dried to furnish 35.1 g (97.3%) of the monoethanesulfonate salt of the compound as yellow crystals.


 ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.26 (s, 11-H); 10.79 (s, 1H, 1-H); 9.44 (s, 1H, 24-H); 7.64 (m, 1H, 32-H); 7.59 (m, 2H, 31-H+33-H); 7.52 (m, 2H, 30-H+34-H); 7.45 (d, J=1.6 Hz, 1H, 7-H); 7.20 (dd, J=8.2; 1.6 Hz, 1H, 5-H); 7.16 (m, 2H, 14-H+16-H); 6.90 (m, 2H, 13-H+17-H); 5.85 (d, J=8.2 Hz, 1H, 4-H); 3.78 (s, 3H, 37-H₃); 3.45-2.80 (broad m, 4H, 23-H₂+25-H₂); 3.08 (s, 3H, 28-H₃); 2.88 (s, 2H, 20-H₂); 2.85-2.30 (broad m, 4H, 22-H₂+26-H₂); 2.75 (s, 3H, 27-H₃); 2.44 (q, J=7.4 Hz, 2H, 39-H₂); 1.09 (t, J=7.4 Hz, 3H, 38-H₃).


¹³C-NMR (126 MHz, DMSO-d₆) δ: 9.8 (C-38); 36.6 (C-28); 42.3 (C-27); 45.1 (C-39); 51.7 (C-37); 48.9 (C-22+C-26); 52.6 (C-23+C-25); 57.5 (C-20); 97.7 (C-3); 109.5 (C-7); 117.3 (C-4); 121.4 (C-5); 123.8 (C-13+C-17); 124.1 (C-6); 127.7 (C-14+C-16); 128.4 (C-30+C-34); 128.8 (C-9); 129.5 (C-31+C-33); 130.5 (C-32); 132.0 (C-29); 168.5 (C-9); 136.3 (C-8); 137.3 (C-12); 139.5 (C-15); 158.1 (C-10); 166.3 (C-35); 168.0 (C-19); 170.1 (C-2).


MS (m/z): 540 (M_(base)+H)⁺.


Anal. calcd. for C₃₃H₃₉N₅O₇S: C, 60.17; H, 6.12; N, 10.63; S, 4.87. Found: C, 60.40; H, 6.15; N, 10.70; S, 4.84.

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 CN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)N/C(=C\3/C4=C(C=C(C=C4)C(=O)OC)NC3=O)/C5=CC=CC=C5

IR TO REMEMBER

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Electron spin resonance (ESR) spectroscopy

Electron spin resonance (ESR) spectroscopy, also referred to as electron paramagnetic resonance (EPR) spectroscopy, is a versatile, nondestructive analytical technique which can be used for a variety of applications including: oxidation and reduction processes, biradicals and triplet state molecules, reaction kinetics, as well as numerous additional applications in biology, medicine and physics. However, this technique can only be applied to samples having one or more unpaired electrons.
Spectroscopy is the measurement and interpretation of the energy difference between atomic or molecular states. According to Plank’s law, electromagnetic radiation will be absorbed if:

ΔE=hν

where ΔE is the difference in energy of the two states, h is Plank’s constant and ν is the frequency of the radiation. The absorption of this energy causes a transition of an electron from the lower energy state to the higher energy state. In EPR spectroscopy the radiation used is in the gigahertz range. Unlike most traditional spectroscopy techniques, in EPR spectroscopy the frequency of the radiation is held constant while the magnetic field is varied in order to obtain an absorption spectrum.

Shown above is a block diagram for a typical EPR spectrometer. The radiation source usually used is called a klystron. Klystrons are vacuum tubes known to be stable high power microwave sources which have low-noise characteristics and thus give high sensitivity. A majority of EPR spectrometers operate at approximately 9.5 GHz, which corresponds to about 32 mm. The radiation may be incident on the sample continuously (i.e., continuous wave, abbreviated cw) or pulsed. The sample is placed in a resonant cavity which admits microwaves through an iris. The cavity is located in the middle of an electromagnet and helps to amplify the weak signals from the sample. Numerous types of solid-state diodes are sensitive to microwave energy and absorption lines then be detected when the separation of the energy levels is equal or very close to the frequency of the incident microwave photons. In practice, most of the external components, such as the source and detector, are contained within a microwave bridge control. Additionally, other components, such as an attenuator, field modulator, and amplifier, are also included to enhance the performance of the instrument.
The basis of EPR spectroscopy lies in the spin of an electron and its associated magnetic moment. When an electron is placed within an applied magnetic field, Bo, the two possible spin states of the electron have different energies. This energy difference is a result of the Zeeman effect.  The lower energy state occurs when the magnetic moment of the electron, μ, is aligned with the magnetic field and a higher energy state occurs where μ is aligned against the magnetic field. The two states are labeled by the projection of the electron spin, MS, on the direction of the magnetic field, where MS = -1/2 is the parallel state, and MS = +1/2 is the antiparallel state.

So for a molecule with one unpaired electron in a magnetic field, the energy states of the electron can be defined as:

E = gμBBoMS = ±1/2gμBBo

where g is the proportionality factor (or g-factor), μB is the Bohr magneton, Bo is the magnetic field, and MS is the electron spin quantum number. From this relationship, there are two important factors to note: the two spin states have the same energy when there is no applied magnetic field and the energy difference between the two spin states increases linearly with increasing magnetic field strength.

Like most spectroscopic techniques, when the radiation is absorbed, a spectrum is produced similar to the one on the left. In EPR spectrometers a phase-sensitive detector is used. This results in the absorption signal being presented as the first derivative. So the absorption maximum corresponds to the point where the spectrum passes through zero. This is the point that is used to determine the center of the signal.
As mentioned earlier, an EPR spectrum is obtained by holding the frequency of radiation constant and varying the magnetic field. Absorption occurs when the magnetic field “tunes” the two spin states so that their energy difference is equal to the radiation. This is known as the field for resonance. As spectra can be obtained at a variety of frequencies, the field for resonance does not provide unique identification of compounds. The proportionality factor, however, can yield more useful information.

g =

For a free electron, the proportionality factor is 2.00232. For organic radicals, the value is typically quite close to that of a free electron with values ranging from 1.99-2.01. For transition metal compounds, large variations can occur due to spin-orbit coupling and zero-field splitting and results in values ranging from 1.4-3.0.
In addition to the applied magnetic field, unpaired electrons are also sensitive to their local environments. Frequently the nuclei of the atoms in a molecule or complex have a magnetic moment, which produces a local magnetic field at the electron. The resulting interaction between the electron and the nuclei is called the hyperfine interaction. Hyperfine interactions can be used to provide a great deal of information about the sample including providing information about the number and identity of nuclei in a complex as well as their distance from the unpaired electron. This interaction expands the previous equation to:

E = gμBBoMS + aMSmI

where a is the hyperfine coupling constant and mI is the nuclear spin quantum number for the neighboring nucleus.

So a single nucleus with a spin ½ will split each energy level into two, as shown above, and then two transitions (or absorptions) can be observed. The energy difference between the two absorptions is equal to the hyperfine coupling constant. It is important to note that if a signal is split due to hyperfine interactions, the center of the signal (which is used to determine the proportionality factor) is the center of the splitting pattern.  So for a doublet, the center would be half way between the two signals and for a triplet, the center would be the center of the middle line.

The coupling patterns that are observed in EPR spectra are determined by the same rules that apply to NMR spectra. However, in EPR spectra it is more common to see coupling to nuclei with spins greater than ½. The number of lines which result from the coupling can be determined by the formula:

2NI + 1

where N is the number of equivalent nuclei and I is the spin. It is important to note that this formula only determines the number of lines in the spectrum, not their relative intensities. Coupling to a single nucleus with spin n/2 gives (n + 1) lines each of equal intensity.

2NI + 1 = 2(1)(n/2) + 1 = n + 1 lines

For example, coupling to a single vanadium nucleus (I = 7/2) will result in a spectrum of eight lines all of equal intensity.

Simulated EPR spectrum showing coupling to one nucleus (/I/ = 7/2)

Coupling to n equivalent nuclei, each with spin ½ again gives (n + 1) lines,

2NI + 1 = 2(n)(1/2) + 1 = n + 1 lines

but, since there are multiple nuclei interacting, the relative intensities of the lines follow the binomial distribution shown below.

# of Equivalent Nuclei	Relative Intensities
1	1:1
2	1:2:1
3	1:3:3:1
4	1:4:6:4:1
5	1:5:10:10:5:1
6	1:6:15:20:15:6:1

An example of this is shown by the EPR spectrum of the radical anion of benzene, [C6H6•]-, in which the electron is delocalized over all six carbon atoms and therefore exhibits coupling to six equivalent hydrogen atoms. As a result, the EPR spectrum shows seven lines with relative intensities of 1:6:15:20:15:6:1. Similar distributions can be derived for n equivalent nuclei with spins greater than ½.

  Spectrum of benzene radical anion

If an electron couples to several sets of nuclei, then the overall pattern is determined by first applying the coupling to the nearest nuclei, then splitting each of those lines by the coupling to the next nearest nuclei, and so on. An example of this can be seen in the radical anion of pyrazine. Where coupling to two equivalent 14N (I = 1) nuclei gives a quintet with the relative intensities of 1:2:3:2:1 which are further split into quintets with relative intensities of 1:4:6:4:1 by coupling to four equivalent hydrogens.

Spectrum of pyrazine radical anion

As NMR spectroscopy does not usually provide useful spectra for paramagnetic compounds, analysis of their EPR spectra can provide additional insight. Analysis of the coupling patterns can provide information about the number and type of nuclei coupled to the electrons. The magnitude of a can indicate the extent to which the unpaired electrons are delocalized and g-factors can show whether unpaired electrons are based on transition metal atoms or on the adjacent ligand

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Circular dichroism

Circular dichroism (CD) is the difference in light 

absorbance between left- (L-CPL) and right-circularly 

polarised light (R-CPL) and circular dichroism 

spectrometers (spectrophotometers) are highly 

specialised variations of the absorbance 

spectrophotometer.

A circular dichroism spectrophotometer is also commonly 

termed a circular dichroism spectropolarimeter or a 

circular dichrograph. Most modern circular dichroism 

instruments operate on the same principles, which is 

demonstrated in the slide show at the bottom of the page. 

There is a source of monochromatic linearly polarised light 

which can be turned into either left- or right-circularly 

polarised light by passing it through a quarter-wave plate 

whose unique axis is at 45 degrees to the linear polarisation 

plane as described in the section about polarised light.

Instead of a static quarter-wave plate, a circular dichroism 

spectrophotometer has a specialised optical element called 

a photo-elastic modulator (PEM). This is a piezoelectric 

element cemented to a block of fused silica. At rest, when 

the piezoelectric element is not oscillating, the silica block is 

not birefringent; when driven, the piezoelectric element 

oscillates at its resonance frequency (typically around 50 

kHz), and induces stress in the silica in such a way that it 

becomes birefringent. The alternating stress turns the fused 

silica element into a dynamic quarter-wave plate, retarding 

first vertical with respect to horizontal components of the 

incident linearly polarised light by a quarter-wave and then 

vice versa, producing left- and then right- circularly polarised 

light at the drive frequency. The amplitude of the oscillation 

is tuned so that the retardation is appropriate for the 

wavelength of light passing through the silica block.

On the other side of the sample position there is a light 

detector. When there is no circularly dichroic sample in the 

light path, the light hitting the detector is constant. If there is a 

circularly dichroic sample in the light path, the recorded light 

intensity will be different for right- and left-CPL. Using a lock-

in amplifier tuned to the frequency of the PEM, it is possible 

to measure the difference in intensity between the two 

circular polarisations (vAC). The average total light intensity 

across many PEM oscillations (vDC) can be used to scale 

the size of the lock-in amplifier signal to take into account 

variations in total light level. Both signals can be recorded 

and from them the circular dichroism signal can be 

calculated easily by dividing the vAC component by the vDC 

signal.

G is a calibration-scaling factor to provide either ellipticity or 

differential absorbance. The section about CD Units and 

their inter-conversion explains how ellipticity and differential 

absorbance are related.

 
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