Axitinib (
AG013736; trade name
Inlyta) is a small molecule
tyrosine kinase inhibitor developed by
Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (
xenograft) models
[2] and has shown partial responses in clinical trials with
renal cell carcinoma (RCC)
[3] and several other tumour types.
[4] It was approved by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival,
[5] though there have been reports of fatal adverse effects.
[6]
Axitinib, a small-molecule indazole derivative chemically known as (
E)-
N-methyl-2-(3-(2-(pyridin-2-yl)-vinyl)-1
H-indazol-6-ylthio)benzamide
developed by Pfizer, was approved in January 2012 by the U.S. FDA with
the trade name Inlyta. It selectively inhibits vascular endothelial
growth factor receptors for the treatment of renal cell carcinoma
On
January 27, 2012, axitinib was approved with the trade name INLYTA for
treatment of patients in the United States with advanced renal cell
carcinoma after failure of one prior systemic therapy.
It has received
FDA (27 January 2012),
EMA (13 September 2012),
MHRA (3 September 2012) and
TGA (26 July 2012) approval for use as a treatment for renal cell carcinoma.
[11][12][13][14]
A study published in 2015
[15] showed that axitinib effectively inhibits a mutated gene (
BCR-ABL1[T315I]) that is common in
chronic myeloid leukemias and
adult acute lymphoblastic leukemias which have become resistant to other
tyrosine kinase inhibitors like
imatinib.
This is one of the first examples of a new indication for an existing
drug being discovered by screening known drugs using a patient's own
cells.
The
discovery and development of an efficient synthesis route to axinitib
is reported. The first-generation route researched by Pfizer implemented
two Pd-catalyzed coupling reactions as key steps. In this work, the
development of Heck-type and C–S coupling reactions catalyzed by CuI is
briefly described, using an economial and practical protocol. Aspects of
this route, such as selecting optimal ligands, solvent, and other
conditions, are discussed in detail. The scale-up experiment was carried
out to provide more than 300 g of active pharmaceutical ingredients of
axitinib in Form XLI with 99.9% purity in 39% yield. In short, we
provide a new choice of synthesis route to axitinib, through two
copper-catalyzed coupling reactions with good yield.
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00123
(
E)-
N-Methyl-2-(3-(2-(pyridin-2-yl)vinyl)-1
H-indazol-6-ylthiol)benzamide
(Axitinib) Form XLI (326.4 g in 96% yield with purity 99.91%). Residual
Cu content was determined to be 2.2 ppm by atomic absorption
spectroscopy:
mp 227.7 °C;
1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.63–7.44 (m, 3H), 7.29 (p, J = 7.4, 6.6 Hz, 3H), 7.19 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 2.78 (d, J = 4.6 Hz, 3H);
13C NMR (75 MHz, DMSO-d6)
δ 167.89, 154.86, 149.54, 142.01, 141.86, 136.92, 136.88, 135.67,
132.52, 130.32, 129.99, 129.25, 127.80, 126.15, 125.59, 123.66, 122.68,
122.50, 121.79, 120.29, 114.76, 26.13.
.............................
Axitinib
(Axitinib, AG-013736, CAS: 319460-85-0) is a Pfizer research and
development by the United States of new, mainly targeting VEGFR kinase
GABA, inhibiting angiogenesis anticancer small molecule drug, trade name
Inlyta, for other systems therapy for advanced renal cell carcinoma
(Renal Cell Carcinoma, RCC), 2008 has been approved in the domestic
clinical, and Pfizer's cancer drug Sutent another similar imatinib
(Sunitinib) , Axitinib also potent and selective multi-targeted tyrosine
kinase inhibitor, can inhibit the vascular endothelial growth factor
receptor (Vascular EndothelialGrowth Factor Rec India tor, VEGFR),
including VEGFl receptor, VECF2 receptors and VECF3 receptor, can
inhibit platelet-derived growth factor receptor (Platelet-derived growth
factor receptor, PDGFR) and c_KIT. Axitinib is called sunitinib second
generation, better than sunitinib adverse reactions.
Axitinib (II)
chemical name 6- [2_ (methylcarbamoyl) phenylsulfanyl] -3-E- [2_
(Batch-2-yl) ethenyl] indazole structural formula as follows:
Axitinib (II)
Assi synthesis method for Nepal mainly in the following three ways:
(I)
Patent US20060094881 (Agouron Pharmaceuticals), EP2163544 (Pfizer)
reported the first synthesis method Axitinib to 3,6-diiodo-indazole as a
starting material, first-iodo-6-position is substituted mercapto group,
protection of the NH group, then the Heck reaction occurs
(pyridine-2-yl) vinyl 3-position, after deprotection Axitinib whole
synthesis route is as follows:
Axitinib Scheme I
This
method although the synthesis route is shorter, but the catalyst and
reagents used relatively expensive and require purified through the
column, the total yield is low, is not conducive to industrial
production.
[0004] (2) The second method of synthesis Axitinib
e.g. W00102369 (Agouron Pharmaceuticals), US6531491 (Agouron
Pharmaceuticals) reported in 6-nitro-indazole as a starting material,
the 3-position first iodo, followed by the protecting group NH, Suzuki
coupling reaction with boronic acid to give 3- styryl styryl-position, a
nitro group reduced to an amino group, an amino diazotization reaction
was iodo, the 3-position of the styrene-based ozone of the obtained
aldehyde, followed by Wittig reaction to give the 3-position
(pyridin-2-yl) ethenyl, 6-position is substituted mercapto iodine,
alkaline hydrolysis then amidated, and finally deprotection Axitinib,
the entire reaction formula as follows:
Axitinib Scheme 2
The
method of synthesis route is long, harsh reaction conditions, complex
process, the total yield is low, does not apply to industrial
production.
[0005] (3) The third method is W02006048745 (Pfizer)
discloses to 6-nitro-indazole as a starting material, the 3-position
iodo first, followed by the protecting group NH, 3- bits Heck coupling
reaction, a nitro group reduced to an amino group, an amino
diazotization reaction was iodo, iodo-6-position is substituted mercapto
group, and finally deprotected to give Axitinib, the entire reaction is
as follows:
This
method has an advantage over the first two methods, it is possible to
enlarge the production, but the reaction was not complete in the
reaction step, will generate new impurities through the column needs to
be purified.
SYNTHESIS
aReagents and conditions: (a) I2, K2CO3, DMF; (b) CH2Cl2, CH3SO3H, dihydrofuran; (c) compound
B, i-Pr2EtN, Pd(OAc)2, (
o-Tol)3P, DMF; (d) iron, EtOH, NH4Cl; (e) AcOH, NaNO2, CH2Cl2, I2/KI; (f) compound
C, Pd(dppf)Cl2, Cs2CO3, DMF; (h) 1,
p-TsOH, MeOH; 2, NaHCO3; (i) AcOH, MeOH, Pd removal, recrystallization.
http://www.google.com/patents/WO2006048745A1?cl=en
Example 15: Final deprotectioπ step to produce 6-r2-(methylcarbamoyl)phenylsulfanyll-3-E-f2- (pyridine-2-yl)ethenyllindazole
N-1
THP
6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole
(355 g) was suspended in 2,485 ml_ of methanol, after which
p-toluenesulfonic acid monohydrate (718 g) was added. The mixture was
then heated to 65
0C (hard reflux) for 4 hours under argon
while the reaction was monitored by HPLC (gluco method). Heating
continued until less than 1% of the N-1 THP protected starting material
persisted. The heating was then removed and the reaction was cooled to
room temperature. The solid was filtered and the wet cake was washed
with methanol (2 volumes, 710 mL) then the solids were rinsed with ethyl
acetate (2 volumes, 710 mL). The wet cake was transferred to a reactor
containing sodium bicarbonate (126.84 g), deionized water (1800 mL), and
ethyl acetate (975 mL), which was then stirred for 2 hours at 2O
0C.
The solids were filtered and washed with 5 volumes of deionized water
(1800 mL), then with 2 volumes of ethyl acetate (760 mL), and then dried
in a vacuum oven at 40
0C for 16 hours. The isolated yield
for the reaction was 92.5% (274 g). The isolated material was identified
as crystalline Form III free base (0.5 ethyl acetate solvate).
1H
NMR, 300 MHz, (DMSO-D6), ppm; 13.35 (1 H, s), 8.60 (1 H, d, J=3.8 Hz),
8.39 (1 H, m), 8.23 (1 H, d, J=8.5 Hz), 7.95 (1 H, d, J=16.4 Hz), 7.82
(1 H, ddd, J=7.7, 7.6, 1.8 Hz), 7.67 (1 H, d, J=7.8 Hz), 7.60 (a H, s),
7.57 (1 H, d, J=16.4 Hz), 7.49 (1 H, dd, J=7.1 , 1.6 Hz), 7.35-7.26 (3
H, m), 7.19 (1 H, d, J=8.4 Hz), 7.04 (1 H, d, J=7.8 Hz), 2.77 (3 H, d,
J=4.6 Hz). 13C NMR, 75 MHz, (DMSO-D6) ppm: 168.23, 155.18,
149.81 , 142.35, 142.22, 137.31 , 136.00, 132.89, 130.64, 130.36, 129.51
, 128.14, 126.50, 125.93, 124.08, 123.01 , 122.85, 122.12, 120.642,
115.08, 26.45.
Example 21 : Preparation of 6-F2-(methylcarbamovDphenylsulfanyll-3-Z-r2-(pyridine-2- vDethenyllindazole
To
a 100 ml_ 3-neck flask containing a solution of 0.95 g of 6-[2-
(methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole
was added 2.5 g of phenyliodide diacetate followed by 1.0 mL of H
2NNH
2 H
2O. After the bubbling had settled, more phenyliodide diacetate and H
2NNH
2 H
2O
were added in small portions, until LC/MS indicated the disappearance
of
6-[2-(methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole
and the formation of
6-[2-(methylcarbamoyl)phenylsuIfanyl]-3-Z-[2-(pyridine-2-yl)ethenyl]indazole.
Example 22: Palladium removal and polymorph control of
6-[2-(methylcarbamoyl)phenylsulfanvn-
3-E-r2-(pyridine-2-vDethenyllindazole
4) MeOH, reflux
Polymorph Form IV
5) HOAc/Xylenes
To
a 12 L 3-neck flask, equipped with a mechanical stirrer, was added
160.20 g of 6-[2-
(methylc'arbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole
and 1.6 L of DMA and 1.6 L of THF. After stirring for 20 minutes, the
mixture became homogeneous. To the clear solution was added 800.99 g of
10% cysteine-silica and the resulting mixture was allowed to stir at
room temperature overnight.
The mixture was filtered through a
medium sintered glass fritted funnel, and the cake was washed with a
solution of 500 mL of DMA and 500 mL of THF. The cake was further washed
with 2.0 L of THF and the filtrate was collected into a separate flask.
The volatile parts in the latter filtrate were removed in vacuo and the
residue was combined with the main filtrate. The combined filtrate was
recharged back into the 12 L flask, followed by 800 g of 10%
cysteine-silica. The flask was equipped with a mechanical stirrer and
stirred over the weekend at room temperature. The mixture was then
filtered through a medium sintered glass fritted funnel and the silica
was washed with a mixture of solvents of 500 ml. of DMA and 500 ml_ of
THF, followed by 3.0 L of THF. The volatile parts in the filtrate were
removed in vacuo and the remaining solution was transferred to a 22 L
3-neck flask and treated with 12 L of water (added over a 20 minute
period of time), a thick precipitate formed at this stage. After
stirring overnight, the mixture was filtered and the cake was washed
with 2.0 L of water and sucked dry.
The cake was charged to a 5 L
3-neck flask, followed by 1.6 L of THF and 160 mL of DMF. The flask was
equipped with a mechanical stirrer, a reflux condenser and the mixture
was heated at reflux for 8 hours. After cooling overnight, the mixture
was filtered through sharkskin filter paper and sucked dry. The cake was
charged to a 5 L 3-neck flask and 1.6 L of MeOH was added. The flask
was equipped with a mechanical stirrer, a water condenser and the
contents were heated at reflux for 6 hours. After cooling overnight, the
mixture was filtered through sharkskin filter paper and sucked dry.
The
cake was dissolved into 1.6 L of HOAc with the assistance of gentle
heating in the water bath of a rotary evaporator. The solution was
filtered through #3 filter paper and the total volume of the filtrate
was reduced to ~500 mL in volume on the rotary evaporator at 60 °C/60
mmHg. At this stage, the bulk of the mixture remained a yellow solution
and a small amount of precipitate formed. To the flask was charged 500
mL of xylenes (precipitate formed) and the total volume was reduced to
-500 mL in volume on the rotary evaporator at 60°C/60 mmHg. The process
was repeated two more times. After cooling, the mixture was filtered,
the cake was washed with 500 mL of xylenes and sucked dry. The cake was
transferred to a glass dish and further dried at 80°C/27 inch vacuum
overnight.
The cake was off-white in color and weighed 108.38g.
X-ray powder diffraction analysis indicated that a crystalline form was
present, which was characterized as Form IV by a powder X- ray
diffraction pattern comprising peaks at the following approximate
diffraction angles (20): 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5,
21.6, 23.2, 24.2, 24.8, 26.2, and 27.5.
While the invention has
been illustrated by reference to specific and preferred embodiments,
those skilled in the art will recognize that variations and
modifications may be made through routine experimentation and practice
of the invention. Thus, the invention is intended not to be limited by
the foregoing description, but to be defined by the appended claims and
their equivalents.
.............................
Chekal, B.
P.; Guinness, S. M.; Lillie, B. M.; McLaughlin, R. W.; Palmer, C. W.;
Post, R. J.; Sieser, J. E.; Singer, R. A.; Sluggett, G. W.;
Vaidyanathan, R.; Withbroe, G. Org. Process Res. Dev. 2014, 18, 266
http://pubs.acs.org/doi/abs/10.1021/op400088k
The manufacturing process of axitinib (
1)
involves two Pd-catalyzed coupling reactions, a Migita coupling and a
Heck reaction. Optimization of both of these pivotal bond-formation
steps is discussed as well as the approach to control impurities in
axitinib. Essential to the control strategy was the optimization of the
Heck reaction to minimize formation of impurities, in addition to the
development of an efficient isolation of crude axitinib to purge
impurities.
Babu, S.; Dagnino, R., Jr.; Ouellette, M. A.; Shi, B.; Tian, Q.; Zook, S. E. PCT Int. Appl. WO/2006/048745, 2006.
.......................
....................................
http://www.google.com/patents/CN103570696A?cl=en
formula:
A
Axitinib intermediate (1) production method, based on 6-nitro-indazole
as a starting material, in the first catalyst is reacted with
3,4-dihydro -2H- pyran, bits of NH the protecting group tetrahydro -2H-
pyran-2-yl, then the three iodide, to give the key intermediate in high
yield 3-iodo-6-nitro-1- (tetrahydro -2H- pyrazol pyran-2-yl) -1H-
indazole (I), comprising the following synthetic steps:
(1)
6-nitro-indazole dissolved in an aprotic solvent, and 3,4-dihydro -2H-
pyran catalyst, 6-nitro-indazole in the catalyst and the 3,4-dihydro -2H
- pyran reaction, the protecting group NH-position, was prepared to
give 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, the reaction
equation is:
Wherein the 3,4-dihydro -2H- pyran an amount of 3 equivalents wide;
Aprotic solvent is acetonitrile, ethyl acetate, toluene or xylene;
The catalyst is 2,3-dichloro-5,6-dicyano-p-benzoquinone, p-toluenesulfonic acid or methanesulfonic acid;
The reaction temperature is 7 (T90 ° C, the reaction time is 1 to 4 hours;
(2)
6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole dissolved in a
polar aprotic solvent, iodine was added and the acid-binding agent, an
inorganic base, to afford 3- iodo-6-nitro-1- (tetrahydro -2H-
pyran-2-yl) -1H- indazole (I), the reaction equation is:
Wherein
the polar aprotic solvent is N, N- dimethylformamide (DMF), N, N-
dimethylacetamide, N, N- diethylformamide, N, N- diethyl-acetamide ;
Inorganic
base acid binding agent is potassium carbonate, sodium carbonate,
potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium
bicarbonate, cesium carbonate, lithium hydroxide;
The reaction temperature is 2 (T40 ° C, the reaction time is 8 to 20 hours.
[0009]
A Axitinib intermediate (1) in preparation for the Nepalese Asif
application, based on intermediate (1) and 2-vinyl pyridine Heck
coupling reaction, followed sequentially nitro reduction and the
diazotization reaction of iodine, and finally with a 2-mercapto--N-
methylbenzamide was prepared by deprotection docking axitinib, including
the following synthetic steps:
(I) Intermediate (1) and be given
2_ vinylpyridine Jie Heck coupling reaction to give (E) _6_ nitro _3-
[2_ (P than-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H-
indazole, the reaction equation is:
(2)
(E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl
-2H-) -1Η- nitro indazole group reduction reaction, to give (E) -6-
amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl)
-1H- indazole, The reaction equation is:
(3)
(E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl
-2H-) -1Η- indazole diazo of the iodide to give (E) -6- iodo-3- [2-
(pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
The reaction equation is:
(4)
(E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl
-2H-) -1Η- indazole with 2- mercapto-methylbenzamide reaction -N-, to
give (E) -N- methyl-2 - {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro
-2H- pyrazol pyran-2-yl) -1H- indazol-6-yl] thio} benzamide, the
reaction equation is:
(5)
(E) -N- methyl-2- {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H-
pyran-2-yl) -1H- indazol-6-yl] thio} benzamide deprotected Axitinib
(II), the reaction equation is:
Example 1
A Assi intermediates for preparing Nigeria, comprising the steps of:
Synthesis of (I) 6- nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
A
5L reaction flask was added acetonitrile (2L), followed by addition of
6-nitro-indazole (163.1g, 1.0mol), 3, 4- dihydro -2H- pyran (168.2g,
2.0mol), 2,3- dichloro-5,6-dicyano-p-benzoquinone (22.7g, 0.1mol), was
heated to 820C under reflux for 2 hours to complete the reaction, cooled
to room temperature, rotary evaporated to dryness, added water and
dichloromethane 2L 2L, stirring I hour, delamination, the organic phase
washed with brine, dried over anhydrous sodium sulfate, filtered, and
rotary evaporated to dryness, and then dissolved in acetonitrile and 2L,
stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered,
the filter cake washed with a small amount of cold acetonitrile,
recrystallized from ethanol, 60 ° C and dried in vacuo 12 hours to give
an off-white solid, 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H-
indazole, 236.3 g, yield 95.6%, m.p. 110 ~ 120 ° C, 1Η NMR (CDCl3): δ
1.30-1.83 (m, 6Η, Η3, _Η5,), 3.82-3.93 (m, 2Η, Η6 '), 5.86 (m , 1Η, Η2
'), 8.10-8.12 (m, 2Η, Η3, Η5), 8.31 (m, 1Η; Η4), 8.55 (s, 1Η, Η7);
The reaction equation is as follows:
(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),
5L
reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_
(tetrahydro -2H- pyran-2-yl) -1H- indazole (225.0g, 0.91mol, l.0eq) and
potassium carbonate ( 251.6g, 1.82mol, 2.0eq), ice-cooled (10 ° C or
less), followed by stirring, iodine (415.8g, 1.64mol, 1.8eq) was
dissolved in DMF 300mL, was added dropwise to the reaction system,
addition time 2 hours , the reaction system was stirred at 25 ° C for 16
hours to complete the reaction, sodium thiosulfate was added (223.0g,
1.41mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution
(1.5L), while maintaining the internal temperature 30 ° C Hereinafter,
stirred for 30 minutes at room temperature, water was added with
stirring 2L, solid precipitated, stirred for 30 minutes at room
temperature, suction filtered, the filter cake was washed with water, 60
° C and dried in vacuo 12 hours to give a pale yellow solid (Ι),
326.5g, yield 96.2%, m.p. 135 ~ 137 ° C / H NMR (DMS0_d6): δ 1.60-1.61
(m, 2H, H4,, H5 '), 1.73-1.76 (m, 1H, H5'), 2.01-2.04 (m, 2H, H3 ',
H4'), 2.35-2.38 (m, 1H, H3 '), 3.81-3.87 (m, 2H, H6'), 6.11-6.14 (dd,
1H, H2 '), 7.70-7.72 (d , 1H, H4),
8.05-8.07 (dd, 1H, H5), 8.79 (s, 1H, H7).
The reaction equation is as follows:
A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:
Synthesis of (I) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
A
5L reaction flask was added DMF (2L), followed by addition of the
intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol),
N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine
(22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and
heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 °
C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted
with water and 5L, stirring at room temperature for I h, suction
filtered, washed with water, isopropanol was added to the filter cake
1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature
for 30 minutes, suction filtered, the filter cake washed with cold
isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6-
nitro-3- [2- (pyridin-2 - yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl)
-1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ
1.63-1.64 (m, 2H, H4 ', H5'), 1.79-1.81 (m, 1H, H5 '), 2.05-2.07 (m,
2H, H3', H4 '), 2.44-2.50 (m, 1H , H3 '), 3.86-3.90 (m, 2H, H6'),
6.15-6.18 (dd, 1H, H2 '), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d,
1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m,
1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd,
1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6),
8.77-8.78 (d, 1H, H7);
The reaction equation is as follows:
Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2Η-) -1H- indazole
5L
reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride
(300.0g, 5.61mol), was dissolved with stirring, followed by addition of
(E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H-
pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder
(162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours
to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran
2L, stirred for I hour at room temperature, filtered through Celite, the
filter cake washed with tetrahydrofuran and the filtrate was rotary
evaporated to dryness, cooled to room temperature, water was added 2L,
stirred for I hour at room temperature, pumping filtered, the filter
cake washed with petroleum ether, 50 ° C and dried under vacuum for 12
hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2-
(pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole,
yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4
', H5 '), 2.02-2.06 (m, 1H, H5'), 2.17-2.18 (m, 1H, H4 '), 2.55-2.60 (m,
1H, H3') 3.70-3.72 (m, 2H, H3 ', H6 '), 3.91 (s, 2H, NH2), 4.04-4.07
(m, 1H, H6'), 5.57-5.60 (dd, 1H, H2 '), 6.64-6.66 (dd, 1H, H5),
6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d,
1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m,
1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d,
1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;
The reaction equation is as follows:
Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole
A
5L reaction flask was added 600mL of water and sodium nitrite (70.2g,
1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2-
(pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
(200.0g, 0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise
added to the system dropwise over I h, a solution process maintain an
internal temperature of 0 ° C, the same temperature for I hour, dropping
HCl solution (concentrated hydrochloric acid 112mL, water 200mL) at O
° C, the dropping time of 10 minutes, with the temperature for I h,
TLC plate tracking point diazonium salt formation reaction (PE: EA = 1:
1). dropwise 800mL dichloromethane between 0 ° C, the dropping time of 5
minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol)
was dissolved water 600mL, in (TC dropwise added to the system at the
same temperature for 2 hours to complete the reaction. The reaction
mixture was poured into the system to 20% sodium thiosulfate solution
(2L) and dichloromethane SOOmL and stirred, layered , the aqueous phase
was extracted with dichloromethane frozen (2x800mL), dichloromethane
phases were combined burning, 3M sodium hydroxide solution was added
dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added
ammonia 200mL 400mL, stirred for 30 minutes , separated and the aqueous
phase was extracted with dichloromethane (2x1.2L), the organic phases
were combined, rotary evaporated to dryness, and purified through silica
gel to give (E) -6- iodo-3- [2- (pyridin-2-yl ) ethenyl] -1-
(tetrahydro -2H- pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p.
142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58- 1.61 (m, 2H, H4 ', H5,)
1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H,
H3,) , 3.79-3.81 (m, 1H, H6,), 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd,
1H, H2,), 7.29-7.31 (m, 1H, pyridine H5), 7.56 -7.60 (d, 1H ,, J = 16Hz,
vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine
H3), 7.80-7.84 (m, 1H, H4 ), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI),
8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7), 8.61-8.62 (d, 1H, pyridine H6) ;
The reaction equation is as follows:
(4) (E) -N- methyl-2 - {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]
A
5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2-
(pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole
(175.0g, 0.41mol), nitrogen, was added [1, I, - bis (diphenylphosphino)
ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol
), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was
added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C
for 16 hours to complete the reaction, spin distilled was removed DMF,
cooled to room temperature, ethyl acetate was added 3L, water 4L,
stirred for 40 minutes, the organic phase was separated, washed with
brine, layered, dried over sodium sulfate, filtered, and rotary
evaporated to dryness, to give (E) -N- methyl-2 - {[3- (2-
(pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H-
indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting
point of 142 ~ 143 ° C;
The reaction equation is as follows:
(5) Synthesis of axitinib
In
a 2L reaction flask was added (E) -N- methyl-2 - {[3- (2-
(pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H -
indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid
monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL),
nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and
ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed
by rotary evaporation, then repeated three times, TLC spot plate
tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of
the reaction, cooled to room temperature, rotary evaporated to dryness,
water was added 500mL, stirred for I h, filtered, and the filter cake
was washed with methanol and ice, and then added to the reaction vessel,
ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to
room temperature, suction filtered, the filter cake washed with ethyl
acetate and freeze paint, water paint, 50 ° C and dried under vacuum for
12 hours to give a white solid 117.5g, Axitinib (II),
yield
95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05
(dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d,
1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J =
16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).
The reaction equation is as follows:
Example 2
A Assi intermediates for preparing Nigeria, comprising the steps of:
Synthesis of (1) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
A
5L reaction flask was added ethyl acetate (2L), followed by addition of
6-nitro-indazole (163.14g, 1.0mol), 3, 4- dihydro -2H- pyran (210.3g,
2.5mol), toluene acid (20.7g, 0.12mol), heated to 78 ° C under reflux
for 3 hours to complete the reaction, cooled to room temperature, rotary
evaporated to dryness, added water and dichloromethane 2L 2L, stirred
for I hour, stratification, the organic phase was washed with brine,
dried over anhydrous sodium sulfate, filtered, and rotary evaporated to
dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt
bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake
washed with a small amount of cold acetonitrile, recrystallized from
ethanol , 60 ° C and dried in vacuo 12 hours to give an off-white solid
223.3g, 6- nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, yield
90.3%, m.p. 110 ^ 11 TC;
The reaction equation is as follows:
(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),
5L
reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_
(tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.81mol, l.0eq) and
sodium hydroxide (64.7g, 1.62mol, 2.0eq), ice-cooled (10 ° C or less),
followed by stirring, iodine (369.6g, 1.46mol, 1.8eq) was dissolved in
DMF 300mL, was added dropwise to the reaction system, addition time 2
hours, the reaction system was stirred at 25 ° C for 12 hours to
complete the reaction, sodium thiosulfate was added (198.2g, 1.25mol,
1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while
maintaining the temperature of 30 ° C or less, and stirred for 30
minutes at room temperature, water was added with stirring 2L, solid
precipitated, stirred for 30 minutes at room temperature, suction
filtered, the filter cake was washed with water, 60 ° C and dried in
vacuo 12 hours to give a pale yellow solid
(1), 294.3g, 97.5% yield, m.p. 136 ~ 137. . .
[0014] The reaction equation is as follows:
A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:
Synthesis (1) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2Η-) -1H- indazole
A
5L reaction flask was added DMF (2L), followed by addition of the
intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol),
N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine
(22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and
heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 °
C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted
with water and 5L, stirring at room temperature for I h, suction
filtered, washed with water, isopropanol was added to the filter cake
1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature
for 30 minutes, suction filtered, the filter cake washed with cold
isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6-
nitro-3- [2- (pyridin _2 _-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl)
-1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6):
δ 1.63-1.64 (m, 2H, H4 ', H5'), 1.79-1.81 (m, 1H, H5 '), 2.05-2.07 (m,
2H, H3', H4 '), 2.44-2.50 (m, 1H , H3 '), 3.86-3.90 (m, 2H, H6'),
6.15-6.18 (dd, 1H, H2 '), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d,
1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m,
1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd,
1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6),
8.77-8.78 (d, 1H, H7);
The reaction equation is as follows:
Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
5L
reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride
(300.0g, 5.61mol), was dissolved with stirring, followed by addition of
(E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H-
pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder
(162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours
to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran
2L, stirred for I hour at room temperature, filtered through Celite, the
filter cake washed with tetrahydrofuran and the filtrate was rotary
evaporated to dryness, cooled to room temperature, water was added 2L,
stirred for I hour at room temperature, pumping filtered, the filter
cake washed with petroleum ether, 50 ° C and dried under vacuum for 12
hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2-
(pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole,
yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4
', H5 '), 2.02-2.06 (m, 1H, H5'), 2.17-2.18 (m, 1H, H4 '), 2.55-2.60 (m,
1H, H3') 3.70-3.72 (m, 2H, H3 ', H6 '), 3.91 (s, 2H, NH2), 4.04-4.07
(m, 1H, H6'), 5.57-5.60 (dd, 1H, H2 '), 6.64-6.66 (dd, 1H, H5),
6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d,
1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m,
1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d,
1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;
The reaction equation is as follows:
Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole
A
5L reaction flask was added 600mL of water and sodium nitrite (70.2g,
1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2-
(pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
(200.0g, 0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise
added to the system dropwise over I h, a solution process maintain an
internal temperature of 0 ° C, the same temperature for I hour, dropping
HCl solution (concentrated hydrochloric acid 112mL, water 200mL) at O
° C, the dropping time of 10 minutes, with the temperature for I h,
TLC plate tracking point diazonium salt formation reaction (PE: EA = 1:
1). dropwise 800mL dichloromethane between 0 ° C, the dropping time of 5
minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol)
was dissolved water 600mL, in (TC dropwise added to the system at the
same temperature for 2 hours to complete the reaction. The reaction
mixture was poured into the system to 20% sodium thiosulfate solution
(2L) and dichloromethane SOOmL and stirred, layered , the aqueous phase
was extracted with dichloromethane frozen (2x800mL), dichloromethane
phases were combined burning, 3M sodium hydroxide solution was added
dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added
ammonia 200mL 400mL, stirred for 30 minutes , separated and the aqueous
phase was extracted with dichloromethane (2x1.2L), the organic phases
were combined, rotary evaporated to dryness, and purified through silica
gel to give (E) -6- iodo-3- [2- (pyridin-2-yl ) ethenyl] -1-
(tetrahydro -2H- pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p.
142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58- 1.61 (m, 2H, H4 ', H5,)
1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H,
H3,) , 3.79-3.81 (m, 1H, H6,), 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd,
1H, H2,), 7.29-7.31 (m, 1H, pyridine H5), 7.56 -7.60 (d, 1H ,, J = 16Hz,
vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine
H3), 7.80-7.84 (m, 1H, H4 ), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI),
8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7), 8.61-8.62 (d, 1H, pyridine H6) ;
The reaction equation is as follows:
(4) (E) -N- methyl-2 - {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]
A
5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2-
(pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole
(175.0g, 0.41mol), nitrogen, was added [1, I, - bis (diphenylphosphino)
ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol
), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was
added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C
for 16 hours to complete the reaction, spin distilled was removed DMF,
cooled to room temperature, ethyl acetate was added 3L, water 4L,
stirred for 40 minutes, the organic phase was separated, washed with
brine, layered, dried over sodium sulfate, filtered, and rotary
evaporated to dryness, to give (E) -N- methyl-2 - {[3- (2-
(pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H-
indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting
point of 142 ~ 143 ° C;
The reaction equation is as follows:
(5) Synthesis of axitinib
In
a 2L reaction flask was added (E) -N- methyl-2 - {[3- (2-
(pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H -
indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid
monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL),
nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and
ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed
by rotary evaporation, then repeated three times, TLC spot plate
tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of
the reaction, cooled to room temperature, rotary evaporated to dryness,
water was added 500mL, stirred for I h, filtered, and the filter cake
was washed with methanol and ice, and then added to the reaction vessel,
ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to
room temperature, suction filtered, the filter cake washed with ethyl
acetate and freeze paint, water paint, 50 ° C and dried under vacuum for
12 hours to give a white solid 117.5g, Axitinib (II),
yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3),
7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 (
d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J =
16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).
The reaction equation is as follows:
Example 3
A Assi intermediates for preparing Nigeria, comprising the steps of:
Synthesis of (1) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
5L
reaction flask in toluene (2L), followed by addition of
6-nitro-indazole (163.lg, 1.0mol), 3,4- dihydro -2H- pyran (193.5g,
2.3mol), methanesulfonic acid (14.4g, 0.15mol), heated to 85 ° C under
reflux for 3.5 hours, to complete the reaction, cooled to room
temperature, rotary evaporated to dryness, added water and
dichloromethane 2L 2L, stirred for I hour, stratification, the organic
phase was washed with brine wash, dried over anhydrous sodium sulfate,
filtered, and rotary evaporated to dryness, and then dissolved in
acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2
hours, suction filtered, the filter cake washed with a small amount of
cold acetonitrile and paint, and recrystallized from ethanol , 60 ° C
and dried in vacuo 12 hours to give an off-white solid, 6-nitro-1-
(tetrahydro -2H- pyran-2-yl) -1H- indazole, 234.4g, 94.8% yield, m.p.
111 ~ 112.. ;
The reaction equation is as follows:
(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),
5L
reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_
(tetrahydro -2H- pyran-2-yl) -1H- indazole (225.0g, 0.91mol, 1.0eq) and
potassium hydroxide ( 102.lg, 1.82mol, 2.0eq), ice-cooled below 10 ° C,
with stirring, iodine (415.8g, 1.64mol, 1.8eq) was dissolved in DMF
300mL, was added dropwise to the reaction system dropwise over 2 hours,
The reaction system was stirred at 30 ° C for 10 hours to complete the
reaction, sodium thiosulfate was added (223.0g, 1.41mol, 1.55eq) and
1.50g of potassium carbonate aqueous solution (1.5L), while maintaining
the internal temperature below 30 ° C , stirred for 45 minutes at room
temperature, water was added with stirring 2L, solid precipitated,
stirred for 45 minutes at room temperature, suction filtered, the filter
cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a
pale yellow solid
(1), 317.2g, 93.4% yield, m.p. 135 ~ 136 ° C.
The reaction equation is as follows:
A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:
Synthesis (1) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
A
5L reaction flask was added DMF (2L), followed by addition of the
intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol),
N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine
(22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and
heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 °
C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted
with water and 5L, stirring at room temperature for I h, suction
filtered, washed with water, isopropanol was added to the filter cake
1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature
for 30 minutes, suction filtered, the filter cake washed with cold
isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6-
nitro-3- [2- (pyridin _2 _-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl)
-1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6):
δ 1.63-1.64 (m, 2H, H4 ', H5'), 1.79-1.81 (m, 1H, H5 '), 2.05-2.07 (m,
2H, H3', H4 '), 2.44-2.50 (m, 1H , H3 '), 3.86-3.90 (m, 2H, H6'),
6.15-6.18 (dd, 1H, H2 '), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d,
1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m,
1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd,
1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6),
8.77-8.78 (d, 1H, H7);
The reaction equation is as follows:
Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
5L
reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride
(300.0g, 5.61mol), was dissolved with stirring, followed by addition of
(E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H-
pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder
(162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours
to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran
2L, stirred for I hour at room temperature, filtered through Celite, the
filter cake washed with tetrahydrofuran and the filtrate was rotary
evaporated to dryness, cooled to room temperature, water was added 2L,
stirred for I hour at room temperature, pumping filtered, the filter
cake washed with petroleum ether, 50 ° C and dried under vacuum for 12
hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2-
(pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole,
yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4
', H5 '), 2.02-2.06 (m, 1H, H5'), 2.17-2.18 (m, 1H, H4 '), 2.55-2.60 (m,
1H, H3') 3.70-3.72 (m, 2H, H3 ', H6 '), 3.91 (s, 2H, NH2), 4.04-4.07
(m, 1H, H6'), 5.57-5.60 (dd, 1H, H2 '), 6.64-6.66 (dd, 1H, H5),
6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d,
1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m,
1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d,
1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;
The reaction equation is as follows:
Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole
A
5L reaction flask was added 600mL of water and sodium nitrite (70.2g,
1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2-
(pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole
(200.0g,
0.62mol) was dissolved in glacial acetic acid 1.3L,
dropwise added to the system dropwise over I hour, added dropwise to
maintain the internal temperature process 0 ° C, the same temperature
for I h, HCl solution was added dropwise at O ° C (112mL of
concentrated hydrochloric acid , water 200mL), was added dropwise for 10
minutes, with the temperature for I h, TLC plate tracking point
diazonium salt formation reaction (PE: EA = 1: 1). Solution of methylene
chloride at 0 ° C and 800mL, dropping time of 5 minutes, potassium
iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) dissolved in water
600mL, at (TC dropwise added to the system, same temperature for 2 hours
to complete the reaction. The reaction system was poured into a mixture
of 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and
stirred, layers were separated, the aqueous phase was extracted with
dichloromethane frozen (2x800mL ), methylene chloride phases were
combined burning, 3M sodium hydroxide solution was added dropwise 3.5L,
adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL
400mL, stirred for 30 minutes, separated and the aqueous phase extracted
with dichloromethane ( 2x1.2L), the organic phases were combined,
rotary evaporated to dryness, and purified through silica gel to give
(E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H -
pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H
NMR (DMS0_d6): δ 1.58-1.61 (m, 2H, H4 ', H5,) 1.72-1.78 (m, 1H, H5,),
1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,), 3.79-3.81 (m, 1H,
H6,) , 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,),
7.29-7.31
(m, 1H, pyridine H5), 7.56-7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59
(m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H,
H4), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25
(s, 1H, H7 ), 8.61-8.62 (d, 1H, pyridine H6); reaction equation is as
follows:
(4) (E) -N- methyl-2 - {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]
A
5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2-
(pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole
(175.0g, 0.41mol), nitrogen, was added [1, I, - bis (diphenylphosphino)
ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol
), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was
added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C
for 16 hours to complete the reaction, spin distilled was removed DMF,
cooled to room temperature, ethyl acetate was added 3L, water 4L,
stirred for 40 minutes, the organic phase was separated, washed with
brine, layered, dried over sodium sulfate, filtered, and rotary
evaporated to dryness, to give (E) -N- methyl-2 - {[3- (2-
(pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H-
indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting
point of 142 ~ 143 ° C;
The reaction equation is as follows:
(5) Synthesis of axitinib
In
a 2L reaction flask was added (E) -N- methyl-2 - {[3- (2-
(pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H -
indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid
monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL),
nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and
ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed
by rotary evaporation, then repeated three times, TLC spot plate
tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of
the reaction, cooled to room temperature, rotary evaporated to dryness,
water was added 500mL, stirred for I h, filtered, and the filter cake
was washed with methanol and ice, and then added to the reaction vessel,
ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to
room temperature, suction filtered, the filter cake washed with ethyl
acetate and freeze paint, water paint, 50 ° C and dried under vacuum for
12 hours to give a white solid 117.5g, Axitinib (II),
yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3),
7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 (
d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J =
16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).
The reaction equation is as follows:
.........................
...........................
...........
NMR source apexbt
http://dmd.aspetjournals.org/content/suppl/2014/03/07/dmd.113.056531.DC1/Supplemental__Data_Figures_56531.pdf
MASS
References
- "Inlyta (axitinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 25 January 2014.
- Wilmes,
LJ; Pallavicini, MG; Fleming, LM; Gibbs, J; Wang, D; Li, KL; Partridge,
SC; Henry, RG; Shalinsky, DR; Hu-Lowe, D; Park, JW; McShane, TM; Lu, Y;
Brasch, RC; Hylton, NM (April 2007). "AG-013736, a novel inhibitor of
VEGF receptor tyrosine kinases, inhibits breast cancer growth and
decreases vascular permeability as detected by dynamic contrast-enhanced
magnetic resonance imaging". Magnetic Resonance Imaging 25 (3): 319–27. doi:10.1016/j.mri.2006.09.041. PMID 17371720.
- Rini,
B; Rixe, O; Bukowski, R; Michaelson, MD; Wilding, G; Hudes, G; Bolte,
O; Steinfeldt, H; Reich, SD; Motzer, R (June 2005). "AG-013736,
a multi-target tyrosine kinase receptor inhibitor, demonstrates
anti-tumor activity in a Phase 2 study of cytokine-refractory,
metastatic renal cell cancer (RCC)". Journal of Clinical Oncology ASCO Annual Meeting Proceedings 23 (16S): 4509.
- Rugo,
HS; Herbst, RS; Liu, G; Park, JW; Kies, MS; Steinfeldt, HM; Pithavala,
YK; Reich, SD; Freddo, JL; Wilding, G (August 2005). "Phase
I trial of the oral antiangiogenesis agent AG-013736 in patients with
advanced solid tumors: pharmacokinetic and clinical results"(PDF). Journal of Clinical Oncology 23 (24): 5474–83. doi:10.1200/JCO.2005.04.192.PMID 16027439.
- "FDA Approves Inlyta for Advanced Renal Cell Carcinoma". Drugs.com. January 27, 2012.
- John Fauber, Elbert Chu (Oct 27, 2014). "The Slippery Slope: Is a Surrogate Endpoint Evidence of Efficacy?". Milwaukee Journal Sentinel/MedPage Today.
- Spano,
JP; Chodkiewicz, C; Maurel, J; Wong, R; Wasan, H; Barone, C;
Létourneau, R; Bajetta, E; Pithavala, Y; Bycott, P; Trask, P; Liau, K;
Ricart, AD; Kim, S; Rixe, O (June 2008). "Efficacy of gemcitabine plus
axitinib compared with gemcitabine alone in patients with advanced
pancreatic cancer: an open-label randomised phase II study". Lancet 371(9630): 2101–2108. doi:10.1016/S0140-6736(08)60661-3. PMID 18514303.
- "Pfizer pancreatic cancer drug fails, trial halted". Reuters. January 30, 2009.
- "Pfizer’s Phase III Trial in mRCC Turns Up Positive Results". 19 Nov 2010.
- "ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma". 7 Dec 2011.
- "INLYTA (axitinib) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]". DailyMed. Pfizer Laboratories Div Pfizer Inc. September 2013. Retrieved 25 January 2014.
- "Inlyta : EPAR - Product Information" (PDF). European Medicines Agency. Pfizer Ltd. 17 December 2013. Retrieved 25 January 2014.
- "Inlyta 1 mg 3mg, 5 mg & 7mg film-coated tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfizer Limited. 5 December 2013. Retrieved25 January 2014.
- "PRODUCT INFORMATION INLYTA (axitinib)" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 5 July 2013. Retrieved 25 January 2014.
- Tea
Pemovska,Eric Johnson,Mika Kontro,Gretchen A. Repasky,Jeffrey
Chen,Peter Wells,Ciarán N. Cronin,Michele McTigue,Olli Kallioniemi,Kimmo
Porkka,Brion W. Murray & Krister Wennerberg. "Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation". Nature. doi:10.1038/nature14119.
- "FDA Prescribing Information" (PDF). 30 Jan 2012.
- Escudier, B; Gore, M. "Axitinib for the Management of Metastatic Renal Cell Carcinoma" (PDF). Drugs in R&d 11 (2): 113–126. doi:10.2165/11591240-000000000-00000. PMC 3585900. PMID 21679004.
- Zhang Y (Jan 2014). "Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways.". J Mol Med Rep 9 (1): 83–90.doi:10.3892/mmr.2013.1781. PMID 24213221.
- [1] http://www.cancer.gov/cancertopics/druginfo/axitinib[2] http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289439.htm[3] Kosugi M, Shimizu T, T. Migita, Chemistry Letters , 1978 , pp 13-14.[4] Organic Process Research & Development 2008 , 12, 869? 876.[5] Furstner A. Chem. Commun ., 2008 , 2873? 2875.[6] Thorarensen A. , Synlett , 2010 , 2 pp 219 - 222.
[7] http://en.wikipedia.org/wiki/Heck_reaction - where you can find the reaction mechanism and many other useful information.
[8] Aoyama, T., Synthesis , 2004 , 8 pp 1183-1186.
http://www.cosmoscience.org/blog/wp-content/uploads/2014/08/GSluggett-Application-of-Topochemical-Principles-and-Solid-State-Photoreactivity.pdf
upda
te
http://www.google.com/patents/US20140248347?cl=en
Axitinib is a potent and selective inhibitor of vascular
endothelial growth factor (VEGF) receptors 1, 2 and 3. These receptors
are implicated in pathologic angiogenesis, tumor growth, and metastatic
progression of cancer. Axitinib has been shown to potently inhibit
VEGF-mediated endothelial cell proliferation and survival. Clinical
trials are currently on-going to study the use of axitinib for the
treatment of various cancers, including liver cancer, melanoma,
mesothelioma, non-small cell lung cancer, prostate cancer, renal cell
carcinoma, soft tissue sarcomas and solid tumors. Inlyta® (axitinib) has
been approved in the United States, Europe, Japan and other
jurisdictions for the treatment of renal cell carcinoma.
Axitinib, as well as pharmaceutically acceptable
salts thereof, is described in U.S. Pat. No. 6,534,524. Methods of
making axitinib are described in U.S. Pat. Nos. 6,884,890 and 7,232,910,
in U.S. Publication Nos. 2006-0091067 and 2007-0203196 and in
International Publication No. WO 2006/048745. Dosage forms of axitinib
are described in U.S. Publication No. 2004-0224988. Polymorphic forms
and pharmaceutical compositions of axitinib are also described in U.S.
Publication Nos. 2006-0094763, 2008-0274192 and 2010-0179329.
Crystalline Form IV of axitinib API was characterized by the solid state NMR spectrum shown in Figure 4. The
13C chemical shifts of crystalline Form IV of axitinib API are shown in Table 9.
Table 9
i
aC Chemical Shifts
Relative Intensity
[ppm]
170.0 46
i aC Chemical Shifts
Relative Intensity
[ppm]
154.3 34
146.8 31
143.2 60
142.0 61
136.9 23
133.5 33
131 .9 48
129.5 88
126.2 80
121 .2 100
1 19.6 46
27.7 41
26.1 36
Crystalline Form IV of axitinib in drug product,
which was prepared as provided in Example 8, as characterized by the
solid state NMR spectrum shown in Figures 5 and 6. The
13C chemical shifts of crystalline Form IV of axitinib in drug product are shown in Table 10.
Table 10
(a) Peak shoulder.
Form IV axitinib in the pharmaceutical composition of the present
invention may be identified by a solid state nuclear magnetic resonance
comprising any one or more of the following
13C chemical
shifts expressed in parts per million: 170.0 ± 0.2, 154.2 ± 0.2, 143.3 ±
0.2, 142.1 ± 0.2, 133.4 ± 0.2, 126.3 ± 0.2, 121 .3 ± 0.2 and 27.8 ±
0.2.
Crystalline Form XXV of axitinib in drug product,
which was prepared as provided in Example 8, was characterized by the
solid state NMR spectrum shown in Figures 7 and 8. The
13C chemical shifts of crystalline Form XXV of axitinib in drug product are shown in Table 1 1 .
Table 1 1
(a) Peak shoulder
Form XXV axitinib in the pharmaceutical composition
of the present invention may be identified by a solid state nuclear
magnetic resonance comprising any one or more of the following
13C
chemical shifts expressed in parts per million: 167.4 ± 0.2, 157.7 ±
0.2, 144.9 ± 0.2, 140.9 ± 0.2, 129.7 ± 0.2, 128.8 ± 0.2, 127.3 ± 0.2,
123.7 ± 0.2, 120.5 ± 0.2, 1 16.5 ± 0.2 and 25.4 ± 0.2.
Crystalline Form XLI of axitinib in drug product,
which was prepared as provided in Example 8, was characterized by the
solid state NMR spectrum shown in Figures 9 and 10. The
13C chemical shifts of crystalline Form XLI of axitinib in drug product are shown in Table 12.
Table 12
Form XLI axitinib in the pharmaceutical composition
of the present invention may be identified by a solid state nuclear
magnetic resonance comprising any one or more of the following
13C
chemical shifts expressed in parts per million: 142.6 ± 0.2, 136.8 ±
0.2, 136.2 ± 0.2, 133.7 ± 0.2, 132.1 ± 0.2, 121 .4 ± 0.2 and 1 19.8 ±
0.2.
Polymorphic Form IV of axitinib API and polymorphic
Forms IV, XXV, and XLI, of axitinib within the drug product or
pharmaceutical composition of the present invention were each
characterized using Raman spectroscopy. The Raman spectra differ for
each of the polymorphic forms of formulated axitinib. For example, Forms
IV, XXV, and XLI of axitinib in drug product can be distinguished from
each other and from other polymorphic forms of formulated axitinib by
using Raman spectroscopy. The detection of characteristic Raman spectra
of axitinib within the drug product or pharmaceutical composition of the
present invention enables unique identification of polymorphic Forms
IV, XXV, and XLI, of axitinib in the drug product or pharmaceutical
composition.
Raman spectra of Form IV of axitinib API were
collected using a Nicolet NXR FT- Raman accessory attached to a Nicolet
6700 FTIR spectrometer equipped with a KBr beamsplitter and a d-TGS KBr
detector. The spectrometer is equipped with a 1064 nm Nd:YVO
4
laser and a liquid nitrogen cooled Germanium detector. Prior to data
acquisition, instrument performance and calibration verifications were
conducted using polystyrene. Samples were analyzed in glass NMR tubes
that were spun during spectral collection. The spectra were collected
using 0.5 W of laser power and 400 co- added scans. The collection range
was 3700-300 cm
"1. The API spectra were recorded using 2 cm
"1 resolution, and Happ-Genzel apodization was utilized for all of the spectra.
A single spectrum was recorded for each sample, which was intensity normalized prior to peak picking.
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Palau Islands
Geographically Located in Micronesia, 7° 30' North Latitude, 133° 30' East Longitude,
Palau
is an island nation comprised of 16 states. Officially the Republic of
Palau, this island nation in the Pacific Ocean is about 500 miles east
of the Philippines and 2000 miles south of Tokyo.
Climate: Palau enjoys a pleasantly warm climate all
year round with an annual mean temperature of 82° degrees F. (27° C.).
Rainfall can occur throughout the year, and the annual average is 150
inches. The average relative humidity is 82%, and although rain falls
more frequently between July and October, there is still much sunshine.
Typhoons are rare as Palau is located outside the typhoon zone.
Getting There: From the western seaboard of the
United States,
you can hop to Hawaii, skip to Guam, then jump to Palau. For a scenic
island route, you can do an island hop across Micronesia to Palau.
Through Asia, there are twice weekly charter services between Taipei,
Taiwan and Palau and additional flights are also available during peak
seasons. From Europe,visitors can fly via Emerates direct to Manila,
Philippines and onwards with Continental Airlines to Palau--this is
possible without overnight stay in Manila.
Getting There: Australia,
Fly from any major cities in Australia to Cairns to make your
connection to Palau. Continental Airlines flies between Cairns and Guam
twice weekly and daily from Guam to Palau. Most carriers service Manila,
and connect via Continental Airlines’ twice-weekly flights to Palau
https://en.wikipedia.org/wiki/Palau
Along with other Pacific Islands, Palau was made a part of the United States-governed Trust Territory of the Pacific Islands in 1947. Having voted against joining ...
Fruit Bat Soup - a delicacy on the island of Palau | The world's ...
Palau Style Broiled Fish Recipe | Island Food | Pinterest
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