FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of a
compound of formula I or its salt,
Formula I,
wherein R is alkyl.
The present invention further relates to an improved process for the conversion of
compound of formula I to a compound of formula V,
Formula V (Venetoclax)
The present invention also relates to an improved process for the preparation of
the compound of formula V.
BACKGROUND OF THE INVENTION
Venetoclax, 4-(4- {[2-(4-chloropheny1)-4,4-dimethylcyclohex-1 - en- 1- yl]methyl)
piperazin- 1 -yl)-N-((3 -nitro-4[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl)
5 sulfonyl)-2-(lH-py~olo[2,3-b]pyridin-5-yloxy)benzamide) is represented by a
compound of formula V.
Formula V
10 Venetoclax (mirketed under the trade name Venclexta, Abbvie Inc.) is an
inhibitor of anti-apoptotic Bcl-2 prpteins. It is indicated for the treatment of
patients with chronic lymphocytic leukemia (CLL).
Venetoclax, as represented by formula V, is disclosed in WO 201 11149492. Various
processes for the preparation of venetoclax have been disclosed in literature.
15
WO 201 11149492 and Bioconjugate Chemistry 2014, 2081 describe a process for the
preparation of compound of formula V as depicted in scheme-1 :
H
Stage-1 Stage-2
I1 111 Ia
I
R=Methyl
EDC, DCM, 4-DMAP IV
Stage3
(Venetoclax)
Scheme -1
5 In stage-1, a reaction of the compound of formula I1 with the compound of
formula I11 is carried out in the presence of dipotassium hydrogen phosphate
(K2HP04) at a temperature of 135 degree Celsius with stirring for about 24 hours.
The compound of formula I obtained at stage-1, is purified by silica gel
chromatography. The yield is ca. 37%. Purity is not reported.
10
In stage-2, the compound of formula I is hydrolysed to obtain a compound of
formula Ia in the presence of sodium hydroxide and dioxane as a solvent.
Subsequently, the compound of formula Ia is coupled with a compound of
15 formula IV to obtain the compound of formula V (stage-3).
In stage-3, coupling of the compound of formula Ia with the compound of formula
IV is performed in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]-
carbodiimide hydrochloride (EDC-HCl) and 4-dimethylaminopyridine in
dichloromethane. The obtained compound of formula V is purified by silica gel
chromatography. The yield is ca. 32%. Purity is not reported.
Another process for the synthesis of the compound of formula I is disclosed in
5 WO 20141165044,
Scheme-2
wherein R=t-Butyl
10 In WO 20141165044, the preparation of the compound of formula I involves use
of a phosphine compound and a palladium compound. The reaction of a
compound of formula 11' with a compound of formula 111' is carried out in the
presence of a phosphine compound, sodium tert-butoxide and Pd2dba3 at 55 to 75
degree Celsius to give the compound of formula I.
15
Sodium tert-butoxide and the compound of formula 11' in toluene solution were
combined in tetrahydrofuran in a suitable reactor and sparged with nitrogen for
NLT 45 min.
Pd2dba3, phosphine and the compound of formula 111' were combined in a second
20 suitable reactor and purged with nitrogen until oxygen level was NMT 40 ppm.
Using nitrogen pressure, the solution containing the compound of formula 11' and
sodium tert-butoxide in tolueneltetrahydrofuran was added through a 0.45 p1-q
inline filter to the second reactor.
The compound of formula I was isolated by solvent-extractions using large
volumes of solvents such as tetrahydrofuran, heptane and cyclohexane.
The process also requires use of amino acids such as L-cysteine. The product was
5 crystallized by seeding. Thereby, the process disclosed in WO 20141165044 is
quite lengthy and complicated.
There are other patent applications, such as CN 20 1411 0582048,
CN 201 711271 772, WO 201 711 56398 and W020181029711 which disclose the
I
10 synthesis of the compound of formula I, used in the synthesis of the compound of
formula V.
Chinese application CN 2014110582048 discloses the synthesis of the compound
of formula I, using intermediates of formula A and B,
CI
COOMe I
H OMe
Me
Me
Chinese application CN 201711271 772 discloses the synthesis of the compound of
formula V using intermediates of formula C and D,
In WO 20171156398, the authors disclose a process for the preparation of the
compound of formula V by using intermediates of formula E and formula F,
In W020181029711, the compound of formula I is prepared using different
5 intermediates of formula G and H,
wherein, R is C1-4 alkyl.
From the forgoing, it is apparent that the reported methods for the preparation of
10 the compound of formula V, require stringent operational conditions which are
not only tedious but also result in significant yield loss. Th~sepr ocesses require
use of silica gel chromatography for purification. The work-up procedure also
involves tedious solvent exchange methods for the isolation of compound of
formula I. Moreover, use of palladium ligands in the synthesis of formula I makes
15 it difficult to control the palladium content in the drug product within the
recommended ICH limit i.e. 4 0 ppm.
Therefore, there remains a need to formulate an efficient, simple and industrially
viable synthetic process which can overcome the drawbacks of the prior art as
well as provide the compound of formula V i.e. venetoclax and its intermediates
in high yield and purity.
OBJECT OF THE INVENTION
It is an object of the present invention to overcome the above-mentioned
drawbacks of the prior art.
10 It is another objective of the present invention to provide a process for the
synthesis of a compound of formula I.
It is another objective of the present invention to avoid tedious and long work-up
process for the synthesis of the compound of formula I or its salts.
15
It is yet another objective of the present invention to provide a process for the
conversion of the compound of formula I or its salts to the compound of formula
v .
20 It is further objective of the present invention to provide an improved and
commercially viable process for the synthesis of the compound of formula V.
SUMMARY OF THE INVENTION
In first aspect, the present invention relates to a process for the preparation of the
25 compound of formula V,
Formula V
5 comprising the reaction of a compound of formula 11,
Formula I1
wherein R is C alkyl;
with a compound of formula 111,
c'?5gH Formula I11
in the presence of an alkyl arnine to obtain a compound of formula I or its salts,
Formula I
wherein R is C alkyl;
and converting the compound of formula I or its salts to the compound of formula
v.
10 Another aspect of the present invention is to provide a process for the preparation
of compound of formula I or its salts,
Formula I
comprising the reaction of a compound of formula 11,
Formula I1
wherein R is C14 alkyl;
5 with a compound of formula 111,
Formula I11
10 in the presence of an alkyl amine .
Another aspect of the present invention is to provide a compound of formula Ib.
Formula Ib
wherein X= K, Na, Li
Another aspect of the present invention is to provide salts of the formula Ia
represented as a compound of formula lal,
Formula 1a'
wherein Y is hydrochloric acid, sulphuric acid, p-toluenesulphonic acid,
trifluoroacetic acid, oxalic acid, dicyclohexylamine;
10 and to provide a process for their preparation.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
The following definitions are used in connection with the present application
15 unless the context indicates otherwise.
The term "coupling agent" as used herein refers to a chemical reagent that couples
together the carboxylic acid functionality of a compound with the amine
functionality of a compound to form an amide (-CONH) linkage. Those skilled in
20 the art will be familiar with the selection of the coupling agents and will
appreciate that many different coupling agents are known in the art, the suitability
of one coupling agent or another being dependent on the particular synthetic
scheme planned.
The term "salt" of a compound refers to an 'acidic salt' or a 'basic salt' of the
5 compound.
The corresponding acidic salt is typically prepared by reacting the compound with
an acid selected from the group of organic or inorganic acids such as hydrochloric
acid, sulphuric acid, p-toluenesulphonic acid, trifluoroacetic acid and oxalic acid.
The corresponding basic salt is typically prepared by reacting the compound with
10 a base, e.g. a base selected from potassium hydroxide, sodium hydroxide, sodium-
2-ethylhexenoate, lithium hydroxide and dicyclohexylamine.
The salt of a compound can be prepared according to the general standard
methods for the preparation of a salt known in the art.
15 As used herein, the terms "comprising" and "comprises" mean the elements
recited, or their equivalents in structure or function, plus any other element or
elements which are not recited and the terms "comprising the steps of' include the
steps recited, or the equivalent steps irrespective of the sequence in which they are
recited.
In one aspect, the present invention relates to a process for the preparation of a
compound of formula V,
Formula V
comprising the steps of:
5 a) reacting a compound of formula 11,
Formula I1
10 with a compound of formula 111,
Formula I11
15 in the presence of an alkyl mine to obtain a compound of formula I or its salts,
Formula I1
Formula 111
Alkylamine
K mM8
Formula I
Scheme3
wherein R is C1-4a lkyl;
b) converting the compound of formula I or its salts to a compound of fonnulav.
The C14 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl
and t-butyl, preferably methyl.
10
The alkylamine may be selected from the group consisting of N,Ndiisopropylethylamine
(DIPEA), trimethylamine (Me3N), triethylamine (Et3N),
N,N-dimethylaniline (DMA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-Diazabicyclo [4.3.0]non-Sene
15 (DBN), preferably N,N-diisopropylethyl amine (DIPEA).
The reaction is preferably carried out in the presence of an aprotic solvent selected
from the group consisting of dichloromethane, dimethylsulphoxide, chloroform,
acetone, acetonitrile, tetrahydrofuran, dimethylformamide, N-methyl pyrrolidine,
20 dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran and mixtures thereof.
Most preferably, the reaction is carried out in dimethylsulphoxide (DMSO).
The reaction is preferably carried out at 90 to 120 degree Celsius, more preferably
at 95 to 105 degree Celsius.
In a preferred embodiment, the compound of formula 11, wherein R is methyl, is
5 reacted with the compound of formula 111, in the presence of a suitable alkylamine
such as N, N-diisopropylethylamine and a suitable solvent such as
dimethylsulphoxide. Preferably, the reaction is carried out at 90 to 115 degree
Celsius, more preferably at 95 to 105 degree Celsius. The reaction mixture is
stirred for 24-28 hours at the same temperature to obtain the compound of formula
10 I.
The salt of the compound of formula I is typically prepared by reacting the
compound of formula I with an acid selected from the group consisting of
hydrochloric acid, sulphuric acid, p-toluenesulphonic acid, trifluoroacetic acid and
15 oxalic acid. Preferably, the salt of the compound of formula I is the hydrochloride
salt.
The salt of the compound of formula I is preferably prepared in the presence of a
solvent selected from methanol, ethanol, water, ethyl acetate, acetone and
20 dichloromethane or a mixture thereof, more preferably methanol.
In a preferred embodiment, the salt of the compound of formula I is prepared by
reacting the compound of formula I with a suitable acid such as concentrated
hydrochloric acid in a suitable solvent such as methanol to give the hydrochloride
25 salt of the compound of formula I.
The methods for the preparation of the compound of formula I as reported in the
prior arts such as WO 201 11149492 involve the use of palladium reagents which
require long and tedious work-up procedures for the isolation and purification of
30 the product. Other processes such as disclosed in WO 20141165044 involve the
use of silica gel column chromatography for purifications which result in
significant yield loss. /
The inventors of the present invention found that using an alkylamine such as
5 diisopropylethyl arnine (DIPEA) in the preparation of the compound of formula I,
surprisingly improves the yield at the first stage and the high yield of the
compound of formula I or its salts, effects the further stages of the synthesis of
venetoclax and as a result venetoclax is obtained in significantly higher yield and
purity without cumbersome isolation or chromatographic purifications.
10
In a preferred embodiment, the yield of the hydrochloride salt of the compound of
formula I is ca.74.14% (purity -99.3%).
The compound of formula I or its salts can be further converted to the compound
15 of formula V by processes well known in the prior art.
In the same aspect, the present invention relates to the conversion of the
compound of formula I or its salts to the compound of formula V.
20 In an embodiment, the compound of formula I or its salt is hydrolyzed to the
compound of formula Ia,
Formula I
Hydrolysis
Base, Acid
Formula Ia
Scheme-4
wherein R is C14 alkyl
The hydrolysis of the compound of formula I or its salts is preferably carried out
in presence of a base selected from potassium hydroxide, lithium hydroxide and
sodium hydroxide or a mixture thereof, preferably potassium hydroxide.
10
The compound of formula I or its salts is preferably hydrolyzed in presence of a
solvent selected from methanol, ethanol, water, ethyl acetate and dichloromethane
or a mixture thereof, preferably methanol.
15 The acid is preferably selected from the group consisting of hydrochloric acid,
sulphuric acid, p-toluenesulphonic acid, trifluoroacetic acid and oxalic acid, more
preferably hydrochloric acid.
The compound of formula I or its salts is preferably hydrolyzed at a temperature
20 of 55-80 degree Celsius.
In a preferred embodiment, the compound of formula I or its salts is hydrolyzed in
the presence of a suitable base such as aqueous potassium hydroxide and a
suitable solvent such as methanol and a suitable acid such as hydrochloric acid to
25 obtain the compound of formula Ia at a temperature of 60-75 degree Celsius.
In an embodiment, the hydrolysis of the compound of formula I to the compound
of formula Ia comprises reacting compound of formula I or its salts
with a base in a solvent to obtain a compound of formula Ib,
5
Hydrolysis
Base
Formula I Formula Ib
Schemed
wherein X= K, Na, Li
The base is preferably selected from potassium hydroxide, lithium hydroxide and
sodium hydroxide or a mixture thereof, more preferably potassium hydroxide.
15 The solvent is preferably selected from methanol, ethanol, water, ethyl acetate and
dichloromethane or a mixture thereof, more preferably methanol.
The compound of formula Ib wherein X is Na can also prepared by treating the
compound of formula Ia with sodium 2-ethylhexenoate.
20 In a preferred embodiment, the compound of formula I or its salts is hydrolyzed in
the presence of a suitable base such as potassium hydroxide and a suitable solvent
such as methanol to obtain the compound of formula Ib, wherein X is potassium.
In another embodiment, the compound of formula Ib is isolated and converted to
the compound of formula lal by treating with an acid,
Acid
Formula Ib Formula la'
wherein X= K, Na, Li and Y is hydrochloric acid, sulphuric acid, p-
10 toluenesulphonic acid, trifluoroacetic acid, oxalic acid, dicyclohexylarnine
The acid is preferably selected from the group consisting of hydrochloric acid,
sulphuric acid, p-toluenesulphonic acid, trifluoroacetic acid and oxalic acid, more
preferably hydrochloric acid.
15
In a preferred embodiment, the compound of formula Ib is isolated and treated
with a suitable acid such as hydrochloric acid to obtain the compound of formula
lal, wherein Y is hydrochloric acid.
20 In another embodiment, the compound of formula Ia is converted into the
compound of formula la1 by treating with an acid or a base, typically in the
presence of a solvent,
Acid or Base
t
Formula Ia
Formula lal
5 Scheme-7
wherein Y is hydrochloric acid, sulphuric acid, p-toluenesulphonic acid
trifluoroacetic acid, oxalic acid, dicyclohexylamine.
The acid is preferably selected from hydrochloric acid, sulphuric acid, p-
10 toluenesulphonic acid, trifluoroacetic acid and oxalic acid.
The base is preferably dicyclohexylamine.
The solvent is preferably selected from ethyl acetate, acetone, methanol, water or
15 a mixture thereof. More preferably, the solvent is methanol.
In a preferred embodiment, the compound of formula Ia is treated with a suitable
acid such as hydrochloric acid to obtain its hydrochloride salt.
20 In an embodiment, the compound of formula Ia or its salt is reacted with a
compound of formula IV,
Formula la
Or its salt
Formula IV
Coupling agent, Base. Solvent
Formula V
5 The reaction is typically carried out in presence of a suitable coupling agent.
The suitable coupling agent may be selected from the group consisting of 1-ethyl-
3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCI),
dicyclohexylcarbodiimide (DCC), 0-benzotriazole-N,N',N'-tetramethyl uronium
10 hexafluoro phosphate (HBTU) and benzotriazol-1-yloxypyrrolidinophosphonium
hexafluorophosphate (PyBOP), preferably 1 -ethyl-3 -(3 -dimethylaminopropyl)
carbodiimide hydrochloride (EDC HC1).
The reaction is carried out in presence of a suitable base.
15
The suitable base may be selected from the group consisting of triethylamine,
N,N-diisopropylethylamine, 4-dimethylaminopyridine, N,N
dimethylethylenediamine or mixture thereof.
20 The reaction is preferably carried out in presence of a suitable solvent.
The suitable solvent may be selected from the group consisting of
dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran,
dimethylformamide, N-methyl pyrrolidine, dioxane, nitromethane, pyridine and 2-
I
methyltetrahydrofuran, preferably dichloromethane.
The compound of formula Ia or its salts is preferably reacted with a compound of
5 formula IV at a temperature of 20-35 degree Celsius.
In a preferred embodiment, the compound of formula Ia or its salts is reacted with
a compound of formula IV in presence of a suitable base such as triethylamine, 4-
dimethylaminopyridine and N,N dimethylethylenediamine and a suitable coupling
10 agent such as N-(3-dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride
(EDC-HCl), preferably in presence of a suitable solvent such as dichloromethane,
preferably at a temperature of 25-30 degree Celsius.
In a preferred embodiment, the yield of the compound of formula V is ca.70.0%.
15 The purity is -99.7%.
Thus, in one aspect, the invention provides the compound of formula I in
significantly high yield and purity as compared to the prior art methods without
using complicated isolation and purification processes and in a further aspect, the
20 compound of formula I is converted to the compound of formula V in high yield
and purity with ease of procedure and less complexity.
The process of the present invention is advantageous in the respect that it is
economical, industrially viable and commercially favourable. Further, the process
25 of the present invention does not involve use of palladium, hence making the
process more attractive.
EXPERIMENTAL
Detailed experimental parameters according to the present invention are provided
by the following examples, which are intended to be illustrative and not limiting
of all possible embodiments of the invention.
Examples
Example-1
Preparation of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-
5,5-dimethyl-3,4,5,6-tetrahydro[l , 1' -biphenyl]-2-1)methyl)piperazin-1 - yl)-
10 benzoate. HC1.
A mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate
15 (500.0 g), 1 -((4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[ l , 1 '-biphenyl]-2-y1)-
methy1)piperazine (1114.0 g) and N,N-diisopropylethylamine (225.8 g) in
dimethylsulphoxide (1500 mL) was heated to 90 to 105 degree Celsius for 26h.
The reaction mixture was diluted with ethyl acetate (2500 ml) and washed with
water (2500 mL). The organic layer was concentrated under vacuum. The residue
20 was taken up in methanol (2500 mL) at 60 to 65 degree Celsius and cooled to 20
to 30 degree Celsius and stirred for 4h, followed by 0 to 5 degree Celsius for 3h.
The resulting slurry was filtered and washed with cold methanol (500 mL). The
filtered solid was treated with concentrated hydrochloric acid (218.3 g) in
methanol (3200 mL) followed by addition of water (1600 mL). The resulting
slurry was cooled to 0 to 5 degree Celsius, filtered and washed with a 2: 1 mixture
of methanol-water and the solid dried under vacuum at 50 to 60 degree Celsius for
16 h to provide methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-
5 5,5-dimethyl-3,4,5,6-tetrahydro[l , 1'-biphenyl]-2-1)methyl)piperazin- 1 -yl)-
benzoate. HC1.
Yield: 74.14% (805g)
HPLC Purity: -99.3%
10
1H NMR data-(DMSO-d6): 6 0.942 (s, 6H), 1.444 (t, J=6.4 Hz, 2H), 2.014 (s,
2H),2.366(t,br,2H),2.723(d,2H),3.281( m,4H), 3.702(m,2H),(m,d,J=12.8
Hz, 8H), 3.542 (s, 2H), 3.659 (s, 3H), 6.385 (dd, J= 1.6, 2.0, 3.2, 3.6Hz, lH),
6.414-6.420 (d, J=2.4Hz, lH), 6.776 (dd, J=2.4, 9.2Hz, lH), 7.105 (d, J=8.4Hz,
15 2H), 7.395( d, J=8.4Hz, 2H), 7.438 (d, J=2.0, lH), 7.483 (t, J=2.8Hz, lH), 7.781
(d, J=9.2Hz, 1 H), 7.999 (d, J=2.8Hz, 1 H), 10.752 (s, br, 1 H), 1 1.666 (s,lH).
Example-la
Preparation of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-
20 5,5-dimethyl-3,4,5,6-tetrahydro[l1,'- biphenyl]-2-1)methyl)piperazin- 1- yl)-
benzoate. oxalic acid salt.
A mixture of methyl 2-((1H-py~olo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-ch10r0-5,5-
dimethyl-3,4,5,6-tetrahydro[l , 1 '-biphenyl]-2-1)methyl)piperazin- 1 -yl)-
benzoate(5.0 g) in acetone (50 mL) was treated with oxalic acid solution (1.53 g
5 oxalic acid in 50 mL of acetone) and stirred at 30-35 degree Celsius for 2-3h
followed by 20-30 degree Celsius for 4-5h. The resulting slurry was filtered,
washed with acetone (25 mL) and the solid dried under vacuum at 40-45 degree
Celsius for 16 h to furnish the oxalate salt of methyl 2-((1H-pyrrolo[2,3-blpyridin-
5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l1,' -biphenyl]-2-
10 1)methyl)piperazin- 1 -yl)-benzoate. oxalic acid salt.
Yield: 29.46% (1.7g)
HPLC Purity: 77.24%
15 1H NMR (DMSO-d6): 6 0.93 (s, 6H), 1.41 (t, J=5.6 Hz, 2H), 1.98 (s, 2H), 2.1 8 (t,
br, 2H) 2.42 (m, 4H), 2.97 (s, 2H), 3.21 (m, 4H), 3.65 (s, 3H),6.37 (dd, J=1.6, 3.2
Hz, 2H), 6.74 (dd, J=2.0, 2.4 Hz, 1 H), 7.08 (m, 2H), 7.34 (m, 2H), 7.42 (d, J=2.8
Hz, lH), 7.47 (t, J=2.8, 2.4 Hz, lH), 7.74 (d, J=8.8 Hz, lH), 7.99 (d, J=2.4 Hz,
1 H), 1 1.63 (s, 1 H, NH).
20
Example-1 b
Preparation of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-
5,5-dimethyl-3,4,5,6-tetrahydro[,ll '-biphenyl]-2-1)methyl)piperazin-1 - yl)-
benzoate. p-toluenesulfonic acid salt.
acid
A mixture of methyl 2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-
dimethyl-3,4,5,6-tetrahydro[l , 1 I-biphenyl]-2-1)methyl)piperazin-1 -yl)-benzoate
5 (1.0 g) in acetone (10 mL) was treated with p-toluenesulfonicacid monohydrate
(0.65 g) and stirred at 20-30 degree Celsius for 4-5h. The resulting slurry was
filtered, washed with acetone (10 mL) and the solid dried under vacuum at 45-50
degree Celsius for 16 h to furnish the methyl 2-((1H-pyrrolo[2,3-blpyridin-5-
yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l1,' -biphenyl]-2-
10 1)methyl)piperazin- 1 -yl)-benzoate. p-toluenesulfonic acid salt.
Yield: 91.05 % (1.12 g)
HPLC Purity: 98.08%
15 1H NMR (DMSO-d6): 6 0.95 (s, 6H), 1.44 (t, 2H), 1.99 (s, lH), 2.03 (s,2H), 2.21
(t, br, 2H), 2.29 (s,6H), 2.75 (m, 2H), 3.08 (m, 2H), 3.28 (m, 2H), 3.60 (m, 2H),
3.66 (s, 3H), 3.74 (m, 2H), 6.36 (dd, J=2.0 Hz, 2H), 6.77 (dd, J=2.4, Hz, 1 H), 7.08
(m, 6H), 7.39 (d, J=8.0 Hz,2H), 7.49 (m, 5H), 7.78 (d, ~=9.2Hz, lH), 7.99(d,
J=2.8 Hz, lH), 11.68 (s, lH, NH).
2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-
tetrahydro[l ,I '-biphenyl] -2-y1)methyl)piperazin- 1 -yl)benzoic acid HCl.
H
HCI
Me Me
A mixture of methanol (2.0 L), methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-
(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydr1o , l'- biphenyl]- 2-y1)methyl)
piperazin-1 -yl)-benzoate hydrochloride (200.0 g), potassium hydroxide (1 06.2 g)
and water (400 mL) was heated to 65 to75 degree Celsius for 9h. The reaction
10 mixture was diluted with water and the product was extracted with
dichloromethane (2.0 L). The dichloromethane layer was then diluted with
acetone (1.0 L) and was treated with concentrated hydrochloric acid (67.0 g) and
stirred at 20 to 30 degree Celsius. The resulting slurry was filtered and the solid
cake was successively washed with 2:l mixture of dichloromethane-acetone
15 (300mL), water (3.0 L) and acetone (200 mL). The solid was dried under vacuum
at 50 to 60 degree Celsius for 16 h to provide 2-((1H-pyrrolo[2,3-blpyridin-5-
yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l, 1 '-biphenyl]-2-
y1)methyl)piperazin- 1 -yl)benzoicacid hydrochloride.
20 Yield: 92.08% (180g)
HPLC Purity: -99.36 %
lH NMR data-(DMSO-d6): 6 0.947 (s, 6H), 1.452 (t, J=6.4Hz, 2H), 2.020 (s, 2H),
2.337 (t, br, 2H), 2.743 (d, 2H), 3.301 (m, 4H), 3.670 (m, 2H), 3.559 (d, J=4.0Hz,
2H), 6.378 (dd, J=1.6, 2.0, 3.2, 3.6Hz, lH), 6.408 (d, J=2.0Hz, lH), 6.761 (dd,
J=2.4, 8.8Hz, 1H) 7.106 (d, J=8.8Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.406 (s, lH),
5 7.476 (t, J=2.8, 3.2Hz, lH), 7.778 (d, J=9.2Hz, lH), 7.985 (d, J=2.4Hz, lH),
10.431 (s, br, lH), 11.634 (s, IH), 12.266 (s, br, 1H).
Example-2a
Preparation of Potassium 2-((1 H-py~olo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-
10 5,5-dimethyl-3,4,5,6-tetrahydro[l , 1'-biphenyl]-2-y1)methyl)piperazin- 1 -
y1)benzoate.
15 A mixture of methanol (1 30.0 L), methyl 2-((1 H-pyrrolo[2,3-blpyridin-5-y1)oxy)-
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrydro[ll1,- biphenyl]-2-
1)methyl)piperazin- 1 -yl)-benzoate. HC1 (1 0.0 g), potassium hydroxide (1 0.6 g)
and distilled water (20 mL) was heated to 60-70 degree Celsius for 3h. The
reaction mixture was diluted with distilled water (40 ml) and extracted the product
20 with dichloromethane (60.0 L). The dichloromethane layer was distilled out
completely followed by slurry formation in acetone (80.0 L). The resulting slurry
was filtered and the solid cake was washed with acetone (20mL). The solid was
dried under vacuum at 30-35 degree Celsius for 17 h to furnish Potassium 2-((1 HYield:
78.9% (4.10 g).
5 HPLC Purity: 94.0%
Example-2b
Preparation of Lithium 2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-
5,5-dimethyl-3,4,5,6-tetrahydro[l , 1'-biphenyl]-2-y1)methyl)piperazin- 1 -
10 y1)benzoate.
A mixture of methanol (65.0 L), methyl 2-((1H-pyrrolo[2,3-blpyridin-5-y1)oxy)-
15 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l,l'-biphenyl]-2-
y1)methyl)piperazin-1-y1)-benzoate. HC1 (5.0 g), lithium hydroxide (3.37 g) and
distilled water (10 mL) was heated to 60-70 degree Celsius for 3h. The reaction
mixture was diluted with distilled water (40 ml) and extracted the product with
dichloromethane (60.0 L). The dichloromethane layer was distilled out completely
20 followed by slurry formation in acetone (50.0 L). The resulting slurry was filtered
and the solid cake was washed with acetone (IOmL). The solid was dried under
vacuum at 35-40 degree Celsius for 17 h to furnish Lithium 2-((1H-pyrrolo[2,3-
b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l1,I -
biphenyl]-2-y1)methyl)piperazin- 1 -yl)benzoate.
Yield: 64.2 % (1.58 g)
Example-2c
Preparation of Sodium 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-
5 5,5-dimethyl-3,4,5,6-tetrahydro[l , 1 I-biphenyl]-2-y1)methyl)piperazin-1-
y1)benzoate.
A solution of sodium-2-ethylhexenoate (0.32 g) in ethyl acetate (5 mL) was added
10 to a mixture of 2-((1H-pymolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-
dimethyl-3,4,5,6-tetrahydro[l , 1 '-biphenyl]-2-y1)methyl)piperazin-1 -yl)benzoic
acid (1.0 g) in ethyl acetate (5 mL) and stirred at 20-30 degree Celsius.The
resulting slurry was filtered, washed with ethyl acetate (5 mL) and the solid was
dried under vacuum at 50-55 degree Celsius for 16 h to furnish sodium 2-((1H-
15 pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-
tetrahydro[l , 1 I-biphenyl]-2-y1)methyl)piperazin- 1 -yl)benzoate.
Yield: 57.80% (0.6g)
20 HPLC Purity: 96.97%
1 H NMR (DMSO-d6): 6 0.93 (s, 6H), 1.37 (t, J= 6.4 Hz, 2H), 1.96 (s, 2H), 2.16
(t, br, 2H) 2.21 (m,4H), 2.73 (s, 2H), 2.97 (s, 4H), 6.26 (dd, J=2.0, 1.2 HZ, 2H),
25 6.57(dd,J=1.6,2.0,Hz,lH),7.05(d,J=8.4,2H),7.29(d,J=2.8Hz,lH),7.34(d,
J=8.4 Hz, 2H), 7.38 (t, J=2.8 Hz, IH), 7.45 (d, J=8.8 Hz, lH), 7.94 (d, J=2.8 Hz,
1 H), 1 1.49 (s, 1 H, NH).
5 Example-2d
Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-
dimethyl-3,4,5,6-tetrahydro[ l ,I '-biphenyl]-2-y1)methyl)piperazin-1 - yl)benzoic
acid. p -toluenesulfonic acid salt.
X p-toluenesulphonic acid
A mixture of 2-((lH-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4~-chloro-5,5-
dimethyl-3,4,5,6-tetrahydro[l , I '-biphenyl]-2-y1)methyl)piperazin- 1 -yl)benzoic
acid (2.0 g) in acetone (20 mL) was treated with p-toluenesulfonicacid
monohydrate (1.33 g) and stirred at 20-30 degree Celsius for 4-5h. The resulting
15 slurry was filtered, washed with acetone (10 mL) and the solid was dried under
vacuum at 45-50 degree Celsius for 16 h to furnish 2-((1H-pyrrolo [2,3-b]
pyridin-5-y1)oxy)-4 -(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l1,I -bi
phenyll-2-yl) methy1)piperazin- 1 -yl) benzoic acid. p -toluenesulfonic acid salt.
20 Yield: 86.92 % (2.26 g)
HPLC Purity: 97.88%
1H NMR (DMSO-d6): 6 0.95 (s, 6H), 1.43 (t, J=2.0, 2.4 Hz, 2H), 2.03 (s, 2H),
2.21 (t, br, 2H), 2.29 (s, 6H), 2.77 (m, 2H), 3.09 (m, 2H), 3.29 (m, 2H), 3.61 (m,
2H), 3.74 (m, 2H), 6.42 (m, 2H), 6.76 (dd, J=2.0 Hz, 2H), 7.09 (m, 6H), 7.39 (d,
J=8.4 Hz, 2H), 7.50 (t, 5H), 7.78 (d, J=9.2 Hz, lH), 8.03 (d, J=2.4 Hz, lH), 11.74
(s, 1 H, NH).
5 Example-2e
Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-
dimethyl-3,4,5,6-tetrahydro[l , 1'-biphenyl]-2-y1)methyl)piperazin-1 -yl)benzoic
acid . dicyclohexylarnine salt.
X Dicyclohexylamine
A mixture of (7:3) acetone-methanol (3 mL), 2-((1H-pyrrolo[2,3-blpyridin-5-
yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l1, '-biphenyl]-2-
y1)methyl)piperazin- 1 -yl)benzoic acid (0.5 g) and dicyclohexylamine (0.19 g)
15 was stirred at 20-30 degree Celsius for 3-4h. The resulting slurry was filtered,
washed with (7:3) acetone-methanol (2 mL) and the solid was dried under vacuum
at 40-50 degree Celsius for 16 h to furnish 2-((1H-pyrrolo[2,3-blpyridin-5-
yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l,1 ' -biphenyl]- 2-
y1)methyl)piperazin- 1 -yl)benzoic acid. dicyclohexylamine salt.
20
Yield: 60.6 % (0.4 g)
HPLC Purity: 97.2 %
1 H NMR (DMSO-d6): 6 0.93 (s, 6H), 1.08 (m, 6H), 1.15 (m, 4H), 1.39 (t, J=6.0,
6.4 Hz, 2H), 1.50 (d, J=12.4 Hz, 2H), 1.60 (d, J=13.2 Hz, 4H), 1.77 (d, J=10.8 Hz,
4H),2.16 (m, br, 6H) 2.58 (m, 2H), 2.73 (s, 2H), 3.04 (s, 4H), 6.31 (d, J=2.8 Hz,
2H), 6.64 (d, J=7.6, Hz, IH), 7.04 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 3H), 7.41
5 (s,lH),7.60(d,J=8.8Hz,lH),7.95(d,J=2.0Hz,lH),11.55(s,lH,NH)
Example3
Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-ch10r0-5,5-
dimethyl-3,4,5,6-tetrahydro[l , 1 '-biphenyl] -2-y1)methyl)piperazin- 1 -yl)benzoic
10 acid. HC1.
H
CI
HCI
A mixture of dichloromethane (30.0 L), Potassium 2-((1H-pyrrolo[2,3-blpyridin-
5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l1,' -biphenyl]-2-
y1)methyl) piperazin- 1 -yl)benzoate (3.0 g)) and acetone (1 5 mL) was treated with
20 conc. hydrochloric acid (1.0 g) and stirred at 20-30 degree Celsius. The resulting
slurry was filtered and the solid cake was successively washed with 2: 1 mixture of
dichloromethane -acetone (9mL), distilled water (51.0 L) and acetone (3.0mL).
The solid was dried under vacuum at 50-60 degree Celsius for 16 h to furnish the
2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-
tetrahydro 1,l '-biphenyl] -2-y1)methyl)piperazin- 1 -yl)benzoic acid. HC1.
Yield: 91.3 % (2.72 g)
5
Example-4
Preparation of 4-(4- {[2-(4-chloropheny1)-4,4-dimethylcyclohex-1 - en-1 -
yllmethyl) -piperazin- 1 -yl)-N-((3 -nitro-4[(tetrahydro-2H-pyran-4ylmethyl)
amino]-phenyl) sulfony1)-2-(1 H-pyrrolo [2,3 -b]pyridin-5-y1oxy)benzamide)
10 (Compound of Formula V)
A mixture of dichloromethane (1 2.0 L), 2-((1 H-pyrrolo [2,3 -b]pyridin-5 -yl)oxy)-
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l1,I -biphenyl]-2-y1)methyl)
piperazin-1-y1)benzoicacid hydrochloride (600.0 g), triethylamine (299.79 g), 4-
15 dimethylaminopyridine (1 80.97 g), 3-nitro-4-(((tetrahydro-2H-pyran-4-
yl)methyl)amino)benzenesulfonamide (342.56 g) and N-(3-
Dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride (283.97 g) was stirred
at 25 to 30 degree Celsius for 8h. The reaction mixture was treated with N,Ndimethylethylenediamine
(217.63 g) at 20 to 30 degree Celsius and stirred for 4h.
20 The organic layer was washed with water (6.0 L) and concentrated under vacuum.
The residue -was dissolved in dichlomethane-methanol mixture (1 :5) (7.2 L) and
treated with acetic acid-methanol mixture (415.1 1 g acetic acid and 600 mL
methanol) and stirred at 20 to 30 degree Celsius. The resulting slurry was cooled
to 0 to 5 degree Celsius, filtered and washed with methanol (600 mL). The solid
25 was dissolved in (9:l) mixture of dicloromethane-methanol (4.8 L) at 35 to 45
degree Celsius, diluted with methanol (1680 mL) and stirred for 8h at 20 to 30
degree Celsius. The resulting slurry was cooled to 0 to 5 degree Celsius, filtered,
washed with methanol (600 mL) and the solid was dried under vacuum at 60 to
65 degree Celsius for 18 h to provide 4-(4-{[2-(4-chloropheny1)-4,4-
30 dimethylcyclohex- 1 -en- 1 -yl]methyl) -piperazin- 1 -yl)-N-((3 -nitro-4 [(tetrahydroYield:
70.0% (600g)
5 HPLC Purity: -99.9%
1H NMR data-(DMSO-d6): 6 0.921 (s, 6H), 1.204-1.308, 1.598-1.626 (m, d,
J=11.2Hz, 4H), 1.382 (t, J=6.4Hz, 4H), 1.883 (m, lH), 1.951 (s, 2H), 2.144 (t, br,
2H), 2.199 ( s, br, 4H), 2.754 (s, 2H), 3.073 (s, br, 4H), 3.237-3.291, 3.829-3.865
10 (m,dd,J=2.8,3.2, 11.2, 11.6Hz,6H),6.189(d, J=2.0Hz, lH),6.388(dd, J=2.0,
3.6Hz, lH), 6.678 (d, J=2.0, 2.4, 9.2, 9.6Hz, lH), 7.037 (d, J=8.8Hz, 2H) 7.1 1 (d,
J=9.2Hz, lH), 7.34 (d, J=8.0Hz, 2H), 7.495 (m, 2H), 7.535 ( d, J=2.4Hz, lH),
7.801 (dd, J=2.0, 2.4, 8.8, 9.2Hz, lH), 8.038 (d, J=2.0Hz, lH), 8.558 (d, J=2.4Hz,
lH), 8.598 (t, lH), 11.366 (s, br, IH), 11.679 (s, 1H).

WE CLAIM:
1. A process for the preparation of a compound of formula V,
Formula V
comprising the steps of:
a) reacting a compound of formula 11,
Formula I1
wherein R is C alkyl;
with a compound of formula 111,
I"NH
c'%d Formula I11
in the presence of an alkyl amine to obtain a compound of formula I or its salts,
Formula I
wherein R is C1-4a lkyl;
b) converting the compound of formula I or its salts to the compound of formula
v.
2. A process for the preparation of a compound of formula I or its salts,
Formula I
wherein R is C14 alkyl;
comprising the reaction of a compound of formula 11,
Formula I1
wherein R is C14 alkyl;
with a compound of formula 111,
Formula I11
in the presence of an alkyl amine.
3. The process according to claim 1, wherein the conversion of step b)
comprises the steps of:
bl) hydrolyzing the compound of formula I or its salt to a compound of
formula Ia,
Formula Ia
or its salt of the compound of formula lal,
Formula 1a'
wherein Y is hydrochloric acid, sulphuric acid, p-toluenesulphonic acid,
trifluoroacetic acid, oxalic acid, or dicyclohexylamine;
b2) reacting the compound of formula Ia or the compound of the formula
lal with a compound of formula IV,
Formula IV
to obtain the compound of Formula V.
4. The process according to claim 3, wherein the conversion of step bl)
15 comprises the steps of:
bl 1) optionally isolating a compound of formula Ib,
Formula Ib
wherein X= K, Na, Li
b12) converting the compound of formula Ib to a compound of formula Ia
or its < lal.
5. A compound of formula Ib,
Formula Ib
wherein X= K, Na, Li
6. The process according to any one of claims 1 to 4, wherein the alkyl mine
is selected from the group consisting of N,N-diisopropylethylmine
(DIPEA), trimethylamine (Me3N), triethylamine (Et3N), N,Ndimethylaniline
(DMA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,s-
Diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-Diazabicyclo [4.3.0]non-5-
ene (DBN), preferably N,N-diisopropylethyl amine (DIPEA).
7. The process according to any one of claims 1 to 4 or 6, wherein the reaction
of the compound of formula I1 with the compound of formula I11 is carried
out in the presence of an aprotic solvent selected from the group consisting
of dichloromethane, dimethylsulphoxide, chloroform, acetone, acetonitrile,
tetrahydrofuran, dimethylformamide, N-methyl pyrrolidine, dioxane,
nitromethane, pyridine, 2-methyltetrahydrofuran or mixture thereof.
8. The process according to claim 7, wherein the solvent is
dimethylsulphoxide.
9. The process according to any one of claims 1 to 4 or 6 to 8, wherein the salt
of the compound of formula I is prepared by reacting the compound of
formula I with an acid selected from hydrochloric acid, sulphuric acid, ptoluenesulphonic
acid, trifluoroacetic acid and oxalic acid.
10. The process according to any one of claims 1 to 4 or 6 to 9, wherein the salt
of the compound of formula I is the hydrochloride salt.
11. The process according to claim 9 or 10, wherein the salt of the compound
of formula I is prepared in the presence of a solvent selected from
methanol, ethanol, acetone, dioxane, water, ethyl acetate and
dichloromethane or a mixture thereof.
12. The process according to claim 3 or 4, wherein the hydrolysis is carried out
in presence of a base selected from potassium hydroxide, lithium hydroxide
and sodium hydroxide or mixture thereof.
13. The process according to claim 3, 4 or 12, wherein the hydrolysis is carried
out in presence of a solvent selected from methanol, ethanol, acetone,
dioxane, water, and dichloromethane or a mixture thereof.
14. The process according to claim 4, wherein the compound of formula Ib is
converted to a compound of formula lal by reacting with an acid selected
from hydrochloric acid, sulphuric acid, p-toluenesulphonic acid,
trifluoroacetic acid and oxalic acid, preferably hydrochloric acid.
15. The process according to claim 3 or 4, wherein the salt of formula 1a' is
prepared by reacting the compound of formula Ia with an acid selected
from hydrochloric acid, sulphuric acid, p-toluenesulphonic acid,
trifluoroacetic acid and oxalic acid or with dicyclohexylamine as base.
16. A compound of formula lal,
Formula 1a'
20 wherein Y is hydrochloric acid, sulphuric acid, p-toluenesulphonic acid,
trifluoroacetic acid, oxalic acid, or dicyclohexylamine.
17. The process according to dlaim 3 or 4, wherein step b3) is carried out in
the presence of a coupling agent selected from the group consisting of 1-
ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCl),
dicyclohexylcarbodiimide (DCC), 0-benzotriazole-N,N1,N'-tetramethyl
uronium hexafluoro phosphate (HBTU) and benzotriazol-lyloxypyrrolidinophosphonium
hexafluorophosphate (PyBOP), preferably
I-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC
HCI).
18. The process according to claim 3,4 or 17, wherein step b3) is carried out in
the presence of a solvent selected from the group consisting of
dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran,
dimethylformamide, N-methyl pyrrolidine, dioxane, nitromethane, pyridine
and 2-methyltetrahydrofuran, preferably dichloromethane.
19. The process according to claim 3, 4, 17 or 18, wherein step b3) is carried
out in the presence of a base selected from triethylamine, N,Ndiisopropylethylamine,
N,N -dimethylethylenediamine, 4-
(dimethy1amino)pyridine or mixture thereof.
20. A process for the preparation of a compound of formula V,
Formula V
comprising the steps of:
a) reacting a compound of formula 11,
Formula I1
wherein R is C14 alkyl;
with a compound of formula 111,
r,''
=Formula II11 yN"
in the presence of diisopropylethylamine to obtain a compound of formula I
or its salts,
Formula I
wherein R is CIma4lk yl;
b) hydrolyzing the compound of formula I or its salts to a compound of
formula Ia,
Formula Ia
c) converting the compound of formula Ia to its salt of formula lal ,
Formula lal
wherein Y is hydrochloric acid
d) reacting the compound of formula lal with a compound of formula IV,
Formula IV
in the presence of 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride, triethylamine, 4-dimethylaminopyridine, N,N
dimethylethylenediamine, and dichloromethane to obtain the compound of
Formula V.