FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
IMPROVED PROCESS FOR THE PREPARATION OF SULFONYLUREA BASED
COMPOUNDS
APPLICANT(S):
a) NAME ZYDUS LIFESCIENCES LIMITED
b) NATIONALITY INDIAN
c) ADDRESS ZYDUS CORPORATE PARK, SCHEME NO. 63,
SURVEY NO. 536, KHORAJ (GANDHINAGAR),
NR. VAISHNODEVI CIRCLE, AHMEDABAD,
GANDHINAGAR, GUJARAT, INDIA, 382481
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it has to be performed.
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FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of sulfonylurea
based compounds of general formula (I). More specifically present invention provides
an improved process for the preparation of compound of formula (I-a). Present
invention also provides some novel impurities generated during process.
Formula (I)
BACKGROUND OF THE INVENTION
WIPO patent application no. WO2020148619 describes the use of certain sulfonylurea
based compounds of formula (I) as NLRP3 modulators which are useful in the
treatment of the diseases or conditions mediated by NLRP3 or conditions in which
interleukin 1β activity is implicates. This includes inflammation, cryopyrin-associated
periodic syndrome (CAPS), gouty arthritis, multiple sclerosis, inflammatory bowel
diseases, Parkinson’s and Alzheimer’s diseases and other diseases related to Central
Nervous System. NLRP3 modulators preferably useful as therapeutics in treatment of
a variety of pathological condition including but not limited to lymphoma, auto-
immune diseases, cancer, inflammatory diseases, neurodegenerative diseases or
conditions.
Compound of formula (I) was prepared according to scheme 1 & 2:
Scheme-1:
3
Scheme -2:
The drawback of process disclosed in WO2020148619 is that it teaches usage of many
hazardous reagents and process requires column chromatographic purification using
highly flammable solvent at one of the stage and purification at multi steps during
synthesis, which is not feasible for bulk production.
Scheme 2 disclosed in WO2020148619 has Seebach approach to proceed with high
selectivity, however, this required the use of unnatural D-proline as a very expensive
starting material and cryogenic conditions with hazardous reagents such as n-Butyl
4
lithium and diisobutylaluminium hydride. In addition, the reported procedure describes
the formation of the acetal as challenging, requiring azeotropic distillation from
pentane and very low yielding stages with low purity of final product. Therefore, there
is need for an improved process for the preparation of (R, E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide formula (I-a) and intermediates thereof.
SUMARY OF THE INVENTION
The present invention discloses an improved process for the preparation of sulfonylurea
based compounds of general formula (I). More specifically invention provides an
improved process for the preparation of compound of formula (I-a). Present invention
also provides some novel impurities generated during process. The compounds
prepared by this method are useful for the diseases or conditions mediated by NLRP3
or conditions in which interleukin 1β activity is implicates.
EMBODIMENTS OF THE INVENTION
In an embodiment, the present invention provides a process for the preparation of
compound of formula (I)
Formula (I)
In another embodiment, the present invention provides a process for the preparation of
compound of following formula (I-a).
Formula (I-a)
In an embodiment, the present invention provides a crystalline form of compound of
formula (I-a).
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In another embodiment, the present invention provides a process for the preparation of
crystalline form of compound of formula (I-a).
In an embodiment is provided an amorphous form of compound of formula (I-a).
In another embodiment the present invention provides a process for the preparation of
amorphous form of compound of formula (I-a).
In another embodiment, the present invention encompasses compounds having
chemical name (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,7-tetrahydro-s-
indacen-4-yl)carbamoyl)ethene-1-sulfonamide (Compound A), (R)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethane-1-sulfonamide (Compound B), chemical name 3-(1,2,3,5,6,7-
hexahydro-s-indacen-4-yl)-1,1-dimethylurea ( Compound C), chemical name 1,3-
bis(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea (Compound D), chemical name (S)-2-
((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbomoyl)-2-hydroxyethane-1-sulfonamide (Compound E), chemical name (R)-2-
((R) -1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)-2-hydroxyethane-1-sulfonamide (Compound F), chemical name (R,E)-
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-
yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate (Compound G), chemical name
1,2,3,5,6,7-hexahydro-s-indacen-4-amine (Compound H), chemical name (R,E)-2-
(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide (Compound I), chemical name
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (Compound J) These compounds were formed as
impurities during the process of preparing the compound of formula (I-a).
In another embodiment the compound of formula (A) is controlled in formula (I-a) with
the limit of 0.01% to 2.0%.
6
In an embodiment the compound of formula (B) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
In an embodiment the compound of formula (C) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
In another embodiment the compound of formula (D) is controlled in formula (I-a) with
the limit of 0.01% to 2.0%.
In another embodiment the compound of formula (E) is controlled in formula (I-a) with
the limit of 0.01% to 2.0%.
In another embodiment the compound of formula (F) is controlled in formula (I-a) with
the limit of 0.01% to 2.0%.
In another embodiment the compound of formula (G) is controlled in formula (I-a) with
the limit of 0.01% to 2.0%.
In another embodiment the compound of formula (H) is controlled in formula (I-a) with
the limit of 0.01% to 2.0%.
In another embodiment the compound of formula (I) is controlled in formula (I-a) with
the limit of 0.01% to 2.0%.
In another embodiment the compound of formula (J) is controlled in formula (I-a) with
the limit of 0.01% to 2.0%.
BRIEF DESCRIPTION OF DRAWING
Figure 1 is the Powder X-ray Diffraction pattern of crystalline Form I of (R,E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (compound I-a).
Figure 2 is the Powder X-ray Diffraction pattern of crystalline Form II of (R,E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (compound I-a).
Figure 3 is the Powder X-ray Diffraction pattern of crystalline Form III of (R,E)-2-
(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (compound I-a).
7
Figure 4 is the Powder X-ray Diffraction pattern of amorphous form (R,E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (compound I-a).
DETAILED DESCRIPTION OF THE INVENTION
Following is the list of abbreviations used in description:
CDCl3: Deuterated chloroform
DCM: Dichloromethane
DBU: 1,8-Diazabicyclo[5,4,0]undec-7-ene
DBN: 1,5-Diazabicyclo[4.3.0]non-5-ene
DABCO: (1,4-diazabicyclo[2.2.2]octane)
DMF: Dimethylformamide
DMSO: Dimethyl sulfoxide
GC: Gas Chromatography
min: Minute(s)
MS: Mass Spectrometry
NMR: Nuclear Magnetic Resonance
HPLC: High Performance Liquid Chromatography
h: Hour
Kg: Kilogram
L: Liter
MeOD: Deuterated methanol
MS: Mass Spectrometry
MTBE: Methyl tert-butyl ether
NMR: Nuclear Magnetic Resonance
RT: Room Temperature [25-35 ºC]
SOR: Specific Rotation
SSR: Stainless Steel Reactor
ESI-MS: Electrospray Ionization Mass Spectrometry
8
Instrument details:
HPLC and Chiral HPLC chromatograms were recorded on Agilent 1260 series.
Mass spectra were recorded on Waters XevoG2a-ToF LCMS instrument.
NMR was recorded with Bruker 400 MHZ instrument.
Specific rotation of chiral compounds was recorded with Jasco Polarimeter, Digital
Polarimeter P-2000.
Spray drying was done on LAB SPRAY DRYER, LU 222 ADVANCED, SD-1000
The ‘aryl’ group used either alone or in combination with other radicals, is selected
from a suitable aromatic system containing one two or three rings wherein such ring
may be attached together in pendant manner or may be fused, more preferably the
groups are selected from optionally substituted phenyl, naphthyl, tetrahydronaphthyl,
biphenyl and the like;
the ‘alkyl’ group either used alone or in combination with other radicals, denotes a
linear or branched radical containing one to six carbons, selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and
the like;
the ‘alkoxy’ refers to the straight or branched chain alkoxides of the number of carbon
atoms specified.
the ‘cycloalkyl’ group used either alone or in combination with other radicals, is
selected from a cyclic radical containing three to six carbons, more preferably
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like;
the term "haloalkyl "means an alkyl structure in which at least one hydrogen is replaced
with a halogen atom. In certain embodiments in which two or more hydrogen atoms
are replaced with halogen atoms, the halogen atoms are all the same as one another.
the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly
attached to an oxygen atom, more preferably groups selected from fluoromethoxy,
chloromethoxy, fluoroethoxy, chloroethoxy and the like;
9
the ‘heteroaryl’ means an aromatic or partially aromatic heterocycle that contains at
least one ring heteroatom selected from O, S and N. Heteroaryls thus include
heteroaryls fused to other kinds of ring’s, such as aryls, cycloalkyls, and heterocycles
that are not aromatic.
In certain other embodiment in which two or more hydrogen atoms are replaced with
halogen atoms, the halogen atoms are not all the same as one another;
The ‘heterocyclyl’ means a saturated, partially saturated or unsaturated aromatic or
non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms
selected from nitrogen, sulfur and oxygen, further optionally including the oxidized
forms of sulfur, namely SO & SO2 Heterocyclyl systems may be attached to another
moiety via any number of carbon atoms or heteroatoms of the radical and may be both
saturated and unsaturated.
The above and other objects of the present invention are attained as described herein
below. In an embodiment, the objects are attained by the improved process for the
preparation of sulfonylurea based compounds of the formula (I) and intermediates
thereof as described herein.
In embodiment, there is provided a process for the preparation of compound of formula
(I):
Formula (I)
wherein
B described above may be selected from following ring system:
10
where in X, Y, Z at each occurrence independently represents C, N, S, SO2, and O,
which may be optionally substituted;
R1 at each occurrence independently represents hydrogen, halogen, haloalkyl
optionally substituted groups selected from (C1-C6)alkyl;
R2 at each occurrence independently represents hydrogen, halogen, haloalkyl,
optionally substituted groups selected from (C1-C6)alkyl;
R3 and R4 at each occurrence independently represents hydrogen;
X is N-R5; O, S, SO2;
R5 at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano,
optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-
C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylSO2(C1-
C6)alkyl, (C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl,
heteroaryl, heterocyclyl, benzyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-
C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-
C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, -CO-
heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered
bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one
or more than one heteroatoms;
Each of R6, R7, R8, R9, R10 and R11 at each occurrence independently selected from
hydrogen, halogen optionally substituted groups selected from (C1-C6)alkyl, (C1-
C6)haloalkyl;
In another embodiment, the present invention provides an improved process for the
preparation of compound of formula (I) as described in Scheme – 3:
11
S N
H
O O BocP
O
Ph
Ph
TBDPMSC
N
CO
S N
H
OO
(R) (E)
X
O
O
S NH2
OO
X
S N
H
O
N
H
OO
X
CF3COOH
Di Boc compound
Mono Boc compound
Boc Urea compound
Urea TFA salt
Isocynate Comp.
X
OH
O
X
H3C
HO
XOHC
H3C
R NH2
CH3
R NH
CH3
Cl
XR
H3C
R N
CH3
Cl
R1
HCl
NH2
(S)H3C
O
OH
(XV)
(XIV)
(XII) (XIII)
(XI)
(IX)
(X)
(III) (IV) (V)
(VI)(VII)
(VIII)
Step 1 Step 2 Step 3
Step 4
Step 5Step 6
Step 7
Step 8
Step 9
Step 10
Step 11
Step 12
B
(II)
B R2
R3
R4R1
R3
R4
R3
R4
(I)
N
H N
H
O
S
O O
B R2
R1
R4
R3
X
N
H N
H
O
S
O O
B R2
R1
R4
R3
X
R1
R1
The process for the preparation of compound of formula (I) comprises the following
steps:
Step – 1: Preparation of compound (III)
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Reacting compound (II) with thionyl chloride in presence of one or more solvents to
obtain compound of formula (III).
In general, the organic solvent used in step – 1 is selected from methanol, ethanol,
isopropyl alcohol, n-butanol, ethyl acetate, toluene, tetrahydrofuran, diisopropyl ether,
methyl tertiary butyl ether and the like.
Step – 2: Preparation of compound (IV)
Reacting compound (III) with 1-bromo-3-chloropropane in presence of base and one
or more solvent to obtain compound (IV).
In general, one or more solvent used in step – 2 is selected from acetonitrile, toluene,
ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, n-
hexane, n-heptane and the like.
The base used in step – 2 is selected from N,N-diisopropylethylamine, triethylamine,
pyridine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium
bicarbonate, DBU, DBN, DABCO and the like.
Step – 3: Preparation of compound (V)
Reacting compound (IV) with Boc anhydride in presence of base to obtain compound
of formula (V).
The base used in step – 3 is selected from imidazole, N,N-diisopropylethylamine,
triethylamine, pyridine, DBU, DBN, DABCO and the like.
Step – 4: Preparation of compound (VI)
Compound (V) is dissolved in one or more solvent in presence of base to obtain
compound of (VI).
One or more solvent used in step – 4 is selected from dimethyl sulfoxide,
dimethylformamide, toluene, tetrahydrofuran, 1,4-dioxane, dimethyl ether, Acetone, n-
hexane, n-heptane and the like.
The base used in step – 4 is selected from sodium hydroxide, potassium hydroxide,
lithium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate,
sodium hydride, potassium hydride, potassium tert-butoxide, or sodium pentoxide,
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lithium diisopropylamide, potassium bis(trimethylsilyl)amide, lithium
bis(trimethylsilyl)amide, sodamide and the like.
Step – 5: Preparation of compound (VII)
Compound (VI) is dissolved in one or more solvent in the presence of suitable base to
obtain compound (VII).
In general, one or more solvent used in step – 5 is selected from water, methanol,
ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, acetonitrile, ethyl acetate,
toluene, dichloromethane, n-hexane, n-heptane and the like.
The base used in step – 5 is selected from sodium hydroxide, potassium hydroxide,
lithium hydroxide, potassium tertiarybutoxide, lithium diisopropylamide, potassium
bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodamide and the like.
Step – 6: Preparation of compound (VIII)
Part-A: Reacting compound (VII) with isobutyl chloroformate in presence of base and
one or more solvent to obtain filterate;
Part-B: Sodium borohydride is dissolved in one or more solvent. Adding filterate
obtained from Part-A to the reaction mixture to obtain compound (VIII).
In general, one or more solvent used in step – 6 is selected from ethers selected from
tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl
ether, water, ethyl acetate and the like.
The base used in step – 6 is selected N-methyl morpholine, N,N-Diisopropylethyl
amine, triethyl amine, pyridine, DBU, DBN, DABCO and the like.
Step – 7: Preparation of compound (X)
Reacting compound (VIII) with oxidizing agent in presence of one or more solvent to
obtain compound (X).
In general, one or more solvent used in step-7 is selected from acetonitrile, toluene,
ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, n-
hexane, n-heptane, cyclohexane and the like.
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The oxidizing agents used in step-7 is selected from pyridinium chloro chromate,
Pyridinium Dichromate, chromium trioxide, Collins reagent, Swern oxidation and the
like.
Step – 8: Preparation of compound (XI)
Compound (IX) is dissolved in one or more solvent in presence of base. Compound
(X) is dissolved in one or more solvent and obtained solution was adding in the mixture
of compound (IX) to obtain compound (XI).
In general, one or more solvent used in step – 8 is selected from N,N-
dimethylformamide, dimethylsulfoxide, toluene, ethers selected from tetrahydrofuran,
1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether and the like.
The base used in step – 8 is selected from sodium hydride, sodium hydroxide,
potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate,
potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydride,
potassium tert-butoxide or sodium pentoxide and the like.
Step – 9: Preparation of compound (XII)
Compound (XI) is dissolved in one or more solvent and heated at suitable temperature
to obtain compound (XII).
In general, one or more solvent used in step – 9 is selected from dimethylformamide,
dimethylsulfoxide, toluene. ethers, methanol, ethanol, isopropanol, 2-propanol, 1-
butanol, and t-butyl alcohol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, diisopropyl
ether, diethyl ether, and methyl tert-butyl ether, n-hexane, n-heptane and the like.
Suitable temperature used in step – 9 is 50ºC to 100ºC.
Step – 10: Preparation of compound (XIV)
Compound (XII) is dissolved in one or more solvent in present of base. Compound
(XIII) is dissolved in one or more solvent and obtained solution was adding dropwise
in the mixture of compound (XII) to obtain compound (XIV).
In general, one or more solvent used in step – 10 is selected from acetonitrile, toluene,
ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide,
cyclohexane, n-hexane and the like.
15
The base used in step – 10 is selected from N-methyl morpholine, N,N-
Diisopropylethylamine, triethyl amine, N,N-diisopropylethylamine, pyridine, DBU,
DBN, DABCO, sodium hydride, sodium hydroxide, potassium hydroxide, lithium
hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, potassium hydride, potassium tert-butoxide, or
sodium pentoxide and the like.
Step – 11: Preparation of compound (XV)
Compound (XIV) is dissolved in one or more solvent. Adding reagent in a mixture of
compound (XIV) to obtain compound (XV).
In general, one or more solvent used in step – 11 is selected from dichloromethane,
dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene, pentane, n-hexane, n-
heptane, cyclohexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethylether,
methyl-tert-butyl ether, ethyl acetate, tetrahydrofuran, acetone, N,N-
dimethylformamide, water and the like.
The reagent used in step – 11 is selected from trifluoroacetic acid, hydrochloric acid,
Methane sulphonic acid, Acetic acid, formic acid and the like.
Step – 12: Preparation of compound (I)
Compound (XV) is dissolved in one or more solvent in presence of base and reagent.
Adding one or more reagent to the reaction mixture of compound (XV) to obtain
compound (I).
In general, one or more solvent used in step – 12 is selected from water,
dichloromethane, dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene,
pentane, n-hexane, n-heptane, cyclohexane, tetrahydrofuran, 1,4-dioxane, diisopropyl
ether, diethylether or methyl tertiary butyl ether and the like.
The base, used in step – 12 is selected from triethylamine, N,N-diisopropylethylamine,
pyridine, DBU, DBN, DABCO and the like.
The reagent used in step – 12 is selected from p-formaldehyde, sodium borohydride,
Pd/C, Raney nickel, vitride, or lithium aluminium hydride and the like.
Purification of compound (I):
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Crude compound of formula (I) obtained from step – 12 is dissolved in one or more
solvent to obtain pure compound (I).
In general, one or more solvent used in purification is selected from acetonitrile,
toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, water,
dimethylformamide, n-hexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl
ether, and methyl tert-butyl ether and the like.
In yet another preferred embodiment, the invention provides an improved process for
the preparation of compound of formula (I-a) as described in Scheme – 3:
17
18
The process for the preparation of compound of formula (I-a) comprises the following
steps:
Step 1-a: Preparation of compound (III-a)
Reacting compound (II-a) with thionyl chloride in presence of one or more solvent to
obtain compound of formula (III-a);
In general, the organic solvent used in step 1-a is selected from methanol, ethanol,
isopropyl alcohol, n-butanol, ethyl acetate, toluene, tetrahydrofuran, diisopropyl ether,
methyl tertiary butyl ether and the like. Preferred solvent are selected from methanol,
ethanol, diisopropyl ether.
Step 2-a: Preparation of compound (IV-a)
Reacting compound (III-a) with 1-bromo-3-chloropropane in presence of base and one
or more solvent to obtain compound (IV-a).
In general, one or more solvent used in step 2-a is selected from acetonitrile, toluene,
ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, n-
hexane, n-heptane and the like. Preferred solvent are selected from acetonitrile and n-
heptane.
The base used in step 2-a is selected from N,N-diisopropylethylamine, triethylamine,
pyridine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium
bicarbonate, DBU, DBN, DABCO and the like. Preferred solvent is N,N-
diisopropylethylamine.
Step 3-a: Preparation of compound (V-a)
Reacting compound (IV-a) with Boc anhydride in presence of base to obtain compound
of formula (V-a).
The base used in step 3-a is selected from imidazole, N,N-diisopropylethylamine,
triethylamine, pyridine, DBU, DBN, DABCO and the like. Preferred base is Imidazole.
Step 4-a: Preparation of compound (VI-a)
Compound (V-a) is dissolved in one or more solvent in presence of base to obtain
compound of (VI-a).
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One or more solvent used in step 4-a is selected from dimethyl sulfoxide, N,N-
dimethylformamide, toluene, tetrahydrofuran, 1,4-dioxane, dimethyl ether, Acetone,
tetrahydrofuran,, n-hexane, n-heptane and the like. Preferred solvent is dimethyl
sulfoxide.
The base used in step 4-a is selected from sodium hydroxide, potassium hydroxide,
lithium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate,
sodium hydride, potassium hydride, potassium tert-butoxide, or sodium pentoxide,
lithium diisopropylamide, potassium bis(trimethylsilyl)amide, lithium
bis(trimethylsilyl)amide, sodamide and the like. Preferred base is potassium hydroxide.
Step 5-a: Preparation of compound (VII-a)
Compound (VI-a) is dissolved in one or more solvent in the presence of suitable base
to obtain compound (VII-a).
In general, one or more solvent used in step 5-a is selected from water, methanol,
ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, acetonitrile, ethyl acetate,
toluene, dichloromethane, n-hexane, n-heptane and the like. Preferred solvent is
ethanol and water.
The base used in step 5-a is selected from sodium hydroxide, potassium hydroxide,
lithium hydroxide, potassium tertiarybutoxide, lithium diisopropylamide, potassium
bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodamide and the like.
Preferred base is potassium hydroxide.
Step 6-a: Preparation of compound (VIII-a)
Part-A: Reacting compound (VII-a) with isobutyl chloroformate in presence of base
and one or more solvent to obtain filterate;
Part-B: Sodium borohydride is dissolved in one or more solvent. Adding filterate
obtained from Part-A to the reaction mixture to obtain compound (VIII-a).
In general, one or more solvent used in step 6-a is selected from ethers selected from
tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether,
water, ethyl acetate and the like. Preferred solvent is tetrahydrofuran.
20
The base used in step 6-a is selected N-methyl morpholine, Diisopropylethyl amine,
triethyl amine, potassium hydroxide, pyridine, DBU, DBN, DABCO and the like.
Preferred base is N-methyl morpholine.
Step 7-a: Preparation of compound (X-a)
Reacting compound (VIII-a) with oxidizing agent in presence of one or more solvent
to obtain compound (X-a).
In general, one or more solvent used in step 7-a is selected from acetonitrile, toluene,
ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, n-
hexane, n-heptane, cyclohexane and the like. Preferred solvent is dichloromethane.
The oxidizing agents used in step 7-a is selected from pyridinium chlorochromate,
Pyridinium Dichromate, chromium trioxide, Collins reagent, Swern oxidation and the
like. Preferred oxidizing agent is pyridinium chlorochromate.
Step 8-a: Preparation of compound (XI-a)
Compound (IX-a) is dissolved in one or more solvent in presence of base. Compound
(X-a) is dissolved in one or more solvent and obtained solution was adding in the
mixture of compound (IX-a) to obtain compound (XI-a).
In general, one or more solvent used in step 8-a is selected from N,N-
dimethylformamide, dimethylsulfoxide, toluene, ethers selected from tetrahydrofuran,
1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether and the like.
Preferred solvent is N,N-dimethylformamide.
The base used in step 8-a is selected from sodium hydride, sodium hydroxide,
potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate,
potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydride,
potassium tert-butoxide or sodium pentoxide and the like. Preferred base is sodium
hydride.
Step 9-a: Preparation of compound (XII-a):
Compound (XI-a) is dissolved in one or more solvent and heated at suitable
temperature to obtain compound (XII-a).
21
In general, one or more solvent used in step 9-a is selected from dimethylformamide,
dimethylsulfoxide, toluene. ethers, methanol, ethanol, isopropanol, 2-propanol, 1-
butanol, and t-butyl alcohol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, diisopropyl
ether, diethyl ether, methyl tert-butyl ether, n-hexane, n-heptane and the like. Preferred
solvent is dimethylsulfoxide.
Suitable temperature for heated used in step 9-a is 50ºC to 100ºC.
Step 10-a: Preparation of compound (XIV-a)
Compound (XII-a) is dissolved in one or more solvent in present of base. Compound
(XIII-a) is dissolved in one or more solvent and obtained solution was adding dropwise
in the mixture of compound (XII-a) to obtain compound (XIV-a).
In general, one or more solvent used in step 10-a is selected from acetonitrile, toluene,
ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide,
cyclohexane, n-hexane and the like. Preferred solvent is N,N-dimethylformamide.
The base used in step 10-a is selected from N-methyl morpholine, N,N-
Diisopropylethylamine, triethyl amine, pyridine, DBU, DBN, DABCO, sodium
hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium
hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium
bicarbonate, potassium hydride, potassium tert-butoxide, or sodium pentoxide and the
like. Preferred base is sodium hydride.
Step 11-a: Preparation of compound (XV-a)
Compound (XIV-a) is dissolved in one or more solvent. Adding reagent in a mixture
of compound (XIV-a) to obtain compound (XV-a).
In general, one or more solvent used in step 11-a is selected from dichloromethane,
dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene, pentane, n-hexane,
heptane, cyclohexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethylether,
methyl tert-butyl ether, ethyl acetate, tetrahydrofuran, acetone, N,N-
dimethylformamide and the like. Preferred solvent is dichloromethane.
22
The reagent used in step 11-a is selected from trifluoroacetic acid, hydrochloric acid,
Methane sulphonic acid, Acetic acid, formic acid and the like. Preferred reagent is
trifluoroacetic acid.
Step 12-a: Preparation of compound (I-a)
Compound (XV-a) is dissolved in one or more solvent in presence of base and reagent.
Adding one or more reagent to the reaction mixture of compound (XV-a) to obtain
compound (I-a).
In general, one or more solvent used in step 12-a is selected from water,
dichloromethane, dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene,
pentane, n-hexane, n-heptane, cyclohexane, tetrahydrofuran, 1, 4-dioxane, diisopropyl
ether, diethylether or methyl tert-tertbutyl ether and the like. Preferred solvent is water.
The base, used in step 12-a is selected from triethylamine, Diisopropylethylamine,
pyridine, DBU, DBN, DABCO and the like. Preferred base is Triethylamine.
The reagent used in step 12-a is selected from p-formaldehyde, sodium borohydride,
Pd/C, Raney nickel, vitride or lithium aluminium hydride and the like. Preferred
reagent is p-formaldehyde and sodium borohydride.
Purification of compound (I-a):
Crude compound of formula (I-a) obtained from step 12-a is dissolved in one or more
solvent to obtain pure compound (I-a).
In general, one or more solvent used in purification is selected from acetonitrile,
toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, water,
dimethylformamide, n-hexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl
ether, and methyl tert-butyl ether and the like. Preferred solvent is acetone.
In one embodiment the compound of formula (I-a) either in crystalline or amorphous
or partially crystalline form.
In a further embodiment of the invention disclosed a crystalline Form I of compound
of formula (I-a).
In another embodiment the crystalline Form I of formula (I-a) has a powder X-ray
diffraction pattern as given in Figure 1.
23
In another further embodiment the crystalline Form I of formula (I-a) has a powder X-
ray diffraction pattern having a peak at about 5.9 ± 0.2, 10.9 ± 0.2, 17.3 ± 0.2, 17.8 ±
0.2, 18.2± 0.2, 20.1 ± 0.2 and 20.6 ± 0.2 degrees 2-theta.
In yet another embodiment the crystalline Form I of formula (I-a) has a powder X-ray
diffraction pattern having a peak at about 17.8 ± 0.2 degrees 2-theta;
In yet another embodiment, the present invention provides process for the preparation
of crystalline Form I of formula (I-a). The process comprises:
(i) dissolving compound of formula (I-a) in one or more solvent or a mixture of solvent to
obtain crystalline Form I of formula (I-a).
solvent used in step (i) is selected from acetonitrile, toluene, ethyl acetate,
dichloromethane, tetrahydrofuran, acetone, water, dimethylformamide, n-hexane,
tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl
ether and the like.
In a further embodiment of the invention disclosed a crystalline Form II of formula (I-
a).
In another embodiment the crystalline Form II of formula (I-a) has a powder X-ray
diffraction pattern as given in Figure 2.
In another further embodiment the crystalline Form II of formula (I-a) has a powder X-
ray diffraction pattern having a peak at about 7.4 ± 0.2, 10.5 ± 0.2, 16.4 ± 0.2, 19.6 ±
0.2, 20.4 ± 0.2 and 20.9 ± 0.2 degrees 2-theta.
In yet another embodiment, the present invention provides process for the preparation
of crystalline Form II of formula (I-a). The process comprises:
(i) dissolving compound of formula (I-a) in one or more solvent or a mixture of solvent to
obtain crystalline compound of formula (I-a).
solvent used in step (i) is selected from methanol, ethanol, Isopropyl alcohol, toluene,
ethyl acetate, dichloromethane, acetone, water, and the like.
In a further embodiment of the invention disclosed a crystalline Form III of formula (I-
a).
24
In another embodiment the crystalline Form III of formula (I-a) has a powder X-ray
diffraction pattern as given in Figure 3.
In another further embodiment the crystalline Form III of formula (I-a) has a powder
X-ray diffraction pattern having a peak at about 5.2 ± 0.2, 10.2 ± 0.2, 13.1 ± 0.2, 18.2±
0.2, and 19.3 ± 0.2 degrees 2-theta.
In yet another embodiment, the present invention provides process for the preparation
of crystalline Form III of formula (I-a). The process comprises:
(i) dissolving compound of formula (I-a) in one or more solvent or a mixture of solvent to
obtain crystalline Form III of formula (I-a).
solvent used in step (i) is selected from methanol, ethanol, isopropyl alcohol,
dichloromethane, water, diisopropyl ether, diethyl ether, and methyl tert-butyl ether
and the like.
In a further embodiment of the invention disclosed an amorphous form of the
compound of formula (I-a).
In another embodiment the amorphous form of formula (I-a) has a powder X-ray
diffraction pattern as given in Figure 4.
In yet another embodiment, the present invention provides process for the preparation
of amorphous form of formula (I-a). The process comprises:
(i) dissolving compound of formula (I-a) in one or more solvent or a mixture of solvent;
(ii) spray drying of feed stock solution from step (i) to get amorphous compound of formula
(I-a).
In an embodiment one or more solvent used in step (i) is selected from
dichloromethane, tetrahydrofuran, acetone, water, n-hexane, tetrahydrofuran, 1,4-
dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether and the like.
In order to obtain marketing approval for a new drug product, manufacturers must
submit the evidence to the regulatory authority that the product is acceptable for
administration to humans. Such a submission must include impurity profile of the
product to demonstrate that the impurities are either absent, or present in a negligible
amount. Different regulatory authorities have promulgated guidelines requiring
25
applicants to identify the impurities present in the product and also disclose their
concentration in the product. They also provide the maximum level of impurities
allowable in the product. Thus for e.g. USFDA recommends that drug applicants
identify all the impurities having concentration of 0.1 % or greater, in the active
ingredient. Therefore, there is a need to check impurity profile and identify the
impurities and also their concentration in the active ingredient.
Following novel compounds (Compound A to J) were also obtained during the
synthesis of the compound of formula (I-a). These compounds may be generated as
generates during process for the preparation of compound of formula (I-a).
The present invention thus provides following a new impurities of compound of
formula (I-a):
(i) Compound A having chemical name (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-
((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide and having the
following chemical structure:
Compound A
In an embodiment the compound of formula (A) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(ii) Compound B having chemical name (R)-2-(1,2-dimethylpyrrolidin-2-yl)-N-
((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethane-1-sulfonamide and which
has the following chemical structure:
26
Compound B
In an embodiment the compound of formula (B) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(iii) Compound C having chemical name 3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,1-
dimethylurea and has the following chemical structure:
Compound C
In an embodiment the compound of formula (C) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(iv) Compound D having chemical name 1,3-bis(1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)urea and has
the following chemical structure:
Compound D
In an embodiment the compound of formula (D) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(v) Compound E having chemical name (S)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-
((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbomoyl)-2-hydroxyethane-1-sulfonamide
and has the following chemical structure:
27
Compound E
In an embodiment the compound of formula (D) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(vi) Compound F having chemical name (R)-2-((R) -1,2-dimethylpyrrolidin-2-yl)-N-
((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-hydroxyethane-1-sulfonamide
and has the following chemical structure:
Compound F
In an embodiment the compound of formula (F) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(vii) Compound G having chemical name (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate
and has the following chemical structure:
Compound G
In an embodiment the compound of formula (G) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(viii) Compound H having chemical name 1,2,3,5,6,7-hexahydro-s-indacen-4-amine and
has the following chemical structure:
28
Compound H
In an embodiment the compound of formula (H) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(ix) Compound I having chemical name (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-
sulfonamide and has the following chemical structure:
Compound I
In an embodiment the compound of formula (I) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
(x) Compound J having chemical name (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-
((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide and has the
following chemical structure:
Compound J
In an embodiment the compound of formula (J) is controlled in formula (I-a) with the
limit of 0.01% to 2.0%.
The invention is further exemplified by the following non-limiting examples, which
are illustrative representing the preferred modes of carrying out the invention. The
invention’s scope is not limited to these specific embodiments only but should be read
in conjunction with what is disclosed anywhere else in the specification together with
29
those information and knowledge which are within the general understanding of a
person skilled in the art.
Example 1: Process for preparation of ethyl L-alaninate hydrochloride -
compound of formula (III-a).
L-alanine (3.0 Kg, 33.67 mol) was added in ethanol (30 L) in a 100 L glass assembly
at room temperature. Reaction mixture was cooled to 0 ºC to 5° C. Thionyl chloride
(12.02 Kg, 101 mol) was added carefully at 0 ºC to 5 oC over a period of 45 minutes.
Heated the reaction mixture to 80 to 85 ºC for 3 h. Concentrated the reaction mixture
in vacuum below at 65 °C to get oily residue which cool to 35 to 45 °C. Diisopropyl
ether (15 L x 2) was added in to oily residue to get off white colored solid and decant
solvent. Dry the solid in vacuum to get ethyl L-alaninate hydrochloride compound of
(III-a) 5.10 Kg.
Yield: 98.6%
Appearance: Off white colored solid.
MS (ESI-MS): m/z 118.10 (M-HCl+H)+.
1H NMR (400 MHz, DMSO-d6): δ 1.22 (t, J = 7.2 Hz, 3H), 1.42 (d, J = 7.2 Hz, 3H),
3.98 (q, J = 14 Hz, 7.2 Hz, 1H), 4.21-4.13 (m, 2H), 8.75 (s, 3H).
Example 2: Process for Preparation of ethyl (3-chloropropyl)-L-alaninate -
compound of formula (IV-a)
Ethyl L-alaninate hydrochloride (III-a) (5.1 Kg, 33.2 mol), diisopropylethyl amine
(12.86 kg, 99.60 mol), 1-Bromo-3-chloropropane (18.29 kg, 116.20 mol) and
tetrabutylammonium bromide (0.535 Kg, 1.660 mol) were added in acetonitrile (20.4
L) in 150 L SSR at room temperature. Reaction mixture was stirred for 72 h at room
temperature and further quenched with 20% aqueous citric acid solution (127.5 L) to
bring pH 3 to 4. Reaction mixture was then washed with n-Heptane (20.4 L x 2) and
aqueous layer was then basify with 4 N sodium hydroxide solution (95 L) to bring pH
9 to 10. Aqueous layer was extracted with methyl tertiary butyl ether (25.5 L x 2).
Organic layer was washed with 10% aqueous sodium bicarbonate solution (15.5 L) and
30
10% sodium chloride solution (10.2 L). Organic layer containing ethyl (3-
chloropropyl)-L-alaninate (IV-a) was used in next reaction without any further
purification.
Example 3: Process for Preparation of ethyl N-(tert-butoxycarbonyl)-N-(3-
chloropropyl)-L-alaninate - compound of formula (V-a)
Organic layer obtained from stage 2 was charged in a 150 L SSR, at room temperature.
Boc anhydride (6.81 kg, 31.2 mol) was added and the reaction mixture was stirred for
16 h at room temperature. Imidazole (0.565 Kg, 8.30 mol) was added and the reaction
mixture was stirred for 2 h at room temperature. The reaction mixture was washed with
aqueous 1 N hydrochloric acid solution (11.2 L x 3). Organic layer was washed with
5% aqueous sodium bicarbonate solution (11.25 L) followed by water (11.25 L) and
10% brine solution (11.25 L). Concentrated solvents in vacuum to get ethyl N-(tert-
butoxycarbonyl)-N-(3-chloropropyl)-L-alaninate (V-a) 7.51 Kg.
Yield: 77% (two steps yield)
Appearance: Pale yellow colored oil
MS (ESI-MS): m/z 194.09 (M-Boc+H)+
1H NMR (400 MHz, CDCl3): δ 1.24 (d, J = 6.8 Hz, 3H), 1.42-1.38 (m, 12H), 2.08-2.00
(m, 2H), 3.20 (d, J= 6.0 Hz, 1H), 3.65-3.43 (m, 3H), 4.17-4.09 (m, 2H).
Example 4: Process for Preparation of 1-(tert-butyl) 2-ethyl (R)-2-
methylpyrrolidine-1,2-dicarboxylate - compound of formula (VI-a)
Ethyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-L-alaninate (V-a) (5 Kg, 17.01
mol) was added in dimethyl sulfoxide (25 L) in a 50 L SSR, at room temperature.
Reaction mixture was cooled at 20 to 25 oC and potassium hydroxide (2.86 Kg, 51.05
mol) was added at 20 to 25oC and further reaction mixture was stirred for 3 h at room
temperature. The reaction mixture was dump in to water (125 L) and aqueous layer was
extracted with ethyl acetate (25 L x 3). Organic layer was washed with 10% aqueous
sodium chloride solution (25 L) and concentrated in vacuum to get 1-(tert-butyl) 2-
ethyl (R)-2-methylpyrrolidine-1, 2-dicarboxylate (VI-a) 4.160 Kg.
31
Yield: 95%
Appearance: Oily compound
MS (ESI-MS): m/z 280.16 (M+Na)+
1H NMR (CDCl3): δ 1.29-1.22 (m, 3H), 1.43 (d, J = 14Hz, 9H), 1.54 (d, J = 18.8 Hz,
3H), 1.95-1.85 (m, 3H), 2.19-2.14 (m, 1H), 3.60-3.48 (m, 2H), 4.23-4.08 (m, 2H)
Example 5: Process for Preparation of (R)-1-(tert-butoxycarbonyl)-2-
methylpyrrolidine-2-carboxylic acid - compound of formula (VII-a)
1-(tert-butyl) 2-ethyl (R)-2-methylpyrrolidine-1, 2-dicarboxylate (VI-a) (6.2 Kg,
24.093 mol) was added to the mixture of ethanol (12.4 L) and water (12.4 L) in 150 L
SSR at room temperature and the reaction mixture was further cooled at 15 to 20 oC.
Potassium hydroxide powder (13.5 Kg, 240.93 mol) was added at 15 to 35 oC and the
reaction mixture was stirred for 16 h at room temperature. The reaction mixture was
quenched with water (124 L) and aqueous layer was washed with dichloromethane (31
L x 2) and then aqueous layer was acidifying with 5 N aqueous hydrochloric acid (52.7
L) to bring pH 3 to 4. Aqueous layer was extracted with ethyl acetate (62 L x 1 and 31
L x 2). Combined all organic layer was concentrated in vacuum to get crude solid
product which was recrystallized with n-heptane (25.6 L) followed by cyclohexane (24
L). Filter the solid and dry it at 50-55 ºC for 16 h to get (R)-1-(tert-butoxycarbonyl)-2-
methylpyrrolidine-2-carboxylic acid (VII-a) 4.255 Kg.
Yield: 77%
Appearance: Off white colored solid
MS (ESI-MS): m/z 228.11 (M-H)+
1H NMR (400 MHz, MeOD): δ 1.45 (d, J = 7.6 Hz, 9H), 1.53 (d, J = 10.4 Hz, 3H),
2.02-1.89 (m, 3H), 2.27-2.18 (m, 1H), 3.56-3.47 (m, 2H)
HPLC Purity: 99.54 %
Chiral Purity: 100.00%
SOR +5.41° (0.5 % in Methanol at 20°C)
32
Example 6: Process for Preparation of tert-butyl (R)-2-(hydroxymethyl)-2-
methylpyrrolidine-1-carboxylate compound of formula (VIII-a)
(R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid - compound of
formula (VII-a) (3.75 Kg, 16.36 mol) was added in tetrahydrofuran ( 37. 5 L) in 100 L
GAR at room temperature under N2 atmosphere the reaction mixture was cooled at 0
to 10 oC. N-methyl morpholine (2.158 L, 19.63 mol.) was added followed by addition
of isobutyl chloroformate (2.58 L , 19.63 mol.) at 0 to 10 oC. Reaction mass was stir at
0 to 10 oC for 45 min. Reaction mixture was filtered and washed with THF (9.4 L x 2)
Collect filtrate i.e. Part A
Sodium borohydride (1.547 Kg, 40.9 mol.) was added in water (8.8 L, 488 mol.) in 100
L GAR at room temperature. The reaction mixture mixture was cooled to 0 to 10 oC,
Part-A filtrate was added dropwise at 0 to 10 oC, reaction mass was stir at room
temperature for 2 h. Reaction mass was quenched with water (22.5 L) filtered it,
aqueous layer was extracted with ethyl acetate (37.5 L x 3). Combined organic layers
were washed with brine (37.5 L), aq. Layer and brine layers were re-extracted with
ethyl acetate (9.36 L), Combined all organic layer was concentrated in vacuum to get
tert-butyl (R)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (VIII-a) as pale
yellow coloured liquid. 3.035 Kg (86 % yield)
Yield: 86%
Appearance: pale yellow coloured liquid
MS (ESI-MS): m/z 228.12 (M-H)+
SOR (0.6 % in chloroform at 21 oC): + 7.68 o
Example 7: Process for Preparation of tert-butyl (R)-2-formyl-2-
methylpyrrolidine-1-carboxylate compound of formula (X-a)
tert-butyl (R)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (XXI) (3.00 Kg,
13.93 mol) was dissolved in dichloromethane ( 30 L, 466 Vol.) in 100 L GAR at room
temperature and the reaction mixture was cooled at 15 to 20 oC. Pyridinium chloro
chromate (6.01 Kg, 27.9 mol.) was added portionwise at 15 to 20 oC. Reaction mass
was stir at room temperature for 16 hrs, n-hexane (30 L) was added stirred it for 30 min
33
and passed through celite bed, washed with n-hexane (15 L x 2), Combined all organic
layer was concentrated in vacuum to get tert-butyl (R)-2-formyl-2-methylpyrrolidine-
1-carboxylate (V) as oily compound 2.295 Kg ( 77 % yield).
Example 8: Process for Preparation of tert-butyl (R,E)-2-(2-(N-(tert-
butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate (XI-a)
tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (IX-a) (3.07 Kg, 7.76
mol) was added in N,N-Dimethyl formamide (23 L) in a 100 L GAR at room
temperature under Nitrogen gas atmosphere, It was cooled to 0 to 5 °C and added NaH
(0.988 Kg, mol). It was gradually warmed to 25 °C and stirred for 30 min. Again
cooled to 0 to 5 °C and a solution of tert-butyl (R)-2-formyl-2-methylpyrrolidine-1-
carboxylate (X-a) (2.3 Kg, 10.78 mol) in DMF (11.5 L) was added dropwise over a
period of 0.5 h at 0 to 10 °C temp. After the addition, reaction mixture was warmed to
r.t. and further stirred for 17 h. Reaction mixture was cooled to 10 to 15 °C and dumped
into ice cold water (105 L) at 10 to 15 ºC. Aqueous layer was washed with
Diisopropylether (23 L) and then aqueous layer was acidify with 50% aqueous citric
acid (11 L) to bring pH 3.5 to 4.5. Aqueous layer was extracted with ethyl acetate (34.5
L x 1 and 23 L x 2). Organic layer was washed with water (23 L x 2), 5% aqueous
sodium bicarbonate solution (11.5 L x 2) followed by 10% brine solution (11.5 L).
Combined aqueous of sodium bicarbonate and brine wash and adjust pH 5.8 to 6.3
using aqueous citric acid. Re-extracted with ethyl acetate (5.75 L x 2) Combined all
organic layer was concentrated in vacuum to get tert-butyl (R,E)-2-(2-(N-(tert-
butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate (XI-a) 2.680
Kg.
Yield: 63.6%
Appearance: Pale yellow colored oil
MS (ESI-MS): m/z 389.15 (M-H)+
Example 9: Process for Preparation of tert-butyl (R,E)-2-methyl-2-(2-
sulfamoylvinyl)pyrrolidine-1-carboxylate (XII-a)
34
tert-butyl(R,E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-
1-carboxylate (XI-a) (2.91 Kg, 7.45 mol) was dissolved in DMSO (14.55 L, 205 mol),
Water (0.145 L, 8.05 mol) & heated to 85oC to 90 oC for 45 min.. The reaction was
cooled, dumped into water (72.5 L) & extracted with EtOAc (29 L x 3). Combined
organic layer was washed with 10% brine solution (87 L). Combined all organic layer
was concentrated in vacuum and purified by Hexane /Diisopropylether to get (R,E)-2-
methyl-2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylate (XII-a) 1.85 Kg.
Yield: 85%
Appearance: Off white colored solid
MS (ESI-MS): m/z 289.15 (M-H)+
1H NMR (400 MHz, DMSO-d6): δ = 6.98 (s, 2H), 6.61 - 6.49 (m, 1H), 6.25 (d, J
= 15.2 Hz, 1H), 3.43 - 3.35 (m, 2H), 1.99 - 1.66 (m, 4H), 1.47 - 1.43 (m, 3H), 1.40 -
1.37 (m, 9H).
Example 10: Process for Preparation of tert-butyl (R,E)-2-(2-(N-((1,2,3,5,6,7-
hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-
carboxylate (XIV-a)
To a solution of the tert-butyl (R,E)-2-methyl-2-(2-sulfamoylvinyl)pyrrolidine-
lcarboxylate (XIII-a) (1.7 Kg, 5.85 mol) in DMF (13.6 bn L) at 0 to 5oC was added
NaH (60% dispersion in mineral oil) (0.307 Kg, 7.03 mol).The reaction was allowed
to warm to r.t. and stirred for 30 minutes. Solution of 4-isocyanato-1,2,3,5,6,7-
hexahydro-s-indacene (1.458 Kg, 7.32 mol) in N,N-dimethylformamide (1.7 L) was
added dropwise at 0 to 5oC the reaction mixture was warm to room temperature and
stirred for 16 h. Reaction mixture was cooled to 0 to 5 °C, cold water (6.8 L) was added
at 0 to 10 °C, dumped reaction mixture into water (78.2 L) at 25 to 35 °C. Stirred it for
1 h at room temperature. Filtered it and washed with water (17 L x 2). Combined filtrate
and acidify with 50% aqueous citric acid (9.0 L) to adjust pH 3 to 4, stirred it for 1 h
at room temperature. precipitate was filtered through Nutsch filter, purified with
hexane & dried to get tert-butyl (R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate (XIV-a) 2.606 Kg
35
Yield: 91%
Appearance: Pale cream colored solid
MS (ESI-MS): m/z 488.18 (M-H)+
1H NMR (400 MHz, DMSO-d6): S = 10.41 (s, 1H), 8.06 (s, 1H), 6.96 (s, 1H), 6.87
- 6.77 (m, 1H), 6.55 (d, J = 15.2 Hz), 3.43 - 3.37 (m, 2H), 2.81 (t, J = 6.8 Hz, 4H), 2.67
(t, J= 6.8 Hz, 4H), 2.00 - 1.93 (m, 5H), 1.86 - 1.65 (m, 3H), 1.41 - 1.43 (m,
3H), 1.40 - 1.38 (s, 9H).
Example 11: Process for Preparation of (R,E)-N-((1,2,3,5,6,7-hexahydro-s-
indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-
trifluoroacetate (XV-a)
To a solution of tert-butyl (R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate (XIV-a) (2.6 Kg,
5.31 mol) in DCM (13 L) was added trifluoroacetic acid (4.09 L, 53.1 mol) and stirred
for 2 h at room temperature. Dumped reaction mixture into mixture of water (52 L) and
diisopropylether (65 L) at room temperature. Stirred it for 1 h at room temperature,
filtered it, washed with diisopropylether (5.2 L x2) and dried to get (R,E)-N-
((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-
yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate (XV-a) 2.315 Kg
Yield: 87%
Appearance: Off white colored solid
MS (ESI-MS): m/z 390.13 (M+H)+.
1H NMR (DMSO-d6): δ = 9.218 (bs,2H), 8.715 (s,1H), 7.126-6.805 ( m,2H), 3.383-
3.317 (m,1H), 3.285-3.221 ( m,1H), 2.704-2.667- (m,4H), 2.139- 1.903 ( m,8H), 1.489
(s,3H).
36
Example 12: Process for Preparation of Form I of (R,E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (I-a)
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-
yl)ethene-1-sulfonamide compound 2,2,2-trifluoroacetaldehyde (XV-a) (2.3 kg, 4.57
mol) was added to water (23 L) in 100 L GAR at room temperature, added
triethylamine (0.764 L, 5.48 mol) followed by paraformaldehyde (1.097 kg, 36.5 mol)
and stir the reaction mixture was room temperature for 30 min. and the reaction mixture
was further cooled at 10 to 15 oC. Sodium borohydride (0.518 kg, 13.70 mol) was added
at 10 to 15 oC and the reaction mixture was stirred for 2 h at room temperature. The
reaction mixture was filtered and wash with water (2.3 L) and then aqueous layer was
acidifying with 20% citric acid soln. (5.1 L) to bring pH 7 to 7.5. Stir the reaction
mixture was 1 h at room temperature. Filter the solid and dry it at 55-60 ºC for 10-12 h
to get (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (I-a) (crude) 1.326 Kg, (R,E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (I-a) (crude) 1.320 Kg was added in Acetone
(13.20L ) a (10 vol.) in 20 L 4NRBF and refluxed for 2 h and further stirred for 2 h at
room temperature. The reaction mixture was filtered and wash with Acetone (1.32 L)
followed by Diisopropyl ether (2.64 L x 2) and dry it at 55-60 ºC for 12-16 h to get
Form I of (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-
4-yl)carbamoyl)ethene-1-sulfonamide (I-a) (pure) 1.181 Kg
Yield: 64%
HPLC=98.22%
Assay by HPLC=97.5%
1H NMR (D2O+NH3): δ = 7.108 (s,1H), 6.706-6.607 (q,2H), 2.920-2.884 (m,5H),
2.810-2.253 ( m,5H), 2.205, (m,3H), 2.106-2.033 ( m,4H), 1.954-1.794 ( m,4H), 1.243
( s,3H).
Polymorphic data (XRPD): Form I
37
2θ d value Relative Intensity
5.9° + 0.2° 14.93 28.3%
10.9° + 0.2° 8.07 17.3%
17.3 + 0.2° 5.11 23.0%
17.8 + 0.2° 4.95 100.0%
18.2+ 0.2° 4.85 38.2%
20.1 + 0.2° 4.39 15.4%
20.6 + 0.2° 4.29 12.5%
Example – 14: Process for preparation of Form-II of (R,E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (I-a)
Dissolve(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-
4-yl)carbamoyl)ethene-1-sulfonamide (I-a) (crude) (1.256 Kg) in a mixture of
Dichloromethane (50.24 Lit.) and Methanol (1.5 Lit.) and stirrer to get clear solution
and charged charcoal powder (62.8 gm) and stirred it for 30 min. at room temperature
. The reaction mixture was filtered through Hyflow and wash with Dichloromethane
(6.28 Lit. X 2) collected filtrate and evaporated under vacuum to get solid materials.
Strip out these solid materials with Acetone (1.256 Lit. X 2) and degas for 1 h at 40 oC
under vacuum to get 1.216 Kg of R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-
((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide (I-a) (Form-
II)
Polymorphic data (XRPD): Form II
2θ d value Relative Intensity
7.45° + 0.2° 11.84 45.9 %
10.5° + 0.2° 8.43 76.8 %
16.4 + 0.2° 5.40 59.6 %
38
19.6 + 0.2° 4.52 36.8 %
20.4 + 0.2° 4.35 100.0 %
20.9 + 0.2° 4.25 17.9 %
Example – 15: Process for preparation of Form-III of (R,E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (I-a)
Charged (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-
4-yl)carbamoyl)ethene-1-sulfonamide (I-a) (crude) (70 g) in a mixture of Isopropyl
alcohol (630 mL) and Water (70 mL) and stirred it for 1 h at room temperature . The
reaction mixture was filtered and wash with Isopropyl alcohol (70 mL) followed by
Diisopropyl ether (140 mL x 2) and dry it at 55-60 ºC for 5-6 h to get 61.5 g of (R,E)-
2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (I-a) (Form-III)
Polymorphic data (XRPD): Form III
2θ d value Relative Intensity
5.2° + 0.2° 17.3 14.0 %
10.2° + 0.2° 8.68 17.3 %
13.1 ± 0.2° 6.75 22.8 %
18.2 + 0.2° 4.86 100.0 %
19.3 + 0.2° 4.59 56.0 %
Example – 16: Process for preparation of amorphous form of (R,E)-2-(1,2-
dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-
yl)carbamoyl)ethene-1-sulfonamide (I-a)
Dissolve (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-
methylpyrrolidin-2-yl)ethene-1-sulfonamide (5 g) in a mixture of Tetrhydrofuran (150
39
mL) and Water (100 mL) to get clear solution. The resultant mass was passed through
a fine filter to remove particulate matter. The solvent is removed by spray drying of
feed stock solution to get amorphous (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-
((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide 1.0 g.
40
We claim:
1. process for the preparation of compound of formula (I):
Formula (I)
Where
B is selected from following ring system:
wherein X, Y, Z at each occurrence is independently selected from C, N, S, SO2, and
O, which may be optionally substituted;
R1 at each occurrence is independently selected from hydrogen, halogen, haloalkyl
optionally substituted groups selected from (C1-C6)alkyl;
R2 at each occurrence is independently selected from hydrogen, halogen, haloalkyl,
optionally substituted groups selected from (C1-C6)alkyl;
R3 and R4 is hydrogen;
X is N-R5; O, S, SO2;
R5 at each occurrence is independently selected from hydrogen, halogen, haloalkyl,
cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-
C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylSO2(C1-
C6)alkyl, (C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl,
heteroaryl, heterocyclyl, benzyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-
C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-
C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, -CO-
heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered
41
bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one
or more than one heteroatoms;
Each of R6, R7, R8, R9, R10 and R11 at each occurrence is independently selected from
hydrogen, halogen optionally substituted groups selected from (C1-C6)alkyl, (C1-
C6)haloalkyl;
Comprising following steps:
42
Step 1) reacting compound (II) with thionyl chloride in presence of one or more
solvents to obtain compound of formula (III);
Step 2) reacting compound (III) with 1-bromo-3-chloropropane in presence of base and
one or more solvent to obtain compound (IV);
Step 3) reacting compound (IV) with Boc anhydride in presence of base to obtain
compound of formula (V);
Step 4) compound (V) is dissolved in one or more solvent in presence of base to obtain
compound of (VI);
Step 5) compound (VI) is dissolved in one or more solvent in the presence of suitable
base to obtain compound (VII);
Step 6)
Part-A: reacting compound (VII) with isobutyl chloroformate in presence of base and
one or more solvent to obtain filterate;
Part-B: Sodium borohydride is dissolved in one or more solvent. Adding filterate
obtained from Part-A to the reaction mixture to obtain compound (VIII);
Step 7) reacting compound (VIII) with oxidizing agent in presence of one or more
solvent to obtain compound (X);
Step 8) compound (IX) is dissolved in one or more solvent in presence of base.
Compound (X) is dissolved in one or more solvent and obtained solution was adding
in the mixture of compound (IX) to obtain compound (XI);
Step 9) Compound (XI) is dissolved in one or more solvent and heated at suitable
temperature to obtain compound (XII);
Step 10) Compound (XII) is dissolved in one or more solvent in present of base.
Compound (XIII) is dissolved in one or more solvent and obtained solution was adding
dropwise in the mixture of compound (XII) to obtain compound (XIV);
Step 11) Compound (XIV) is dissolved in one or more solvent. Adding reagent in a
mixture of compound (XIV) to obtain compound (XV);
43
Step 12) Compound (XV) is dissolved in one or more solvent in presence of base and
reagent. Adding one or more reagent to the reaction mixture of compound (XV) to
obtain compound (I).
2. The process according to claim 1 in step 1, wherein one or more solvent is selected
from methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, toluene,
tetrahydrofuran, diisopropyl ether, methyl tertiary butyl ether and the like.
3. The process according to claim 1 in step 2, wherein one or more solvent is selected
from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone,
N,N-dimethylformamide, n-hexane, n-heptane and the like and the base used in step 2
is selected from N,N-diisopropylethylamine, triethylamine, pyridine, sodium
hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, DBU,
DBN, DABCO and the like.
4. The process according to claim 1 in step 3, wherein base is selected from imidazole,
N,N-diisopropylethylamine, triethylamine, pyridine, DBU, DBN, DABCO and the
like.
5. The process according to claim 1 in step 4, wherein one or more solvent is selected
from dimethyl sulfoxide, dimethylformamide, toluene, tetrahydrofuran, 1,4-dioxane,
dimethyl ether, Acetone, n-hexane, n-heptane and the like; base used in step 3 is
selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium
hydroxide, sodium carbonate, potassium bicarbonate, sodium hydride, potassium
hydride, potassium tert-butoxide, or sodium pentoxide, lithium diisopropylamide,
potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodamide and the
like.
6. The process according to claim 1 in step 5, wherein one or more solvent is selected
from water, methanol, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane,
acetonitrile, ethyl acetate, toluene, dichloromethane, n-hexane, n-heptane and the like;
base used in step 5 is selected from sodium hydroxide, potassium hydroxide, lithium
hydroxide, potassium tertiarybutoxide, lithium diisopropylamide, potassium
bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodamide and the like.
44
7. The process according to claim 1 in step 6, one or more solvent is selected from ethers
selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl
tert-butyl ether, water, ethyl acetate and the like; base used in step 6 is selected from
N-methyl morpholine, N,N-Diisopropylethyl amine, triethyl amine, pyridine, DBU,
DBN, DABCO and the like.
8. The process according to claim 1 in step 7, wherein one or more solvent is selected
from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone,
N,N-dimethylformamide, n-hexane, n-heptane, cyclohexane and the like; oxidizing
agents used in step-7 is selected from pyridinium chloro chromate, Pyridinium
Dichromate, chromium trioxide, Collins reagent, Swern oxidation and the like.
9. The process according to claim 1 in step 8, wherein one or more solvent is selected
from N,N-dimethylformamide, dimethylsulfoxide, toluene, ethers selected from
tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether
and the like; base used in step 8 is selected from sodium hydride, sodium hydroxide,
potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate,
potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydride,
potassium tert-butoxide or sodium pentoxide and the like.
10. The process according to claim 1 in step 9, wherein one or more solvent is selected
from dimethylformamide, dimethylsulfoxide, toluene. ethers, methanol, ethanol,
isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol, ethyl acetate, tetrahydrofuran,
1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether, n-hexane, n-
heptane and the like.
11. The process according to claim 1 in step 10, wherein one or more solvent is selected
from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone,
N,N-dimethylformamide, cyclohexane, n-hexane and the like; base used in step 10 is
selected from N-methyl morpholine, N,N-Diisopropylethylamine, triethyl amine,
N,N-diisopropylethylamine, pyridine, DBU, DBN, DABCO, sodium hydride, sodium
hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium
45
carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate,
potassium hydride, potassium tert-butoxide, or sodium pentoxide and the like.
12. The process according to claim 1 in step 11, wherein one or more solvent is selected
from dichloromethane, dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene,
pentane, n-hexane, n-heptane, cyclohexane, tetrahydrofuran, 1,4-dioxane, diisopropyl
ether, diethylether, methyl-tert-butyl ether, ethyl acetate, tetrahydrofuran, acetone,
N,N-dimethylformamide, water and the like; reagent used in step 11 is selected from
trifluoroacetic acid, hydrochloric acid, Methane sulphonic acid, Acetic acid, formic
acid and the like.
13. The process according to claim 1 in step 12, wherein one or more solvent is selected
from water, dichloromethane, dichloroethane, chlorobenzene, toluene, xylene,
ethylbenzene, pentane, n-hexane, n-heptane, cyclohexane, tetrahydrofuran, 1,4-
dioxane, diisopropyl ether, diethylether or methyl tertiary butyl ether and the like; base,
used in step 12 is selected from triethylamine, N,N-diisopropylethylamine, pyridine,
DBU, DBN, DABCO and the like; reagent is selected from p-formaldehyde, sodium
borohydride, Pd/C, Raney nickel, vitride, or lithium aluminium hydride and the like.
14. The process for the preparation of compound of formula (1-a)
46
comprising following steps:
47
Step 1-a) reacting compound (II-a) with thionyl chloride in presence of one or more
solvent are selected from methanol, ethanol, diisopropylether to obtain compound of
formula (III-a);
Step 2-a) reacting compound (III-a) with 1-bromo-3-chloropropane in presence of base
selected from N,N-diisopropylethylamine and one or more solvent are selected from
acetonitrile and n-heptane to obtain compound (IV-a).
Step 3-a) reacting compound (IV-a) with Boc anhydride in presence of imidazole to
obtain compound of formula (V-a).
Step 4-a) compound (V-a) is dissolved in one or more solvent is dimethylsulfoxide in
presence of potassium hydroxide to obtain compound of (VI-a).
Step 5-a) compound (VI-a) is dissolved in one or more solvent selected from ethanol,
water in the presence of suitable base selected from potassium hydroxide to obtain
compound (VII-a).
Step 6-a)
Part-A: reacting compound (VII-a) with isobutyl chloroformate in presence of N-
methyl morpholine and one or more solvent selected from tetrahydrofuran to obtain
filtrate;
Part-B: Sodium borohydride is dissolved in one or more solvent selected from
tetrahydrofuran. Adding filtrate obtained from Part-A to the reaction mixture to obtain
compound (VIII-a).
Step 7-a) reacting compound (VIII-a) with pyridinium chlorochromate in presence of
one or more solvent selected from dichloromethane to obtain compound (X-a).
Step 8-a: compound (IX-a) is dissolved in one or more solvent selected from N,N-
dimethylformamide in presence of base selected from sodium hydride. Compound (X-
a) is dissolved in one or more solvent selected from N,N-dimethylformamide and
obtained solution was adding in the mixture of compound (IX-a) to obtain compound
(XI-a).
48
Step 9-a) compound (XI-a) is dissolved in one or more solvent selected from
dimethylsulfoxide and heated at suitable temperature at 50ºC to 100ºC to obtain
compound (XII-a).
Step 10-a) compound (XII-a) is dissolved in one or more solvent is selected from N,N-
dimethylformamide in present of sodium hydride. Compound (XIII-a) is dissolved in
one or more solvent is N,N-dimethylformamide and obtained solution was adding
dropwise in the mixture of compound (XII-a) to obtain compound (XIV-a).
Step 11-a) compound (XIV-a) is dissolved in one or more solvent is dichloromethane.
Adding reagent trifluoroacetic acid in a mixture of compound (XIV-a) to obtain
compound (XV-a).
Step 12-a) compound (XV-a) is dissolved in one or more solvent selected from water,
acetone in presence of base selected from triethylamine, diisopropylethylamine and
reagent is p-formaldehyde. Adding one or more reagent sodium borohydride to the
reaction mixture of compound (XV-a) to obtain compound (I-a).
15. The compound of formula (I-a) either in crystalline or amorphous or partially
crystalline form.
16. The crystalline Form I of formula (I-a)
17. The crystalline Form I of formula (I-a) as claimed in claim 16 has a powder X-ray
diffraction pattern as given in Figure 1.
18. The crystalline Form I of formula (I-a) as claimed in claim 16 has characteristic powder
X-ray diffraction pattern peaks expressed at about 5.9 ± 0.2, 10.9 ± 0.2, 17.3 ± 0.2, 17.8
±0.2, 18.2± 0.2, 20.1 ± 0.2 and 20.6 ± 0.2 degrees 2-theta.
19. The crystalline Form II of formula (I-a).
20. The crystalline Form II of formula (I-a) as claimed in claim 19 has a powder X-ray
diffraction pattern as given in Figure 2.
21. The crystalline Form II of formula (I-a) as claimed in claim 19 has characteristic
powder X-ray diffraction pattern peaks expressed at about 7.4 ± 0.2, 10.5 ± 0.2, 16.4 ±
0.2, 19.6 ± 0.2, 20.4 ± 0.2 and 20.9 ± 0.2 degrees 2-theta.
22. The crystalline Form III of formula (I-a).
49
23. The crystalline Form III of formula (I-a) as claimed in claim 22 has a powder X-ray
diffraction pattern as given in Figure 3.
24. The crystalline Form III of formula (I-a) as claimed in claim 22 has characteristic
powder X-ray diffraction pattern peaks expressed at about 5.1 ± 0.2, 10.2 ± 0.2, 13.1 ±
0.2, 18.2± 0.2, and 19.3 ± 0.2 degrees 2-theta.
25. The amorphous compound of formula (I-a).
26. The amorphous compound of formula (I-a) as claimed in claim 24 has a powder X-ray
diffraction pattern as given in Figure 4.
27. Compound of Formula (A) to Formula (J).