DESC:FIELD OF INVENTION
The present invention relates to method of synthesizing an amine derivative
intermediate 2-(tert-butyl dimethylsilyl) oxy 2-(3-chlorophenyl).
5 BACKGROUND OF INVENTION
In Eur. J. Med. Chem (1994) R Cecchil, T Crocil, R Boigegrainz et al, Elsevier
discloses the synthesis of atypical P-adrenergic phenylethanolaminotetralin
stereoisomers.
10 In Chinese Chemical Letters 23 (2012), Shi Wen Xia a, et al, discloses the preparation
of (R)-2-chloro-1-(m-chlorophenyl)ethanol by using enzyme namely Lipozyme TL IMcatalyzed second resolution. Discloses a novel and practical preparation of said
intermediate with 40% yield by using Lipozyme TL IM in the presence of vinyl acetate
based on the second resolution strategy (R)-2-chloro-1-(m-chlorophenyl)ethanol, a
15 precursor of a very important key intermediate for b- adrenergic receptor agonists.
AU688165B2 discloses an indole derivatives and their method of synthesis 2-[3-(7-
ethoxyindol-3-yl)-2-propylamino]-1- (3-chlorophenyl)ethanol, or a salt thereof that are
being potent to beta-adrenergic receptor stimulating agent with excellent
20 adrenoreceptor.
In Chem. Pharm. Bull. 53(2) 184—198 (2005), Hiroshi HARADA, Discovery of a
Novel and Potent Human and Rat b 3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-
Chlorophenyl)-2-hydroxyethyl]amino]propyl]- 1H-indol-7-yloxy]acetic Acid. Finally,
25 optical resolution led to the identification of the most promising compound, [3-[(2R)-
[[(2R)-(3-chlorophenyl)-2-hydroxyethyl] amino]propyl]-1H-indol-7-yloxy]acetic acid
(96, AJ-9677). A novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were
prepared.
30 WO2004089936A1 discloses a novel hetero aryl sulphonanilide derivative represented
by the general formula [I]. It has potent ß3 receptor-stimulating activity, shows
3
excellent selectivity, and is useful as a ß3 adrenergic receptor agonist having excellent
pharmacokinetic activity.
In EP1366016B1 discloses an improved process for preparing aryl ethanol diamine
5 derivatives. The process of the present invention offers the advantage of achieving
higher yields than previous processes: the process is shorter involving fewer steps, the
reactions are more selective, e.g. the regioselectivity of epoxide opening is highly
selective.
Compounds which are agonists at atypical ß-adrenoceptors are described, for example,
10 in WO 97/21665, WO 97/21666, WO 98/43953, WO 99/65877, WO95/33724,
EP0455006 and EP 0543662.
In US7709677 discloses the improved process for preparing aryl ethanol diamine
derivatives. Process is shorter involving fewer steps, the reactions are more selective,
15 e.g. the regioselectivity of epoxide opening is highly selective.
US20170114005A1 application also relates to methods of preparing Solabegron
hydrochloride from the Solabegron Zwitterion. These compounds are useful in the
processes for the preparation of Solabegron and compositions comprising compounds
20 useful for therapeutic purposes.
Phenethanolamine derivatives having activity at ß-adrenoceptors are disclosed in, for
example, European Patent Applications EP-A-0455006 and EP-A-0543662.
All the above process for the synthesis of phenethanolamine derivatives more specially
25 Rafabegron, Amibegron & Solabegron are lengthiest routes, less stable regiospecific
isomers and are expensive in nature.
Besides the non-availability of methods for the preparation of amine derivative
intermediate in state of the art, there is a need for an improved synthesis of stable amine
30 derivative intermediate 2-(tert-butyl dimethylsilyl) oxy 2-(3-chlorophenyl) that is
simple and economically significant at a large scale.
4
OBJECT OF THE PRESENT INVENTION
The object of the invention is to provide an improved method of synthesizing an amine
derivative intermediate 2-(tert-butyl dimethylsilyl) oxy 2-(3-chlorophenyl) formula (V)
from formula (A).
5 Another object of the invention is method of synthesizing a 1,1'-biphenyl derivative of
formula (Va) or a pharmaceutically acceptable salt or a solvate thereof.
Another object of the invention is method of synthesizing a tetrahydronaphthalenyloxy
derivative of formula (Vb) or a pharmaceutically acceptable salt or a solvate thereof.
Another object of the invention is method of synthesizing an indolyloxy derivative of
10 formula (Vc) or a pharmaceutically acceptable salt or a solvate thereof.
Yet another object of the invention is to provide the preparation formula (I) from (Va)
and their pharmaceutically acceptable salt or a solvate thereof.
Yet another object of the invention is to provide the preparation formula (II) from (Vb)
and their pharmaceutically acceptable salt or a solvate thereof.
15 Yet another object of the invention is to provide the preparation formula (III) from (Vc)
and their pharmaceutically acceptable salt or a solvate thereof.
SUMMARY OF THE PRESENT INVENTION:
Accordingly, there is provided an improved method of synthesizing an amine derivative
20 intermediate 2-(tert-butyl dimethylsilyl) oxy 2-(3-chlorophenyl) formula (V).
The main aspect of the invention is to provide a method of synthesizing an intermediate
(R)-2-((tert-butyldimethylsilyl) oxy)-2-(3-chlorophenyl) ethan-1-amine derivative of
formula (V), from 2-bromo-1-(3-chlorophenyl) ethan-1-one of formula (A).
(A)
Cl
O
Br
25
comprising of the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), followed by the
protection of hydroxy group of formula (VI) is carried out using protecting agents
5
Pivaloyl chloride, tert butyl ether, THP, TBDMS or TMS, more preferably TBDMS
to obtain formula (VII);
a) optional amination of (A) is carried in the presence of ammonia or ammonia
substitutes such as NHR3 where R3 is H, benzyl halide, 1-Bromo-2-
5 chloroethane/1,2-dibromo ethane in acetone, Toluene, DMF, methanol THF,
isopropyl alcohol, ethanol or 1,4-Dioxane using base K2CO3, Na2CO3, Cs2CO3
to obtain formula (Aa);
b) optional reaction of 1,2-dibromo ethane to formula (Aa) to obtain formula
(VIa);
Cl
OH
Br
(VI)
Cl
O
Br
(VII)
Si
Cl
O
Br
(A)
(Aa)
Cl
O
N
Br
(VIa)
Cl
O
H
N
10
ii) amination of formula (VII) is carried in presence of ammonia or ammonia
substitutes such as NHR3 where R3 is H, benzyl halide, 1-Bromo-2-chloroethane/1,2-
dibromo ethane in acetone, Toluene, DMF, methanol THF, isopropyl alcohol, ethanol
or 1,4-Dioxane using base K2CO3, Na2CO3, Cs2CO3 to obtain formula (VIII) or
15 formula (VIIIa);
a) optional asymmetric reduction of formula (VIa), and protection of alcohol
group of formula (VIa) is carried out using protecting agents Pivaloyl chloride,
tert-butyl ether, THP, TBDMS or TMS, more preferably TBDMS to obtain
formula (VIIIa);
20
6
iii) condensation of formula (VIII) with R2 followed by deprotection to obtain
formula (V); where R1 is H and R2 is (or)
(or)
N
H
HN
O
OMe
O
.
Another aspect of the invention is to provide the preferred synthesizing formula
5 (V), comprising the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS to
obtain formula (VII);
a) optional amination of formula (Aa) is carried in presence of ammonia
10 or ammonia substitutes such as NHR3 further protection of R3 with
benzyl bromide, 1,2-dibromo DMF/K2CO3 or acetonitrile/ K2CO3 to
obtain formula (VIa);
ii) amination of formula (VII) in presence of ammonia derivative in methanol
followed by protection of NHR3 is carried out using benzyl bromide in
15 acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (VIII) further with 1,2-
dibromoethane in acetonitrile/K2CO3 or DMF/K2CO3 to obtain and formula
(VIIIa);
a) optional asymmetric reduction of formula (VIa) followed by protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS
20 to obtain formula (VIIIa);
iii) condensation of formula (VIIIa) with methyl 3'-(benzylamino)-[1,1'-
biphenyl]-3-carboxylate(R2) in acetonitrile/K2CO3 or DMF/K2CO3 to obtain
formula (Va’) or (Va”);
7
iv) deprotection of formula (Va’) or (Va”) using 10% Pd/C and methanol or
ethanol to obtain formula (V), preferably formula (Va) with the substitution of
R1 is H and R2 is
5
Another aspect of the invention is to provide the preferred synthesizing formula
(V), comprising the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
alcohol group of formula (VI) is carried out using TBDMS to obtain formula
10 (VII);
a) optional amination of formula (Aa) is carried in presence of ammonia or
ammonia substitutes such as NHR3 further protection of R3 with benzyl
bromide, 1,2-dibromo ethane DMF/K2CO3 or acetonitrile/ K2CO3 to obtain
formula (VIa);
15 ii) amination of formula (VII) in presence of ammonia derivative in methanol
followed by protection of NHR3 is carried out using benzyl bromide in
8
acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (VIII) further with 1,2-
Dibromoethane in acetonitrile/K2CO3 or DMF/K2CO3 to obtain and formula
(VIIIa);
iii) condensation of formula (VIII) with ethyl (S)-2-((7-amino-5,6,7,8-
5 tetrahydronaphthalen-2-yl)oxy)acetate [Amine derivative of R2] or formula
(VIIIa) with ethyl 2-((5,6,7,8-tetrahydro naphthalen-2-yl) oxy) acetate (R2) in
acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (Vb);
a) optional asymmetric reduction of formula (VIa) followed by protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS to
10 obtain formula (VIIIa);
Cl
O R3
N
Si
O
O
O
(VIIIa)
(R2
)
Cl N O
O
O
O
Si
(Vb)
Cl
O
Br
(VII)
amine derivative of
(R2
)
O
O
O
HN
Si
iv) deprotection of formula (Vb) using 10% Pd/C and methanol to obtain
formula (V), preferably formula (Vb) with the substitution of R1 is H and R2 is
or
O
O
O
HN
15
9
Another aspect of the invention is to provide the preferred synthesizing formula
(V), comprising the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS
5 obtain formula (VII);
ii) condensation of formula (VIII) with (R)-2-((3-(2-(benzylamino)propyl)-1Hindol-7-yl) oxy)acetic acid (R2) in acetonitrile/K2CO3 or DMF/K2CO3,
isopropanol or toluene to obtain formula (Vc);
a) optional condensation of formula (A) with (R)-2-((3-(2-(benzylamino)
10 propyl)-1H-indol-7-yl)oxy)acetic acid (R2) in acetonitrile/K2CO3 to obtain
formula (X);
Cl
O
N
CH3
N
H
(X) O
HN
CH3
N
H
O
Amine derivative of R2
Cl
O
Br
(VII)
Si
Si
OH
O
OH
O
Cl
O
Br
(A)
Cl
O
R1
N
N
H
O
O
H
O
(VIII)
HN
CH3
N
H
O
Amine derivative of R2
OH
O
iii) deprotection of formula (X) using 10% Pd/C in methanol, ethanol to obtain
formula (Vc), preferably formula (Vc) with the substitution of R1 is H and R2 is
HN
CH3
N
H
O OH
O
15
10
Yet another aspect of the invention is a compound represented by the following
chemical formula (V), or a pharmaceutically acceptable salt or a solvate thereof:
5 wherein,
R2 is H, (or) (or)
HN
CH3
N
H
O OH
O
; and
R
1
is H; substituted or unsubstituted straight or branched C1 to C5 alkyl group,
alkoxy group, aryloxy group, phenyl group; benzyl group.
10
Yet another aspect of the invention is a compound represented by the following
chemical formula (Va), or a pharmaceutically acceptable salt or a solvate
thereof:
where R1 is H or benzyl and R2 is
HN
CO2Me
15 .
11
Yet another aspect of the invention is a compound represented by the following
chemical formula (Vb), or a pharmaceutically acceptable salt or a solvate
thereof:
where R1 is H or benzyl and R2 is
5 .
Yet another aspect of the invention is a compound represented by the following
chemical formula (Vc), or a pharmaceutically acceptable salt or a solvate
thereof:
where R1 is H or benzyl and R2 is
HN
CH3
N
H
O OH
O
10
Still another aspect of the invention is to provide a method of synthesizing
formula (I) from intermediate formula (Va).
Still another aspect of the invention is to provide a method of synthesizing
15 formula (II) from intermediate formula (Vb).
Still another aspect of the invention is to provide a method of synthesizing
formula (III) from intermediate formula (Vc).
Yet another aspect of the invention is to provide an alternative route of
synthesizing formula (I) comprising the steps of:
12
i) chiral epoxidation of 3-chlorobenzaldehyde of formula (IX) with chiral
sulphide derivative formula (X), in presence of base such as potassium
hydroxide, sodium hydroxide, or lithium hydroxide, and in tert-butyl alcohol,
isopropyl alcohol, or methanol to obtain (R)-2-(3-Chloro phenyl) oxirane of
5 formula (XI);
ii) condensation of formula (XI) with formula (XII) in Toluene and NH4OH to
obtain formula (XIII);
iii) reduction of formula (XIII) to formula (I)
10
Yet another aspect of the invention is to provide an alternative route of
synthesizing formula (I) comprising the steps of:
i) chiral epoxidation of 3-chlorobenzaldehyde of formula (IX) with chiral
sulphide derivative formula (X), in presence of base such as potassium
15 hydroxide, sodium hydroxide, or lithium hydroxide, and in tert-butyl alcohol,
isopropyl alcohol, or methanol to obtain (R)-2-(3-Chloro phenyl)oxirane of
formula (XI);
ii) condensation of formula (XI) with ethyl (S)-2-((7-amino-5,6,7,8-
tetrahydronaphthalen-2-yl)oxy)acetate in Toluene and NH4OH to obtain formula
20 (II);
.
Yet another aspect of the invention is to provide an alternative route of
25 synthesizing formula (I) comprising the steps of:
13
i) chiral epoxidation of 3-chlorobenzaldehyde of formula (IX) with chiral
sulphide derivative formula (X), in presence of base such as potassium
hydroxide, sodium hydroxide, or lithium hydroxide, and in tert-butyl alcohol,
isopropyl alcohol, or methanol to obtain (R)-2-(3-Chlorophenyl) oxirane of
5 formula (XI);
ii) condensation of formula (XI) with (R)-2-((3-(2-aminopropyl)-1H-indol-7-
yl)oxy)acetic acid ester in Toluene and NH4OH to obtain formula (III).
10
BRIEF DESCRIPTION OF DRAWINGS
Fig 1: Illustrates the schematic route of synthesis of formula (Va)
Fig 2: Illustrates the schematic route of synthesis of formula (Vb)
Fig 3: Illustrates the schematic route of synthesis of formula (Vc)
15
DETAILED DESCRIPTION OF INVENTION
The invention describes a method of synthesizing an amine derivative intermediate
2-(tert-butyl dimethylsilyl) oxy 2-(3-chlorophenyl) formula (V).
In some embodiment of the invention is to provide a method of synthesizing an
20 intermediate (R)-2-((tert-butyldimethylsilyl) oxy)-2-(3-chlorophenyl) ethan-1-
amine derivative of formula (V), from 2-bromo-1-(3-chlorophenyl) ethan-1-one of
formula (A).
(A)
Cl
O
Br
comprising of the following steps:
25 i) asymmetric reduction of formula (A) to obtain formula (VI), followed by
protection of alcohol group of formula (VI) is carried out using protecting agents
14
Pivaloyl chloride, tert butyl ether, THP, TBDMS or TMS, more preferably TBDMS
to obtain formula (VII);
a) optional amination of (A) is carried in presence of ammonia or ammonia
substitutes such as NHR3 where R3 is H, benzyl halide, 1,2-dibromo ethane in
5 acetone, Toluene, DMF, methanol THF, isopropyl alcohol, ethanol or 1,4-
Dioxane using base K2CO3, Na2CO3, Cs2CO3 to obtain formula (Aa);
b) optional reaction of ethyl bromine to formula (Aa) to obtain formula (VIa);
Cl
OH
Br
(VI)
Cl
O
Br
(VII)
Si
Cl
O
Br
(A)
(Aa)
Cl
O
N
Br
(VIa)
Cl
O
H
N
ii) amination of formula (VII) is carried in presence of ammonia or ammonia
10 substitutes such as NHR3 where R3 is H, benzyl halide, 1,2-dibromo ethane in acetone,
Toluene, DMF, methanol THF, isopropyl alcohol, ethanol or 1,4-Dioxane using base
K2CO3, Na2CO3, Cs2CO3 to obtain formula (VIII) or formula (VIIIa);
a) optional asymmetric reduction of formula (VIa), and protection of alcohol
group of formula (VIa) is carried out using protecting agents Pivaloyl chloride,
15 tert-butyl ether, THP, TBDMS or TMS, more preferably TBDMS to obtain
formula (VIIIa);
15
iii) condensation of formula (VIII) with R2 followed by deprotection to obtain
formula (V); where R1 is H and R2 is (or)
(or)
N
H
HN
O
OMe
O
.
5 Another embodiment of the invention is to provide the preferred synthesizing
formula (V), comprising the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS to
obtain formula (VII);
10 a) optional amination of formula (Aa) is carried in presence of ammonia
or ammonia substitutes such as NHR3 further protection of R3 with
benzyl bromide, 1,2-dibromo DMF/K2CO3 or acetonitrile/ K2CO3 to
obtain formula (VIa);
Cl
OH
Br
(VI)
Cl
O
Br
(VII)
Si
Cl
O
Br
(A)
(Aa)
Cl
O
N
Br
(VIa)
Cl
O
H
N
15 ii) amination of formula (VII) in presence of ammonia derivative in methanol
followed by protection of NHR3 is carried out using benzyl bromide in
acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (VIII) further with 1,2-
Dibromoethane in acetonitrile/K2CO3 or DMF/K2CO3 to obtain and formula
(VIIIa);
16
a) optional asymmetric reduction of formula (VIa) followed by protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS
to obtain formula (VIIIa);
5 iii) condensation of formula (VIIIa) with methyl 3'-(benzylamino)-[1,1'-
biphenyl]-3-carboxylate(R2) in acetonitrile/K2CO3 or DMF/K2CO3 to obtain
formula (Va’) or (Va”);
iv) deprotection of formula (Va’) or (Va”) using 10% Pd/C and methanol or
ethanol to obtain formula (V), preferably formula (Va) with the substitution of
10 R1 is H and R2 is
Another embodiment of the invention is to provide the preferred synthesizing
formula (V), comprising the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
15 alcohol group of formula (VI) is carried out using TBDMS to obtain formula
(VII);
a) optional amination of formula (Aa) is carried in presence of ammonia or
ammonia substitutes such as NHR3 further protection of R3 with benzyl
bromide, 1,2-dibromo DMF/K2CO3 or acetonitrile/ K2CO3 to obtain formula
20 (VIa);
Cl
OH
Br
(VI)
Cl
O
Br
(VII)
Si
Cl
O
Br
(A)
(Aa)
Cl
O
N
Br
(VIa)
Cl
O
H
N
17
ii) amination of formula (VII) in presence of ammonia derivative in methanol
followed by protection of NHR3 is carried out using benzyl bromide in
acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (VIII) further with 1,2-
Dibromoethane in acetonitrile/K2CO3 or DMF/K2CO3 to obtain and formula
5 (VIIIa);
iii) condensation of formula (VIII) with ethyl (S)-2-((7-amino-5,6,7,8-
tetrahydronaphthalen-2-yl)oxy)acetate [Amine derivative of R2] or formula
(VIIIa) with ethyl 2-((5,6,7,8-tetrahydro naphthalen-2-yl) oxy) acetate (R2) in
acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (Vb);
10 a) optional asymmetric reduction of formula (VIa) followed by protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS
to obtain formula (VIIIa);
iv) deprotection of formula (Vb) using 10% Pd/C and methanol to obtain
15 formula (V), preferably formula (Vb) with the substitution of R3 is H and R2 is
(or)
O
O
O
HN
Another embodiment of the invention is to provide the preferred synthesizing
formula (V), comprising the following steps:
20 i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS
obtain formula (VII);
ii) condensation of formula (VIII) with (R)-2-((3-(2-(benzylamino)propyl)-1Hindol-7-yl) oxy)acetic acid (R2) in acetonitrile/K2CO3 or DMF/K2CO3,
25 isopropanol or toluene to obtain formula (Vc);
18
a) optional condensation of formula (A) with (R)-2-((3-(2-(benzylamino)
propyl)-1H-indol-7-yl)oxy)acetic acid (R2) in acetonitrile/K2CO3 to obtain
formula (X);
Cl
O
N
CH3 N
H
(X) O
HN
CH3 N
H
O
Amine derivative of R2
Cl
O
Br
(VII)
Si
Si
OH
O
OH
O
Cl
O
Br
(A)
Cl
O
R1 N
N
H
O
O
H
O
(VIII)
HN
CH3 N
H
O
Amine derivative of R2
OH
O
5 iii) deprotection of formula (X) using 10% Pd/C in methanol, ethanol to obtain
formula (Vc), preferably formula (Vc) with the substitution of R1 is H and R2 is
HN
CH3
N
H
O OH
O
Yet another embodiment of the invention is a compound of formula (V),
Cl
O
N
Si
R1
R2
10
(A)
where R2 is H, or or
HN
CH3
N
H
O OH
O
; and
19
R1 is H; substituted or unsubstituted straight or branched C1 to C5 alkyl group,
alkoxy group, aryloxy group, phenyl group; benzyl group, results in three
different intermediates with the above said R2 substitutes,
more preferably chemical formula (Va), or a pharmaceutically acceptable salt or
5 a solvate thereof:
where R1 is H or benzyl and R2 is
HN
CO2Me
.
more preferably chemical formula (Vb), or a pharmaceutically acceptable salt or
10 a solvate thereof:
where R1 is H or benzyl and R2 is
O
O
O
.
more preferably chemical formula (Vc), or a pharmaceutically acceptable salt or
a solvate thereof:
20
where R1 is H or benzyl and R2 is
HN
CH3
N
H
O OH
O
Still another embodiment of the invention is to provide a method of synthesizing
formula (I) from intermediate formula (Va).
5 Still another embodiment of the invention is to provide a method of synthesizing
formula (II) from intermediate formula (Vb).
Still another embodiment of the invention is to provide a method of synthesizing
formula (III) from intermediate formula (Vc).
Yet another embodiment of the invention is to provide an alternative route of
10 synthesizing formula (I) comprising the steps of:
i) chiral epoxidation of 3-chlorobenzaldehyde of formula (IX) with chiral
sulphide derivative formula (X), in presence of base such as potassium
hydroxide, sodium hydroxide, or lithium hydroxide, and in tert-butyl alcohol,
isopropyl alcohol, or methanol to obtain (R)-2-(3-Chloro phenyl) oxirane of
15 formula (XI);
ii) condensation of formula (XI) with formula (XII) in Toluene and NH4OH to
obtain formula (XIII);
iii) reduction of formula (XIII) to formula (I)
20
21
Yet another embodiment of the invention is to provide an alternative route of
synthesizing formula (I) comprising the steps of:
i) chiral epoxidation of 3-chlorobenzaldehyde of formula (IX) with chiral
sulphide derivative formula (X), in presence of base such as potassium
5 hydroxide, sodium hydroxide, or lithium hydroxide, and in tert-butyl alcohol,
isopropyl alcohol, or methanol to obtain (R)-2-(3-Chloro phenyl)oxirane of
formula (XI);
ii) condensation of formula (XI) with ethyl (S)-2-((7-amino-5,6,7,8-
tetrahydronaphthalen-2-yl)oxy)acetate in Toluene and NH4OH to obtain formula
10 (II);
.
Yet another embodiment of the invention is to provide an alternative route of
15 synthesizing formula (I) comprising the steps of:
i) chiral epoxidation of 3-chlorobenzaldehyde of formula (IX) with chiral
sulphide derivative formula (X), in presence of base such as potassium
hydroxide, sodium hydroxide, or lithium hydroxide, and in tert-butyl alcohol,
isopropyl alcohol, or methanol to obtain (R)-2-(3-Chlorophenyl) oxirane of
20 formula (XI);
ii) condensation of formula (XI) with (R)-2-((3-(2-aminopropyl)-1H-indol-7-
yl)oxy)acetic acid ester in Toluene and NH4OH to obtain formula (III).
25 The method of synthesizing of formula (V) of the above reactions the amination is
carried out using ammonia in methanol, THF, Isopropyl alcohol, ethanol, or 1,4-
Dioxane.
22
The method of synthesizing of formula (V) of the above reactions the protection of
OH is carried out using protecting agents such as THP, TBDMS, TMS; and NH
protection is carried out using protecting agents such as benzyl bromide, benzyl
5 chloride, benzyl iodide, in solvents such as acetone, THF, DMF, acetonitrile, 2-
methyl THF, MIBK, halo solvents using base K2CO3, Na2CO3, Cs2CO3, imidazole.
The method of synthesizing of formula (V) of the above reactions, the deprotection
is carried out using Pd/C.
The above methods for synthesis of amine derivative intermediate 2-(tert-butyl
10 dimethylsilyl) oxy 2-(3-chlorophenyl) is highly stable, pure and economically
significant at a large scale.
Examples:
Example 1: Synthesis of 2-bromo-1-(3-chlorophenyl)ethan-1-one (A):
Cl
O
Br
(A)
Cl
O
(IV)
15
Under a nitrogen atmosphere, 3'-chloroacetophenone (154.6 g, 1 mol) and methanol
(310 ml) dried with molecular sieves were charged in a four-necked flask. Bromine
(158.2 g, 1.0 mol) was added dropwise with stirring at a temperature in a range
from 35° to 45°C, over one hour, and the mixture was maintained at the same
20 temperature for 10 minutes. After water (160 g) was added, the solution was cooled
to -10°C to precipitate crystals which were filtered to obtain 250 g of a crude cake.
This crude cake was dissolved in heptane (750 g), and the solution was washed
twice with water (200g), dried over anhydrous sodium sulfate, filtered, washed, and
then concentrated to obtain 212.5 g of title with 91% yield.
25 Example 2: Synthesis of (R)-2-bromo-1-(3-chlorophenyl)ethan-1-ol (VI):
Cl
OH
Br
(VI)
Cl
O
Br
(A)
23
Under a nitrogen atmosphere, R-Methyl-CBS (0.05m.eq.) and Borane-DMS (1.0
m.eq.) was taken in a four-necked flask contains 100ml THF. Compound (A)
(10.0gr, 0.043 moles) was dissolved in 50ml THF and was added to the above
mixture solution at -100C for 15-30min. The mixture was maintained at the same
5 temperature for another 120 minutes. After TLC, the reaction mass was quenched
with methanol and added with 150ml water. Extracted the product into ethyl
acetate 3 x 50ml. Combined ethyl acetate layers was washed with water and dried
over anhydrous sodium sulfate, and then concentrated to obtain crude product.
Crude product stirred in hexane 75ml for 2 – 3hours. Filtered, washed, and dried at
450
10 C to get the product with 90% yield.
Example 3: Synthesis of (R)-(2-bromo-1-(3-chlorophenyl)ethoxy)(tertbutyl)dimethylsilane (VII):
Charge (R)-2-bromo-1-(3-chlorophenyl)ethan-1-ol, Chloroform (50ml) and
15 Imidazole into a 4 neck RBF. A solution of TBDMSCl and Chloroform (50ml) was
added to the above RM at RT for 30 – 45min. Heat the RM to reflux and maintain
the RM at reflux for 2 – 3hours. Check TLC for the reaction completion. If TLC
complies, cool the RM to RT. Add 3% aq. HCl solution to the RM at 10 – 200C for
15 – 30 min. Stir the RM for 15 – 30min at the same temperature. Separate the
20 layers. Extract aqueous layer into chloroform (50ml). Combine both the organic
layers and wash with water (100ml). Distill off the solvent under vacuum at below
500C. Add cyclohexane-(25ml) to the crude compound and cool the RM to 15 –
200C. Maintain at the same temperature for 30 - 60min. Filter and wash the
product with cyclohexane (12.5ml) to get the product with 85% yield.
25 Example 4: Synthesis of (R)-N-benzyl-2-((tert-butyldimethylsilyl)oxy)-2-(3-
chlorophenyl)ethan-1-
amine (VIII):
24
3.4 gr(0.032moles) of Benzyl amine, 4.9gr (0.036moles) of potassium carbonate,
0.1 eq of KI, 0.05eq of TBAB were charged into a RB flask contains 50ml DMF.
Prepare a solution of VII (10gr, 0.0286moles) in DMF 50ml was added to the above
5 mixture slowly for 15 – 20 min at room temperature. Heat the reaction mass to 100
– 1100C and maintain at the same temperature till reaction completes. Cool the
reaction mass to RT after reaction completion. Add water 250ml and extract into
ethyl acetate 3 x 75ml. Combined ethyl acetate washed with water, dried over
anhydrous sodium sulphate. Distill off the solvent under vacuum at below 500C to
10 get the product with 85% yield.
Example 5: Synthesis of (R)-N-benzyl-N-(2-bromoethyl)-2-((tertbutyldimethylsilyl)oxy)-2-(3-chlorophenyl) ethan-1-amine (VIIIa):
15 5.0 gr(0.013moles) of VIII, 2.3gr (0.017 moles) of potassium carbonate, 0.1 eq of
KI, 0.05eq of TBAB were charged into a RB flask contains 50ml DMF. Prepare a
solution of 1-Bromo-2-chloroethane (2.8gr, 0.02moles) in DMF 50ml was added to
the above mixture slowly for 15 – 20 min at room temperature. Heat the reaction
mass to 100 – 1100C and maintain at the same temperature till reaction completes.
20 Cool the reaction mass to RT after reaction completion. Add water 250ml and
extract into ethyl acetate 3 x 75ml. Combined ethyl acetate washed with water,
dried over anhydrous sodium sulphate. Distill off the solvent under vacuum at
below 500C to get the product (VIIIa) with 80% yield.
25 Example 6: Synthesis of 2-(benzylamino)-1-(3-chlorophenyl)ethan-1-one (Aa):
25
Cl
O
Br
(A)
Cl
O
H
N
(Aa)
5.07 gr(0.047moles) of Benzyl amine, 7.4gr (0.054moles) of potassium carbonate,
0.1 eq of KI, 0.05eq of TBAB were charged into a RB flask contains 50ml DMF.
Prepare a solution of A (10gr, 0.043moles) in DMF 50ml was added to the above
5 mixture slowly for 15 – 20 min at room temperature. Heat the reaction mass to 100
– 1100C and maintain at the same temperature till reaction completes. Cool the
reaction mass to RT after reaction completion. Add water 250ml and extract into
ethyl acetate 3 x 75ml. Combined ethyl acetate washed with water, dried over
anhydrous sodium sulphate. Distill off the solvent under vacuum at below 500C to
10 get the product with 87% yield.
Example 7: Synthesis of 2-(benzyl(2-bromoethyl)amino)-1-(3-
chlorophenyl)ethan-1-one (VIa):
Cl
O
NH
(Aa)
Cl
O
N
Br
(VIa)
15 5.0 gr(0.013moles) of VIII, 2.3gr (0.017 moles) of potassium carbonate, 0.1 eq of
KI, 0.05eq of TBAB were charged into a RB flask contains 50ml DMF. Prepare a
solution of 1-Bromo-2-chloroethane (2.8gr, 0.02moles) in DMF 50ml was added to
the above mixture slowly for 15 – 20 min at room temperature. Heat the reaction
mass to 100 – 1100C and maintain at the same temperature till reaction completes.
20 Cool the reaction mass to RT after reaction completion. Add water 250ml and
extract into ethyl acetate 3 x 75ml. Combined ethyl acetate washed with water,
dried over anhydrous sodium sulphate. Distill off the solvent under vacuum at
below 500C to get the product (VIIIa) with 80% yield.
25 Example 8: Alternate process for the synthesis of (R)-N-benzyl-N-(2-
bromoethyl)-2-((tert-butyldimethylsilyl)oxy)-2-(3-chlorophenyl)ethan-1-amine
26
(VIIIa) & (R)-N-benzyl-N-(2-bromoethyl)-2-((tert-butyldimethylsilyl) oxy)-2-
(3-chlorophenyl)ethan-1-amine (VIIa):
or
5
Part-A: Under a nitrogen atmosphere, R-Methyl-CBS (0.05 m.eq.) and BoraneDMS (1.0 m.eq.) was taken in a four-necked flask contains 100ml THF. Compound
(VIa) (10.0g, 0.039 moles) was dissolved in 50ml THF and was added to the above
mixture solution at -100C for 15-30min. The mixture was maintained at the same
10 temperature for another 120 minutes. After TLC, the reaction mass was quenched
with methanol and added 150ml water. Extracted the product into ethyl acetate 3 x
75ml. Combined ethyl acetate layers was washed with water and dried over
anhydrous sodium sulfate, filtered, washed, and then concentrated to obtain crude
product. Crude product stirred in hexane 75ml for 2 – 3hours. Filtered, washed,
and dried at 450
15 C.
Part-B: Compound obtained above (10.0 grams) was added to a mixture of
chloroform (90.0 mL), and imidazole (7.3 grams), a solution of tertbutyldimethylsilyl chloride (TBDMS-C1) in chloroform 50ml were added at 25-30
°C and refluxed for 4 hours. The progress of the reaction was monitored by TLC.
20 After the completion of the reaction, the reaction mass was cooled to 15-20 °C,
washed with 5% HC1 solution and distilled under vacuum at 45-50 °C to obtain a
residue. The residue was mixed with cyclohexane (50.0 mL) and stirred for 1 hour
at 25-30 °C. The resultant solid was filtered, washed with cyclohexane and dried at
60-65 °C for 5 hours to get the title compound. Yield: 80%
27
Example 9: Condensation of formula (VIIIa) with methyl 3'-(benzylamino)-
[1,1'-biphenyl]-3-carboxylate(R2):
5 10.84 gr (0.034moles) of (R2), 8.57gr (0.062 moles) of potassium carbonate, KI
(0.52g, 0.0031 moles), TBAB(0.5g, 0.002moles) were charged into a RB flask
contains 50ml DMF. Prepare a solution of Compound (VIIIa) (15gr, 0.031moles)
in DMF 50ml was added to the above mixture slowly for 15 – 20 min at room
temperature. Heat the reaction mass to 100 – 1100C and maintain at the same
10 temperature till reaction completes. Cool the reaction mass to RT after reaction
completion. Add water 250ml and extract into ethyl acetate 3 x 75ml. Combined
ethyl acetate washed with water, dried over anhydrous sodium sulphate. Distill off
the solvent under vacuum at 500C to get the product (VIIIa) with 78% yield.
15 Example 10: Deprotection of formula (Va’) to obtain formula (V):
To the compound (Va’) (25g) in 25 ml of methanol was added 10% Pd/C (2.50g).
The solution was placed in a stainless-steel reactor, which was then charged with
hydrogen gas (150 psi). After being stirred for 24 h at 500
20 C, the mixture was filtered
through Celite to remove the catalyst. The filtrate thus obtained was evaporated to
give the product (V) (96% yield).
28
Example 11: Condensation of formula (VIIIa) with methyl 3'-(benzylamino)-
[1,1'-biphenyl]-3-carboxylate(R2):
5 10.68 gr(0.031moles) of (R2), 5.0g (0.062 moles) of potassium carbonate, KI
(0.48g, 0.0029 moles), TBAB(0.47g, 0.0015moles) were charged into a RB flask
contains 50ml DMF. Prepare a solution of Compound (VII) (10gr, 0.029moles) in
DMF 50ml was added to the above mixture slowly for 15 – 20 min at room
temperature. Heat the reaction mass to 100 – 1100C and maintain at the same
10 temperature till reaction completes. Cool the reaction mass to RT after reaction
completion. Add water 250ml and extract into ethyl acetate 3 x 75ml. Combined
ethyl acetate washed with water, dried over anhydrous sodium sulphate. Distill off
the solvent under vacuum at 500C to get the product (Vb) with 78% yield.
15 Example 12: Alternative process for the condensation of formula (VIIIa) with
methyl 3'-(benzylamino)-[1,1'-biphenyl]-3-carboxylate(R2):
20 Take 10g (0.027moles) of compound (VIIIa) in THF dry 100ml and added 6.96g
(0.0297moles) of (R2) into a clean and dry RB flask. Cool the reaction mass to -
200C. Add a chilled solution of KOBt (6.28g, 0.056moles) in THF 100ml for 1 -2
hours at -20 to -100C. Maintain the reaction mass at the same temperature for 3 –
4hours. Add water 200ml and extract into ethyl acetate 3 x 75ml. Combine all the
29
ethyl acetate layers and wash with water, dry over anhydrous sodium sulfate.
Distill off the solvent at below 500C to get the product (Vb) with 85% yield.
Example 13: Deprotection of formula (Vb) to obtain formula (V):
5
To the compound (Vb) (20g) in 25 ml of methanol was added 10% Pd/C (2.0g). The
solution was placed in a stainless-steel reactor, which was then charged with
10 hydrogen gas (150 psi). After being stirred for 24 h at 500C, the mixture was
filtered through Celite to remove the catalyst. The filtrate thus obtained was
evaporated to give the product (V) (96% yield).
Example 14: Condensation of formula (VII) with amine derivative of R2 2-(3-
15 ((R)-2-aminopropyl)-1H-indol-7-yloxy)acetic acid.
10.80 gr (0.032Smoles) of (Amine derivative of R2), 5.0g (0.036 moles) of
potassium carbonate, KI (0.48g, 0.0029 moles), TBAB (0.47g, 0.0015moles) were
20 charged into a RB flask contains 50ml DMF. Prepare a solution of Compound
(VII) (10gr, 0.029moles) in DMF 50ml was added to the above mixture slowly for
15 – 20 min at room temperature. Heat the reaction mass to 100 – 1100C and
maintain at the same temperature till reaction completes. Cool the reaction mass to
RT after reaction completion. Add water 250ml and extract into ethyl acetate 3 x
30
75ml. Combined ethyl acetate washed with water, dried over anhydrous sodium
sulphate. Distill off the solvent under vacuum at below 500C to get the product (X)
with 82% yield.
Example 15: Deprotection of formula (Vb) to obtain formula (V):
5
To the compound (X) (20g) in 25 ml of methanol was added 10% Pd/C (2.0g). The
solution was placed in a stainless-steel reactor, which was then charged with
hydrogen gas (150 psi). After being stirred for 24 h at 500
10 C, the mixture was filtered
through Celite to remove the catalyst. The filtrate thus obtained was
evaporated to give the product (Vc) (96% yield).
Example 16: Synthesis of formula (I):
Si
Cl
H
N
N
H
OH
O O
(Va)
(I)
Cl
H
N
N
H
OH
OH O
15
Cl
H
N O
O
O
O
Si
(Vb)
Cl
H
N
OH
O
O
O
(II)
31
Take compound (V) (10g, 0.019 moles) into a RB flask, added 50ml water and
added 4ml conc.HCl. Stir the reaction mass at RT for 4 – 6hrs. Check TLC for
reaction completion. Cool the mass to 0 – 100C after reaction completion. Filter
the separated product, wash with chilled water. Dry the product at 600
5 C for 5hrs to
get the product with 75% yield. Further its HCl salt formation gives 85% yield in
IPA/IPA HCl.
Example 17: Synthesis of (R)-2-(3-chlorophenyl)oxirane (XI):
10
A mixture of aldehyde (IX) (2.5g, 0.0089mol), sulfonium perchlorate (X) (3.2g,
0.011mol) and powdered KOH (0.62g, 0.011mol) in tert-butyl alcohol (40 mL) was
stirred at room temperature for 48 h. Then the mixture was quenched with water
and extracted with dichloromethane (30 mL x 3). The combined extracts were
15 washed with sat. NaCl and dried over MgSO4. Evaporation of the solvent followed
by purification on silica gel using a mixture of EtOAc - hexane as an eluent gave
the epoxide (VII) in 80% yield. ,CLAIMS:We Claim
1. A method of synthesizing an intermediate (R)-2-((tert-butyldimethylsilyl) oxy)-2-
(3-chlorophenyl) ethan-1-amine derivative of formula (V),
from 2-bromo-1-(3-chlorophenyl) ethan-1-one of formula (A), comprising of the
following steps:
(A)
Cl
O
Br
i) asymmetric reduction of formula (A) to obtain formula (VI), followed by
protection of alcohol group of formula (VI) is carried out using protecting agents
Pivaloyl chloride, tert butyl ether, THP, TBDMS or TMS, preferably TBDMS to
obtain formula (VII);
a) optional amination of (A) is carried in presence of ammonia or ammonia
15 substitutes such as NHR3 where R3 is H, benzyl halide, 1,2-dibromo ethane in
acetone, Toluene, DMF, methanol THF, isopropyl alcohol, ethanol or 1,4-Dioxane
using base K2CO3, Na2CO3, Cs2CO3 to obtain formula (Aa);
b) optional reaction of ethyl bromine to formula (Aa) to obtain formula (VIa);
Cl
OH
Br
(VI)
Cl
O
Br
(VII)
Si
Cl
O
Br
(A)
(Aa)
Cl
O
N
Br
(VIa)
Cl
O
H
N
20 ii) amination of formula (VII) is carried in presence of ammonia or ammonia
substitutes such as NHR3 where R3 is H, benzyl halide, 1,2-dibromo ethane in acetone,
33
Toluene, DMF, methanol THF, isopropyl alcohol, ethanol or 1,4-Dioxane using base
K2CO3, Na2CO3, Cs2CO3 to obtain formula (VIII) or formula (VIIIa);
a) optional asymmetric reduction of formula (VIa), and protection of alcohol
group of formula (VIa) is carried out using protecting agents Pivaloyl chloride,
5 tert-butyl ether, THP, TBDMS or TMS, preferably TBDMS to obtain formula
(VIIIa);
iii) condensation of formula (VIII) with R2 followed by deprotection to obtain
formula (V); where R1 is H and R2 is or
or
N
H
HN
O
OMe
O
10 .
2. The method as claimed in claim 1, wherein the preferred synthesis of formula (V),
R1 is H & R2 is comprising the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
15 alcohol group of formula (VI) is carried out using protecting agent TBDMS to
obtain formula (VII);
a) optional amination of formula (Aa) is carried in presence of ammonia or
ammonia substitutes such as NHR3 further protection of R3 with benzyl
bromide, 1,2-dibromo DMF/K2CO3 or acetonitrile/ K2CO3 to obtain formula
20 (VIa);
ii) amination of formula (VII) in presence of ammonia derivative in methanol
followed by protection of NHR3 is carried out using benzyl bromide in
34
acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (VIII) further with 1,2-
Dibromoethane in acetonitrile/K2CO3 or DMF/K2CO3 to obtain and formula (VIIIa);
a) optional asymmetric reduction of formula (VIa) followed by protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS
5 to obtain formula (VIIIa);
iii) condensation of formula (VIIIa) with methyl 3'-(benzylamino)-[1,1'-biphenyl]-
3-carboxylate(R2) in acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (Va’) or
(Va”);
10 iv) deprotection of formula (Va’) or (Va”) using 10% Pd/C and methanol or ethanol
to obtain formula (V)

3. The method as claimed in claim 1, wherein the preferred synthesis of formula (V),
15 R1 is H & R2 is
O
O
O
(or)
O
O
O
HN
comprising the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
alcohol group of formula (VI) is carried out using TBDMS to obtain formula (VII);
35
a) optional amination of formula (Aa) is carried in presence of ammonia or
ammonia substitutes such as NHR3 further protection of R3 with benzyl
bromide, 1,2-dibromo DMF/K2CO3 or acetonitrile/ K2CO3 to obtain formula
(VIa);
5 ii) amination of formula (VII) in presence of ammonia derivative in methanol
followed by protection of NHR3 is carried out using benzyl bromide in
acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (VIII) further with 1,2-
Dibromoethane in acetonitrile/K2CO3 or DMF/K2CO3 to obtain and formula (VIIIa);
iii) condensation of formula (VIII) with ethyl (S)-2-((7-amino-5,6,7,8-
10 tetrahydronaphthalen-2-yl)oxy)acetate [Amine derivative of R2] or formula (VIIIa)
with ethyl 2-((5,6,7,8-tetrahydro naphthalen-2-yl) oxy) acetate (R2) in
acetonitrile/K2CO3 or DMF/K2CO3 to obtain formula (Vb);
a) optional asymmetric reduction of formula (VIa) followed by protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS to
15 obtain formula (VIIIa);
iv) deprotection of formula (Vb) using 10% Pd/C and methanol to obtain formula
(V)
.
20
36
4. The method as claimed in claim 1, wherein the preferred synthesis of formula (V),
R1 is H & R2 is
HN
CH3
N
H
O OH
O
comprising the following steps:
i) asymmetric reduction of formula (A) to obtain formula (VI), and protection of
alcohol group of formula (VI) is carried out using protecting agent TBDMS obtain
5 formula (VII);
ii) condensation of formula (VIII) with (R)-2-((3-(2-(benzylamino)propyl)-1Hindol-7-yl) oxy)acetic acid (R2) in acetonitrile/K2CO3 or DMF/K2CO3, isopropanol
or toluene to obtain formula (Vc);
a) optional condensation of formula (A) with (R)-2-((3-(2-(benzylamino)
10 propyl)-1H-indol-7-yl)oxy)acetic acid (R2) in acetonitrile/K2CO3 to obtain
formula (X);
Cl
O
N
CH3 N
H
(X) O
HN
CH3 N
H
O
Amine derivative of R2
Cl
O
Br
(VII)
Si
Si
OH
O
OH
O
Cl
O
Br
(A)
Cl
O
R1 N
N
H
O
O
H
O
(VIII)
HN
CH3 N
H
O
Amine derivative of R2
OH
O
iii) deprotection of formula (X) using 10% Pd/C in methanol, ethanol to obtain
formula (V)
15
5. The method as claimed in claim 2, wherein the intermediate of formula (Va) is
utilized to synthesize formula (I).
37
6. The method as claimed in claim 3, wherein the intermediate of formula (Vb) is
utilized to synthesize formula (II).
7. The method as claimed in claim 4, wherein the intermediate of formula (Vc) is
5 utilized to synthesize formula (III).
8. A compound represented by the following chemical formula (V), or a
pharmaceutically acceptable salt or a solvate thereof:
10 wherein,
R2 is H, (or) (or)
HN
CH3
N
H
O OH
O
; and
R1 is H; substituted or unsubstituted straight or branched C1 to C5 alkyl group,
alkoxy group, aryloxy group, phenyl group; benzyl group.
15
9. The compound as claimed in claim 2, wherein chemical formula (Va), or a
pharmaceutically acceptable salt or a solvate thereof:
38
where R1 is H or benzyl and R2 is
HN
CO2Me
10. The compound as claimed in claim 3, wherein chemical formula (Vb), or a
5 pharmaceutically acceptable salt or a solvate thereof:
where R1 is H or benzyl and R2 is
O
O
O

11. The compound as claimed in claim 4, wherein chemical formula (Vc), or a
pharmaceutically acceptable salt or a solvate thereof:
10 where R1 is H or benzyl and R2 is
HN
CH3
N
H
O OH
O
12. The method as claimed in claim 2 to claim 5, wherein amination is carried out using
ammonia in methanol, THF, Isopropyl alcohol, ethanol, or 1,4-Dioxane.
15
39
13. The method as claimed in claim 2 to claim 5, wherein protection of OH is carried
out using protecting agents such as THP, TBDMS, TMS; and NH protection is
carried out using protecting agents such as benzyl bromide, benzyl chloride, benzyl
iodide, in solvents such as acetone, THF, DMF, acetonitrile, 2-methyl THF, MIBK,
5 halo solvents using base K2CO3, Na2CO3, Cs2CO3, imidazole.
14. The method as claimed in claim 2 to claim 5, wherein deprotection is carried out
using Pd/C using alcohol as a solvent.