FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Raltegravir compound of Formula (I)
N-N "3^N
HsC-vvvN „
Q H3C CH3 Q
Formula (I) or its salts using an intermediate compound of Formula (II)
o
,OH
H3C CH3 Q

Formula (II)
or its salts, wherein Ri and Ri' are independently selected from hydrogen, alkyl or N-
protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and
carboxylic acids. "aT
U)
ca
Q- The present invention more particularly relates to an improved process for the
2
CN

amino]ethyl]-6-oxo-4-pynmidinecarboxamide monopotassium salt. The empirical formula is C2oH2oFKN605 and the molecular weight is 482.51. The structural formula is:
o
II u f V>U_ II
Q H3C CH3 Q
Raltegravir was specifically disclosed in US 7,169,780 B2, this patent also discloses process for preparing Raltegravir. The process is shown in the scheme given below:
The drawback of this route of synthesis is the use of LiH which is highly pyrophonc and difficult to handle on industrial scale. Hence, the above process is not recommended at commercial level.
US 8,357,798 B2 describes an alternative process for preparing Raltegravir and its intermediate, in which the alkylation step does not include a step for protecting the 5-hydroxy group. The process is described in the following reaction scheme:
5, M.T Q 1= F l <~ fe V W *»*A v- :"-. i, .* s

The above process is somehow advantageous over the process disclosed in US '780. However, this process is currently under patent protection and not available for commercial scale-up.
WO 2016/075605 Al discloses an alternative process for the preparation of Raltegravir and its intermediate, wherein the process is shown in the scheme given below:
Consequently, there still exists a need for an efficient synthesis of Raltegravir and £.^its'intennediates^whichisJsuitable-for large-scale production. -■ - - - -
4

OBJECT OF THE INVENTION
The main object of the invention is to provide a simple, cost effective, improved and robust process for the preparation of Raltegravir compound of Formula (I)
o


QH3C CH3 Q

Formula (I) or its salts using an intermediate compound of Formula (II)
o
H3C CH3 Q
Formula (II) or its salts, wherein Ri, and Ri' are independently selected from hydrogen, alkyl or N-protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and carboxylic acids.
U)
ca
0- Another, main objective of the present invention is to provide an improved process
_ ^
ji - Ft, -t T:. W, -t xz i- \- %. v \j
O CN

O
II U P /~T\J 'I
0"3L *-H3 0
Formula (I)
or its salts which comprises
a) reacting compound of Formula (II)
o
HN'
H3C CH3 Q
Formula (II) or its salts, wherein Ri and R^ are independently selected from hydrogen, alkyl or N-protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and carboxylic acids, with a methylating agent in the presence of a base and optionally in the presence of a phase transfer catalyst to give compound of Formula (IIA)

CD U) CO Q_
R3
S2 „ ;;N^^„X.OCH3
CN
E
O or its salts, wherein R\, R|* and R3 are as defined above,
o
Formula (IIA)

^5 b) converting compound of Formula (IIA) to Raltegravir or its salts.
10
h-CN CN
o In a preferred aspect, the present invention provides an improved process for the
h-
O CN
CN
preparation of Raltegravir compound of Formula (I)


5 r^
o
CN

0 H3C CH3 Q
Formula (I)
jlTPIAT ft if' V- i - — ■• ."■•— »*.— " ' * ■ ■' •■ - ■■■■■,

O CN

or its salts which comprises: a) reacting compound of Formula (II)
o
OH
VVVY
H3C CH3 Q
Formula (II) or its salts, wherein R] and R,' are independently selected from hydrogen, alkyl or N-protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and carboxylic acids, with a methylating agent in the presence of a base to give compound of Formula (IIA)
o
,OCH3 O
Formula (IIA) or its salts, wherein Ri, Ri' and R3 are as defined above, b) reacting compound of Formula (IIA) with compound of Formula (III)
Formula (III) in the presence of base and solvent to give compound of Formula (IV) or its salts
o
H3CL A R3

O
Formula (IV) wherein R], Ri' and R3 are as defined above,
c) optional deprotection of compound of Formula (IV) when R|, Rj' independently
represents nitrogen protecting group,
d) reacting compound of Formula (IV) with compound of Formula (V) or its salts
E ti. 1 (J i- i- : l.> 5 ■"» r. v r'- •*■'• ---■ '■ ' '■■= : -■■'■ '- ' : '■■■ : . •. -u •• i.

N-N
O
O
Formula (V) wherein X represents leaving group to give Raltegravir, e) optionally converting Raltegravir to its salts.
In another preferred aspect, the present invention provides a process for preparing compound of Formula (IIA)


,OCH3 H3C CH3 Q
Formula (IIA) or its salts which comprises reacting compound of Formula (II)
. o
H3C CH3 Q
Formula (II) or its salts, wherein Ri and Ri' are independently selected from hydrogen, alkyl or N-protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and carboxylic acids, with a methylating agent in the presence of a base to give compound of Formula (IIA).
In yet another preferred aspect, the present invention provides compound of Formula (II).
o
H3C CH3 Q
Formula (II)

1
Kl T
U\ ■ -y-irv- i vr '>

8

or its salts, wherein Ri and Rt' are independently selected from hydrogen, alkyl or N-protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and carboxylic acids.
In yet another preferred aspect, the present invention provides a process for the preparation of compound of Formula (II)
o
H3C CH3 Q
Formula (II) or its salts, wherein R[ and Rj' are independently selected from hydrogen, alkyl or N-protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and carboxylic acids, which comprises hydrolyzing compound of Formula (IIB)
o
CD U) CO Q_
CD
R3 ,OR4
Formula (IIB)
:E or its salts, wherein R|, R(', R3 are as defined above, R4 is alkyl group, in the presence of
oT base and a solvent.
E
o
LL In yet another preferred aspect, the present invention provides compound of
CD
10 Formula (IIC)
O
CN
O H3C CH3 Q
JN
5 Formula (IIC)
o or its salts, wherein R] and Ri' are independently selected from hydrogen, alkyl or N-
r^ protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and
° carboxylic acids.
■
O CN

In yet another preferred aspect, the present invention provides a process for the preparation of compound of Formula (IIC)
o
,OH O
Formula (IIC) or its salts, wherein Rt and Rj' are independently selected from hydrogen, alkyl or N-protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and carboxylic acids, which comprises selective n-methylation of compound of Formula (II)
o
,OH O
Formula (II) or its salts, wherein Ri, Ri' and R3 are as defined above, using a methylating agent in the presence of a base to given compound of Formula (IIC).
U)
Q_ In yet another preferred aspect, the present invention provides polymorphic forms

d> 10
CN

or its salts, wherein Ri and Ri' are independently selected from hydrogen, alkyl or N-protecting group, R3 is selected from hydroxy, hydroxy protected, halo, sulfonates, and carboxylic acids, R4 is alkyl group, which comprises methylating compound of Formula (IIB)
o
H3C CH3 Q
Formula (IIB) or its salts, wherein Ri, Ri', R3 and R4are as defined above, with a methylating agent in the presence of a phase transfer catalyst.
DETAILED DESCRIPTION OF THE INVENTION
Inventors of the present invention have developed an efficient industrial process for the preparation of Raltegravir and its intermediates or its pharmaceutically acceptable salts.
According to the present invention N-protecting group is preferably selected from selected from carbobenzyloxy (cbz), tert-butyloxycarbonyl (boc), p-methoxybenzyl carbonyl (moz or meoz), 9-fluorenylmethyloxycarbonyl (frnoc), acetyl (ac), benzoyl (bz), benzyl (bn), benzyl carbamate, p-methoxybenzyl (pmb), 3,4-dimethoxybenzyl (dmpm), p-methoxyphenyl (pmp), tosyl (ts), sulfonamides.
The term hydroxy protected groups are selected from ethers such as methyl ethers, methoxymethyl ethers, methoxyethoxyrriethyl ethers, benzyloxymethyl ethers, tetrahydropyranyl ethers, benzyl ethers, p-methoxybenzyl ethers, silyl ethers, nitrobenzyl ethers, esters such as acetates, pivaloates.
The term leaving group is preferably a halo group such as chloro, bromo, fluoro and iodo.
:ri.T iti v v"-"-*.- '-.» VI'W.T; ''- " ; *" '" -
11

The present invention provides a process for the preparation of Raltegravir or its salts by using compound of Formula (II)
„OH
H3C CH3 Q

Formula (II) In a preferred embodiment one of the Rj and Ri' of compound of Formula (II) is hydrogen and other is nitrogen protecting group which is preferably carbobenzyloxy (Cbz) and R3 represents a hydroxyl group.
In another preferred embodiment compound of Formula (II) is reacted with a methylating agent preferably methyl iodide or trimethylsulfonium iodide in the presence of a base preferably magnesium hydroxide in a solvent preferably n-methyl pyrrolidine to give compound of Formula (IIA).
o
H3%_
Methylation of compound of Formula (II) can be carried out in the presence of phase transfer catalyst.
The compound of Formula (IIA) as prepared according to the present invention is further coupled with compound of Formula (III)
JfY
Formula (III) in the presence of a base preferably triethyl amine in a solvent preferably alcoholic solvents such as methanol or ethanol to give compound of Formula (IV)
12

H3C CH3 Q
Formula (IV) Compound of Fonnula (IV) deprotected when one of Ri and Ri' represents benzyloxycarbonyl, wherein the deprotection is carried out in the presence of Pd/C in methanol followed by coupling with compound of Formula (V)
N-N
O
Formula (V) to give Raltegravir or its salts.
In a preferred embodiment compound of Formula (II) is prepared by hydrolyzing compound of Formula (IIB)
o
-A^R3
R HN^V
H3C CH3 Q
Formula (IIB) in the presence of a base preferably lithium hydroxide monohydrate in THF or water or mixture of THF or water to give compound of Formula (II).
In yet another preferred embodiment, the present invention provides selective n-methylation of compound of Formula (II) to give compound of Formula (IIC).
o


•W v 4*f-i- ivt' "u.-r-

13

The present invention provides an improved process for the preparation of Raltegravir compound of Formula (I)

Q H3C CH3
o

Formula (I) or its salts which comprises a) reacting compound of Formula (LID)
o

H H? Q H3C CH3
Formula.(IID) with a methyiating agent in the presence of a base and optionally in the presence of a phase transfer catalyst to give compound of Formula (HE)
o
Q H3C CH3
a,
Formula (HE) b) converting compound of Formula (HE) to Raltegravir or its salts.
In a preferred embodiment, the present invention provides an improved process for the preparation of Raltegravir compound of Formula (I)
o
N-N H3aN-V0H ^rl
II ti n V>u II
Q H3C CH3 Q
Formula (I) or its salts which comprises a) reacting compound of Formula (IID)
14

Formula (IID) with a methylating agent in the presence of a base and optionally in the presence of phase transfer catalyst to give compound of Formula (IIE)
o

VVNVCH3
O **3C CH3 Q
Formula (IIE) b) reacting compound of Formula (IIE) with compound of Formula (III)
Formula (III) to give compound of Formula (IVA)
cx^jr^"
o
OH

O H3C CH3 0
Formula (IVA) c) deprotecting compound of Formula (IVA) to give compound of Formula (IVB)
o
H3C CH3 Q
Formula (IVB) d) reacting compound of Formula (IVB) with compound of Formula (VA)
N-N
HJC-VYC'
o
,. _ „ _ Formula (VA)
15

to Raltegravir or its salts.

In another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula (HE)
o
f^ H3c.NXyOH
kJ^OY^X^N7fOCH3
O H3C CH3 O
Formula (HE) or its salts which comprises reacting compound of Formula (IID)
o
II u-r1 Vu. II
,OH 0 H3C CH3 Q
Formula (IID) with a methylating agent in the presence of a base and optionally in the presence of a phase transfer catalyst to give compound of Formula (HE).
U)
co
Q- In yet another preferred embodiment, the present invention provides compound of
Li2C03, CaC03, MgC03, sodium hydride, potassium tert butoxide, sodium tert butoxide, magnesium hydroxide, MgH2, Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt, CaH2, Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof. Organic base is selected from pyridine and its derivative, piperidine, nitrogen containing base. The example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
The term solvent as used in the present invention is selected from water or acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol or benzene, toluene, xylene, heptane, hexane and cyclohexane or acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone or methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or acetonitrile, propionitrile, butyronitrile and isobutyronitrile or di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, N-methyl morpholine, 2-pyrrolidone, l-ethenyl-2-pyrroIidone and/or mixtures thereof.
The term phase transfer catalyst used in the present invention is selected from the
group consisting of a quaternary ammonium salt and a quaternary phosphonium salt.
Preferably the phase transfer catalyst is selected from quaternary ammonium salts
selected from the group consisting of benzyltriethylarnmonium halide,
hexadecyltrimethylammonium halide, tetrabutylammonium halide,
tetramethylammonium halide, tetraethylammonium halide, tetrabutylammonium acetate and mixtures thereof.
Hi . vH-s-r'-'''" .•.-.■,-,"„-,■.-.•:■.■ •.- ,• - -• -.-
19

The term pharmaceutical^ acceptable salts or salts as used in the present invention is selected from sodium, potassium, calcium, magnesium and ammonium salts.
The compounds of formulae (II) (IIA), (IIB), (IIC), (IID), (HE), (IIF) or their salts used in the present invention may be isolated or not. Any of the above reactions may be carried out in-situ reactions to obtain Raltegravir or its intermediates. The above compounds may isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions. Further, the above compound may isolated as crystalline Forms or isolated as an amorphous form or optionally recrystallized and used for further reactions.
The compounds of Formulae (II), (IIC), (IID) and (IIG) may exist in different polymorphic forms including crystalline or amorphous forms, further the above compounds may contain water to form their hydrates or they can exist in anhydrous forms.
In a preferred embodiment, the compounds of Formulae (II), (IIC), (IID) and (IIG) used in the preparation of Raltegravir or its salts.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
Examples:
Example 1: Preparation of compound of Formula (HE)
400 ml of n-methyl pyrrolidine charged to a round bottol flask at 25-30°C under nitrogen atmosphere, 100 gms of compound of Formula (IID) is added to the above reaction mass at 25-30°C. 33.6 gms of magnesium hydroxide is charged to the above reaction mass at same temperature. Stirr the reaction mass for 10 minutes at same
feW !, !J r r I V (a ''■>'- *~ *'■"" "':' "" ' -■ ' ■■■■>-■'■ * ■■ ■■■■■■■ •■ ■■■ • ■>■ -■ ••
20

temperature, to the above mass 31.6 gms of trimethyl sulphoxanium iodide Lot-1 is added, slowly the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-2 of 31.6 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-3 of 15.8 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-4 of 15.8 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-5 of 15.8 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-6 of 15.8 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reaction completion was monitored by HPLC/TLC, cool the reaction mass to 25-30°C, 200 ml of isopropanol was charged to the reaction mass at 25-30°C, degas the reaction mass with nitrogen bubbling for 15 minutes. Reaction mass was further cooled to 10-15°C, pH of the reaction mass was adjusted to 1.5-2.0 with 290 ml of 2N HC1 solution at same temperature, 50 ml of 5% sodium bisulfite solution was added at same temperature, maintain the reaction mass for 30 minutes at same temperature, the pH was adjusted to 1.5-2.0 with 10 ml of 2N HC1 solution at same temperature, 50 ml of 5% sodium bisulfite solution was added at same temperature, 2000 ml of DM water was added lot wise at the same temperature for 2 hours, stir the reaction mass and maintained for 8 hrs, the reaction mass was filtered and wash the wet cake with 200 ml of DM water followed by washing with isopropanol and water mixture (100 ml of water + 100 ml of isopropanol), dried for 30 minutes, unload the wet material, dry the wet material 25-30°C for 2 hrs in hot air oven and dried at 50-55°C under vaccum till constant weight obtained. Wet weight yield= 110-125 gms, Dry weight= 70-100 gms, ..
21

Purity by HPLC= 99%
Example 2: Preparation of compound of Formula (HE)
400 ml of n-methyl pyrrolidine charged to a round bottol flask at 25-30°C under nitrogen atmosphere, 100 gms of compound of Formula (IID) is added to the above reaction mass at 25-30°C. 33.6 gms of magnesium hydroxide is charged to the above reaction mass at same temperature. Stirr the reaction mass for 10 minutes at same temperature, to the above mass 5 g of tetra butyl ammonium acetate and 31.6 gms of trimethyl sulphoxanium iodide Lot-1 is added, slowly the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was maintained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-2 of 31.6 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was maintained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-3 of 15.8 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C,*lot-4 of 15.8 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-5 of 15.8 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reation mass was cooled to 85-90°C, lot-6 of 15.8 gms of trimethyl sulphoxanium iodide was added to the above reaction mass, the reaction mass was heated to 95-105°C for 1-2 hours, reaction mass was manitained for 90 mints at 95-105°C, reaction completion was monitored by HPLC/TLC, cool the reaction mass to 25-30°C, 200 ml of isopropanol was charged to the reaction mass at 25-30°C, degas the reaction mass with nitrogen bubbling for 15 minutes. Reaction mass was further cooled to 10-15°C, pH of the reaction mass was adjusted to 1.5-2.0 with 290 ml of 2N HCl solution at same temperature, 50 ml of 5% sodium bisulfite solution was added at same temperature, maintain the reaction mass for 30 minutes at same temperature, the pH was adjusted to 1.5-2.0 with 10 ml of 2N ,HC1 solution at same temperature, 50 ml of 5% sodium bisulfite solution was added at
22

same temperature, 2000 ml of DM water was added lot wise at the same temperature for 2 hours, stir the reaction mass and maintained for 8 hrs, the reaction mass was filtered and wash the wet cake with 200 ml of DM water followed by washing with isopropanol and water mixture (100 ml of water + 100 ml of isopropanol), dried for 30 minutes, unload the wet material, dry the wet material 25-30°C for 2 hrs in hot air oven and dried at 50-55°C under vaccum till constant weight obtained. Wet weight yield= 110-125 gms, Dry weight= 70-100 gms, Purity by HPLO 99%
Example 3: Preparation of compound of Formula (IVA)
100 gms of compound of Formula (HE) was added to a round bottom flask at 25-30°C under nitrogen atmosphere, 700 ml methanol was charged to the above flask at 25-30°C, reaction mass was stirred for 15 minutes at same temperature, to the above reaction mass 29.6 gms of triethylamine was added at the same temperature, reaction mass was stirred for 15 minutes. 50 gms of compound of Formula (III) was charged at 25-30°C for 30 minutes, reflux the reaction mass, the completion of the reaction mass was checked by HPLC, otter HPLC complies, cool the reaction mass to 50-5 5°C, 30ml of acetic acid was added to adjust the pH of the reaction mass to 3-3.5, water was added lot wise manner, maintain the reaction mass for 1.5-2 hrs at same temperature, cool the reaction mixture to 20-25°C and stirr for 90-120 minutes, filter the reaction mass washed with chilled water at 5-10°C, suck thoroughly and unload the mass. Dry the material at 50-55°C till moisture content NMT 1%. Wet weight yield= 130-140 gms, Dry weight= 110-115 gms, Yield=88-92%.
Example 4: Preparation of compound of Formula (TVB)
10% Pd/C paste (2.0 gms pf 10% Pd/C with 2.0 ml of water) (Lot-I) was added to a clean and dry autoclave at 25-30°C under nitrogen atmosphere. 700 ml of methanol and .10.0 gms. of Formula.(IVA) and 21.5 gms of methanesulfonic acid was charged to the
23

above autoclave at 25-30°C, flushed with methanol, close the autoclave and flush with nitrogen 2 kg/cm , 4.5-5.0 kg/cm hydrogen gas pressure was applied, the reaction mixture was heated up to 50-55°C, maintained the reaction mass. Afetr completion of the reaction, cool the reaction mass to 25-35°C, filtered the reaction mass and washed with 200 ml of 80% aqueous methanol (160 ml of methanol(lot-2) in 40 ml of water (lot-2), trasfer the clear filtrate to round bottom flask. Adjust the pH of the reaction mass to 6.5-7.5 with IN sodium hydroxide solution, cool the reaction mass to 0-5°C and stirred for 4 hrs, filtered the reaction mass and washed with chilled water (2 X 150 ml (lot-4 & Iot-5)), suck thoroughly and unload the mass. Dry the material at 45-50°C. Dry weight= 57-62 gms, Yield=80-87%.
Example 5: Preparation of compound of Raltegravir.
Part-A: 100 gms of compound of Formula (IVB) was added to the round bottom flask, 300 ml of cyclohexanc was added to the reaction mass, 16.7 gms of triethylamine was added to the above reaction mass, temperature was raised to the reflux, solvent was distilled out atmospherically upto 2 volumes in the reaction mass, reaction mass was cooled to 45-50°C, 620 ml of tetrahydrofuran was added lot wise manner to the above reaction mass, vacum applied, distilled out completely under vacum. Reaction mass was cooled to -7 to -5 °C, 35.5 gms of n-methyl morpholine slowly added to the reaction mass at same temperature over 30-45 minutes, stirred for 30 minutes.
Part-B: 64.5 gms of potassium salt of 5-methyl-l,3,4-oxadiazole-2-carboxylate was added to the round bottom flask, 385 ml of THF (lot-4) was added to the above mass at 25-30°C, 1.6 ml of DMF was added to the above reaction mass at same temperature. Stir for 5 minutes, reactiom mass was cooled to -7 to -5°C, 45.3 gms of oxalyl chloride was slowly added to the above mass, maintain the reaction mass at -7 to -5°C for 90 minutes.
Part-C: Part-B solution was slowly added to the part-A solution at -7 to -5°C, maintain the reaction mass at the same temperature for 3-3.5 hrs, HPLC/TLC was checked, 195 ml ^of. DM water (lpt-1). was added after the HPLC/TLC complies, stirred for 15 mints,
24

potassium hydroxide solution (prepared by dissolving 80.5 gms of potassium hydroxide in 80.5 gms of water and cool to 20-25°C) was added to the above reaction mass 3±3°C, the reaction mass was maintained for 60-90 mints, the reaction mass was monitored by HPLC/TLC. pH of the reaction mass was adjusted to 3-3.5 using dilute hydrochloric acid (prepared by diluting 45 ml of HC1 in 325 ml of water). 485 ml of THF (lot-5) was added to the reaction mixture and stirred for 15 mints. Layeres were separated, solvent was distilled under vacum at below 45°C. 150 ml of n-butanol was added to the residue, stirred for 2 hrs at 25-30°C, cool the reaction mass to 10-15°C, stirred for 2 hrs, reaction mass was filtered, washed wetcake with 50 ml of chilled n-butanol. Dry the mass under vacum initially at 25-30°C for 2 hrs and then temperature was raised to 50-55°C for 8 hrs. Dry weight: 55-60 grms Purity by HPLC: 99.8-% Yield 83-90%.
Dated this Twenty Third (23rd) day of June 2017
Authorized Signatory
(HAVALE SHRIKANT HANUMANTAPPA) SMS Pharmaceuticals Ltd
25