FIELD OF THE INVENTION
The present invention relates to an industrially advantageous and efficient
process for the preparation of crystalline Form 3 of raltegravir potassium.
BACKGROUND OF THE INVENTIO5 N
Raltegravir is an antiretroviral drug used to treat HIV infection. It is marketed as
potassium salt, the chemical name of raltegravir potassium is N-(4-
fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-
2-yl)carbonyl] amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
10 monopotassium salt and is structurally represented by formula I:
N
N
O
O-K+
HN
O
F
HN
O
N N
O
H3C
H3C CH3
Formula I
Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic
material into human chromosome, a critical step in pathogenesis of HIV.
15 Raltegravir potassium has been approved by FDA for the treatment of HIV in
25, 100, 400 mg tablets for oral administration and is currently marketed under
the trade name ISENTRESS by Merck.
It can be noted that in the recent year, solid state properties of drugs have
20 received great attention in the pharmaceutical market. The ability of some
substances to exist in more than one crystalline form called polymorphism was
accredited as one of the most important solid-state property of the drug. While
polymorphs have the same chemical composition, they differ in packing and
geometrical arrangement thereof, and exhibit different physical properties such
3
as melting point, shape, color, X-ray diffraction pattern, infrared absorption,
density, hardness, deformability, stability, dissolution, and the like. Although
these differences disappear once the compound is dissolved, they can
appreciably influence pharmaceutically relevant properties of solid form, such
as handling properties, dissolution rate and stability. Such properties ca5 n
significantly influence the processing, shelf life, and commercial acceptance of a
polymorph. It is therefore important to investigate all solid forms of a drug,
including all polymorphic forms, and to determine the stability, dissolution and
flow properties of each polymorph. Depending on their temperature-stability
10 relationship, one crystalline form may give rise to thermal behavior different
from that of another crystalline form. Thermal behavior can be measured in the
laboratory by techniques such as capillary melting point, thermo-gravimetric
analysis (TGA) and differential scanning calorimetry (DSC), which have been
used to distinguish polymorphic forms.
15
Other examples are known, where different crystalline forms behave differently
during physical and mechanical processing like milling, grinding and
micronizing. Many process-induced solid-solid transitions of substances are
known, that lead to either other crystalline forms or an amorphous form of the
20 substance.
Additionally solvent medium and mode of crystallization play very important
role in obtaining a crystalline form over the other.
25 Raltegravir potassium exists in different polymorphic Forms, which differ from
each other in the term of stability, physical properties, spectral data and methods
of preparation.
4
The preparation and therapeutic use of raltegravir and its pharmaceutically
acceptable salts were first disclosed in US patent 7,169,780 [US'780]. Although
this document discloses potassium salt but preparation of raltegravir potassium
is not exemplified. According to US'780, raltegravir is prepared by reacting 5-
methyl-1,3,4-oxadiazole-2-carboxylic acid chloride with 2-(1-amino-5 1-
methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-
dihydropyrimidine-4-carboxamide in acetonitrile in the presence of triethyl
amine.
10 US patent 7,754,731 [US '731] discloses three crystalline Forms of raltegravir
potassium such as anhydrous Form1, hydrated Form 2 and anhydrous Form 3
and processes for their preparation. According to US '731 Form 1 is prepared
by treating a suspension of raltegravir in ethanol and water with aqueous
potassium hydroxide to form a solution, filtered, and seeded with crystalline
15 Form 1 to form the suspension. The resulting suspension is diluted with ethanol
and cooled to prepare Form 1. Form 2 is prepared by treating solid potassium
hydroxide with raltegravir in acetone and the resulting solution is sonicated
until a precipitate formed. Anhydrous Form 3 of raltegravir potassium is
prepared by reacting raltegravir in acetonitrile with aqueous solution of
20 potassium hydroxide and resulting solution is freeze dried to obtain amorphous
form. Amorphous form is then dissolved in hot ethanol and crystallized to give
anhydrous Form 3 of raltegravir potassium. Major drawback of this process lies
in use of freeze drying technique,, making this process economically unviable
for large scale synthesis at industrial level.
25
International patent publication WO 2011/024192 discloses processes for the
preparation of amorphous and crystalline Forms 1, 2 and 3 of raltegravir
potassium.
5
In this publication, it is disclosed that amorphous form is prepared by treating a
solution of raltegravir in acetonitrile or acetone with aqueous potassium
hydroxide and the resulting solution is distilled out or subjected to spray drying.
Form 1 is prepared by either treating a solution of raltegravir in acetonitrile or
acetone with methanolic potassium hydroxide and the resulting solid is filtere5 d
or by heating a suspension of amorphous raltegravir potassium salt in
nitromethane to form a solution followed by filtering and cooling the resulting
solution. Form 2 is prepared by suspending amorphous raltegravir potassium salt
in dichloromethane, stirred for 2 days and isolating the resulting compound by
10 filtration. Form 3 is prepared by two methods. First method involves treating a
solution of raltegravir in a mixture of methanol and acetone with methanolic
potassium hydroxide solution and thereafter adding an antisolvent like
isopropyl ether to precipitate the solid, which is then isolated by filtration.
Second method involves treating a solution of raltegravir in ethyl acetate with
15 methanolic potassium hydroxide solution and isolation of resulting solid by
filtration.
As the processes describe above for the preparation of crystalline Form 3
involve two or more solvents, hence these processes are not reasonably cost
effective for the preparation of crystalline Form 3 of raltegravir potassium.
20
International patent publication WO 2011/123754 discloses several crystalline
Forms of raltegravir potassium including Form IV, V, VI, VII, VIII, IXa, IXb,
X, XI, XII, XIII, XIV, XV and XVI . In this publication, it is disclosed that
Form IV is prepared by treating a solution of raltegravir in N-methylpyrrolidone
25 with an aqueous solution of potassium hydroxide, stirring and diluted with Nmethylpyrrolidone.
The resulting solution is isolated by filtration. Form V is
prepared by concentrating a mixture of raltegravir potassium or amorphous
raltegravir potassium in water using a rotary evaporator. Form V is also
6
prepared by treating raltegravir or its Form A1 with aqueous potassium
hydroxide solution in suitable solvents such as cyclohexane or mixture of
heptane, water or toluene with or without seeding, isolating the resulting solid
by filtration. Other forms are prepared by either treating amorphous raltegravir
potassium with suitable solvent or by treating raltegravir free base with aque5 ous
potassium hydroxide solution in a suitable solvent.
International patent publication WO 2011/148381 discloses crystalline Form H1
of raltegravir potassium. The process for the preparation of crystalline Form H1
10 involves treating a suspension of raltegravir in ethanol with potassium hydroxide
for 18 hours at 25 to 30° C and isolating Form H1. Another process involves
treating a suspension of raltegravir in ethanol or isopropyl alcohol with aqueous
solution of potassium hydroxide for 17 hours at 25 to 30° C and isolating Form
H1
15 The processes described above are of long duration and may be because of this,
does not results in pure form, consistently. It is observed that following said
process, either the polymorph obtained is not consistent or polymorph obtained
is not pure, it is mixed with other polymorphs.
20 In view of above, it is therefore necessary to solve the problems associated with
prior art and to provide an alternate, efficient, economically viable and
reproducible process for the preparation of Form 3 of raltegravir potassium,
which avoids use of expensive freeze drying technique, mixture of solvents as
well as long time duration. In addition of this, process for the preparing such
25 polymorph should be robust and efficient in producing commercial quantity of
crystalline compound consistently. This question arises because very often the
most suitable polymorph for use as a drug substance is difficult to reproduce.
Therefore it is of greatest importance for pharmaceutical industry to ensure a
7
reliable, robust, cost effective as well as efficient process for the synthesis of
Form 3 of raltegravir potassium.
Thus, the present invention provides an easy, industrially advantageous and
efficient process for the preparation of polymorphs of raltegravir potassium5 ,
mainly crystalline Form 3 which does not involve use of freeze drying technique
and use of two or more different solvents.
OBJECTIVE OF THE INVENTION
10 The objective of present invention is to provide an improved, efficient and
economically viable process for the preparation of crystalline Form 3 of
raltegravir potassium,
Another objective of present invention is to provide a process for the preparation
15 of Form 3 of raltegravir potassium using an alcoholic solvent.
Yet another objective of present invention is to provide a process for the
preparation of Form 3 of raltegravir potassium using an alcoholic solvent, which
consistently generates pure Form 3.
20
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an efficient and industrially
advantageous process for the preparation of raltegravir potassium polymorph.
25 According to another embodiment, the present invention provides a process for
the preparation of Form 3 of raltegravir potassium having formula I by using
alcoholic solvent, which comprises steps of :
a) suspending raltegravir in an alcoholic solvent;
8
b) optionally seeding with raltegravir potassium Form 3;
c) adding an alcoholic solution of potassium base;
d) diluting the reaction mixture with an alcoholic solvent;
e) optionally heating the resultant reaction mixture to reflux temperature;
f) stirring the reaction mixture for 5 up to 5 hrs;
g) isolating raltegravir potassium Form 3.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : shows X-ray diffraction pattern of crystalline raltegravir potassium
10 Form 3 prepared according to present invention
Figure 2 : shows differential scanning calorimetry (DSC) of crystalline
raltegravir potassium Form 3 prepared according to present invention
DETAILED DESCRIPTION OF THE INVENTION
15 As used herein "Form 3" means a crystalline raltegravir potassium having X-ray
diffraction pattern and DSC that substantially correspond to as given in Figures
1 and 2.
As used herein "substantially corresponds" means it covers differences or
20 variations in the pattern that would not be understood by the person skilled in
the art to represent a difference in a crystal structure, but rather differences in
techniques, sample preparation and instrument etc.
As used herein "ambient temperature" means temperature of the surrounding. It
25 means any suitable temperature found in the laboratory or the other working
quarter, and is generally not below about 15 °C to and not above about 35 °C.
9
Accordingly, present invention provides an industrially advantageous and
efficient, reproducible process for the preparation of raltegravir potassium
polymorph. Specifically the present invention provides process for the
preparation of crystalline raltegravir potassium Form 3.
5
Generically, the process involves providing a suspension of raltegravir in a
suitable alcoholic solvent or mixture thereof at ambient temperature. Suitable
solvent can be selected amongst alcohols such as methanol, ethanol, propanol,
isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol and like or mixture
10 thereof. Thereafter the reaction mixture can be optionally seeded with raltegravir
potassium Form 3, followed by adding suitable alcoholic solution of potassium
base. The suitable solvent can be selected from alcohols such as methanol,
ethanol, propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol
and like or mixture thereof. The potassium base can be selected from hydroxides
15 such as potassium hydroxide, alkoxide such as potassium methoxide,
potassium ethoxide, potassium isopropoxide, potassium tertiary butoxide,
preferably potassium hydroxide. Potassium base can be employed in any
proportion with respect to raltegravir which result in the formation of at least
some of the desired potassium salt. The base can suitably be added in an amount
20 in the range of from about 0.1 to about 3 mole equivalents to per equivalent of
raltegravir base. The alcoholic solution of base can be added at a temperature of
15 °C to 35 °C, preferable at a temperature of 20 °C to 30 °C. After addition of
base, the reaction mixture can be stirred for few minutes to few hours, followed
by dilution of reaction mixture with a suitable alcoholic solvent. The suitable
25 solvent can be same or different from the solvent of reaction mixture and
selected from alcohols such as methanol, ethanol, propanol, isopropanol, nbutanol,
isobutanol, n-pentanol, isopentanol, and like or mixture thereof. The
solvent can be added at a temperature of 15 °C to 35 °C, preferable at a
10
temperature of 20 °C to 30 °C. The reaction mixture can be stirred at a
temperature of 15 °C to reflux temperature of solvent. Preferably the reaction
mixture can be stirred at a temperature of 20 °C to 30 °C and/or optionally
followed by stirring at reflux temperature of the solvent. The time for stirring of
reaction mixture can be few minutes to maximum of 5 hours, preferably at 5 t 20 °C
to 30 °C for 30 minutes to 5 hours and/or at 15 °C to 35 °C for few minutes
followed by at reflux temperature of the solvent for few hours then cooled at
15°C to 35°C, and stirred for 1 to 4 hours; preferably at 20°C to 30 °C for 10
to 30 minutes followed by at reflux temperature of the solvent for 1 to 2 hours
10 then cooled at 20°C to 30°C and stirred for 1 to 2 hours.
Raltegravir potassium Form 3, thus formed, by the process of the present
invention can be isolated by a suitable technique known in the art such as
filtration, centrifugation, decantation and the like. Typically, the product is
15 isolated by filtration. The isolation can be optionally done under the nitrogen
atmosphere by providing a blanket of nitrogen.
The polymorphs are characterized by their X-ray powder diffraction pattern.
Thus, the X-ray diffraction patterns were measured on PAN analytical, X'pert
20 PRO powder diffractrometer equipped with goniometer of θ/θ configuration and
X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and
30mA. The experiments were conducted over the 2θ range of 2.0°- 50.0°. One
with ordinary skills in the art understand that experimental differences may be
arise due to difference in the instrument, sample preparation and other factors.
25
The DSC measurements were carried out on TA Q1000 of TA instruments. The
experiments were performed at heating rate of 5 or 10.0 °C/min over a
temperature range of 30 °C to 300 °C purging with nitrogen at a flow rate of
11
50ml/min. Standard aluminum crucibles covered by lids with pin hole were
used.
Raltegravir base used in the process of the present invention can be prepared by
any one of the method known in prior art as described in US patent 5 nt no.
US7,169,780 and US7,754,731 etc. Typically, raltegravir base can be prepared
by treating acetone cyanohydrin with ammonia gas followed by reacting the
resulting corresponding amino nitrile compound with benzylchloroformate in
the presence of a base to form benzyl 1-cyano-1-methylethylcarbamate which is
10 then reacted with hydroxyl amine in the presence of a base to form benzyl 2-
amino-2-(hydroxyimino)-1,1-dimethylethylcarbamate and reacted with
dimethylacetylenedicarboxylate to form corresponding cyclized
dihydroxypyrimidine compound. The resultant dihydroxypyrimidine compound
is then condensed with 4-fluoromethyl amine using base and then methylated to
15 form N-methylated intermediate. The amine protected group of the Nmethylated
intermediate is removed using Pd/C to form corresponding amino
compound namely, 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-
methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide. It is advantageous to
isolate amino compound in anhydrous form because it has to react with
20 corresponding acid chloride in next step. The present invention achieve desired
anhydrous amino compound by distilling the reaction mass in acetonitrile at
atmospheric pressure.
Potassium salt of 5-methyl-1,3,4-oxadiazole-2-carboxylic acid is reacted with
oxalyl chloride in the presence of methylene dichloride and N,N25
dimethylformamide to form corresponding acid chloride, which is then reacted
with 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-
1,6-dihydropyrimidine-4-carboxamide using suitable solvent to form raltegravir
base. Raltegravir base can be isolated from the reaction mixture and purified by
12
any of the methods known in literature. Generically raltegravir base can be
purified using alcoholic solvents selected from lower alcohols such as methanol,
ethanol, isopropanol, butanol, and the like. Particularly raltegravir base is
purified using ethanol to remove impurities. Specifically impurity of following
structure has been removed along with other known impurities 5 s during
purification.
N
N
O
OH
HN
O
F
HN
O H3C CH3
NH
O
The resulting raltegravir is highly pure, having purity greater than 99.5% and
10 preferably greater than 99.8% by HPLC.
The order and manner of combining the reactants at any stage of the process are
not important and may be varied. The reactants may be added to the reaction
mixture as solids, or may be dissolved individually and combined as solutions.
15 Further, any of the reactants may be dissolved together as sub-groups, and those
solutions may be combined in any order. The time required for the completion
of the reaction may also vary widely, depending on many factors, notably the
reaction temperature and the nature of the reagents and solvents employed.
Wherever required, progress of the reaction may be monitored by suitable
20 chromatographic techniques such as High performance liquid chromatography
(HPLC), thin layer chromatography (TLC) or ultra performance liquid
chromatography (UPLC).
Thus, raltegravir as well as intermediates described here in the present invention
may be optionally purified to enhance the purity of the product. Any suitable
25 purification procedure such as, for example, crystallization, derivatisation, slurry
13
wash, salt preparation, various chromatographic techniques, solvent anti-solvent
system or combination of these procedures, may be employed to obtain the
purified material. However, other equivalent procedures such as acid-base
treatment could also be used to purify the intermediates as well as the final
product. The solvents used for the purification of raltegravir and intermediate5 s
of the present invention may be selected depending upon the nature of the
compound to be purified. However the solvent can be chosen from amongst
water, C1-6 alcohols, aliphatic C3-6 ketones, aliphatic or aromatic hydrocarbons,
C2-10 esters, C3-6 ethers, aliphatic C2-C4 nitrile, a halogenated solvents, aprotic
10 polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, Nmethylpyrrolidinone,
dimethylsulfoxide, sulfolane, tetrahydrofuran, 2-methyl
tetrahydrofuran, 1,2-dimethoxy or diethoxy ethane and the like or mixtures
thereof in suitable proportion.
15 As used herein the term “conventional methods for the isolation of intermediates
as well as final product” may be varied depending upon the nature of the
reactions, nature of product of the reaction, medium of the reaction and the like.
The suitable conventional methods can be selected from amongst but not limited
to distillation of the solvent, addition of water to the reaction mixture followed
20 by extraction with water immiscible solvents, removal of the insoluble particles
from the reaction mixture, if present, by filtration or centrifugation or by
decantation, addition of water immiscible organic solvent, addition of a solvent
to the reaction mixture which precipitate the product, neutralizing the reaction
mixture with a suitable acid or base whichever is applicable.
25
The main advantage of the present invention lies with a process for the
preparation of crystalline Form 3 of raltegravir potassium, which avoids use of
freeze drying technique and mixture of two or more solvents. Moreover the
14
process of the present invention involves shorter time duration, which in turn
saves time, resources and is highly efficient in term of reproducibility.
Although the following examples illustrate the present invention in more detail,
but the examples are not intended in any way to limit the scope of the prese5 nt
invention.
EXAMPLES
10 Example 1:Preparation of raltegravir potassium Form 3
Raltegravir base (2.0 g) was suspended in ethanol (32 ml) at 20-30 °C. A
solution of potassium hydroxide in ethanol (300 mg; 12ml) was added to the
above reaction mass. Ethanol (84 ml) was added slowly and the reaction mass
15 was stirred for 30 minutes at 20-30 °C. Thereafter, the reaction mass was stirred
at reflux temperature for 2.0 hours. The reaction mass was cooled to 20-30 °C
and stirred for 2.0 hours. The product thus formed was filtered, washed with
ethanol (20ml) and dried under vacuum at 40-50 °C to afford 1.5 g of title
compound.
20
Example 2:Preparation of raltegravir potassium Form 3
Raltegravir base (2.0 g) was suspended in ethanol (32 ml) at 20-30 °C, followed
by addition of seed of raltegravir potassium Form 3. A solution of potassium
25 hydroxide in ethanol (300 mg; 12ml) was added to the above reaction mass.
Ethanol (84 ml) was added slowly and the reaction mass was stirred for 30
minutes at 20-30 °C. Thereafter, the reaction mass was stirred at reflux
temperature for 2.0 hours. The reaction mass was cooled to 20-30 °C and stirred
15
for 2.0 hours. The product thus formed was filtered, washed with ethanol (20ml)
and dried under vacuum at 40-50 °C to afford title compound.
Example 3:Preparation of raltegravir potassium Form 3
5
Raltegravir base (2.0 g) was suspended in ethanol (32 ml) at 20-30 °C. A
solution of potassium hydroxide in ethanol (300 mg; 12ml) was added to the
above reaction mass. Ethanol (84 ml) was added slowly to the reaction mass.
Thereafter, the reaction mass was stirred at 20-30 °C for 4 hours. The product
10 thus formed was filtered, washed with ethanol (20ml) and dried under vacuum
at 40-50 °C to afford 1.7g of title compound.
Example 4:Preparation of raltegravir potassium Form 3
15 Raltegravir base (2.0 g) was suspended in isopropyl alcohol (35 ml) at 20-30 °C.
A solution of potassium hydroxide in isopropyl alcohol (300 mg; 15ml) was
added to the above reaction mass. Isopropyl alcohol (85 ml) was added slowly to
the reaction mass and the reaction mass was stirred for 30 minutes at 20-30 °C.
Thereafter, the reaction mass was stirred at reflux temperature for 2.0 hours.
20 The reaction mass was cooled to 20-30 °C and stirred for 2.0 hours. The
product thus formed was filtered, washed with isopropyl alcohol (15 ml) and
dried under vacuum at 40-50 °C to afford 1.5g of title compound.
Example 5:Preparation of raltegravir potassium Form 3
25
Raltegravir base (2.0 g) was suspended in ethanol (20 ml) at 20-30 °C. A
solution of potassium hydroxide in ethanol (300 mg;15ml) was added to the
above reaction mass. Ethanol (20 ml) was added slowly to the reaction mass and
16
stirred at 20-30 °C for 90 minutes The product thus formed was filtered, washed
with ethanol (10 ml) and dried under vacuum 40-50 °C to afford 1.7g of title
compound.
Example 6:Preparation of {1-[4-(4-fluoro-benzylcarbamoyl)-5-hydroxy-5 6-
oxo-1,6-dihydro-pyrimidin-2-yl]-1-methyl-ethyl}-carbamic acid benzyl ester
2-(1-Benzyloxycarbonylamino-1-methyl-ethyl)-5,6-dihydroxy-pyrimidine-4-
carboxylic acid methyl ester (100.0 g) was charged in methanol (200 ml). The
reaction mass was heated to 55o10 C and triethylamine ( 46.20 ml) was added. The
temperature of the reaction mass was further raised to 60-70oC and then 4-
fluorobenzylamine ( 38.10 ml) was added slowly and the reaction mass was
stirred for further for 5 hours. After completion of reaction ( monitored by
HPLC), the reaction mass was cooled to 55oC, and acetic acid (31.60 ml) was
15 added slowly followed by DM water ( 34 ml). The reaction mass was seeded
with title compound and further stirred at 58-65oC for 30 minutes. DM water
(130 ml) was added slowly at 58-65oC. The reaction mass was cooled to 15-
25oC and stirred for two hours. The solid was filtered and washed with 1:1
mixture (500 ml) of DM water and methanol and dried at 50-60oC for 12 hours
20 to obtain 124 g of title compound having purity 90.9 % by HPLC.
Example 7:Preparation of {1-[4-(4-fluoro-benzylcarbamoyl)-5-hydroxy-1-
methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-1-methyl-ethyl}-carbamic acid
benzyl ester
25
A mixture of {1-[4-(4-fluoro-benzylcarbamoyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidin-
2-yl]-1-methyl-ethyl}-carbamic acid benzyl ester (100.0g),
17
magnesium hydroxide (32.0g), trimethyl- sulfoxonium iodide (121.0g) and DM
water (2.29 ml) in N-methyl pyrrolidinone (200 ml) was prepared at room
temperature and then the reaction mass was heated at 100-105oC for 5-6 hours.
After completion of reaction (monitored by HPLC), the reaction mass was
cooled to 20oC, methanol (173.70 ml) was added followed by slow addition 5 ion of
dilute hydrochloric acid (85.90 ml). Seeding material of title compound was
added to reaction mixture followed by slow addition of aqueous sodium
bisulfite solution. Temperature of reaction mixture was raised to 30-35oC and
stirred for 2 hours. Dilute hydrochloric acid (85.90 ml) was added slowly at 30-
35oC. The reaction mixture was cooled to 10o10 C and maintained under stirring for
1 hour. The resulting solid was filtered, washed with aqueous methanol (960
ml) followed by water ( 1.0 L ), and dried at 50-60oC for 16 hours to obtain
91.0 g of title compound having purity 99.7% by HPLC.
15 Example 8:Preparation of 2-(1-amino-1-methyl-ethyl)-5-hydroxy-1-methyl-
6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid 4-fluoro-benzylamide
To {1-[4-(4-fluoro-benzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-
2-yl]-1-methyl-ethyl}-carbamic acid benzyl ester (90.0 g), in
20 methanol (900 ml), glycolic acid (17.53 g) and 10% Pd-C (9.0 gm) were added
and the reaction mass was hydrogenated under 1.0-3.0 kg/cm2 hydrogen
pressure at 35-55oC for about 60 minutes. After completion of reaction, DM
water (90 ml) was added and the reaction mass was stirred for 30 minutes. The
reaction mass was filtered through hyflo bed, and hyflo bed was washed with a
25 mixture of methanol (288 ml) and DM water (72 ml). The combined filtrate was
treated with dilute aqueous sodium hydroxide solution and pH of the reaction
mass was adjusted between 7.4-7.8. Thereafter, reaction mass was cooled to 0-
5oC and maintained at same temperature for 2-4 hours. The resulting solid was
18
filtered, washed with cooled DM water (450 ml) and finally dried at 50-55oC.
The resulting hydrated compound was taken in acetonitrile (500 ml) and then
acetonitrile was distilled off at atmospheric pressure to obtain 58.2 g of title
compound having purity 99.7% by HPLC.
5
Example 9:Preparation of Raltegravir base
Potassium-5-methyl-1,3,4-oxadiazole-2-carboxylate ( 49.59 g) was charged in
methylene chloride (500 ml), N,N-dimethylformamide (1.25 ml) was added and
then the reaction mass was cooled to -10o10 C under inert atmosphere. Oxalyl
chloride (50.50 ml) was slowly added at -10 to 0oC to the reaction mass and then
the reaction conditions were maintained for 45 minutes. Solvent was distilled off
under reduced pressure. Acetonitrile ( 100 ml ) was added and distilled off under
reduced pressure. Acetonitrile (300 ml) was added and the reaction mass was
15 stirred to obtain a suspension ( Solution-A).
Meanwhile in another vessel, 2-(1-amino-1-methyl-ethyl)-5-hydroxy-1-methyl-
6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid 4-fluoro-benzylamide (50.0 g)
was taken in acetonitrile (500 ml) and the reaction mass was cooled to -10oC
under inert atmosphere. N-methyl morpholine ( 82.50 ml) was added and the
reaction mass was stirred for 20 minutes at -15 to 0o20 C. Solution-A, as prepared
above, was added slowly at same temperature and then the reaction mass was
stirred for 45 minutes, while maintaining temperature at -15 to 0oC. Thereafter,
40% aqueous methylamine solution (50. gm) was added slowly at -15 to 0oC and
the reaction mass was maintained at -15 to 0oC for further 45 minutes. Dilute
25 hydrochloric acid solution was slowly added to the reaction mass to adjust the
pH to 3 to 4. The resulting reaction mass was extracted with ethyl acetate (250
ml). Aqueous layer was again extracted with ethyl acetate (250 ml). The
combined organic layer was washed twice with 10% aqueous sodium chloride
19
solution (2x 500 ml)and then dried over sodium sulphate. Solvent was distilled
off completely under reduced pressure. Ethanol (100 ml) was added and distilled
under reduced pressure Ethanol (500 ml) was added and the reaction mass was
stirred at reflux temperature for 15 minutes. The reaction mass was cooled to 5
to -5oC and maintained for 60 minutes. The solid was filtered and washed 5 with
chilled ethanol (100 ml). The solid was suck dried for 15 minutes. The wet solid
was charged in ethanol (500 ml) and refluxed for 30 minutes. The reaction mass
was cooled to 5 to -5oC and maintained for 60 minutes. The resulting solid was
filtered and dried at 50-60oC for 16 hours to obtain 44.0 g of raltegravir having
10 purity 99.90% by HPLC.
It will be apparent to those skilled in the art that various modifications and
variations can be made in the present invention and specific examples provided
herein without departing from the spirit and scope of the invention. Thus, it is
intended that the present invention covers the modifications and variations of
15 this invention that come within the scope of any claims and their equivalents.

WE CLAIM:
1. A process for the preparation of Form 3 of raltegravir potassium having
formula I, which comprises steps of :
N
N
O
O-K+
HN
O
F
HN
O
N N
O
H3C
H3C CH3
Formula I
5 a) suspending raltegravir in an alcoholic solvent;
b) optionally seeding with raltegravir potassium Form 3;
c) adding an alcoholic solution of potassium base;
d) diluting the reaction mixture with an alcoholic solvent;
e) optionally heating the resultant reaction mixture to reflux temperature;
10 f) stirring the reaction mixture for up to 5 hours; and
g) isolating raltegravir potassium Form 3.
2. The process as claimed in claim 1, wherein in step a) alcoholic solvent is
selected from methanol, ethanol, propanol, isopropanol, n-butanol,
15 isobutanol, n-pentanol and isopentanol.
3. The process as claimed in claim 1, wherein in step a) alcoholic solvent is
preferably ethanol.
20 4. The process as claimed in claim 1, wherein in step c) potassium base is
selected from hydroxides such as potassium hydroxide, alkoxide such as
potassium methoxide, potassium ethoxide, potassium isopropoxide,
potassium tertiary butoxide; and alcoholic solvent is selected from methanol,
21
ethanol, propanol, isopropanol, n-butanol, isobutanol, n-pentanol and
isopentanol.
5. The process as claimed in claim 1, wherein in step c) potassium base in
alcoholic solvent is added to reaction mass at 15°C 5 to 35°C.
6. The process as claimed in claim 1, wherein in step c) potassium base is
preferably potassium hydroxide and alcoholic solvent is preferably ethanol.
10 7. The process as claimed in claim 1, wherein in step d) alcoholic solvent added
for dilution, is selected from methanol, ethanol, propanol, isopropanol, nbutanol,
isobutanol, n-pentanol and isopentanol.
8. The process as claimed in claim 1, wherein in step d) alcoholic solvent is
15 preferably ethanol.
9. The process as claimed in claim 1, wherein in step f), the reaction mass is
stirred at 15°C to 35°C.
20 10. The process as claimed in claim 1, wherein in step f), the reaction mass is
stirred at 20°C to 30°C.