WO2016092527A1 - A process for the preparation of dolutegravir - Google Patents

A process for the preparation of dolutegravir Download PDF

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WO2016092527A1
WO2016092527A1 PCT/IB2015/059599 IB2015059599W WO2016092527A1 WO 2016092527 A1 WO2016092527 A1 WO 2016092527A1 IB 2015059599 W IB2015059599 W IB 2015059599W WO 2016092527 A1 WO2016092527 A1 WO 2016092527A1
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formula
compound
process according
sodium
acid
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Amar Parekh
Harish Kumar
Suresh Allada
Satish Manohar Bhoge
Satyanarayana M
Anand Prakash Tiwari
Kaptan Singh
Mohan Prasad
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Sun Pharmaceutical Industries Limited
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The present invention provides processes for the preparation of dolutegravir sodium of Formula I, and intermediate compounds of Formula V, Formula VII, Formula VIII, Formula X, and Formula XII. The present invention further provides a crystalline form of the compound of Formula X.

Description

A PROCESS FOR THE PREPARATION OF DOLUTEGRAVIR
Field of the Invention
The present invention provides processes for the preparation of dolutegravir sodium of Formula I, and intermediate compounds of Formula V, Formula VII, Formula VIII, Formula X, and Formula XII. The present invention further provides a crystalline form of the compound of Formula X.
Background of the Invention
Dolutegravir sodium chemically is sodium (4i?, 12aS)-9-{[(2,4- difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3 ,4,6,8, 12, 12a-hexahydro-2H- pyrido[l',2':4,5]pyrazino[2, l-6][l,3]oxazin-7-olate, represented by Formula I.
Figure imgf000002_0001
Formula I
Dolutegravir sodium is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor.
U.S. Patent No. 8,624,023; U.S. Publication Nos. 2014/0011995 and
2013/0172551; and PCT Publication No. WO 2014/128545 describes processes for the preparation of dolutegravir.
Summary of the Invention
The present invention provides processes for the preparation of dolutegravir sodium of Formula I, and intermediate compounds of Formula V, Formula VII, Formula VIII, Formula X, and Formula XII. The present invention further provides a crystalline form of the compound of Formula X. The processes of the present invention are simple, environmentally friendly, and make use of inexpensive, non-hazardous, and safe chemicals that are easy to handle. The process of the present invention requires fewer steps, therefore making it commercially viable and cost-effective. Brief Description of the Drawings
Figure 1 depicts an X-ray powder diffraction (XRPD) pattern of the crystalline form of the compound of Formula X.
Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of the crystalline form of the compound of Formula X.
Figure 3 depicts a Thermogravimetric Analysis (TGA) thermogram of the crystalline form of the compound of Formula X.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ± 10% of the value .
The term "lower alkyl," as used herein, includes both straight chain and branched chain alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and iso- hexyl.
A first aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000003_0001
Formula I
comprising:
a) reacting a compound of Formula II,
Figure imgf000003_0002
Formula II
wherein R is lower alkyl,
with benzyl alcohol to obtain a compound of Formula III,
Figure imgf000004_0001
Formula III
wherein R1 is lower alkyl;
b) protecting the compound of Fonnula III to obtain a compound of Formula IV,
Figure imgf000004_0002
Formula IV
wherein R1 is lower alkyl;
c) hydrolyzing the compound of Fonnula IV to obtain a compound of Fonnula V;
Figure imgf000004_0003
Formula V
d) reacting the compound of Fonnula V with a compound of Fonnula VI
Figure imgf000004_0004
Formula VI
to obtain a compound of Fonnula VII;
Figure imgf000005_0001
Formula VII
e) deprotecting the compound of Formula VII to obtain a compound of Formula VIII:
Figure imgf000005_0002
Formula VIII
f) reacting the compound of Formula VIII with a compound of Formula IX
Figure imgf000005_0003
Formula IX
to obtain a compound of Formula X;
Figure imgf000005_0004
Formula X
g) reacting the compound of Formula X with a compound of Formula XI
Figure imgf000006_0001
Formula XI
a compound of Formula XII;
Figure imgf000006_0002
Formula XII
reacting the compound of Formula XII with a compound of Formula XIII
Figure imgf000006_0003
Formula XIII
to obtain a compound of Formula XIV and
Figure imgf000006_0004
Formula XIV
converting the compound of Formula XIV to a compound of Formula XV,
Figure imgf000007_0001
Formula XV
or alternatively, reacting the compound of Formula XII
Figure imgf000007_0002
Formula XII
with the compound of Formula XIII to give a mixture, and
Figure imgf000007_0003
Formula XIII
subsequently treating the mixture with an acid to obtain the compound of Formula XV;
Figure imgf000007_0004
Formula XV i) reacting the compound of Formula XV with a compound of Formula XVI
Figure imgf000008_0001
Formula XVI
to obtain a compound of Formula XVII;
Figure imgf000008_0002
Formula XVII
debenzylating the compound of Formula XVII to obtain a compound of Formula XVIII; and
Figure imgf000008_0003
Formula XVIII
k) converting the compound of Formula XVIII to dolutegravir sodium of Formula I.
A second aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000009_0001
Formula I
comprising:
a) hydrolyzing a compound of Formula IV,
Figure imgf000009_0002
Formula IV
wherein R1 is lower alkyl,
to obtain a compound of Formula V;
Figure imgf000009_0003
Formula V
b) reacting the compound of Formula V with a compound of Formula VI
Figure imgf000009_0004
Formula VI to obtain a compound of Formula VII;
Figure imgf000010_0001
Formula VII
c) deprotecting the compound of Formula VII to obtain a compound of Formula VIII:
Figure imgf000010_0002
Formula VIII
d) reacting the compound of Formula VIII with a compound of Formula IX
Figure imgf000010_0003
Formula IX
to obtain a compound of Formula X;
Figure imgf000010_0004
Formula X
e) reacting the compound of Formula X with a compound of Formula XI
Figure imgf000011_0001
Formula XI
a compound of Formula XII; and
Figure imgf000011_0002
Formula XII
f) converting the compound of Formula XII to dolutegravir sodium of Formula I.
A third aspect of the present invention provides a process for the preparation of a compound of Formula V,
Figure imgf000011_0003
Formula V
comprising hydrolyzing a compound of Formula IV
Figure imgf000011_0004
Formula IV wherein R1 is lower alkyl.
A fourth aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000012_0001
Formula I
comprising:
a) hydrolyzing a compound of Formula IV,
Figure imgf000012_0002
Formula IV
wherein R1 is lower alkyl,
to obtain a compound of Formula V; and
Figure imgf000012_0003
Formula V
b) converting the compound of Formula V to dolutegravir sodium of Formula I. A fifth aspect of the present invention provides a process for the preparation of a compound of Formula VII,
Figure imgf000013_0001
Formula VII
comprising reacting a compound of Formula V
Figure imgf000013_0002
Formula V
with a compound of Formula VI.
Figure imgf000013_0003
Formula VI
A sixth aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000013_0004
Formula I
comprising:
a) reacting a compound of Formula V
Figure imgf000014_0001
Formula V
with a compound of Formula VI
Figure imgf000014_0002
Formula VI
to obtain a compound of Formula VII; and
Figure imgf000014_0003
Formula VII
b) converting the compound of Formula VII to dolutegravir sodium of Formula I. A seventh aspect of the present invention provides a process for the preparation of a compound of Formula VIII,
Figure imgf000014_0004
Formula VIII
comprising deprotecting a compound of Formula VII.
Figure imgf000015_0001
An eighth aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000015_0002
Formula I
comprising:
a) deprotecting a compound of Formula VII
Figure imgf000015_0003
Formula VII
to obtain a compound of Formula VIII; and
Figure imgf000015_0004
Formula VIII
b) converting the compound of Formula VIII to dolutegravir sodium of Formula I. A ninth aspect of the present invention provides a process for the preparation of a compound of Formula X,
Figure imgf000016_0001
Formula X
comprising reacting a compound of Formula VIII
Figure imgf000016_0002
Formula VIII
with a compound of Formula IX.
N
H3C\ ^ . /C H3
Formula IX
A tenth aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000016_0003
Formula I
comprising:
a) reacting a compound of Formula VIII
Figure imgf000017_0001
Formula VIII
with a compound of Formula IX
Figure imgf000017_0002
Formula IX
to obtain a compound of Formula X; and
Figure imgf000017_0003
Formula X
b) converting the compound of Formula X to dolutegravir sodium of Formula I. An eleventh aspect of the present invention provides a process for the preparation of a compound of Formula XII,
Figure imgf000017_0004
Formula XII
comprising reacting a compound of Formula X
Figure imgf000018_0001
Formula X
with a compound of Formula XI.
Figure imgf000018_0002
Formula XI
A twelfth aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000018_0003
Formula I
comprising:
a) reacting a compound of Formula X
Figure imgf000018_0004
Formula X
with a compound of Formula XI
Figure imgf000019_0001
Formula XI
to obtain a compound of Formula XII; and
Figure imgf000019_0002
Formula XII
b) converting the compound of Formula XII to dolutegravir sodium of Formula I.
A thirteenth aspect of the present invention provides a process for the preparation of a compound of Formula XIV,
Figure imgf000019_0003
Formula XIV
comprising reacting a compound of Formula XII
Figure imgf000019_0004
Formula XII with a compound of Formula XIII.
Figure imgf000020_0001
Formula XIII
A fourteenth aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000020_0002
comprising:
a) reacting a compound of Formula XII
Figure imgf000020_0003
Formula XII
with a compound of Formula XIII
Figure imgf000020_0004
Formula XIII
to obtain a compound of Formula XIV; and
Figure imgf000021_0001
Formula XIV
b) converting the compound of Formula XIV to dolutegravir sodium of Formula I.
A fifteenth aspect of the present invention provides a process for the preparation of a compound of Formula XV,
Figure imgf000021_0002
Formula XV
comprising reacting a compound of Formula XII
Figure imgf000021_0003
Formula XII
with a compound of Formula XIII to give a mixture, and
Figure imgf000021_0004
Formula XIII subsequently treating the mixture with an acid to obtain the compound of Formula XV.
A sixteenth aspect of the present invention provides a process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000022_0001
Formula I
comprising:
a) reacting a compound of Formula XII
Figure imgf000022_0002
Formula XII
with a compound of Formula XIII to give a mixture, and
Figure imgf000022_0003
Formula XIII
subsequently treating the mixture with an acid to obtain the compound of Formula XV: and
Figure imgf000022_0004
Formula XV b) converting the compound of Formula XV to dolutegravir sodium of Formula I.
The reaction of the compound of Formula II with benzyl alcohol to obtain the compound of Formula III is carried out in the presence of a base in a solvent.
The base is selected from the group consisting of potassium tert-butoxide, sodium tert-pentoxide, sodium tert-butoxide, potassium tert-pentoxide, sodium hydride, and lithium hydride.
The solvent is selected from the group consisting of toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.
The reaction of the compound of Formula II with benzyl alcohol is carried out for about 1 hour to about 7 hours, for example, for about 2 hours to about 6 hours.
The reaction of the compound of Formula II with benzyl alcohol is carried out at a temperature of about 0°C to about 85 °C, for example, about 0°C to about 80°C.
The compound of Formula III may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula III may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The protection of the compound of Formula III to obtain the compound of Formula IV is carried out with ethylene glycol in the presence of a dehydrating agent in a solvent.
The dehydrating agent is selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, acetic anhydride, and trifluoroacetic acid.
The solvent is selected from the group consisting of toluene, xylene, cyclohexane, dichloromethane, and mixtures thereof.
The protection of the compound of Formula III is carried out for about 1 hour to about 5 hours, for example, for about 2 hours to about 4 hours.
The protection of the compound of Formula III is carried out at a temperature of about 50°C to about 150°C, for example, of about 60°C to about 120°C.
The compound of Formula IV may be used as such for the further reaction.
The compound of Formula IV may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula IV may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The hydrolysis of the compound of Formula IV to obtain the compound of Formula V is carried out in the presence of a hydrolyzing agent in a solvent.
The hydrolyzing agent is selected from the group consisting of sodium hydroxide, hydrochloric acid, and potassium hydroxide.
The solvent is selected from the group consisting of water, toluene,
dichloromethane, tetrahydrofuran, methanol, ethanol, and isopropyl alcohol.
The hydrolysis of the compound of Formula IV is carried out for about 0.5 hours to about 25 hours, for example, for about 1 hour to about 20 hours.
The hydrolysis of the compound of Formula IV is carried out at a temperature of about 15°C to about 95°C, for example, of about 20°C to about 90°C.
The compound of Formula V may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula V may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The reaction of the compound of Formula V with the compound of Formula VI to obtain the compound of Formula VII is carried out in the presence of an activating agent in a solvent, optionally in the presence of a base.
The activating agent is selected from the group consisting of ethyl chloroformate, boric acid, triisopropyl borate, methyl chloroformate, and isobutyl chloroformate.
The base is selected from the group consisting of triethylamine, dimethylamino- pyridine, isopropylamine, diisopropylethylamine, pyridine, and tributylamine.
The solvent is selected from the group consisting of toluene, dichloromethane, and tetrahydrofuran.
The reaction of the compound of Formula V with the compound of Formula VI is carried out for about 10 minutes to about 40 hours, for example, for about 20 minutes to about 35 hours. The reaction of the compound of Formula V with the compound of Formula VI is carried out at a temperature of about 0°C to about 120°C, for example, about 0°C to about 115°C.
The compound of Formula VII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula VII may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The deprotection of the compound of Formula VII to obtain the compound of Formula VIII is carried out with a deprotecting agent.
The deprotecting agent is selected from the group consisting of hydrochloric acid, acetic acid, hydrobromic acid, sulfuric acid, perchloric acid, nitric acid, p-toluenesulfonic acid, formic acid, oxalic acid, and mixtures thereof.
The deprotection of the compound of Formula VII is carried out for about 30 minutes to about 30 hours, for example, for about 1 hour to about 25 hours.
The deprotection of the compound of Formula VII is carried out at a temperature of about 5°C to about 55°C, for example, of about 10°C to about 50°C.
The compound of Formula VIII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula VIII may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The reaction of the compound of Formula VIII with the compound of Formula IX to obtain the compound of Formula X is carried out in the optional presence of a base in a solvent.
The base is selected from the group consisting of triethylamine, dimethylamino- pyridine, isopropylamine, diisopropylethylamine, pyridine, l,8-diazabicyclo[5.4.0]undec- 7-ene, and tributylamine.
The solvent is selected from the group consisting of toluene, ethyl acetate, and dichloromethane.
The compound of Formula IX may also serve as a solvent. The reaction of the compound of Formula VIII with the compound of Formula IX is carried out for about 30 minutes to about 15 hours, for example, for about 1 hour to about 12 hours.
The reaction of the compound of Formula VIII with the compound of Formula IX is carried out at a temperature of about 10°C to about 40°C, for example, of about 20°C to about 35°C.
The compound of Formula X may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula X may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The reaction of the compound of Formula X with the compound of Formula XI to obtain the compound of Formula XII is carried out in the presence of a solvent.
The solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tert-butanol, dichloromethane, chloroform, carbon tetrachloride,
tetrahydrofuran, and mixtures thereof.
The reaction of the compound of Formula X with the compound of Formula XI is carried out for about 10 minutes to about 4 hours, for example, for about 30 minutes to about 2 hours.
The reaction of the compound of Formula X with the compound of Formula XI is carried out at a temperature of about 10°C to about 40°C, for example, of about 20°C to about 35°C.
The compound of Formula XII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula XII may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The reaction of the compound of Formula XII with the compound of Formula XIII to obtain the compound of Formula XIV is carried out in the presence of a base in a solvent. The base is selected from the group consisting of potassium tert-butoxide, sodium- tert-butoxide, N,N-diisopropylethylamine, tert-butylamine, sodium ethoxide, sodium methoxide, l,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydride, lithium hydride, potassium carbonate, and cesium carbonate.
The solvent is selected from the group consisting of methanol, toluene, ethanol, n- propanol, isopropanol, tert-butanol, dichloromethane, chloroform, carbon tetrachloride, and mixtures thereof.
The reaction of the compound of Formula XII with the compound of Formula XIII is carried out for about 30 minutes to about 5 hours, for example, for about 1 hour to about 4 hours.
The reaction of the compound of Formula XII with the compound of Formula XIII is carried out at a temperature of about 20°C to about 70°C, for example, of about 30°C to about 65°C.
The compound of Formula XIV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula XIV may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The conversion of the compound of Formula XIV to the compound of Formula XV is carried out with an acid in a solvent.
The acid is selected from the group consisting of formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, and ethanesulfonic acid.
The solvent is selected from the group consisting of acetonitrile, dioxane, water, acetone, n-propanol, isopropanol, methanol, ethanol, toluene, dimethylformamide, tetrahydrofuran, and mixtures thereof.
The conversion of the compound of Formula XIV to the compound of Formula XV is carried out for about 10 minutes to about 6 hours, for example, for about 30 minutes to about 5 hours.
The conversion of the compound of Formula XIV to the compound of Formula XV is carried out at a temperature of about 15°C to about 95°C, for example, of about 20°C to about 90°C. The compound of Formula XV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula XV may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
Alternatively, the compound of Formula XV is obtained by the reaction of the compound of Formula XII with the compound of Formula XIII to give a mixture, in the presence of a base in a solvent, and subsequent treatment of the mixture with an acid.
The base is selected from the group consisting of potassium tert-butoxide, sodium- tert-butoxide, N,N-diisopropylethylamine, tert-butylamine, cesium carbonate, potassium carbonate, lithium hydride, sodium hydride, and l,8-diazabicyclo[5.4.0]undec-7-ene.
The solvent is selected from the group consisting of methanol, water, toluene, ethanol, n-propanol, isopropanol, tert-butanol, dichloromethane, chloroform, carbon tetrachloride, and mixtures thereof.
The reaction of the compound of Formula XII with the compound of Formula XIII is carried out for about 2 hours to about 10 hours, for example, for about 3 hours to about 5 hours.
The reaction of the compound of Formula XII with the compound of Formula XIII is carried out at a temperature of about 15°C to about 70°C, for example, of about 20°C to about 55°C.
The acid is selected from the group consisting of formic acid, sulfuric acid, p- toluene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, and mixtures thereof.
The treatment of the mixture with the acid is carried out for about 5 hours to about 25 hours, for example, for about 10 hours to about 20 hours.
The treatment of the mixture with the acid is carried out at a temperature of about
10°C to about 35°C, for example, of about 15°C to about 30°C.
The compound of Formula XV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula XV may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying. The reaction of the compound of Formula XV with the compound of Formula XVI is carried out in the optional presence of an acid and a solvent.
The acid is selected from the group consisting of acetic acid, formic acid, p- toluenesulfonic acid, methanesulfonic acid, and sulfuric acid.
The solvent is selected from the group consisting of toluene, methanol, methyl isobutyl ketone, acetonitrile, diglyme, and monoglyme.
The reaction of the compound of Formula XV with the compound of Formula XVI is carried out for about 30 minutes to about 35 hours, for example, for about 1 hour to about 30 hours.
The reaction of the compound of Formula XV with the compound of Formula XVI is carried out at a temperature of about 25°C to about 110°C, for example, of about 30°C to about 100°C.
The compound of Formula XVII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of
Formula XVII may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The debenzylation of the compound of Formula XVII to obtain the compound of Formula XVIII is carried out in the presence of hydrogen gas and a catalyst in a solvent.
The catalyst is selected from the group consisting of palladium-carbon and palladium hydroxide-carbon.
The solvent is selected from the group consisting of tetrahydrofuran,
dichloromethane, methanol, acetone, ethanol, n-propanol, isopropanol, toluene, acetonitrile, dimethylformamide, and mixtures thereof.
The debenzylation of the compound of Formula XVII is carried out for about 30 minutes to about 4 hours, for example, for about 1 hour to about 3 hours.
The debenzylation of the compound of Formula XVII is carried out at a temperature of about 15°C to about 50°C, for example, of about 20°C to about 45°C.
The compound of Formula XVIII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula XVIII may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The compound of Formula XVIII can be converted to dolutegravir sodium of Formula I by reacting the compound of Formula XVIII with a sodium-containing reagent in a solvent.
The sodium-containing reagent is selected from the group consisting of sodium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide, sodium-2 -ethyl hexanoate, and sodium octanoate.
The solvent is selected from the group consisting of methanol, water, ethanol, isopropyl alcohol, tert-butanol, and mixtures thereof.
The reaction of the compound of Formula XVIII with a sodium-containing reagent is carried out for about 10 minutes to about 6 hours, for example, for about 30 minutes to about 4 hours.
The reaction of the compound of Formula XVIII with a sodium-containing reagent is carried out at a temperature of about 20°C to about 75°C, for example, of about 25°C to about 70°C.
Dolutegravir sodium of Formula I may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. Dolutegravir sodium of Formula I may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
A seventeenth aspect of the present invention provides a compound of Formula V.
Figure imgf000030_0001
Formula V eighteenth aspect of the present invention provides a compound of Formula
Figure imgf000031_0001
Formula VIII
A twentieth aspect of the present invention provides a compound of Formula X.
Figure imgf000031_0002
Formula X
A twenty-first aspect of the present invention provides a compound of Formula
Figure imgf000031_0003
Formula XII A twenty-second aspect of the present invention provides the use of a compound of Formula V for the preparation of dolutegravir sodium of Formula I.
Figure imgf000032_0001
Formula V
A twenty-third aspect of the present invention provides the use of a compound of
Formula VII for the preparation of dolutegravir sodium of Formula I.
Figure imgf000032_0002
Formula VII
A twenty -fourth aspect of the present invention provides the use of a compound of Formula VIII for the preparation of dolutegravir sodium of Formula I.
Figure imgf000032_0003
Formula VIII
A twenty-fifth aspect of the present invention provides the use of a compound of Formula X for the preparation of dolutegravir sodium of Formula I.
Figure imgf000032_0004
Formula X A twenty-sixth aspect of the present invention provides the use of a compound of Formula XII for the preparation of dolutegravir sodium of Formula I.
Figure imgf000033_0001
Formula XII
A twenty-seventh aspect of the present invention provides a crystalline form of compound of Formula X, characterized by an XRPD pattern having peaks at d-spacings of about 18.8, 9.5, 5.6, and 3.9 A, and additional peaks at d-spacings of about 10.1, 4.8, 4.5, and 3.5 A.
Table 1 provides the d-spacing values (A), the corresponding 2Θ values, and the relative intensity of the crystalline form of compound of Formula X.
Table 1
Figure imgf000033_0002
3.2 27.8 15.1
3.1 28.4 12.9
3.0 29.3 11.8
2.9 30.8 11.1
2.9 31.3 9.3
2.8 31.7 5.6
2.7 33.4 3.5
2.6 34.1 4.5
2.6 35.2 4.1
2.5 35.9 2.6
2.4 37.5 3.2
2.3 39.4 4.5
The crystalline form of the compound of Formula X is characterized by a DSC thermogram having an endothermic peak at about 93.6°C.
The crystalline form of the compound of Formula X is also characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, or a TGA thermogram substantially as depicted in Figure 3.
A twenty-eighth aspect of the present invention provides the use of a crystalline form of the compound of Formula X for the preparation of dolutegravir sodium of Formula I.
While the present invention has been described in terms of its specific aspects and 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 following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
Methods
NMR spectrum was recorded using a Bruker® AVANCE III (400 MHz) NMR spectrometer.
Mass spectrum was recorded on a MASS (API2000) LC/MS-MS system, Q Trap® LC/MS-MS system (Applied Biosystems®).
HPLC purity was determined using a Waters® Alliance® HPLC e2695 Separations
Module and a Waters® 2487 DAD detector.
Examples Example 1 : Preparation of ethyl 4-(benzyloxy)-3 -oxobutanoate (Formula III, when R1 is ethyl)
A solution of benzyl alcohol (1 18.2 g) in toluene (200 mL) was added to a suspension of potassium tert-butoxide (286.6 g) in toluene (1800 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at 70°C to 75 °C for 4 hours and then cooled to 0°C. A solution of ethyl 4-chloro-3 -oxobutanoate (Formula II when R1 is ethyl, 200 g) in toluene (200 mL) was added drop-wise to the reaction mixture at 0°C to 10°C. The reaction mixture was stirred at room temperature for 1 hour, then hydrochloric acid (IN, 1200 mL) was added to the mixture at 0°C to 10°C. After separating the layers, the toluene layer was washed with saturated sodium bicarbonate (800 mL). The solvent was distilled off to obtain the title compound as an oily product.
Yield: 260 g
Example 2: Preparation of {2-[(benzyloxy)methyl]-1.3-dioxolan-2-yl}acetic acid (Formula
Y)
Ethylene glycol (136.6 g) was added to a mixture of ethyl 4-(benzyloxy)-3- oxobutanoate (Formula III, Example 1, 130 g), p-toluene sulfonic acid (1.3 g), and toluene (650 mL) at room temperature. The reaction mixture was stirred at 1 10°C for 3 hours, and then cooled to room temperature. A solution of sodium hydroxide (44 g) in water (650 mL) was added to the mixture at room temperature, then the reaction mixture was stirred for 15 hours at the same temperature. The layers were separated, and the pH of the aqueous layer was adjusted to 2 to 3 by using hydrochloric acid (2N). The product was extracted with toluene, and then the organic layer was concentrated to obtain the title compound as an oily product.
Yield: 98 g
1HNMR (CDC13) δ: 2.84 (2H, s), 3.53 (2H, s), 3.96-4.04 (4H, m), 4.55 (2H, s), 7.22-7.34 (5H, m)
Mass (m/z): 253.5 [M+H]+ Example 3: Preparation of 2-{2-r(benzyloxy)methyll-1.3-dioxolan-2-yl}-N-(2.4- difluorobenzvDacetamide (Formula VII)
A solution of ethyl chloroformate (35.2 g) in toluene (80 mL) was added slowly to a mixture of {2-[(benzyloxy)methyl]-l,3-dioxolan-2-yl}acetic acid (Formula V, Example 2, 80 g), triethylamine (36 g) and toluene (800 mL) at 0°C to 5°C. The reaction mixture was stirred for 30 minutes at 0°C to 5°C and then a solution of l-(2,4- difluorophenyl)methanamine (Formula VI, 50.4 g) in toluene (80 mL) was added slowly to the mixture. The reaction mixture was heated to 30°C to 35°C, then stirred for 2 hours, then hydrochloric acid (2Ν, 800 mL) was added to the mixture. After separating the layers, the aqueous layer was extracted with toluene (160 mL). The combined extracts were sequentially washed with water and sodium bicarbonate (5%). The solvent was distilled off, and the resulting residue was treated with cyclohexane (320 mL). The mixture was stirred at room temperature. The solid obtained was filtered, then washed, and then dried to obtain the title compound.
Yield: 95 g
1HNMR (CDC13) δ: 2.71 (2H, s), 3.43 (2H, s), 3.90-3.98 (4H, m), 4.36 (2H, d), 4.54 (2H, s), 6.6 (1H, s), 6.85-6.75 (3H, m), 7.22-7.34 (5H, m)
Mass (m/z): 377.4 [M+H]+
Example 4: Preparation of 4-(benzyloxy)-N-(2.4-difluorobenzyl)-3-oxobutanamide (Formula VIII)
A mixture of 2-{2-[(benzyloxy)methyl]-l,3-dioxolan-2-yl}-N-(2,4- difluorobenzyl)acetamide (Formula VII, Example 3, 80 g), concentrated hydrochloric acid (80 mL), and acetic acid (400 mL) was stirred for 2 hours at 40°C to 45°C, and then cooled to room temperature. Water (500 mL) was added to the reaction mixture, then the product was extracted with toluene (400 mL). The organic extract was sequentially washed with water and saturated sodium bicarbonate, and then the solvent was distilled off to obtain the title compound as an oily residue.
Yield: 70 g
1ΗΝΜΡν (CDC13) δ: 2.08 (1H, s), 3.46 (2H, s), 4.09 (2H, s), 4.44 (2H, d), 4.58 (2H, s), 6.74-6.84 (2H, m), 7.17-7.36 (6H, m)
Mass (m/z): 334.4 [M+H]+ Example 5 : Preparation of (2£)-4-(benzyloxy)-N-(2.4-difluorobenzyl)-2- r(dimethylamino)methylidenel-3-oxobutanamide (Formula X)
A mixture of 4-(benzyloxy)-N-(2,4-difluorobenzyl)-3-oxobutanamide (Formula VIII, Example 4, 25 g) and l, l-dimethoxy-N,N-dimethylmethanamine (Formula IX, 75 mL) was stirred at room temperature for 2 hours. Water (250 mL) was added to the reaction mixture, and then the product was extracted with ethyl acetate (135 mL). The organic layer was washed with saturated sodium bicarbonate, then the solvent was distilled off to obtain a residue. Methyl tert-butyl ether (100 mL) was added to the residue, then the mixture was stirred for 12 hours at room temperature. The white crystals obtained were filtered, then washed with methyl tert-butyl ether (25 mL), and then dried under vacuum to obtain the title compound.
Yield: 13 g
1HNMR (CDC13) δ: 3.07 (6H, s), 4.25 (2H, s), 4.50 (2H, d), 4.58 (2H, s), 6.75-6.81 (2H, m), 7.26-7.38 (6H, m), 7.89 (1H, s), 8.46 (1H, s)
Mass (m/z): 389.2 [M+H]+
Example 6: Preparation of a crystalline form of (2£)-4-(benzyloxy)-N-(2.4- difluorobenzyl)-2-r(dimethylamino)methylidenel-3-oxobutanamide (Formula X)
A mixture of 4-(benzyloxy)-N-(2,4-difluorobenzyl)-3-oxobutanamide (Formula VIII, Example 4, 25 g), l, l-dimethoxy-N,N-dimemylmethanamine (Formula IX, 100 g), and triethylamine (25 g) in toluene (500 mL) was stirred at room temperature for 10 hours to 12 hours. The reaction mixture was washed with water (2 χ 500 mL). The solvent from the organic layer was distilled off to obtain a residue. Methyl tert-butyl ether (800 mL) was added to the residue, and then the mixture was stirred at 5°C to 10°C for 2 hours to 3 hours. The resulting reaction mixture was filtered, then washed with methyl tert-butyl ether (500 mL), and then dried under vacuum to obtain the title compound.
Yield: 95 g
1HNMPv (CDCI3) δ: 3.07 (6H, s), 4.25 (2H, s), 4.50 (2H, d), 4.58 (2H, s), 6.75-6.81 (2H, m), 7.26-7.38 (6H, m), 7.89 (1H, s), 8.46 (1H, s)
Mass (m/z): 389.2 [M+H]+ Example 7: Preparation of (2£)-4-(benzyloxy)-N-(2.4-difluorobenzyl)-2-{r(2.2- dimethoxyethyl)aminolmethylidene}-3-oxobutanamide (Formula XII)
A mixture of (2£)-4-(benzyloxy)-N-(2,4-difluorobenzyl)-2- [(dimethylamino)methylidene]-3-oxobutanamide (Formula X, Example 5, 2 g), 2,2- dimethoxyethanamine (Formula XI, 1.9 g), and methanol (25 mL) was stirred at room temperature for 1 hour. The solvent was distilled off to obtain the title compound as a brown oil.
Yield: 2.3 g
1HNMR (CDC13) δ: 3.34 (2H, d), 3.37 (6H, s), 4.26 (2H, s), 4.35 (1H, t), 4.50 (2H, d), 4.55 (2H, s), 6.72-6.83 (2H, m), 7.26-7.37 (6H, m), 9.90 (1H, s), 10.8 (1H, t)
Mass (m/z): 449.5 [M+H]+
Example 8: Preparation of methyl 3-(benzyloxy)-5-[(2.4-difluorobenzyl)carbamoyl]-l- (2.2-dimethoxyethyl)-4-oxo- 1.4-dihydropyridine-2-carboxylate (Formula XIV)
Potassium tert-butoxide (43.7 g) was added to pre-chilled methanol (200 mL) at 5°C to 10°C. The mixture was added to a solution of dimethyl ethanedioate (Formula XIII, 39.5 g), (2£ -4-(benzyloxy)-N-(2,4-difluorobenzyl)-2-{ [(2,2- dimethoxyethyl)amino]methylidene}-3-oxobutanamide (Formula XII, Example 7, 50 g) and methanol (50 mL) at room temperature. The reaction mixture was stirred at 45°C to 50°C for 4 hours, then cooled to room temperature. The pH of the reaction mixture was adjusted to about 6.5 to 7 with hydrochloric acid (6 Ν). Water was added to the reaction mixture, and then the mixture was extracted with toluene (250 mL). The extract was washed with saturated sodium bicarbonate (250 mL), then the solvent was distilled off to obtain the title compound as an oily residue.
Yield: 52.13 g
Example 9: Preparation of methyl 3-(benzyloxy)-5-[(2.4-difluorobenzyl)carbamoyl]-4- oxo-l-(2-oxoethyl)- 1.4-dihvdropyridine-2-carboxylate (Formula XV)
Formic acid (125 mL) and water (62.5 mL) were added to a solution of methyl 3- (benzyloxy)-5-[(2,4-difluorobenzyl)carbamoyl]- l-(2,2-dimethoxyethyl)-4-oxo-l,4- dihydropyridine-2-carboxylate (Formula XIV, Example 8, 25 g) in acetonitrile (125 mL) at room temperature. The reaction mixture was heated to 60°C to 65 °C, then stirred for 1 hour, and then concentrated to obtain a residue. Dichloromethane ( 10 mL) was added to the residue, then the solution was sequentially washed with sodium bicarbonate (5%) and water. The solvent was distilled off to obtain the title compound.
Yield: 15 g
Example 10: Preparation of methyl 3-(benzyloxy)-5-r(2.4-difluorobenzyl)carbamoyll-4- oxo-l-(2-oxoethyl)-1.4-dihvdropyridine-2-carboxylate (Formula XV)
Dimethyl ethanedioate (Formula XIII, 3.95 g) was added to a mixture of (2£)-4- (benzyloxy)-N-(2,4-difluorobenzyl)-2-{ [(2,2-dimethoxyethyl)amino]methylidene}-3- oxobutanamide (Formula XII, Example 7, 5 g) and methanol (25 mL). The mixture was cooled to 15°C. Potassium tert-butoxide (4.06 g) was added to the mixture while maintaining the reaction temperature below 25°C. The reaction mixture was stirred at 45 °C to 50°C for 4 hours, and then cooled to room temperature. Toluene (50 mL) was added to the reaction mixture, then the pH of the reaction mass was adjusted to neutral with hydrochloric acid (4Ν). The organic layer was washed with water (50 mL). Formic acid ( 10 mL), sulfuric acid (0.5 mL), and water (0.4 mL) were added to the organic layer at room temperature, then the mixture was stirred for 14 hours at room temperature. The reaction was quenched with sodium carbonate solution (20%, 75 mL), and then the layers were separated. The organic layer was washed with water followed by brine, then concentrated to obtain the title compound.
Yield: 4.26 g
Example 1 1 : Preparation of (4R.12aS)-7-(benzyloxy)-N-(2.4-difluorobenzyl)-4-methyl- 6.8-dioxo-3.4.6.8.12.12a-hexahvdro-2H-pyridorr.2':4.51pyrazinor2.1-6iri.31oxazine-9- carboxamide (Formula XVII)
(3i?)-3-Aminobutan-l -ol (Formula XVI, 0.28 g) and acetic acid (1 mL) were added to a solution of methyl 3-(benzyloxy)-5-[(2,4-difluorobenzyl)carbamoyl]-4-oxo- l-(2- oxoethyl)- l,4-dihydropyridine-2-carboxylate (Formula XV, Example 9 or Example 10, 1 g) in toluene (10 mL) at room temperature. The reaction mixture was heated to 85°C to 90°C, then stirred for 2 hours, and then concentrated to obtain a residue. Dichloromethane (10 mL) was added to the residue, and then the solution was sequentially washed with water, sodium bicarbonate (5%), and water. The solvent was distilled off to obtain the title compound.
Yield: 1 g Example 12: Preparation of (4R.12aS)-N-(2.4-difluorobenzyl)-7-hvdroxy-4-methyl-6.8- dioxo-3.4.6.8.12.12a-hexahvdro-2H-pyridor .2':4.51pyrazinor2.1-6iri.31oxazine-9- carboxamide (Formula XVIII)
A mixture of (4R, 12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8- dioxo-3,4,6,8, 12, 12a-hexahydro-2H-pyrido[r,2':4,5]pyrazino[2,l-6][l,3]oxazine-9- carboxamide (Formula XVII, Example 11, 7 g) and 10% palladium-carbon (50% wet, 1.75 g) in tetrahydrofuran (84 mL) was stirred at 30°C to 35°C for 1 hour under hydrogen atmosphere. The palladium-carbon was filtered off, then the mixture was washed with tetrahydrofuran (21 mL). The combined filtrate was concentrated to obtain a residue. The resulting residue was dissolved in methanol (175 mL) at reflux temperature. Activated carbon (0.35 g) was added to the mixture, and subsequently filtered off. The mixture was washed with methanol (14 mL), then cooled to room temperature, and then stirred for 3 hours to 5 hours at room temperature. The crystals obtained were filtered, then washed with methanol (14 mL), and then dried under vacuum to obtain the title compound.
Yield: 3.6 g
Example 13 : Preparation of sodium (4i?.12aS)-9-{r(2.4- difluorophenyl)methyllcarbamoyl}-4-methyl-6.8-dioxo-3.4.6.8.12.12a-hexahydro-2H- pyridorr.2':4.51pyrazinor2.1-6iri.31oxazin-7-olate (Formula I)
(4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12, 12a- hexahydro-2H-pyrido[r,2':4,5]pyrazino[2,l-6][l,3]oxazine-9-carboxamide (Formula XVIII, Example 12, 10 g) was dissolved in methanol (210 mL) at 60°C to 65°C.
Activated carbon (0.5 g) was added to the reaction mixture, and was subsequently filtered off. Sodium hydroxide solution (2Ν, 3 mL) in water was added to the filtrate at reflux temperature, then the mixture was cooled gradually to room temperature. The crystals obtained were filtered, then washed with methanol, then dried under vacuum to obtain the title compound.
Yield: 10.2 g
HPLC purity: 99.42 %

Claims

We claim:
1. A crystalline form of a compound of Formula X,
Figure imgf000041_0001
Formula X
characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d- spacings of about 18.8, 9.5, 5.6, and 3.9 A.
The crystalline form of claim 1 characterized by an XRPD pattern having additional peaks at d-spacings of about 10.1, 4.8, 4.5, and 3.5A.
The crystalline form of claim 1 characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 93.6°C.
The crystalline form of claim 1 characterized by an XRPD pattern substantially as depicted in Figure 1.
The crystalline form of claim 1 characterized by a DSC thermogram substantially as depicted in Figure 2.
The crystalline form of claim 1 characterized by a TGA thermogram substantially as depicted in Figure 3.
A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000041_0002
Formula I
comprising:
a) reacting a compound of Formula II,
Figure imgf000042_0001
Formula II
wherein R1 is lower alkyl,
with benzyl alcohol to obtain a compound of Formula III
Figure imgf000042_0002
Formula III
wherein R1 is lower alkyl;
b) protecting the compound of Formula III to obtain a compound of Formula IV,
Figure imgf000042_0003
Formula IV
wherein R1 is lower alkyl;
c) hydrolyzing the compound of Formula IV to obtain a compound of Formula V;
Figure imgf000042_0004
Formula V
d) reacting the compound of Formula V with a compound of Formula VI
Figure imgf000043_0001
Formula VI
to obtain a compound of Formula VII;
Figure imgf000043_0002
Formula VII
e) deprotecting the compound of Formula VII to obtain a compound of Formula VIII;
Figure imgf000043_0003
Formula VIII
f) reacting the compound of Formula VIII with a compound of Formula IX
Figure imgf000043_0004
Formula IX
to obtain a compound of Formula X;
Figure imgf000043_0005
Formula X g) reacting the compound of Formula X with a compound of Formula XI
Figure imgf000044_0001
Formula XI
to obtain a compound of Formula XII;
Figure imgf000044_0002
Formula XII
h) reacting the compound of Formula XII with a compound of Formula XIII
Figure imgf000044_0003
Formula XIII
to obtain a compound of Formula XIV and
Figure imgf000044_0004
Formula XIV
converting the compound of Formula XIV to a compound of Formula XV,
Figure imgf000045_0001
Formula XV
or alternatively, reacting the compound of Formula XII
Figure imgf000045_0002
Formula XII
with the compound of Formula XIII to give a mixture, and
Figure imgf000045_0003
Formula XIII
subsequently treating the mixture with an acid to obtain the compound of Formula XV;
Figure imgf000045_0004
Formula XV
reacting the compound of Formula XV with a compound of Formula XVI
Figure imgf000046_0001
Formula XVI
to obtain a compound of Formula XVII;
Figure imgf000046_0002
Formula XVII
j) debenzylating the compound of Formula XVII to obtain a compound of Formula XVIII: and
Figure imgf000046_0003
Formula XVIII
k) reacting the compound of Formula XVIII with a sodium containing agent to obtain dolutegravir sodium of Formula I.
A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000046_0004
Formula I
comprising: a) hydrolyzing a compound of Formula IV,
Figure imgf000047_0001
Formula IV
wherein R1 is lower alkyl,
to obtain a compound of Formula V;
Figure imgf000047_0002
Formula V
b) reacting the compound of Formula V with a compound of Formula VI
Figure imgf000047_0003
Formula VI
a compound of Formula VII;
Figure imgf000047_0004
Formula VII
c) deprotecting the compound of Formula VII to obtain a compound of Formula VIII:
Figure imgf000048_0001
Formula VIII
d) reacting the compound of Fonnula VIII with a compound of Formula IX
Figure imgf000048_0002
Formula IX
to obtain a compound of Fonnula X;
Figure imgf000048_0003
Formula X
e) reacting the compound of Fonnula X with a compound of Formula XI
H2NT CH3
Formula XI
to obtain a compound of Fonnula XII; and
Figure imgf000048_0004
Formula XII
converting the compound of Formula XII to dolutegravir sodium of Formula I.
9. A process for the preparation of a compound of Formula V,
Figure imgf000049_0001
Formula V
comprising hydrolyzing a compound of Formula IV,
Figure imgf000049_0002
Formula IV
wherein R1 is lower alkyl.
10. A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000049_0003
Formula I
comprising:
a) hydrolyzing a compound of Formula IV,
Figure imgf000049_0004
Formula IV wherein R1 is lower alkyl,
to obtain a compound of Formula V; and
Figure imgf000050_0001
Formula V
b) converting the compound of Formula V to dolutegravir sodium of Formula I. 1 1. A process for the preparation of a compound of Formula VII,
Figure imgf000050_0002
Formula VII
comprising reacting a compound of Formula V
Figure imgf000050_0003
Formula V
with a compound of Formula VI.
Figure imgf000050_0004
Formula VI
12. A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000051_0001
Formula I
comprising:
a) reacting a compound of Formula V
Figure imgf000051_0002
Formula V
with a compound of Formula VI
Figure imgf000051_0003
Formula VI
to obtain a compound of Formula VII; and
Figure imgf000051_0004
Formula VII
b) converting the compound of Formula VII to dolutegravir sodium of Formula I.
13. A process for the preparation of a compound of Formula VIII,
Figure imgf000052_0001
Formula VIII
comprising deprotecting a compound of Formula VII.
Figure imgf000052_0002
Formula VII
14. A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000052_0003
comprising:
a) deprotecting a compound of Formula VII
Figure imgf000052_0004
Formula VII
to obtain a compound of Formula VIII; and
Figure imgf000053_0001
Formula VIII
b) converting the compound of Formula VIII to dolutegravir sodium of Formula I. 15. A process for the preparation of a compound of Formula X,
Figure imgf000053_0002
Formula X
comprising reacting a compound of Formula VIII
Figure imgf000053_0003
with a compound of Formula IX.
Figure imgf000053_0004
Formula IX
16. A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000053_0005
a) reacting a compound of Formula VIII
Figure imgf000054_0001
Formula VIII
with a compound of Formula IX
Figure imgf000054_0002
Formula IX
to obtain a compound of Formula X; and
Figure imgf000054_0003
Formula X
b) converting the compound of Formula X to dolutegravir sodium of Formula I. 17. A process for the preparation of a compound of Formula XII,
Figure imgf000054_0004
Formula XII
comprising reacting a compound of Formula X
Figure imgf000055_0001
Formula X
with a compound of Formula XI.
H2N CH,
*CH,
Formula XI
18. A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000055_0002
comprising:
a) reacting a compound of Formula X
Figure imgf000055_0003
Formula X
with a compound of Formula XI
Figure imgf000055_0004
Formula XI
to obtain a compound of Formula XII; and
Figure imgf000056_0001
Formula XII
b) converting the compound of Formula XII to dolutegravir sodium of Formula I. 19. A process for the preparation of a compound of Formula XIV,
Figure imgf000056_0002
Formula XIV
comprising reacting a compound of Formula XII
Figure imgf000056_0003
Formula XII
with a compound of Formula XIII.
Figure imgf000056_0004
Formula XIII
20. A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000057_0001
Formula I
comprising:
a) reacting a compound of Formula XII
Figure imgf000057_0002
Formula XII
with a compound of Formula XIII
Figure imgf000057_0003
Formula XIII
to obtain a compound of Formula XIV; and
Figure imgf000057_0004
Formula XIV
b) converting the compound of Formula XIV to dolutegravir sodium of Formula I.
21. A process for the preparation of a compound of Formula XV,
Figure imgf000058_0001
Formula XV
comprising reacting a compound of Formula XII
Figure imgf000058_0002
Formula XII
with a compound of Formula XIII to give a mixture, and
Figure imgf000058_0003
Formula XIII
subsequently treating the mixture with an acid to obtain the compound of Formula XV. 22. A process for the preparation of dolutegravir sodium of Formula I,
Figure imgf000058_0004
a) reacting a compound of Formula XII
Figure imgf000059_0001
Formula XII
with a compound of Formula XIII to give a mixture, and
Figure imgf000059_0002
Formula XIII
subsequently treating the mixture with an acid to obtain the compound of Formula XV; and
Figure imgf000059_0003
Formula XV
b) converting the compound of Formula XV to dolutegravir sodium of Formula I. 23. A compound of Formula V.
Figure imgf000059_0004
Formula V
24. A compound of Formula VII.
Figure imgf000060_0001
Formula VII 25. A compound of Formula VIII.
Figure imgf000060_0002
Formula VIII 26. A compound of Formula X
Figure imgf000060_0003
28. Use of a compound of Formula V for the preparation of dolutegravir sodium of Formula I.
Figure imgf000061_0001
Formula V
29. Use of a compound of Formula VII for the preparation of dolutegravir sodium of Formula I.
Figure imgf000061_0002
Formula VII
30. Use of a compound of Formula VIII for the preparation of dolutegravir sodium of Formula I.
Figure imgf000061_0003
Formula VIII
31. Use of a compound of Formula X for the preparation of dolutegravir sodium of Formula I.
Figure imgf000061_0004
Formula X
32. Use of a compound of Formula XII for the preparation of dolutegravir sodium of Formula I.
Figure imgf000062_0001
Formula XII
33. The process according to claim 7, wherein the reaction of the compound of Formula II with benzyl alcohol is carried out in the presence of a base in a solvent.
34. The process according to claim 33, wherein the base is selected from the group
consisting of potassium tert-butoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, sodium hydride, and lithium hydride.
35. The process according to claim 33, wherein the solvent is selected from the group consisting of toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.
36. The process according to claim 7, wherein the protection of the compound of Formula III is carried out with ethylene glycol in the presence of a dehydrating agent in a solvent.
37. The process according to claim 36, wherein the dehydrating agent is selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, acetic anhydride, and trifluoroacetic acid.
38. The process according to claim 36, wherein the solvent is selected from the group consisting of toluene, xylene, cyclohexane, dichloromethane, and mixtures thereof. 39. The process according to any one of claims 7, 8, 9, or 10, wherein the hydrolysis of the compound of Formula IV is carried out in the presence of a hydrolyzing agent in a solvent.
40. The process according to claim 39, wherein the hydrolyzing agent is selected from the group consisting of sodium hydroxide, hydrochloric acid, and potassium hydroxide.
41. The process according to claim 39, wherein the solvent is selected from the group consisting of water, toluene, dichloromethane, tetrahydrofuran, methanol, ethanol, and isopropyl alcohol.
42. The process according to any one of claims 7, 8, 11, or 12, wherein the reaction of the compound of Formula V with the compound of Formula VI is carried out in the presence of an activating agent in a solvent, optionally in the presence of a base. 43. The process according to claim 42, wherein the activating agent is selected from the group consisting of ethyl chloroformate, boric acid, triisopropyl borate, methyl chloroformate, and isobutyl chloroformate.
44. The process according to claim 42, wherein the base is selected from the group
consisting of triethylamine, dimethylamino-pyridine, isopropylamine,
diisopropylethylamine, pyridine, and tributylamine.
45. The process according to claim 42, wherein the solvent is selected from the group consisting of toluene, dichloromethane, and tetrahydrofuran.
46. The process according to any one of claim 7, 8, 13, or 14, wherein the deprotection of the compound of Formula VII is carried out with a deprotecting agent.
47. The process according to claim 46, wherein the deprotecting agent is selected from the group consisting of hydrochloric acid, acetic acid, hydrobromic acid, sulfuric acid, perchloric acid, nitric acid, p-toluenesulfonic acid, formic acid, oxalic acid, and mixtures thereof.
48. The process according to any one of claims 7, 8, 15, and 16, wherein the reaction of the compound of Formula VIII with the compound of Formula IX is carried out in the optional presence of a base in a solvent.
49. The process according to claim 48, wherein the base is selected from the group
consisting of triethylamine, dimethylamino-pyridine, isopropylamine,
diisopropylethylamine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene, and tributylamine.
50. The process according to claim 48, wherein the solvent is selected from the group consisting of toluene, ethyl acetate, and dichloromethane.
51. The process according to claim 48, wherein the compound of Formula IX serves as a solvent.
52. The process according to any one of claims 7, 8, 17, or 18, wherein the reaction of the compound of Formula X with the compound of Formula XI is carried out in the presence of a solvent.
53. The process according to claim 52, wherein the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tert-butanol,
dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, and mixtures thereof.
54. The process according to any one of claims 7, 19, or 20, wherein the reaction of the compound of Formula XII with the compound of Formula XIII is carried out in the presence of a base in a solvent.
55. The process according to claim 54, wherein the base is selected from the group
consisting of potassium tert-butoxide, sodium-tert-butoxide, N,N- diisopropylethylamine, tert-butylamine, sodium ethoxide, sodium methoxide, 1,8- diazabicyclo[5.4.0]undec-7-ene, sodium hydride, lithium hydride, potassium carbonate, and cesium carbonate.
56. The process according to claim 54, wherein the solvent is selected from the group consisting of methanol, toluene, ethanol, n-propanol, isopropanol, tert-butanol, dichloromethane, chloroform, carbon tetrachloride, and mixtures thereof.
57. The process according to claim 7, wherein the conversion of the compound of Formula XIV is carried out with an acid in a solvent.
58. The process according to claim 57, wherein the acid is selected from the group
consisting of formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, and ethanesulfonic acid.
59. The process according to claim 57, wherein the solvent is selected from the group consisting of acetonitrile, dioxane, water, acetone, n-propanol, isopropanol, methanol, ethanol, toluene, dimethylformamide, tetrahydrofuran, and mixtures thereof.
60. The process according to any one of claims 7, 21, or 22, wherein the reaction of the compound of Formula XII with the compound of Formula XIII to give a mixture is carried out in the presence of a base in a solvent, and subsequent treatment of the mixture with an acid is carried out to obtain the compound of Formula XV.
61. The process according to claim 60, wherein the base is selected from the group consisting of potassium tert-butoxide, sodium-tert-butoxide, N,N- diisopropylethylamine, tert-butylamine, cesium carbonate, potassium carbonate, lithium hydride, sodium hydride, and l,8-diazabicyclo[5.4.0]undec-7-ene.
62. The process according to claim 60, wherein the solvent is selected from the group consisting of methanol, water, toluene, ethanol, n-propanol, isopropanol, tert-butanol, dichloromethane, chloroform, carbon tetrachloride, and mixtures thereof.
63. The process according to claim 60, wherein the acid is selected from the group
consisting of formic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and mixtures thereof.
64. The process according to claim 7, wherein the reaction of the compound of Formula XV with the compound of Formula XVI is carried out in the presence of an acid and a solvent.
65. The process according to claim 64, wherein the acid is selected from the group
consisting of acetic acid, formic acid, p-toluenesulfonic acid, methanesulfonic acid, and sulfuric acid.
66. The process according to claim 64, wherein the solvent is selected from the group consisting of toluene, methanol, methyl isobutyl ketone, acetonitrile, diglyme, and monoglyme.
67. The process according to claim 7, wherein the debenzylation of the compound of Formula XVII is carried out in the presence of hydrogen gas and a catalyst in a solvent.
68. The process according to claim 67, wherein the catalyst is selected from the group consisting of palladium-carbon and palladium hydroxide -carbon.
69. The process according to claim 67, wherein the solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, methanol, acetone, ethanol, n-propanol, isopropanol, toluene, acetonitrile, dimethylformamide, and mixtures thereof.
70. The process according to claim 7, wherein the reaction of the compound of Formula XVIII with the sodium-containing reagent is carried out in a solvent.
71. The process according to claim 70, wherein the sodium-containing reagent is selected from the group consisting of sodium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide, sodium-2-ethyl haxanoate, and sodium octanoate.
72. The process according to claim 70, wherein the solvent is selected from the group consisting of methanol, water, ethanol, isopropyl alcohol, tert-butanol, and mixtures thereof.
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