WO2011119566A1 - Process for preparing carbamoylpyridone derivatives and intermediates - Google Patents

Process for preparing carbamoylpyridone derivatives and intermediates Download PDF

Info

Publication number
WO2011119566A1
WO2011119566A1 PCT/US2011/029369 US2011029369W WO2011119566A1 WO 2011119566 A1 WO2011119566 A1 WO 2011119566A1 US 2011029369 W US2011029369 W US 2011029369W WO 2011119566 A1 WO2011119566 A1 WO 2011119566A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
methyloxy
bis
contacting
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/029369
Other languages
French (fr)
Inventor
Huan Wang
Steven N Goodman
Douglas Mans
Matthew Kowalski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline LLC
Original Assignee
GlaxoSmithKline LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP17165935.2A priority Critical patent/EP3260457B1/en
Priority to LTEP11760040.3T priority patent/LT2549870T/en
Priority to KR1020127027667A priority patent/KR101440278B1/en
Priority to MEP-2017-132A priority patent/ME02703B/en
Priority to HRP20170961TT priority patent/HRP20170961T1/en
Priority to US13/636,237 priority patent/US8889877B2/en
Priority to ES11760040.3T priority patent/ES2632346T3/en
Priority to PL17165935T priority patent/PL3260457T3/en
Priority to JP2013501383A priority patent/JP5490305B2/en
Priority to EP11760040.3A priority patent/EP2549870B1/en
Priority to SI201131218A priority patent/SI2549870T1/en
Priority to SG2012070124A priority patent/SG184186A1/en
Priority to SM20170323T priority patent/SMT201700323T1/en
Priority to DK11760040.3T priority patent/DK2549870T3/en
Priority to PL11760040T priority patent/PL2549870T3/en
Application filed by GlaxoSmithKline LLC filed Critical GlaxoSmithKline LLC
Priority to RS20170586A priority patent/RS56072B1/en
Priority to CN201180015527.6A priority patent/CN102933080B/en
Publication of WO2011119566A1 publication Critical patent/WO2011119566A1/en
Anticipated expiration legal-status Critical
Priority to US14/513,265 priority patent/US9120817B2/en
Priority to US14/810,518 priority patent/US9643981B2/en
Priority to US15/475,377 priority patent/US9938296B2/en
Priority to CY20171100654T priority patent/CY1119143T1/en
Priority to US15/907,683 priority patent/US10233196B2/en
Priority to US15/907,626 priority patent/US10174051B2/en
Priority to US16/207,243 priority patent/US10654870B2/en
Priority to US16/207,273 priority patent/US10647728B2/en
Priority to US16/207,288 priority patent/US10654871B2/en
Priority to CY20211100112T priority patent/CY1123958T1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to the preparation of carbamoylpyridone derivatives and intermediates which are useful as HIV integrase inhibitors.
  • the present invention provides an improved process for preparing the following compounds:
  • the present invention is a method comprising contacting methyl 3- ⁇ [2,2- bis(methyloxy)ethyl] amino ⁇ -2- [(methyloxy)acetyl] -2-propenoate (formula I) :
  • the present invention method comprising selectively hydrolyzing a pyridinone of formula III:
  • R is alkyl, aryl, or benzyl with a selective hydrolyzing reagent to form a pyridinone carboxylic acid of formula IV where R is alkyl, aryl, or benzyl:
  • the present invention is a method comprising contacting a compound of formula VII:
  • the present invention is a compound selected from the group consisting of:
  • the present invention is a process comprising contacting a compound of formula IV where R is alkyl, aryl, or benzyl:
  • the process of the present invention is useful for the preparation of compounds with HIV integrase inhibitory activity.
  • oxalate ester II
  • M + OR pyridinone
  • R is Ci-C 5 -alkyl, aryl, or benzyl
  • M + is an alkali metal cation such as lithium, sodium, or potassium.
  • the alkali metal cation is lithium and the R group of the oxalate ester is the same as the R group from M + OR.
  • R is a Q-Cs-alkyl, especially a C 1 -C 2 -alkyl.
  • Particularly preferred oxalate esters are dimethyl ethanedioate and diethyl ethanedioate.
  • alkali metal alkoxides are lithium methoxide and lithium ethoxide.
  • the alkali metal alkoxide is lithium methoxide.
  • the alkali metal alkoxide is lithium ethoxide.
  • Pyridinone (III) is selectively hydrolyzed with LiOH to form pyridinone carboxylic acid (IV).
  • the methyl ester at the 5-position of pyridinone (III) is hydrolyzed with at least 90% selectivity over the ester at the 2-position.
  • Pyridinone carboxylic acid (IV) is contacted with acetic acid and a catalytic amount of a strong protic acid to form pyridinone carboxylic acid aldehyde (V).
  • suitable strong protic acids include methanesulfonic acid, sulfuric acid, toluene sulfonic acid, and hydrochloric acid.
  • Aldehyde (V) is then contacted with (2S)-2-amino-l-propanol to form ((35,1 lai?)-3- methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,l l,l la-hexahydro[l,3]oxazolo[3,2- ]pyrido[l,2- i ]pyrazine-8-carboxylic acid) (VI).
  • Compound VI is contacted with 2.4-difluorobenzylamine under coupling conditions to form (3S, 11 aR)-N- [(2,4-difluorophenyl)methyl] -3 -methyl-6-(methyloxy)-5 ,7-dioxo- 2,3,5,7,11,1 la-hexahydro[l,3]oxazolo[3,2-a]pyrido[l,2-t ]pyrazine-8-carboxamide (VII).
  • compound VII is demethylated with a Lewis acid to form the product (3S,1 lai?)- N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,l 1,11a- hexahydro[l,3]oxazolo[3,2-a]pyrido[l,2-i ]pyrazine-8-carboxamide (VIII).
  • suitable Lewis acids include magnesium, lithium, and calcium salts, as well as boron trihalides and trialkylsilyl halides.
  • Preferred Lewis acids are magnesium and lithium salts.
  • Magnesium salts include salts such as magnesium chloride, magnesium bromide, magnesium iodide, and magnesium sulfide.
  • Lithium salts include salts such as lithium chloride, lithium bromide, lithium iodide, and lithium sulfide. Lithium bromide is preferred.
  • compound V can be contacted with (3R)-3-amino-l-butanol to form a compound of formula Via:
  • Compound Vila can be demethylated with MgX n or LiX n (wherein X is a halide, e.g., Br, CI, F, or I) to form the compound of Villa:
  • the reaction mixture was cooled to -5 °C and LiOH (14.82 g) was added while maintaining the reaction temperature below 5 °C. When addition was complete, the mixture was stirred for a further 2 h at 3-5 °C for 1 h. The reaction mixture was quenched with aqueous HC1 (2 N, 367 mL), maintaining the reaction temperature below 5 °C. When addition was complete, EtOAc (450 mL) was added and the mixture was warmed to 20 °C. The reaction mixture was filtered and the aqueous layer discarded. Water (225 mL) was added and the organic layer was removed under reduced pressure. The product was collected by filtration and dried in a vacuum oven overnight at 50 °C. The product was obtained as a solid. B.
  • the demethylation can be carried out with LiBr: (3S,l lai?)-iV-[(2,4- Difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7, 11,11a- hexahydro[l,3]oxazolo[3,2- ]pyrido[l,2-i ]pyrazine-8-carboxamide (8.609 g) was dissolved in THF (90 mL) and LiBr (3.942 g) was added. The mixture was heated to reflux for 12 h and quenched with H 2 S0 4 (0.5 M, 94.467 g).
  • the resultant suspension was stirred at 20 °C for 2 h and filtered.
  • the solid product was re-slurried in water-THF (50 mL-50 mL) at 20 °C for 2 h.
  • the product was collected by filtration, rinsed with water-THF (1-1, 30 mL), and dried under vacuum to afford the product.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • AIDS & HIV (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the preparation of carbamoylpyridone derivatives and intermediates.

Description

PROCESS FOR PREPARING CARBAMOYLPYRIDONE DERIVATIVES AND
INTERMEDIATES
Field of the Invention
The present invention relates to the preparation of carbamoylpyridone derivatives and intermediates which are useful as HIV integrase inhibitors.
Background of the Invention
Compounds having HIV integrase inhibitory activity are described in WO 2006/116764 (corresponding to U.S. Serial No. 11/919386 assigned to Shionogi & Co. Ltd.). The compounds are disclosed as polycyclic carbamoylpyridone deriviatives. Processes for making them are also disclosed. Among the examples of these compounds, the following polycyclic
carbamoylpyridone derivatives are included:
Figure imgf000002_0001
The processes disclosed for preparing these compounds are quite arduous, involving as many as 14 steps. It would therefore be an advance in the art to find ways of making these compounds with greater efficiency.
Summary of the Invention
The present invention provides an improved process for preparing the following compounds:
Figure imgf000003_0001
In one aspect, the present invention is a method comprising contacting methyl 3- {[2,2- bis(methyloxy)ethyl] amino} -2- [(methyloxy)acetyl] -2-propenoate (formula I) :
M
Figure imgf000003_0002
with an oxalate ester of formula II:
Figure imgf000003_0003
II in the presence of M+ OR, where R is alkyl, aryl, or benzyl; and M+ is an alkali metal cation; to form a pyridinone of formula III:
Figure imgf000003_0004
III. In a second aspect, the present invention method comprising selectively hydrolyzing a pyridinone of formula III:
Figure imgf000004_0001
III where R is alkyl, aryl, or benzyl with a selective hydrolyzing reagent to form a pyridinone carboxylic acid of formula IV where R is alkyl, aryl, or benzyl:
Figure imgf000004_0002
IV with greater than 90% selectivity.
In a third aspect, the present invention is a method comprising contacting a compound of formula VII:
Figure imgf000004_0003
VII with a magnesium or lithium cation and a nucleophilic anion to form a compound of formula VIII:
Figure imgf000005_0001
In a fourth aspect, the present invention is a compound selected from the group consisting of:
Figure imgf000005_0002
In a fifth aspect, the present invention is a process comprising contacting a compound of formula IV where R is alkyl, aryl, or benzyl:
Figure imgf000005_0003
IV with acetic acid and a catalytic amount of a strong protic acid to form a pyridinone carboxylic acid aldehyde of formula V where R is alkyl, aryl, or benzyl:
Figure imgf000006_0001
V.
The process of the present invention is useful for the preparation of compounds with HIV integrase inhibitory activity.
Detailed Description of the Invention
The following schematic illustrates a general process for the preparation of the compound of formula VIII, ((3S,1 lai?)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo 2,3,5,7, 11,11 a-hexahydro[l ,3]oxazolo[3,2-fl]pyrido[l ,2-i¾pyrazine-8-carboxamide).
Scheme:
Figure imgf000006_0002
VIII
VII In the above schematic, 4-Methoxyacetoacetate is contacted with DMFDMA (N,N- dimethyl-l,l-bis(methyloxy)methanamine) under conditions sufficient to form methyl 3- (dimethylamino)-2-[(methyloxy)acetyl]-2-propenoate. Reaction of this intermediate with aminoacetaldehyde dimethyl acetal results in the formation of methyl 3- {[2,2- bis(methyloxy)ethyl] amino } -2- [(methyloxy)acetyl] -2-propenoate (I) .
Compound I is then contacted with oxalate ester (II) in the presence of M+ OR to form pyridinone (III). Each R is Ci-C5-alkyl, aryl, or benzyl; M+ is an alkali metal cation such as lithium, sodium, or potassium. Preferably, the alkali metal cation is lithium and the R group of the oxalate ester is the same as the R group from M+ OR. Preferably R is a Q-Cs-alkyl, especially a C1-C2-alkyl. Particularly preferred oxalate esters are dimethyl ethanedioate and diethyl ethanedioate. Particularly preferred alkali metal alkoxides are lithium methoxide and lithium ethoxide. Preferably, when the oxalate ester is dimethyl ethanedioate, the alkali metal alkoxide is lithium methoxide. Preferably, when the oxalate ester is diethyl ethanedioate, the alkali metal alkoxide is lithium ethoxide.
Pyridinone (III) is selectively hydrolyzed with LiOH to form pyridinone carboxylic acid (IV). Surprisingly, the methyl ester at the 5-position of pyridinone (III) is hydrolyzed with at least 90% selectivity over the ester at the 2-position.
Pyridinone carboxylic acid (IV) is contacted with acetic acid and a catalytic amount of a strong protic acid to form pyridinone carboxylic acid aldehyde (V). Examples of suitable strong protic acids include methanesulfonic acid, sulfuric acid, toluene sulfonic acid, and hydrochloric acid. Aldehyde (V) is then contacted with (2S)-2-amino-l-propanol to form ((35,1 lai?)-3- methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,l l,l la-hexahydro[l,3]oxazolo[3,2- ]pyrido[l,2- i ]pyrazine-8-carboxylic acid) (VI).
Compound VI is contacted with 2.4-difluorobenzylamine under coupling conditions to form (3S, 11 aR)-N- [(2,4-difluorophenyl)methyl] -3 -methyl-6-(methyloxy)-5 ,7-dioxo- 2,3,5,7,11,1 la-hexahydro[l,3]oxazolo[3,2-a]pyrido[l,2-t ]pyrazine-8-carboxamide (VII).
Finally, compound VII is demethylated with a Lewis acid to form the product (3S,1 lai?)- N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,l 1,11a- hexahydro[l,3]oxazolo[3,2-a]pyrido[l,2-i ]pyrazine-8-carboxamide (VIII). Examples of suitable Lewis acids include magnesium, lithium, and calcium salts, as well as boron trihalides and trialkylsilyl halides. Preferred Lewis acids are magnesium and lithium salts. Magnesium salts include salts such as magnesium chloride, magnesium bromide, magnesium iodide, and magnesium sulfide. Lithium salts include salts such as lithium chloride, lithium bromide, lithium iodide, and lithium sulfide. Lithium bromide is preferred.
Alternatively, and in another aspect of the present invention, compound V can be contacted with (3R)-3-amino-l-butanol to form a compound of formula Via:
Figure imgf000008_0001
Via
Compound Via can be reacted with 2,4-difluorobenzylamine under coupling conditions to form a compound of formula Vila:
Figure imgf000008_0002
Vila.
Compound Vila can be demethylated with MgXn or LiXn (wherein X is a halide, e.g., Br, CI, F, or I) to form the compound of Villa:
Figure imgf000009_0001
Villa.
Examples
The following example illustrates the process of the present invention. Solvents and reaction conditions are not intended to limit the scope of the invention. Starting materials are known in the art and are readily prepared or commercially available. Preferably, chemicals employed in the examples were obtained commercially (from Aldrich®, for example).
A. l-[2,2-Bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyIoxy)carbonyl]-4-oxo-l,4-dihydro- 3-pyridinecarboxylic acid
A mixture of methyl 4-methoxyacetoacetate (20 mL) and DMFDMA (24 mL) was stirred at room temperature for 1.5 h. The reaction mixture was diluted with MeOH (50 mL) and aminoacetaldehyde dimethyl acetal (16.7 mL) was added. The mixture was stirred for 1 h at room temperature, concentrated, and then diluted with MeOH (113 mL). Dimethyl oxalate (45.66 g) was charged followed by portion-wise addition of LiH (2.15 g) while maintaining the reaction temperature below 25 °C. The reaction content was heated to 40 °C for 14 h. The reaction mixture was cooled to -5 °C and LiOH (14.82 g) was added while maintaining the reaction temperature below 5 °C. When addition was complete, the mixture was stirred for a further 2 h at 3-5 °C for 1 h. The reaction mixture was quenched with aqueous HC1 (2 N, 367 mL), maintaining the reaction temperature below 5 °C. When addition was complete, EtOAc (450 mL) was added and the mixture was warmed to 20 °C. The reaction mixture was filtered and the aqueous layer discarded. Water (225 mL) was added and the organic layer was removed under reduced pressure. The product was collected by filtration and dried in a vacuum oven overnight at 50 °C. The product was obtained as a solid. B. (3S,llaR)-3-Methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,ll,lla-hexahydro[l,3]oxazolo[3,2- a] p rido [1 ,2-d] pyrazine-8-carboxylic acid l-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l,4-dihydro- 3-pyridinecarboxylic acid (22.54 g) was dissolved in 220 mL of CH3CN. HOAc (20 mL) and CH3S03H (1.4 mL) were added at room temperature and the mixture was heated to 58-65 °C for 19.5 h. Alaninol (7.51 lg) in CH3CN (15 mL) was added slowly and the resultant mixture was stirred at 64 °C for 18.5 h. The mixture was concentrated, and the residue was redissolved in CH2C12 (170 mL). HC1 (1 N, 170 mL) was added and the layers were separated. The aqueous layer was extracted with CH2C12 (170 mL*2) and the organic layers were combined and concentrated. MeOH (50 mL) was added and the resultant mixture was again concentrated. MeOH (80 mL) was added and the resultant mixture was heated at reflux for 4 h, gradually cooled to 20 °C and held at 20 °C for 15 h. The product was collected by filtration and dried under vacuum.
C. (3S,llaR)-N-[(2,4-Difluorophenyl)methyl]-3-methyI-6-(methyloxy)-5,7-dioxo- 2,3,5,7,11,1 la-hexahydro [1,3] oxazolo [3,2-a]pyrido [l,2-<f|pyrazine-8-carboxamide
(3S,1 laR)-3-Methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,l 1,1 1a- hexahydro[l,3]oxazolo[3,2-a]pyrido[l,2-d]pyrazine-8-carboxylic acid (3.00 g) and 1,1 '- carbonyldiimidazole (CDI) (2.15 g) were slurried in 1,2-dimethoxyethane (DME) (30 mL). The mixture was heated to 80 °C for 1 h. The resulting solution was cooled to 20 °C, then treated with 2,4-difiuorobenzylamine (1.45 mL). After stirring for 1 h, the mixture was quenched with water (30 mL) and DME was removed under reduced pressure. The product was collected by filtration and dried in a vacuum oven overnight at 50 °C. The product was obtained as a solid.
D. (3S,llaR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyI-5,7-dioxo-2,3,5,7,ll,lla- hexahydro[l,3]oxazolo[3,2-fl]pyrido[l,2-< ]pyrazine-8-carboxamide
(3S, 1 1 a ?)-N-[(2,4-Difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo- 2,3,5,7,11,1 la-hexahydro[l,3]oxazolo[3,2-a]pyrido[l,2-i ]pyrazine-8-carboxamide (193.1 mg) was dissolved in CH3CN (4 mL) and MgBr2 (206.3 mg) was added. The mixture was heated to 50 °C for 2 h and quenched with HCl (0.2 N, 10 mL). The mixture was diluted with CH2C12 and pH further adjusted to ~1. The aqueous layer was extracted with CH2C12 (10 mLx2). The combined organic layers were dried and concentrated to afford the product.
Alternatively, the demethylation can be carried out with LiBr: (3S,l lai?)-iV-[(2,4- Difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7, 11,11a- hexahydro[l,3]oxazolo[3,2- ]pyrido[l,2-i ]pyrazine-8-carboxamide (8.609 g) was dissolved in THF (90 mL) and LiBr (3.942 g) was added. The mixture was heated to reflux for 12 h and quenched with H2S04 (0.5 M, 94.467 g). The resultant suspension was stirred at 20 °C for 2 h and filtered. The solid product was re-slurried in water-THF (50 mL-50 mL) at 20 °C for 2 h. The product was collected by filtration, rinsed with water-THF (1-1, 30 mL), and dried under vacuum to afford the product.

Claims

Claims: What is claimed is:
1. A method comprising contacting methyl 3-{[2,2-bis(methyloxy)ethyl] amino }-2- [(methyloxy)acetyl]-2-propenoate (formula I):
Figure imgf000012_0001
with an oxalate ester of formula II:
Figure imgf000012_0002
II in the presence of M+ OR, where R is alkyl, aryl, or benzyl; and M+ is an alkali metal cation; to form a pyridinone of formula III:
Figure imgf000012_0003
III.
2. The method of Claim 1 wherein M OR is lithium methoxide or lithium ethoxide; and the oxalate ester is dimethyl ethanedioate or diethyl ethanedioate; wherein the compound of formula III is hydrolyzed in the presence of lithium hydroxide to form the pyridinone carboxylic acid of formula IV:
Figure imgf000013_0001
IV.
3. The method of Claim 2 wherein the pyridinone carboxylic acid is contacted with acetic acid and a catalytic amount of a strong protic acid to form a pyridinone carboxylic acid aldehyde of formula V:
Figure imgf000013_0002
V wherein R is alkyl, aryl, or benzyl.
4. The method of Claim 3 wherein the pyridinone carboxylic acid aldehyde of formula V is contacted with (2S)-2-amino-l-propanol to form the compound of formula VI: VI.
5. The method of Claim 4 wherein the compound of formula VI is contacted with 2,4- difluorobenzylamine under coupling conditions to form a compound of formula VII:
Figure imgf000014_0001
VII.
6. The method of Claim 5 wherein the compound of formula VII is contacted with a magnesium halide or lithium halide to form a compound of formula VIII:
Figure imgf000014_0002
VIII.
7. A method comprising selectively hydrolyzing a pyridinone of formula III: PU64170WO
Figure imgf000015_0001
with a selective hydrolyzing reagent to form a pyridinone carboxylic acid of formula IV where R is alkyl, aryl, or benzyl:
Figure imgf000016_0001
IV
with greater than 90% selectivity.
8. The method of Claim 7 wherein the hydrolyzing reagent is LiOH.
9. A method comprising contacting a compound of formula VII:
Figure imgf000016_0002
VII
with a Lewis acid to form a compound of formula VIII:
Figure imgf000016_0003
VIII.
10. The method of Claim 9 wherein the Lewis acid is a magnesium halide or a lithium halide.
11. A method comprising the steps of: a) contacting methyl-4-methoxyacetoacetate with N,N-dimethyl- 1,1- bis(methyloxy)methanamine under suitable conditions to form methyl 3-(dimethylamino)-2- [(methyloxy)acetyl]-2 -propenoate; b) contacting the methyl 3 -(dimethylamino)-2-[(methyloxy)acetyl]-2 -propenoate with 2,2-bis(methyloxy)ethanamine to form methyl 3-{[2,2-bis(methyloxy)ethyl]amino}-2- [(methyloxy)acetyl]-2-propenoate; c) contacting the methyl 3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy)acetyl]-2- propenoate with dimethylethanedioate in the presence of lithium methoxide to form dimethyl 1- [2,2-bis(methyloxy)ethyl]-3-(methyloxy)-4-oxo-l,4-dihydro-2,5-pyridinedicarboxylate; d) hydrolyzing the dimethyl l-[2,2-bis(methyloxy)ethyl]-3-(methyloxy)-4-oxo-l,4- dihydro-2,5-pyridinedicarboxylate in the presence of lithium hydroxide to form l-[2,2- bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l,4-dihydro-3- pyridinecarboxylic acid; e) contacting the l-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4- oxo-l,4-dihydro-3-pyridinecarboxylic acid with (2S)-2-amino-l-propanol in the presence of acetic acid and a catalytic amount of methanesulfonic acid to form a compound of formula VI:
Figure imgf000017_0001
VI ί) contacting the compound of formula VI with 2,4-difluorobenzylamine under coupling conditions to form a compound of formula VII:
Figure imgf000018_0001
VII; and g) contacting the compound of formula VII with magnesium bromide to form a compound of formula VIII:
Figure imgf000018_0002
12. The method of Claim 3 wherein the pyridinone carboxylic acid aldehyde of formula V is contacted with (3R)-3-amino-l-butanol to form the compound of formula Via:
Figure imgf000018_0003
Via.
13. The method of Claim 12 wherein the compound of Via is contacted with 2,4- difluorobenzylamine under coupling conditions to form a compound of formula Vila:
Figure imgf000019_0001
Vila.
14. The method of Claim 13 wherein the compound of formula Vila is contacted with a Lewis acid to form a compound of formula Villa:
Figure imgf000019_0002
Villa.
15. The method of Claim 14 wherein the Lewis acid is a magnesium halide or a lithium halide.
16. A compound selected from the group consisting of:
17. A compound according to Claim 16 having the formula:
Figure imgf000020_0001
18. A compound of Claim 16 having the formula:
Figure imgf000020_0002
19. A process comprising contacting a compound of formula IV where R is alkyl, aryl, or benzyl:
Figure imgf000020_0003
IV with acetic acid and a catalytic amount of a strong protic acid to form a pyridinone carboxylic acid aldehyde of formula V: V wherein R is selected from the group consisting of alkyl, aryl, and benzyl.
PCT/US2011/029369 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates Ceased WO2011119566A1 (en)

Priority Applications (27)

Application Number Priority Date Filing Date Title
PL11760040T PL2549870T3 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
KR1020127027667A KR101440278B1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derⅳatⅳes and intermediates
MEP-2017-132A ME02703B (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
HRP20170961TT HRP20170961T1 (en) 2010-03-23 2011-03-22 PROCEDURE FOR THE PREPARATION OF CARBAMOILPYRIDONE DERIVATIVES AND INTERMEDIATES
US13/636,237 US8889877B2 (en) 2010-03-23 2011-03-22 Processes for preparing pyridinone carboxylic acid aldehydes
ES11760040.3T ES2632346T3 (en) 2010-03-23 2011-03-22 Preparation procedure for derivatives and intermediates of carbamoylpyridone
PL17165935T PL3260457T3 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
JP2013501383A JP5490305B2 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
EP11760040.3A EP2549870B1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
SI201131218A SI2549870T1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
SG2012070124A SG184186A1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
SM20170323T SMT201700323T1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
DK11760040.3T DK2549870T3 (en) 2010-03-23 2011-03-22 Process for the preparation of carbamoylpyridone derivatives and intermediates
EP17165935.2A EP3260457B1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
RS20170586A RS56072B1 (en) 2010-03-23 2011-03-22 PROCESS FOR MAKING DERIVATIVES AND INTERMEDIATES OF CARBAMOYLPYRIDONE
LTEP11760040.3T LT2549870T (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
CN201180015527.6A CN102933080B (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpridone derivatives and intermediates
US14/513,265 US9120817B2 (en) 2010-03-23 2014-10-14 Process for preparing (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′ ,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid
US14/810,518 US9643981B2 (en) 2010-03-23 2015-07-28 Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12A-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
US15/475,377 US9938296B2 (en) 2010-03-23 2017-03-31 Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
CY20171100654T CY1119143T1 (en) 2010-03-23 2017-06-21 PROCESSING FOR THE PRODUCTION OF PRODUCTS AND INTERMEDIATE CARBAMOULOPYRIDONES
US15/907,683 US10233196B2 (en) 2010-03-23 2018-02-28 Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US15/907,626 US10174051B2 (en) 2010-03-23 2018-02-28 Substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US16/207,288 US10654871B2 (en) 2010-03-23 2018-12-03 Process for preparing (3S,11aR)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
US16/207,243 US10654870B2 (en) 2010-03-23 2018-12-03 Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US16/207,273 US10647728B2 (en) 2010-03-23 2018-12-03 Process for preparing (3S,11aR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid
CY20211100112T CY1123958T1 (en) 2010-03-23 2021-02-10 METHOD OF PREPARATION OF CARBAMOYLPYRIDONE DERIVATIVES AND INTERMEDIATES

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US31642110P 2010-03-23 2010-03-23
US61/316,421 2010-03-23

Related Child Applications (3)

Application Number Title Priority Date Filing Date
EP17165935.2A Previously-Filed-Application EP3260457B1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates
US13/636,237 A-371-Of-International US8889877B2 (en) 2010-03-23 2011-03-22 Processes for preparing pyridinone carboxylic acid aldehydes
US14/513,265 Division US9120817B2 (en) 2010-03-23 2014-10-14 Process for preparing (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′ ,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid

Publications (1)

Publication Number Publication Date
WO2011119566A1 true WO2011119566A1 (en) 2011-09-29

Family

ID=44673569

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/029369 Ceased WO2011119566A1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates

Country Status (20)

Country Link
US (9) US8889877B2 (en)
EP (2) EP2549870B1 (en)
JP (1) JP5490305B2 (en)
KR (1) KR101440278B1 (en)
CN (1) CN102933080B (en)
CY (2) CY1119143T1 (en)
DK (2) DK2549870T3 (en)
ES (2) ES2632346T3 (en)
HR (2) HRP20170961T1 (en)
HU (2) HUE033863T2 (en)
LT (2) LT2549870T (en)
ME (1) ME02703B (en)
PL (2) PL3260457T3 (en)
PT (2) PT2549870T (en)
RS (2) RS61436B1 (en)
SG (1) SG184186A1 (en)
SI (2) SI2549870T1 (en)
SM (2) SMT202100087T1 (en)
TW (1) TWI582097B (en)
WO (1) WO2011119566A1 (en)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012018065A1 (en) * 2010-08-05 2012-02-09 塩野義製薬株式会社 Process for preparing compound having hiv integrase inhibitory activity
US8552187B2 (en) 2008-12-11 2013-10-08 Shionogi & Co., Ltd. Processes and intermediates for carbamoylpyridone HIV integrase inhibitors
US8580967B2 (en) 2008-07-25 2013-11-12 Shionogi & Co., Ltd. Methyl 3-(benzyloxy)-1-(2,2-dihydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate and processes for the preparation thereof
US8624023B2 (en) 2008-12-11 2014-01-07 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
WO2014128545A2 (en) 2013-02-19 2014-08-28 Aurobindo Pharma Limited An improved process for the preparation of dolutegravir
US8865907B2 (en) 2009-03-26 2014-10-21 Shionogi & Co., Ltd. Method of producing pyrone and pyridone derivatives
US8889877B2 (en) 2010-03-23 2014-11-18 Viiv Healthcare Company Processes for preparing pyridinone carboxylic acid aldehydes
WO2015019310A1 (en) * 2013-08-07 2015-02-12 Mylan Laboratories Ltd Process for the preparation of dolute-gravir and intermediates thereof
WO2015110897A2 (en) 2014-01-21 2015-07-30 Laurus Labs Private Limited Novel process for the preparation of dolutegravir and pharmaceutically acceptable salts thereof
WO2015177537A1 (en) * 2014-05-20 2015-11-26 Cipla Limited Process for preparing polycyclic carbamoyl pyridone derivatives and intermediates thereof
US9216996B2 (en) 2012-12-21 2015-12-22 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections
EP3045461A1 (en) 2015-01-16 2016-07-20 LEK Pharmaceuticals d.d. Processes for preparing dolutegravir and analogues thereof
WO2016125192A2 (en) 2015-02-06 2016-08-11 Mylan Laboratories Limited Process for the preparation of dolutegravir
US9421214B2 (en) 2013-07-12 2016-08-23 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9458159B2 (en) 2013-07-12 2016-10-04 Gilead Sciences, Inc. Substituted pyrido[1′,2′:4,5]pyrazino[1,2-a]azepines for treating viral infections
US9522912B2 (en) 2014-12-23 2016-12-20 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9630978B2 (en) 2015-04-02 2017-04-25 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9682084B2 (en) 2014-06-20 2017-06-20 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9,-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
US9808428B2 (en) 2014-01-14 2017-11-07 Board Of Regents Of The University Of Nebraska Compositions and methods for the delivery of therapeutics
WO2017205585A1 (en) * 2016-05-27 2017-11-30 Viiv Healthcare Company Combinations and uses treatments thereof
EP3157932B1 (en) 2014-06-20 2018-01-10 Gilead Sciences, Inc. Sodium (2r, 5s, 13ar) -7, 9-dioxo-10- ( (2,4,6-trifluorobenzyl) carbamoyl) -2, 3, 4, 5, 7, 9, 13, 13a-octahydro-2, 5-methanopyrido [1',2' : 4.5]pyrazino [2, 1-b]oxazepin-8-olate
EP3363802A1 (en) 2017-02-16 2018-08-22 Sandoz AG Crystalline form of cabotegravir sodium
WO2018149608A1 (en) 2017-02-16 2018-08-23 Sandoz Ag Crystalline forms of cabotegravir sodium
CN110128448A (en) * 2019-05-22 2019-08-16 博诺康源(北京)药业科技有限公司 The synthetic method of diastereoisomer impurity in a kind of Du Lutewei raw material and intermediate
WO2019159199A1 (en) * 2018-02-16 2019-08-22 Cipla Limited Continues flow process for the preparation of active pharmaceutical ingredients - polycyclic carbamoyl pyridone derivatives and intermediates thereof
US10479801B2 (en) 2016-12-02 2019-11-19 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
CN112500336A (en) * 2020-12-15 2021-03-16 内蒙古永太化学有限公司 Preparation method of dolutegravir mother nucleus intermediate
US11248005B2 (en) 2019-07-08 2022-02-15 Lupin Limited Process for preparation of intermediates used for the synthesis of HIV integrase inhibitor
US11311545B2 (en) 2014-10-09 2022-04-26 Board Of Regents Of The University Of Nebraska Compositions and methods for the delivery of therapeutics
US11358711B2 (en) 2019-06-20 2022-06-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
US11458136B2 (en) 2018-04-09 2022-10-04 Board Of Regents Of The University Of Nebraska Antiviral prodrugs and formulations thereof
US11839623B2 (en) 2018-01-12 2023-12-12 Board Of Regents Of The University Of Nebraska Antiviral prodrugs and formulations thereof

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557686A (en) * 2014-12-29 2015-04-29 徐俊烨 Synthesis method for pyridinone compound
US10696636B2 (en) 2015-12-21 2020-06-30 Lupin Limited Process for the preparation of HIV integrase inhibitors
CN106565747A (en) * 2016-11-10 2017-04-19 顾世海 Novel method for preparing dolutegravir
WO2020012408A2 (en) 2018-07-12 2020-01-16 Laurus Labs Limited A process for purification of protected polycyclic carbamoylpyridone derivatives
CN109438334A (en) * 2018-10-29 2019-03-08 南京杰运医药科技有限公司 A kind of synthetic method of Du Lutewei intermediate
CN109293675A (en) * 2018-11-19 2019-02-01 遵义医学院 An improved preparation process of dolutegravir
RU2717101C1 (en) 2019-06-03 2020-03-18 Андрей Александрович Иващенко Anellated 9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2h-pyrido[1,2-a]pyrazine-7-carboxamides - integrase inhibitors, methods for preparing and using thereof
CN111620891B (en) * 2020-05-27 2023-07-14 上海启讯医药科技有限公司 Polyteplavir key intermediate solvate polymorph and preparation method and application thereof
CN114835730B (en) * 2021-02-02 2026-05-01 齐鲁制药有限公司 Method for preparing polycyclic carbamoyl pyridone compound
CN115572257B (en) * 2021-06-21 2024-07-09 江西帝劢药业有限公司 Synthesis method of pyridone compound
CN116003435A (en) * 2021-09-10 2023-04-25 河南师范大学 Efficient green preparation method of dolutegravir
CN113816972B (en) * 2021-11-17 2022-03-18 奥锐特药业(天津)有限公司 Preparation method of HIV inhibitor and intermediate crystal form thereof
CN114605437A (en) * 2022-04-01 2022-06-10 遵义医科大学 Synthesis process for preparing three telaprevir medicaments by continuous one-pot method

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4524149A (en) * 1982-03-15 1985-06-18 Sterling Drug Inc. 5-Alkanoyl-6-alkyl-2(1H)-pyridinones, their preparation and their cardiotonic use
US20010051732A1 (en) * 1998-02-25 2001-12-13 Sumitomo Pharmaceuticals Company, Limited Pyridone derivatives and process for preparing the same
US20060019996A1 (en) * 2001-08-02 2006-01-26 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
WO2006116764A1 (en) 2005-04-28 2006-11-02 Smithkline Beecham Corporation Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US20070024968A1 (en) * 2005-07-27 2007-02-01 Samsung Electronics Co., Ltd. Glassless stereoscopic display
WO2010011814A1 (en) * 2008-07-25 2010-01-28 Smithkline Beecham Corporation Chemical compounds

Family Cites Families (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4769380A (en) 1983-04-29 1988-09-06 Merrell Dow Pharmaceuticals Inc. Cardiotonic 5-benzoyl-1,2-dihydro-2-oxo-3-pyridinecarboxylates
US4812474A (en) 1984-08-16 1989-03-14 G. D. Searle & Co. Kojic acid ether-ester derivatives
US4735964A (en) 1984-08-16 1988-04-05 G. D. Searle & Co. Kojic acid ether-ester derivatives
US4603144A (en) 1984-08-16 1986-07-29 G. D. Searle & Co. Kojic acid ether-ester derivatives
GB2280435A (en) 1993-07-29 1995-02-01 Merck & Co Inc Anti-viral agent
ES2244967T3 (en) 1995-09-29 2005-12-16 Novartis Ag NEW HYDROXIPIRIDINONES.
GB9711093D0 (en) 1997-05-29 1997-07-23 British Tech Group Novel orally active iron (III) chelators
US7256286B2 (en) 1999-11-30 2007-08-14 The Board Of Trustees Of The Leland Stanford Junior University Bryostatin analogues, synthetic methods and uses
US6426418B1 (en) 2001-11-02 2002-07-30 Apotex, Inc. Processes for the manufacturing of 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide
CA2379370A1 (en) 2002-03-28 2003-09-28 Apotex Inc. Carboxylic acid derivatives of 3-hydroxy-4-oxo-1,4-dihydropyridine as iron chelators
US7517532B2 (en) 2002-09-11 2009-04-14 Merck & Co., Inc. Dihydroxypyridopyrazine-1,6-dione compounds useful as HIV integrase inhibitors
WO2004035577A2 (en) 2002-10-16 2004-04-29 Gilead Sciences, Inc. Pre-organized tricyclic integrase inhibitor compounds
TW200510425A (en) 2003-08-13 2005-03-16 Japan Tobacco Inc Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
DE10349500A1 (en) 2003-10-23 2005-06-02 Bayer Cropscience Ag A process for producing 2-dihaloacyl-3-amino-acrylic acid esters and 3-dihalomethyl-pyrazole-4-carboxylic acid esters
US7645292B2 (en) 2003-10-27 2010-01-12 Boston Scientific Scimed, Inc. Vaso-occlusive devices with in-situ stiffening elements
CA2557926A1 (en) 2004-03-09 2005-09-22 Monica Donghi Hiv integrase inhibitors
JP2007528394A (en) 2004-03-09 2007-10-11 メルク　エンド　カムパニー　インコーポレーテッド HIV integrase inhibitor
ATE411030T1 (en) 2004-04-14 2008-10-15 Gilead Sciences Inc PHOSPHONATE ANALOGUES OF HIV INTEGRASE INHIBITOR COMPOUNDS
CN101014572B (en) * 2004-09-15 2011-07-06 盐野义制药株式会社 Carbamoyl pyridone derivatives having HIV integrase inhibitory activity
CA2488034C (en) 2004-11-19 2009-10-06 Apotex Inc. Process for the manufacture of 3-hydroxy-n-alkyl-1-cycloalkyl-6-alkyl-4-oxo-1,4-dihydropyridine-2-carboxamide and its related analogues
JP5068663B2 (en) 2004-12-16 2012-11-07 ジェネラル・ケーブル・テクノロジーズ・コーポレーション Electrical cable with filler elements with reduced crosstalk
WO2006066414A1 (en) 2004-12-23 2006-06-29 Virochem Pharma Inc. Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase
ATE516026T1 (en) 2005-02-21 2011-07-15 Shionogi & Co BICYCLIC CARBAMOYLPYRIDONE DERIVATIVE WITH HIV INTEGRASE INHIBITING EFFECT
CN101212903B (en) * 2005-04-28 2013-07-24 史密丝克莱恩比彻姆公司 Polycyclic carbamoyl pyridone derivatives with HIV integrase inhibitory activity
EP1888581A2 (en) 2005-05-16 2008-02-20 Gilead Sciences, Inc. Hiv-integrase inhibitor compounds
JP2006342115A (en) 2005-06-10 2006-12-21 Shionogi & Co Ltd Polycyclic compound having HIV integrase inhibitory activity
EP1762250A1 (en) 2005-09-12 2007-03-14 Fresenius Kabi Deutschland GmbH Conjugates of hydroxyalkyl starch and an active substance, prepared by chemical ligation via thiazolidine
WO2007049676A1 (en) 2005-10-27 2007-05-03 Kao Corporation Oxygen scavenger, oxygen scavenger intermediate, oxygen scavenger composite, and process for producing the same
AU2006307101A1 (en) 2005-10-27 2007-05-03 Shionogi & Co., Ltd. Polycyclic carbamoylpyridone derivative having inhibitory activity on HIV integrase
US8314087B2 (en) 2007-02-16 2012-11-20 Amgen Inc. Nitrogen-containing heterocyclyl ketones and methods of use
SI2320908T1 (en) 2008-07-25 2014-05-30 Viiv Healthcare Company Dolutegravir Prodrugs
WO2010011819A1 (en) 2008-07-25 2010-01-28 Smithkline Beecham Corporation Chemical compounds
KR101678563B1 (en) 2008-12-11 2016-11-22 비이브 헬쓰케어 컴퍼니 Processes and intermediates for carbamoylpyridone hiv integrase inhibitors
KR101733625B1 (en) 2008-12-11 2017-05-10 시오노기세야쿠 가부시키가이샤 Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates
TWI518084B (en) 2009-03-26 2016-01-21 鹽野義製藥股份有限公司 Process for pyrone and pyridone derivatives
TWI582097B (en) 2010-03-23 2017-05-11 Ｖｉｉｖ醫療保健公司 Process for preparing carbamoylpyridone derivatives and intermediates
PT2602260T (en) 2010-08-05 2016-12-27 Shionogi & Co Process for preparing compound having hiv integrase inhibitory activity

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4524149A (en) * 1982-03-15 1985-06-18 Sterling Drug Inc. 5-Alkanoyl-6-alkyl-2(1H)-pyridinones, their preparation and their cardiotonic use
US20010051732A1 (en) * 1998-02-25 2001-12-13 Sumitomo Pharmaceuticals Company, Limited Pyridone derivatives and process for preparing the same
US20060019996A1 (en) * 2001-08-02 2006-01-26 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
WO2006116764A1 (en) 2005-04-28 2006-11-02 Smithkline Beecham Corporation Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US20090318421A1 (en) * 2005-04-28 2009-12-24 Brian Alvin Johns Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US20070024968A1 (en) * 2005-07-27 2007-02-01 Samsung Electronics Co., Ltd. Glassless stereoscopic display
WO2010011814A1 (en) * 2008-07-25 2010-01-28 Smithkline Beecham Corporation Chemical compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KO ET AL.: "A New and Facile Synthesis of 2-Pyridones.", BULL. KOREAN CHEM. SOC., vol. 22, no. 2, 2001, pages 234 *

Cited By (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8765965B2 (en) 2008-07-25 2014-07-01 Shionogi & Co., Ltd. 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid of the formula P-6 and/or methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate of the formula P-7
US9707246B2 (en) 2008-07-25 2017-07-18 Shionogi & Co., Ltd. Substituted (3S,11AR)-N-[(2,4-difluorophenyl)methyl]-6-oxy-3-methyl-5,7-dioxo-2,3,5,7,11,11A-hexahydro[1,3]oxazolo[3,2-A]pyrido[1,2-D]pyrazine-8-carboxamides as HIV agents
US9012650B2 (en) 2008-07-25 2015-04-21 Shionogi & Co., Ltd. Substituted (3S, 11aR)-N-[(2,4-difluorophenyl)methyl]-6-oxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamides of formula (I) useful as HIV agents
US8580967B2 (en) 2008-07-25 2013-11-12 Shionogi & Co., Ltd. Methyl 3-(benzyloxy)-1-(2,2-dihydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate and processes for the preparation thereof
US9133216B2 (en) 2008-07-25 2015-09-15 Shionogi & Co., Ltd. (3S,11aR)-6-[(phenylmethyl)oxy]-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-9 and/or (3S,11aR)-6-[(phenymethyl)oxy]-8-bromo-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-10
US8981129B2 (en) 2008-07-25 2015-03-17 Shionogi & Co., Ltd. 2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one of the formula P-3 and/or 2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-Pyran-4-one of the formula P-4
US8940912B2 (en) 2008-07-25 2015-01-27 Viiv Healthcare Company 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid
US8624023B2 (en) 2008-12-11 2014-01-07 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US9365587B2 (en) 2008-12-11 2016-06-14 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US8754214B2 (en) 2008-12-11 2014-06-17 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US9242986B2 (en) 2008-12-11 2016-01-26 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US8669362B2 (en) 2008-12-11 2014-03-11 Shiongi & Co., Ltd. Processes and Intermediates for carbamoylpyridone HIV integrase inhibitors
US8552187B2 (en) 2008-12-11 2013-10-08 Shionogi & Co., Ltd. Processes and intermediates for carbamoylpyridone HIV integrase inhibitors
US9505783B2 (en) 2009-03-26 2016-11-29 Shionogi & Co., Ltd. Method of producing pyrone and pyridone derivatives
US8865907B2 (en) 2009-03-26 2014-10-21 Shionogi & Co., Ltd. Method of producing pyrone and pyridone derivatives
US9260453B2 (en) 2009-03-26 2016-02-16 Shionogi & Co., Ltd. Method for producing pyrone and pyridone derivatives
US10654871B2 (en) 2010-03-23 2020-05-19 Viiv Healthcare Company Process for preparing (3S,11aR)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
US9643981B2 (en) 2010-03-23 2017-05-09 Viiv Healthcare Company Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12A-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
US10654870B2 (en) 2010-03-23 2020-05-19 Viiv Healthcare Company Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US9120817B2 (en) 2010-03-23 2015-09-01 Viiv Healthcare Company Process for preparing (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′ ,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid
US10647728B2 (en) 2010-03-23 2020-05-12 Viiv Healthcare Company Process for preparing (3S,11aR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid
US10233196B2 (en) 2010-03-23 2019-03-19 Viiv Healthcare Company Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US8889877B2 (en) 2010-03-23 2014-11-18 Viiv Healthcare Company Processes for preparing pyridinone carboxylic acid aldehydes
US10174051B2 (en) 2010-03-23 2019-01-08 Viiv Healthcare Company Substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US9938296B2 (en) 2010-03-23 2018-04-10 Viiv Healthcare Company Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
WO2012018065A1 (en) * 2010-08-05 2012-02-09 塩野義製薬株式会社 Process for preparing compound having hiv integrase inhibitory activity
US10125146B2 (en) 2010-08-05 2018-11-13 Shionogi & Co., Ltd. Crystalline methyl (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylate
US9321789B2 (en) 2010-08-05 2016-04-26 Shinogi & Co., Ltd. Methods of producing substituted (4R,12AS)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12A-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-B][1,3]oxazine-9-carboxamides
EP3456721A3 (en) * 2010-08-05 2019-03-27 Shionogi & Co., Ltd Method of producing compounds having hiv integrase inhivitory activity
US10125147B2 (en) 2010-08-05 2018-11-13 Shionogi & Co., Ltd. Crystalline methyl (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylate
US10000508B2 (en) 2010-08-05 2018-06-19 Shionogi & Co., Ltd Crystalline dimethyl 3-(benzyloxy)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate
US9969750B2 (en) 2010-08-05 2018-05-15 Shionogi And Co., Ltd. Method of producing (3S,11aR)-6,8-dihalo-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-diones
US9802959B2 (en) 2010-08-05 2017-10-31 Shionogi & Co., Ltd. Method of producing (4R,12aS)-7,9-dihalo-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-diones
EP3127908A3 (en) * 2010-08-05 2017-02-15 Shionogi & Co., Ltd Process for preparing compound having hiv integrase inhibitory activity
EP2602260A1 (en) 2010-08-05 2013-06-12 Shionogi&Co., Ltd. Process for preparing compound having hiv integrase inhibitory activity
US9650394B2 (en) 2010-08-05 2017-05-16 Shionogi & Co., Ltd. Methods of producing substituted (3S,11aR)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamides
US9663528B2 (en) 2012-12-21 2017-05-30 Gilead Sciences, Inc. Substituted 1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazines and methods for treating viral infections
US9216996B2 (en) 2012-12-21 2015-12-22 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections
US10689399B2 (en) 2012-12-21 2020-06-23 Gilead Sciences, Inc. Substituted 3,4,5,6,8,10,14,14a-octahydro-2h-2,6-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazocines and methods for treating viral infections
CN116640140A (en) * 2012-12-21 2023-08-25 吉利德科学公司 Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9732092B2 (en) 2012-12-21 2017-08-15 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]OXAZEPINES and methods for treating viral infections
US10035809B2 (en) 2012-12-21 2018-07-31 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydro-1,5-methanopyrido[1′,2′:4,5]pyrazino[1,2-a][1,3]diazepines and methods for treating viral infections
US11548901B2 (en) 2012-12-21 2023-01-10 Gilead Sciences, Inc. Substituted 1,4-methanopyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidines for treating viral infections
WO2014128545A3 (en) * 2013-02-19 2014-11-06 Aurobindo Pharma Limited An improved process for the preparation of dolutegravir
WO2014128545A2 (en) 2013-02-19 2014-08-28 Aurobindo Pharma Limited An improved process for the preparation of dolutegravir
US11883397B2 (en) 2013-07-12 2024-01-30 Gilead Sciences, Inc. Substituted pyrido[1,2-a]pyrrolo[1,2-d]pyrazines for treating viral infections
US9458159B2 (en) 2013-07-12 2016-10-04 Gilead Sciences, Inc. Substituted pyrido[1′,2′:4,5]pyrazino[1,2-a]azepines for treating viral infections
US10456395B2 (en) 2013-07-12 2019-10-29 Gilead Sciences, Inc. Substituted dipyrido[1,2-a:1′,2′-d]pyrazines for treating viral infections
US11213523B2 (en) 2013-07-12 2022-01-04 Gilead Sciences, Inc. Substituted pyrido[1,2-a]pyrrolo[1,2-d]pyrazines for treating viral infections
US10668064B2 (en) 2013-07-12 2020-06-02 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US12521388B2 (en) 2013-07-12 2026-01-13 Gilead Sciences, Inc. Substituted dipyrido[1,2-a:1′,2′-d]pyrazines for treating viral infections
US9421214B2 (en) 2013-07-12 2016-08-23 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9700554B2 (en) 2013-07-12 2017-07-11 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2015019310A1 (en) * 2013-08-07 2015-02-12 Mylan Laboratories Ltd Process for the preparation of dolute-gravir and intermediates thereof
US9808428B2 (en) 2014-01-14 2017-11-07 Board Of Regents Of The University Of Nebraska Compositions and methods for the delivery of therapeutics
WO2015110897A2 (en) 2014-01-21 2015-07-30 Laurus Labs Private Limited Novel process for the preparation of dolutegravir and pharmaceutically acceptable salts thereof
WO2015177537A1 (en) * 2014-05-20 2015-11-26 Cipla Limited Process for preparing polycyclic carbamoyl pyridone derivatives and intermediates thereof
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US10098886B2 (en) 2014-06-20 2018-10-16 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13A- octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-B] [1,3] oxazepine-10-carboxamide
US10975096B2 (en) 2014-06-20 2021-04-13 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US11202780B2 (en) 2014-06-20 2021-12-21 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
EP3321270B1 (en) 2014-06-20 2024-12-04 Gilead Sciences, Inc. Sodium (2r, 5s, 13ar)-7, 9-dioxo-10- ((2,4,6-trifluorobenzyl)carbamoyl)-2, 3, 4, 5, 7, 9, 13,13a-octahydro-2,5-methanopyrido [1',2':4.5] pyrazino [2, 1-b] oxazepin-8-olate
US10385067B2 (en) 2014-06-20 2019-08-20 Gilead Sciences, Inc. Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate
EP3157932B1 (en) 2014-06-20 2018-01-10 Gilead Sciences, Inc. Sodium (2r, 5s, 13ar) -7, 9-dioxo-10- ( (2,4,6-trifluorobenzyl) carbamoyl) -2, 3, 4, 5, 7, 9, 13, 13a-octahydro-2, 5-methanopyrido [1',2' : 4.5]pyrazino [2, 1-b]oxazepin-8-olate
US9682084B2 (en) 2014-06-20 2017-06-20 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9,-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
US11311545B2 (en) 2014-10-09 2022-04-26 Board Of Regents Of The University Of Nebraska Compositions and methods for the delivery of therapeutics
US9795602B2 (en) 2014-12-23 2017-10-24 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9522912B2 (en) 2014-12-23 2016-12-20 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US10646486B2 (en) 2014-12-23 2020-05-12 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
EP3045461A1 (en) 2015-01-16 2016-07-20 LEK Pharmaceuticals d.d. Processes for preparing dolutegravir and analogues thereof
US10335394B2 (en) 2015-01-16 2019-07-02 Lek Pharmaceuticals D.D. Processes for preparing dolutegravir and cabotegravir and analogues thereof
WO2016113372A1 (en) 2015-01-16 2016-07-21 Lek Pharmaceuticals D.D. Processes for preparing dolutegravir and cabotegravir and analogues thereof
WO2016125192A2 (en) 2015-02-06 2016-08-11 Mylan Laboratories Limited Process for the preparation of dolutegravir
US10730888B2 (en) 2015-02-06 2020-08-04 Mylan Laboratories Limited Process for the preparation of dolutegravir
WO2016125192A3 (en) * 2015-02-06 2016-10-20 Mylan Laboratories Limited Processes for the preparation of dolute-gravir
CN107531614A (en) * 2015-02-06 2018-01-02 迈兰实验室有限公司 De Luogewei preparation method
CN107531614B (en) * 2015-02-06 2020-04-10 迈兰实验室有限公司 Preparation method of delogevir
US9630978B2 (en) 2015-04-02 2017-04-25 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2017205585A1 (en) * 2016-05-27 2017-11-30 Viiv Healthcare Company Combinations and uses treatments thereof
US10829499B2 (en) 2016-12-02 2020-11-10 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
US10479801B2 (en) 2016-12-02 2019-11-19 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
WO2018149608A1 (en) 2017-02-16 2018-08-23 Sandoz Ag Crystalline forms of cabotegravir sodium
US11040986B2 (en) 2017-02-16 2021-06-22 Sandoz Ag Crystalline forms of cabotegravir sodium
AU2022200513B2 (en) * 2017-02-16 2023-11-02 ViiV Healthcare UK (No.3) Limited Crystalline forms of cabotegravir sodium
EP3363802A1 (en) 2017-02-16 2018-08-22 Sandoz AG Crystalline form of cabotegravir sodium
US11839623B2 (en) 2018-01-12 2023-12-12 Board Of Regents Of The University Of Nebraska Antiviral prodrugs and formulations thereof
WO2019159199A1 (en) * 2018-02-16 2019-08-22 Cipla Limited Continues flow process for the preparation of active pharmaceutical ingredients - polycyclic carbamoyl pyridone derivatives and intermediates thereof
US11458136B2 (en) 2018-04-09 2022-10-04 Board Of Regents Of The University Of Nebraska Antiviral prodrugs and formulations thereof
CN110128448A (en) * 2019-05-22 2019-08-16 博诺康源(北京)药业科技有限公司 The synthetic method of diastereoisomer impurity in a kind of Du Lutewei raw material and intermediate
US11358711B2 (en) 2019-06-20 2022-06-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
US11248005B2 (en) 2019-07-08 2022-02-15 Lupin Limited Process for preparation of intermediates used for the synthesis of HIV integrase inhibitor
CN112500336A (en) * 2020-12-15 2021-03-16 内蒙古永太化学有限公司 Preparation method of dolutegravir mother nucleus intermediate

Also Published As

Publication number Publication date
RS61436B1 (en) 2021-03-31
TW201202253A (en) 2012-01-16
KR20130026433A (en) 2013-03-13
JP5490305B2 (en) 2014-05-14
US9938296B2 (en) 2018-04-10
US20190100533A1 (en) 2019-04-04
DK3260457T3 (en) 2021-02-22
US20190106435A1 (en) 2019-04-11
SG184186A1 (en) 2012-10-30
DK2549870T3 (en) 2017-07-03
US20130172551A1 (en) 2013-07-04
EP2549870A1 (en) 2013-01-30
US20180186812A1 (en) 2018-07-05
EP2549870B1 (en) 2017-04-19
US10174051B2 (en) 2019-01-08
SI2549870T1 (en) 2017-07-31
ES2632346T3 (en) 2017-09-12
PT3260457T (en) 2021-03-03
EP3260457B1 (en) 2020-12-02
US9120817B2 (en) 2015-09-01
PL2549870T3 (en) 2017-12-29
US8889877B2 (en) 2014-11-18
SI3260457T1 (en) 2021-04-30
CN102933080A (en) 2013-02-13
US10654870B2 (en) 2020-05-19
SMT201700323T1 (en) 2017-09-07
US10233196B2 (en) 2019-03-19
LT3260457T (en) 2021-04-26
US10647728B2 (en) 2020-05-12
CN102933080B (en) 2015-05-27
HRP20170961T1 (en) 2017-09-22
LT2549870T (en) 2017-07-10
JP2013522366A (en) 2013-06-13
US20180186811A1 (en) 2018-07-05
US20150057444A1 (en) 2015-02-26
HUE052848T2 (en) 2021-05-28
EP2549870A4 (en) 2013-10-16
ME02703B (en) 2017-10-20
CY1123958T1 (en) 2022-05-27
TWI582097B (en) 2017-05-11
US10654871B2 (en) 2020-05-19
US9643981B2 (en) 2017-05-09
KR101440278B1 (en) 2014-10-30
HUE033863T2 (en) 2018-01-29
PT2549870T (en) 2017-07-05
SMT202100087T1 (en) 2021-03-15
US20190100532A1 (en) 2019-04-04
US20150329559A1 (en) 2015-11-19
HRP20210255T1 (en) 2021-04-02
EP3260457A1 (en) 2017-12-27
PL3260457T3 (en) 2021-06-28
RS56072B1 (en) 2017-10-31
CY1119143T1 (en) 2018-02-14
ES2856020T3 (en) 2021-09-27
US20170204117A1 (en) 2017-07-20

Similar Documents

Publication Publication Date Title
EP2549870A1 (en) Process for preparing carbamoylpyridone derivatives and intermediates
EP2376453B1 (en) Intermediates for carbamoylpyridone hiv integrase inhibitors
US20130072688A1 (en) Method for preparing an intermediate of pitavastatin or of the salt thereof
JP5711669B2 (en) Method for producing spiroketal derivative
Yeo Kinetic resolution by lithiation of substituted 1, 2-dihydroquinolines and dihydrobenzoxazines

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201180015527.6

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11760040

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2013501383

Country of ref document: JP

Ref document number: 2777/KOLNP/2012

Country of ref document: IN

REEP Request for entry into the european phase

Ref document number: 2011760040

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2011760040

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 20127027667

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 13636237

Country of ref document: US