1206102-09-1

Basic information

• Product Name: (4R,12aS)-7-(benzyloxy)-4-Methyl-3,4-dihydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-6,8(12H,12aH)-dione
• Synonyms: (4R,12aS)-7-(benzyloxy)-4-Methyl-3,4-dihydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-6,8(12H,12aH)-dione;Dolutegravir interMediate;(4R,12aS)-7-(Benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione;2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione, 3,4,12,12a-tetrahydro-4-methyl-7-(phenylmethoxy)-, (4R,12aS)-;Intermediate of Dolutegravir
• CAS NO: 1206102-09-1
• Molecular Formula: C₁₉H₂₀N₂O₄
• Molecular Weight: 340.3731
• EINECS: -0
• Mol File: 1206102-09-1.mol
• Article Data: 5

Chemical Properties

• Appearance: /
• CAS DataBase Reference: (4R,12aS)-7-(benzyloxy)-4-Methyl-3,4-dihydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-6,8(12H,12aH)-dione(CAS DataBase Reference)
• NIST Chemistry Reference: (4R,12aS)-7-(benzyloxy)-4-Methyl-3,4-dihydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-6,8(12H,12aH)-dione(1206102-09-1)
• EPA Substance Registry System: (4R,12aS)-7-(benzyloxy)-4-Methyl-3,4-dihydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-6,8(12H,12aH)-dione(1206102-09-1)

Safety Data

• Hazardous Substances Data: 1206102-09-1(Hazardous Substances Data)

Usage

General Description

The chemical compound (4R,12aS)-7-(benzyloxy)-4-Methyl-3,4-dihydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-6,8(12H,12aH)-dione is a complex heterocyclic compound with a fused ring system. It contains a pyrazine ring fused to an oxazine ring and a pyrido ring, and it also has a benzyloxy and a methyl group attached at specific positions. (4R,12aS)-7-(benzyloxy)-4-Methyl-3,4-dihydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-6,8(12H,12aH)-dione has potential applications in medicinal chemistry and drug discovery due to its unique structure, which may confer specific biological activities or target binding properties. However, further research is needed to explore its potential uses and properties.

Synthetic route

(R)-3-amino-1-butanol (61477-40-5) + methyl 1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate (1206102-08-0) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
With acetic acid In toluene at 90℃; for 3.5h;	96%
With acetic acid In toluene at 90℃; for 2.5h; Product distribution / selectivity;	83%
With acetic acid In methanol; toluene at 90℃; for 2.5h; Reagent/catalyst; Temperature;	83%
With acetic acid In toluene at 90℃; for 2h; diastereoselective reaction;	80%

2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one (1206102-04-6) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: triethylamine; methanesulfonyl chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.5 h / 30 °C 2.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 2.2: 1.5 h / 25 °C 3.1: ethanol / 8.5 h / 65 - 80 °C 4.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 5.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 6.1: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine; methanesulfonyl chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.5 h / 30 °C 2.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 2.2: 1.5 h / 25 °C 3.1: ethanol / 8.5 h / 65 - 80 °C 4.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 5.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 6.1: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1: methanesulfonyl chloride 2: ruthenium trichloride; sodium periodate 3: sodium periodate View Scheme
Multi-step reaction with 7 steps 1.1: triethylamine; methanesulfonyl chloride / tetrahydrofuran / 1 h / 20 °C / Large scale 1.2: 1 h / Large scale 2.1: ruthenium trichloride; sodium periodate; sulfuric acid / acetonitrile; water / 20 °C / Large scale 3.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium hypochlorite / acetonitrile; water; ethyl acetate / 20 °C / Large scale 4.1: ethanol / 3.5 h / 65 - 75 °C / Large scale 5.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 30 °C / Large scale 6.1: sodium periodate; acetic anhydride / acetonitrile; water / 30 °C / Large scale 7.1: acetic acid / toluene / 2 h / 90 °C View Scheme

C20H16O3 (1229006-11-4) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 1.2: 1.5 h / 25 °C 2.1: ethanol / 8.5 h / 65 - 80 °C 3.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 4.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 5.1: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 5 steps 1.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 1.2: 1.5 h / 25 °C 2.1: ethanol / 8.5 h / 65 - 80 °C 3.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 4.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 5.1: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 2 steps 1: ruthenium trichloride; sodium periodate 2: sodium periodate View Scheme

4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid (119736-16-2) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: ethanol / 8.5 h / 65 - 80 °C 2: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 3: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 4: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 4 steps 1: ethanol / 8.5 h / 65 - 80 °C 2: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 3: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 4: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 4 steps 1: ethanol / 1 h / Reflux 2: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 5 h / 20 °C 3: sodium periodate / methanol; water / 1 h / 20 °C 4: acetic acid / toluene / 3.5 h / 90 °C View Scheme
Multi-step reaction with 4 steps 1: ethanol / 3.5 h / 65 - 75 °C / Large scale 2: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 30 °C / Large scale 3: sodium periodate; acetic anhydride / acetonitrile; water / 30 °C / Large scale 4: acetic acid / toluene / 2 h / 90 °C View Scheme

1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid (1206102-06-8) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 2: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 3: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 2: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 3: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 5 h / 20 °C 2: sodium periodate / methanol; water / 1 h / 20 °C 3: acetic acid / toluene / 3.5 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 30 °C / Large scale 2: sodium periodate; acetic anhydride / acetonitrile; water / 30 °C / Large scale 3: acetic acid / toluene / 2 h / 90 °C View Scheme

1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid methyl ester (1206102-07-9) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 2: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 2 steps 1: sodium periodate / methanol; water / 1 h / 20 °C 2: acetic acid / toluene / 3.5 h / 90 °C View Scheme
Multi-step reaction with 2 steps 1: sodium periodate; acetic anhydride / acetonitrile; water / 30 °C / Large scale 2: acetic acid / toluene / 2 h / 90 °C View Scheme

Maltol (118-71-8) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 7 steps 1: potassium carbonate / acetonitrile / 5 h / 13 - 80 °C / Large scale 2: bromobenzene; selenium(IV) oxide / 13 h / 140 °C / Dean-Stark 3: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 4: ethanol / 8.5 h / 65 - 80 °C 5: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 6: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 7: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 7 steps 1: potassium carbonate / acetonitrile / 5 h / 13 - 80 °C / Large scale 2: bromobenzene; selenium(IV) oxide / 13 h / 140 °C / Dean-Stark 3: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 4: ethanol / 8.5 h / 65 - 80 °C 5: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 6: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 7: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate / acetonitrile / 5 h / 13 - 80 °C / Large scale 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -60 °C 2.2: 1 h / -60 °C 3.1: triethylamine; methanesulfonyl chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.5 h / 30 °C 4.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 4.2: 1.5 h / 25 °C 5.1: ethanol / 8.5 h / 65 - 80 °C 6.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 7.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 8.1: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme

3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (500371-01-7) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 2: ethanol / 8.5 h / 65 - 80 °C 3: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 4: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 5: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 5 steps 1: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 2: ethanol / 8.5 h / 65 - 80 °C 3: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 4: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 5: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 5 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium hypochlorite / acetonitrile; water; ethyl acetate / 20 °C / Large scale 2: ethanol / 3.5 h / 65 - 75 °C / Large scale 3: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 30 °C / Large scale 4: sodium periodate; acetic anhydride / acetonitrile; water / 30 °C / Large scale 5: acetic acid / toluene / 2 h / 90 °C View Scheme

benzyl bromide (100-39-0) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 7 steps 1: potassium carbonate / acetonitrile / 5 h / 13 - 80 °C / Large scale 2: bromobenzene; selenium(IV) oxide / 13 h / 140 °C / Dean-Stark 3: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 4: ethanol / 8.5 h / 65 - 80 °C 5: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 6: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 7: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 7 steps 1: potassium carbonate / acetonitrile / 5 h / 13 - 80 °C / Large scale 2: bromobenzene; selenium(IV) oxide / 13 h / 140 °C / Dean-Stark 3: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 4: ethanol / 8.5 h / 65 - 80 °C 5: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 6: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 7: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate / acetonitrile / 5 h / 13 - 80 °C / Large scale 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -60 °C 2.2: 1 h / -60 °C 3.1: triethylamine; methanesulfonyl chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.5 h / 30 °C 4.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 4.2: 1.5 h / 25 °C 5.1: ethanol / 8.5 h / 65 - 80 °C 6.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 7.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 8.1: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme

3-O-benzylmaltol (61049-69-2) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: bromobenzene; selenium(IV) oxide / 13 h / 140 °C / Dean-Stark 2: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 3: ethanol / 8.5 h / 65 - 80 °C 4: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 5: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 6: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 6 steps 1: bromobenzene; selenium(IV) oxide / 13 h / 140 °C / Dean-Stark 2: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 3: ethanol / 8.5 h / 65 - 80 °C 4: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 5: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 6: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme
Multi-step reaction with 7 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -60 °C 1.2: 1 h / -60 °C 2.1: triethylamine; methanesulfonyl chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.5 h / 30 °C 3.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 3.2: 1.5 h / 25 °C 4.1: ethanol / 8.5 h / 65 - 80 °C 5.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 6.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 7.1: acetic acid / methanol; toluene / 2.5 h / 90 °C View Scheme

benzyl chloride (100-44-7) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium carbonate / methanol / 1 h / Reflux 2: periodic acid; chromium(VI) oxide / acetonitrile / 1.5 h / 20 °C 3: ethanol / 1 h / Reflux 4: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 5 h / 20 °C 5: sodium periodate / methanol; water / 1 h / 20 °C 6: acetic acid / toluene / 3.5 h / 90 °C View Scheme

(R)-3-amino-1-butanol (61477-40-5) + 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid methyl ester (1206102-07-9) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Stage #1: 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid methyl ester With sodium periodate Stage #2: (R)-3-amino-1-butanol

C21H20O6S → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene 2: ruthenium trichloride; sodium periodate 3: sodium periodate View Scheme

2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-pyran-4-one (1206102-05-7) → (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: ruthenium trichloride; sodium periodate; sulfuric acid / acetonitrile; water / 20 °C / Large scale 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium hypochlorite / acetonitrile; water; ethyl acetate / 20 °C / Large scale 3: ethanol / 3.5 h / 65 - 75 °C / Large scale 4: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 30 °C / Large scale 5: sodium periodate; acetic anhydride / acetonitrile; water / 30 °C / Large scale 6: acetic acid / toluene / 2 h / 90 °C View Scheme

(4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1) → (4R,12aS)-7-(benzyloxy)-9-bromo-4-methyl-3,4,12,12atetrahydro-2H-pyrido [1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-10-4)

Conditions	Yield
With N-Bromosuccinimide In 1-methyl-pyrrolidin-2-one at 20℃; for 2h; Product distribution / selectivity;	89%
With N-Bromosuccinimide In 1-methyl-pyrrolidin-2-one; water at 5 - 20℃; for 4h; Solvent; Temperature;	89%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 1.5h;	86%
With N-Bromosuccinimide In dichloromethane at 20℃; for 0.5h; Large scale;	85%
With N-Bromosuccinimide

(4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1) → dolutegravir

Conditions	Yield
Multi-step reaction with 3 steps 1: N-Bromosuccinimide / 1-methyl-pyrrolidin-2-one; water / 4 h / 5 - 20 °C 2: N-ethyl-N,N-diisopropylamine; tetrakis(triphenylphosphine) palladium(0) / dimethyl sulfoxide / 5.5 h / 90 °C 3: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; methanol / 2.5 h View Scheme
Multi-step reaction with 3 steps 1: N-Bromosuccinimide / dichloromethane / 0.5 h / 20 °C / Large scale 2: tetrakis(triphenylphosphine) palladium(0) / dimethyl sulfoxide / 5 h / 90 °C / Large scale 3: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran; water / 2 h / 40 °C View Scheme

(4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1) → (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 sodium salt (1051375-19-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / 1-methyl-pyrrolidin-2-one; water / 4 h / 5 - 20 °C 2: N-ethyl-N,N-diisopropylamine; tetrakis(triphenylphosphine) palladium(0) / dimethyl sulfoxide / 5.5 h / 90 °C 3: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; methanol / 2.5 h 4: sodium hydroxide / ethanol / 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide 2.1: tetrakis(triphenylphosphine) palladium(0) 3.1: hydrogen; palladium 10% on activated carbon / tetrahydrofuran; methanol / 2.5 h 3.2: 80 °C View Scheme
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / dichloromethane / 0.5 h / 20 °C / Large scale 2: tetrakis(triphenylphosphine) palladium(0) / dimethyl sulfoxide / 5 h / 90 °C / Large scale 3: hydrogen; 5%-palladium/activated carbon / tetrahydrofuran; water / 2 h / 40 °C 4: sodium hydroxide / water; ethanol / 3 h / 25 °C View Scheme

(4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (1206102-09-1) → (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-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 (1206102-11-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-Bromosuccinimide 2: tetrakis(triphenylphosphine) palladium(0) View Scheme
Multi-step reaction with 2 steps 1: N-Bromosuccinimide / dichloromethane / 0.5 h / 20 °C / Large scale 2: tetrakis(triphenylphosphine) palladium(0) / dimethyl sulfoxide / 5 h / 90 °C / Large scale View Scheme

Upstream product

• 61477-40-5 (R)-3-amino-1-butanol 
• 1206102-08-0 methyl 1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 
• 100-44-7 benzyl chloride 
• 1206102-05-7 2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-pyran-4-one 
• 61049-69-2 3-O-benzylmaltol 
• 100-39-0 benzyl bromide 
• 500371-01-7 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde 
• 118-71-8 Maltol 
• 1206102-07-9 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid methyl ester 
• 1206102-06-8 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid 
• 119736-16-2 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester 
• 1229006-11-4 C₂₀H₁₆O₃ 
• 1206102-04-6 2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one 

Downstream Products

• 1206102-10-4 (4R,12aS)-7-(benzyloxy)-9-bromo-4-methyl-3,4,12,12atetrahydro-2H-pyrido [1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione 
• 1051375-16-6 dolutegravir 
• 1051375-19-9 (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 sodium salt 
• 1206102-11-5 (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-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 

Relevant articles and documents

Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis

A practical and scalable synthetic method to obtain dolutegravir sodium (1) was established starting from the readily accessible material maltol (2). This synthetic method includes a scalable oxidation process of maltol and palladium-catalyzed amidation for introduction of an amide moiety, leading to a practical manufacturing method in short synthetic steps. The synthetic method demonstrated herein enables multikilogram scale manufacturing of 1 of high purity.

Improved method for synthesizing dolutegravir

The invention relates to an improved method for synthesizing dolutegravir and belongs to the field of medicinal chemistry. The method takes maltol (compound 1) as a raw material, and a target is synthesized by the following route. The process raw material is cheap and easy to obtain, a reaction solvent can be recycled, the post-treatment operation is simple, the yield and the purity are high, especially the carbamoylation and debenzylation reaction are carried out in one step, the synthesis route is simplified, the cost is reduced, and the large-scale industrial production is facilitated.

PROCESSES AND INTERMEDIATES FOR CARBAMOYLPYRIDONE HIV INTEGRASE INHIBITORS

Processes are provided which create an aldehyde methylene, or hydrated or hemiacetal methylene attached to a heteroatom of a 6 membered ring without going through an olefinic group and without the necessity of using an osmium reagent. In particular, a comopound of formula (I) can be produced from (II) and avoid the use of an allyl amine: (formulae I and II) where R, P 1 P3, R3 and Rx are as described herein.