714269-57-5

Usage

Uses

Used in Pharmaceutical Industry:
(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol is used as an intermediate for the synthesis of various pharmaceutical compounds. Its unique structure and functional groups make it a valuable building block for the development of new drugs with potential therapeutic applications.
Used in Chemical Research:
In the field of chemical research, (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol can be used as a starting material for the synthesis of more complex molecules with specific properties. Its chiral centers and functional groups can be exploited to create novel compounds with potential applications in various industries, such as materials science, agrochemicals, and environmental science.
Used in Material Science:
(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol may be utilized in the development of new materials with specific properties, such as improved mechanical strength, thermal stability, or chemical resistance. Its unique molecular structure could contribute to the creation of advanced materials for various applications, including aerospace, automotive, and electronics industries.
Used in Agrochemical Industry:
(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol could potentially be used in the agrochemical industry as a starting material for the synthesis of new pesticides, herbicides, or fertilizers. Its specific functional groups and stereochemistry may allow for the development of more effective and targeted agrochemicals with reduced environmental impact.
Used in Environmental Science:
(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol may also find applications in environmental science, particularly in the development of new methods for pollution control, waste management, or environmental remediation. Its unique properties could be harnessed to create innovative solutions for addressing environmental challenges.

Synthetic route

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene; (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With TurboGrignard In tetrahydrofuran at -30 - -20℃; for 1h; Inert atmosphere; Stage #2: With methanesulfonic acid In tetrahydrofuran; methanol at -10 - 30℃; for 2h; Inert atmosphere;	81.8%

methanesulfonic acid (75-75-2) + C33H56ClO7Si4(1-)*Li(1+) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
In methanol at 20℃; for 10h;	81.4%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + C18H42O6Si4 → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	78.6%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With sec.-butyllithium In tetrahydrofuran; cyclohexane at -78 - -68℃; for 1h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; n-heptane; cyclohexane at -78 - -68℃; for 30h;	78.3%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Large scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 3h; Large scale;	78%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Inert atmosphere; Industrial scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With methanesulfonic acid In tetrahydrofuran; methanol; hexane; toluene at -78 - 40℃; for 14h; Industrial scale;	78%
Multi-step reaction with 2 steps 1.1: N,N,N',N'',N'''-pentamethyldiethylenetriamine; n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C / Inert atmosphere 2.1: methanol / 10 h / 20 °C View Scheme

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + methanesulfonic acid (75-75-2) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions

Yield

Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Inert atmosphere; Large scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -78℃; for 3h; Large scale; Stage #3: methanesulfonic acid In methanol at 0 - 40℃; for 11h; Large scale;

78%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone (318967-97-4) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	77.3%

methanol (67-56-1) + (2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
With toluene-4-sulfonic acid at 20℃; for 12h; Inert atmosphere;	71.6%
With n-butyllithium; toluene-4-sulfonic acid at 20℃; for 12h;	141.5 g

(2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
With toluene-4-sulfonic acid In methanol at 20 - 30℃; for 12h; Inert atmosphere;	71.6%

methanol (67-56-1) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -30℃; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -30 - -24℃; Stage #3: methanol In tetrahydrofuran; hexane; toluene at -10 - 35℃; for 23h; Acidic conditions;

(3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C / Inert atmosphere 1.2: 5 h / -78 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / 12 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C 1.2: 5 h / -78 °C 2.1: n-butyllithium; toluene-4-sulfonic acid / 12 h / 20 °C View Scheme

methanol (67-56-1) + 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -65℃; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -65℃; for 2h; Stage #3: methanol With hydrogenchloride; water In tetrahydrofuran; hexane; toluene at 20℃;
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene; (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran at -85 - -70℃; for 2h; Inert atmosphere; Stage #2: methanol With methanesulfonic acid In tetrahydrofuran at -75 - 15℃; for 18h; Inert atmosphere;
With n-butyllithium; methanesulfonic acid In tetrahydrofuran; toluene at -15 - 5℃; for 0.0113889h;

2-chloro-5-iodobenzoylchloride (281652-58-2) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / -3 - 5 °C 1.2: 12 h / 0 - 25 °C 1.3: polymethylhydrosiloxane (PMHS) / 16 h / 30 °C 2.1: TurboGrignard / tetrahydrofuran / 1.5 h / -5 - 0 °C / Inert atmosphere 2.2: 1 h / -5 - 0 °C 2.3: 16 h / -10 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 2 h / 0 - 5 °C 1.2: polymethylhydrosiloxane / 26 h / 25 - 30 °C 2.1: TurboGrignard / tetrahydrofuran / 0.67 h / -60 - -50 °C / Inert atmosphere 2.2: 5.67 h / -60 - -50 °C / Inert atmosphere 2.3: 18 h / -10 - 15 °C View Scheme

Phenetole (103-73-1) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 15 h / 25 - 30 °C 1.2: 2 h / 0 - 10 °C 2.1: aluminum (III) chloride; sodium tetrahydroborate / Dimethyl ether / 30 h / 0 - 65 °C 3.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 3.2: 3 h / -75 - -60 °C 3.3: 18 h / -75 - 25 °C View Scheme

D-Glucono-1,5-lactone (90-80-2) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 17 h / 5 - 25 °C / Inert atmosphere; Large scale 2.1: TurboGrignard / tetrahydrofuran / 0.67 h / -60 - -50 °C / Inert atmosphere 2.2: 5.67 h / -60 - -50 °C / Inert atmosphere 2.3: 18 h / -10 - 15 °C View Scheme
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 10 h / 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C / Inert atmosphere 2.2: 5 h / -78 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / 12 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 8 h / 20 - 30 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C / Inert atmosphere 2.2: 5 h / -78 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / methanol / 12 h / 20 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 10 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C 2.2: 5 h / -78 °C 3.1: n-butyllithium; toluene-4-sulfonic acid / 12 h / 20 °C View Scheme

2-chloro-5-iodobenzoic acid (19094-56-5) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 16.17 h / 10 - 25 °C 2.1: aluminum (III) chloride / dichloromethane / 0.5 h / -3 - 5 °C 2.2: 12 h / 0 - 25 °C 2.3: polymethylhydrosiloxane (PMHS) / 16 h / 30 °C 3.1: TurboGrignard / tetrahydrofuran / 1.5 h / -5 - 0 °C / Inert atmosphere 3.2: 1 h / -5 - 0 °C 3.3: 16 h / -10 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 16 h / 10 - 25 °C 2.1: aluminum (III) chloride / dichloromethane / 2 h / 0 - 5 °C 2.2: polymethylhydrosiloxane / 26 h / 25 - 30 °C 3.1: TurboGrignard / tetrahydrofuran / 0.67 h / -60 - -50 °C / Inert atmosphere 3.2: 5.67 h / -60 - -50 °C / Inert atmosphere 3.3: 18 h / -10 - 15 °C View Scheme

methanol (67-56-1) + (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (960404-86-8) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran at -10 - 15℃; for 18h; Temperature;
With methanesulfonic acid In neat (no solvent) at 20℃; for 6h; Inert atmosphere;

methanol (67-56-1) + 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With TurboGrignard In tetrahydrofuran at -5 - 0℃; for 1.5h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With TurboGrignard In tetrahydrofuran; n-heptane at -5 - 0℃; for 1h; Stage #3: methanol With hydrogenchloride In tetrahydrofuran; n-heptane; water at -10 - 20℃; for 16h; Concentration; Temperature;
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With TurboGrignard In tetrahydrofuran at -60 - -50℃; for 0.666667h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; n-heptane at -60 - -50℃; for 5.66667h; Inert atmosphere; Stage #3: methanol With hydrogenchloride; water In tetrahydrofuran at -10 - 15℃; for 18h; Temperature; Time;

C34H59ClO7Si4 (1528636-28-3) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
With water; sodium hydroxide In tetrahydrofuran; hexane; toluene for 1h;	7.69 kg

(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C / Inert atmosphere 1.2: 5 h / -78 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / methanol / 12 h / 20 - 30 °C / Inert atmosphere View Scheme

D-glucono-1,4-lactone (1198-69-2) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / 1 h / -10 - 45 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / -10 - 45 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere View Scheme

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5) + C21H27ClO7

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With TurboGrignard In tetrahydrofuran at -5 - 0℃; for 1h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at 5℃; for 3h; Inert atmosphere; Stage #3: With hydrogenchloride; methanol In tetrahydrofuran Inert atmosphere;

5-bromo-2-chlorobenzoic acid (21739-92-4) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 15 h / 25 - 30 °C 1.2: 2 h / 0 - 10 °C 2.1: aluminum (III) chloride; sodium tetrahydroborate / Dimethyl ether / 30 h / 0 - 65 °C 3.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 3.2: 3 h / -75 - -60 °C 3.3: 18 h / -75 - 25 °C View Scheme

(5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone (461432-22-4) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride; sodium tetrahydroborate / Dimethyl ether / 30 h / 0 - 65 °C 2.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 2.2: 3 h / -75 - -60 °C 2.3: 18 h / -75 - 25 °C View Scheme

3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 15 h / 0 - 40 °C 2.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 2.2: 3 h / -75 - -60 °C 2.3: 18 h / -75 - 25 °C View Scheme

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 3,4,5-tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; toluene at -75 - -60℃; for 1h; Stage #2: 3,4,5-tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one In tetrahydrofuran; toluene at -75 - -60℃; for 3h; Stage #3: With methanesulfonic acid In tetrahydrofuran; methanol; toluene at -75 - 25℃; for 18h;	82 g

2-chloro-benzaldehyde (89-98-5) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / dichloromethane / 10.5 h / 5 °C / Large scale 2.1: sodium tetrahydroborate / ethanol / 4 h / 20 °C / Large scale 3.1: thionyl chloride / 3 h / 70 °C / Large scale 4.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Large scale 5.2: 3 h / -78 °C / Large scale View Scheme

2-chloro-5-bromobenzaldehyde (189628-37-3) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / ethanol / 4 h / 20 °C / Large scale 2.1: thionyl chloride / 3 h / 70 °C / Large scale 3.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Large scale 4.2: 3 h / -78 °C / Large scale View Scheme

5-bromo-2-chlorobenzyl alcohol (149965-40-2) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / 3 h / 70 °C / Large scale 2.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Large scale 3.2: 3 h / -78 °C / Large scale View Scheme

4-bromo-1-chloro-2-(chloromethyl)benzene → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Large scale 2.2: 3 h / -78 °C / Large scale View Scheme

4-bromo-aniline (106-40-1) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: water; methanol / 5 h / 20 °C / Cooling with ice; Large scale 2.1: aluminum (III) chloride / ethyl acetate / 8 h / Cooling with ice; Reflux; Large scale 3.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Large scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 4.2: 4 h / 20 - 80 °C / Large scale 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Large scale 5.2: 3 h / -78 °C / Large scale 5.3: 11 h / 0 - 40 °C / Large scale View Scheme
Multi-step reaction with 5 steps 1.1: water; methanol / 5.5 h / 20 °C / Cooling with ice; Industrial scale 2.1: hydrogen fluoride / ethyl acetate / 8.5 h / Cooling with ice; Industrial scale 3.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Industrial scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 °C / Industrial scale 4.2: 4 h / 20 - 80 °C / Industrial scale 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Industrial scale 5.2: 14 h / -78 - 40 °C / Industrial scale View Scheme

Upstream product

• 461432-23-5 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene 
• 32469-28-6 (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one 
• 67-56-1 methanol 
• 90-80-2 D-Glucono-1,5-lactone 
• 19094-56-5 2-chloro-5-iodobenzoic acid 
• 960404-86-8 (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol 
• 1528636-28-3 C₃₄H₅₉ClO₇Si₄ 
• 318967-97-4 2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone 
• 1198-69-2 D-glucono-1,4-lactone 
• 1103738-29-9 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene 
• 21739-92-4 5-bromo-2-chlorobenzoic acid 
• 461432-22-4 (5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone 
• 1335-57-5 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one 
• 123-08-0 4-hydroxy-benzaldehyde 

Downstream Products

• 461432-26-8 dapagliflozin 
• 960404-59-5 C₄H₆O₂*C₂₂H₂₇ClO₇ 
• 461432-28-0 methyl-2,3,4,6-tetra-O-acetyl-1-C-(2-chloro-4'ethoxydiphenylmethan-3yl)-α-D-glucopyranose 
• 1528636-29-4 ((2R,3R,4S,5R,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxy-3,4,5-tris-(trimethylsilyloxy)tetrahydro-2H-pyran-2-yl)methanol 
• 1528636-33-0 (2S,3R,4S,5R,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxy-3,4,5-tris-(trimethylsilyloxy)tetrahydro-2H-pyran-2-carbaldehyde 
• 1528636-39-6 (2S,3R,4S,5S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 1210344-57-2 Ertugliflozin 
• 1528636-28-3 C₃₄H₅₉ClO₇Si₄ 

Relevant academic research and scientific papers

AN EFFICIENT PROCESS FOR THE PREPARATION OF ERTUGLIFLOZIN L-PYROGLUTAMIC ACID AND INTERMEDIATES THEREOF

The present invention relates to an efficient process for the preparation of Ertugliflozin L-pyroglutamic acid of formula (I) and intermediate thereof, in environment friendly conditions. The present invention further relates to a process for the preparation of substantially pure intermediate of formula (IV).

Method for preparing intermediates of gliflozin hypoglycemic drugs

The invention belongs to the technical field of medicine synthesis, and relates to a novel method for preparing key intermediates of gliflozin hypoglycemic drugs, in particular to a preparation methodof key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin. The method comprises the following steps: 1) in the presence of a cosolvent, carrying out halogen metal exchange on a raw material, namely aryl bromide 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and carrying out a nucleophilic addition reaction on the aryl lithium reagent 3 and TMS-protected glucolactone 4 to obtain a transition product 5; and 2) removing a TMS protecting group from the transition product 5, and converting hemiketal into ketal to obtain the key intermediate 1with a single configuration. According to the method, the key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin can be stereoselectively synthesized, reaction yield isrelatively high (more than 75%), and product purity is high (wherein HPLC purity is about 95%); so reduction preparation of a final product in the next step is facilitated.

Refining method of SGLT-2 inhibitor intermediate

The invention discloses a refining method of an SGLT-2 inhibitor intermediate; the SGLT-2 inhibitor intermediate is represented by the formula (I), wherein the definition of substituent groups in theformula (I) is detailed in the specification. The refining method includes the following steps: the SGLT-2 inhibitor intermediate is dissolved in a polar organic solvent and cooled to ultra-low temperature, the non-polar organic solvent is added, and the solid SGLT-2 inhibitor intermediate is obtained. The refining method is different from a conventional recrystallization technology, and can refine materials that are not easy to solidify at room temperature. A new choice is provided for refining the materials with low melting point and high viscosity. The refining method is suitable for industrialized scale-up production.

Preparation method of sugar-reducing medicine dapagliflozin

The invention discloses a preparation method for hypoglycemic drugdapagliflozin. The method comprises the steps that 4-hydroxybenzaldehyde is adopted as a starting raw material, alkylation, carbonyl reduction, chlorination and alkylation reaction with asepsin, diazotization and chlorination are performed to obtain a dapagliflozinmidbody 5-bromo-2-chloro-4'-ethyoxyl diphenylmethane, then, the midbody and 2,3,4,6-tetra-O-trimethyl silicone-D-glucolactone are subjected to condensation, etherification and methoxyl removal to obtain the hypoglycemic drugdapagliflozin. The raw materials adopted by the technological path are low in price and easy to obtain, the technology can achieve industrialization easily, and the final product is high in purity; the technological path is novel, the syntheticroute is short, no risky or complex technology exists in the reactions, equipment is simple, operation is easy and convenient, and the method is suitable for industrial production.

Synthetic method of dapagliflozin

Disclosed is a synthesis method of dapagliflozin. The method includes providing a microreactor having at least 4 reaction units in series, delivering a 5-bromo-2-chloro-4'-ethoxydiphenylmethane solution and an alkyllithium solution into a first reaction unit and controlling the reaction temperature in the first reaction unit to be -5 to -40 DEG C; after the reaction is completed, making a reactionsolution flow into a second reaction unit, and delivering trimethylsilyl protected gluconolactone or a solution thereof to the second reaction unit; after the reaction is completed, making a reactionsolution flow into a third reaction unit and delivering a mixed solution of methanol and methane sulfonic acid to the third reaction unit; making a reaction solution flow into a fourth reaction unitafter the reaction is completed and delivering a mixed solution of boron trifluoride diethyl etherate and Triethylsilane into the fourth reaction unit.

Dapagliflozin preparation method

The invention relates to a Dapagliflozin preparation method, which comprises the following steps: using 2-chlorobenzaldehyde as a starting material, carrying out bromination, reducing, chlorinating tosynthesize 5-bromo-2-chlorobenzyl chloride, carrying out Friedel-Crafts alkylation reaction between 5-bromo-2-chlorobenzyl chloride and phenetole to synthesize 5-bromo-2-chloro-4'-ethyoxyldiphenylmethane, conducting condensation between 5-bromo-2-chloro-4'-ethyoxyldiphenylmethane and 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone, carrying out trimethylsilyl deprotection, conducting etherification, and reducing for demethylation to obtain a hypoglycemic drug Dapagliflozin. The invention has the following advantages: according to the Dapagliflozin preparation method, 2-chlorobenzaldehyde, whichis used as a starting material, is cheaper and easily available in comparison with 5-bromo-2-chlorobenzoic acid, and the technology is easy for industrialization; during the synthetic process, no rawmaterials which cause severe toxicity will be used and furthermore there is no dangerous process; the synthetic route is short and novel and the operation is simple; and through the synthetic route,purity of the final product can be raised, and the purity can reach 99% and above.

Synthetic method for dapagliflozin

The invention relates to a synthetic method for dapagliflozin. The synthetic method is characterized in that 4-methylphenol is taken as a starting raw material, alkylation and bromination are performed, an alkylation reaction is performed with antisepsin, diazotization and chlorination are performed, and condensation, etherification and desmethoxy are performed with 2,3,4,6-tetrakis-O-trimethylsilyl-D-gluconolactone to obtain a hypoglycemic drug (dapagliflozin). The synthetic method has the following advantages: 4-methylphenol is taken as the starting raw material, and 4-methylphenol is low inprice and easily accessible than 5-bromo-2-chlorobenzoic acid; by adoption of the process, industrialization can be easily realized; in the synthesis process, raw materials which are highly toxic arenot used, so that dangerous processes are avoided; the synthesis path is short and novel, so that the operation is simple and convenient; and by adoption of the synthesis path, the purity of a finalproduct can be improved, and the purity can be 99% or above.

PROCESSES FOR THE PREPARATION OF ERTUGLIFLOZIN

The present invention relates to processes for the preparation of ertugliflozni. The present invention also provides compounds of Formula (III), Formula (IV), and Formula (VII), processes for their preparation, and their use for the preparation of ertugliflozin. The processes of the present invention involve protecting the ertugliflozin intermediate compound with a suitable protecting group which provides ertugliflozin having high purity and yield.

Dapagliflozin impurity compound

The invention discloses an II type sodium ion dependent-glucose co-transporter (SGTL2) inhibitor and an impurity compound of II type diabetes treatment medicine dapagliflozin, and particularly relates to a prepration method of organically synthesized glucose open-loop impurities: 1-[4-chlorine-3-(4-methoxyl benzyl)-phenyl] hexane-1,2,3,4,5,6-n-hexanehexol (a compound 1).

PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN AND ITS SOLVATE THEREOF

The present invention provides for crystalline Dapagliflozin butane –1,2– diol solvate (VIII), crystalline Dapagliflozin (S) butane –1,2– diol solvate (VIIIa) and Dapagliflozin (R) butane –1,2– diol solvate (VIIIb). The present invention also provides industrial methods for production of crystalline Dapagliflozin butane –1,2– diol solvate (VIII), crystalline 5 Dapagliflozin (S) butane –1,2– diol solvate (VIIIa) and Dapagliflozin (R) butane –1,2– diol solvate (VIIIb). The present invention further provides an industrial method production of amorphous Dapagliflozin.